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Sample records for ataxia telangiectasia mutated

  1. The Development of Ataxia Telangiectasia Mutated Kinase Inhibitors

    Czech Academy of Sciences Publication Activity Database

    Andrs, M.; Kobarecny, J.; Nepovimova, E.; Jun, D.; Hodný, Zdeněk; Moravcová, Simona; Hanzlíková, Hana; Kuca, K.

    2014-01-01

    Roč. 14, č. 10 (2014), s. 805-811 ISSN 1389-5575 R&D Projects: GA MŠk(CZ) CZ.1.07/2.3.00/30.0044 Grant - others:MH CZ - DRO (University Hospital Hradec Kralove(CZ) 00179906 Institutional support: RVO:68378050 Keywords : Ataxia telangiectasia mutated * cancer * chemosensitization * DNA damage response Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.903, year: 2014

  2. ATM (ataxia-telangiectasia mutated) abnormality and diseases

    International Nuclear Information System (INIS)

    Takagi, Masatoshi; Nakata, Shinichiro; Mizutani, Shuki

    2007-01-01

    Ataxia-Telangiectasia (A-T) is an autosomal recessive inherited disease due to mutation of ATM gene on chromosome 11q22.3, with major symptoms of ataxia, telangiectasia, immunodeficiency and frequent complication of cancer, and the cells have characters of chromosomal break, high sensitivity to radiation and inappropriate continuation of DNA synthesis after radiation. This review describes past and present studies of ATM functions with clinical features in the following order: Clinical symptoms and epidemiology; ATM gene mutation in A-T patients, mainly by frame-shift (80-90%); ATM, whose gene consisted from 66 exons (150 kb), functions in phosphoinositide-3-kinase related kinase family which protecting cells from stress and integrating their system, at response to DNA double strand break, and in the cell cycle checkpoints at G1/S, S and G2/M phases; ATM nonsense/missense mutations in embryonic cells leading to carcinogenesis and role of ATM in the suppression of carcinogenesis in somatic cells; Chromosomal translocation which relating to carcinogenesis, by functional defect of ATM; and Other functions of ATM in neuronal growth, immunodeficiency, carbohydrate and lipid metabolism, early senescence, and virus infection. ATM is thus an essential molecule to maintain growth and homeostasis. (T.I.)

  3. Health risks for ataxia-telangiectasia mutated heterozygotes : a systematic review, meta-analysis and evidence-based guideline

    NARCIS (Netherlands)

    van Os, N J H; Roeleveld, N; Weemaes, C M R; Jongmans, M C J; Janssens, G O; Taylor, A M R; Hoogerbrugge, N; Willemsen, Michel A A P

    Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers

  4. Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong; Kim, Min Ju; Park, Sang-Min; Ryu, Junghyun; Ahn, Jin Seop; Heo, Soon Young; Kang, Jee Hyun; Choi, You Jung [Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan (Korea, Republic of); Choi, Seong-Jun [Institute of Tissue Regeneration Engineering, Dankook University, Cheonan (Korea, Republic of); Shim, Hosup, E-mail: shim@dku.edu [Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan (Korea, Republic of); Institute of Tissue Regeneration Engineering, Dankook University, Cheonan (Korea, Republic of); Department of Physiology, Dankook University School of Medicine, Cheonan (Korea, Republic of)

    2014-10-03

    Highlights: • ATM gene-targeted pigs were produced by somatic cell nuclear transfer. • A novel large animal model for ataxia telangiectasia was developed. • The new model may provide an alternative to the mouse model. - Abstract: Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None of the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies.

  5. Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer

    International Nuclear Information System (INIS)

    Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong; Kim, Min Ju; Park, Sang-Min; Ryu, Junghyun; Ahn, Jin Seop; Heo, Soon Young; Kang, Jee Hyun; Choi, You Jung; Choi, Seong-Jun; Shim, Hosup

    2014-01-01

    Highlights: • ATM gene-targeted pigs were produced by somatic cell nuclear transfer. • A novel large animal model for ataxia telangiectasia was developed. • The new model may provide an alternative to the mouse model. - Abstract: Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None of the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies

  6. Ataxia telangiectasia: a review

    Directory of Open Access Journals (Sweden)

    Cynthia Rothblum-Oviatt

    2016-11-01

    Full Text Available Abstract Definition of the disease Ataxia telangiectasia (A-T is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome. Epidemiology The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births. Clinical description A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations. Etiology A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress. Diagnosis The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels. Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the

  7. Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case–control study

    International Nuclear Information System (INIS)

    Tamimi, Rulla M; Hankinson, Susan E; Spiegelman, Donna; Kraft, Peter; Colditz, Graham A; Hunter, David J

    2004-01-01

    The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. We conducted a nested case–control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (χ 2 = 3.43, five degrees of freedom, P = 0.63). There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk

  8. Hashimoto thyroiditis associated with ataxia telangiectasia.

    Science.gov (United States)

    Patiroglu, Turkan; Gungor, Hatice Eke; Unal, Ekrem; Kurtoglu, Selim; Yikilmaz, Ali; Patiroglu, Tahir

    2012-01-01

    Ataxia telangiectasia is a rare genetic disease characterized by neurological manifestations, infections, and cancers. In addition to these cardinal features, different autoimmune diseases can be seen in patients with ataxia telangiectasia. Although there were reports of positive autoimmune thyroid antibodies associated with ataxia telangiectasia, to our knowledge, we report the first cases of nodular Hashimoto thyroiditis in two patients with ataxia telangiectasia in the English medical literature. These cases illustrate that despite the rarity of nodular Hashimoto thyroiditis associated with ataxia telangiectasia, physicians should be aware of this possibility. Furthermore, thyroid examination of patient with ataxia telangiectasia is recommended for early diagnosis.

  9. Role of ataxia-telangiectasia mutated (ATM) in porcine oocyte in vitro maturation.

    Science.gov (United States)

    Lin, Zi-Li; Kim, Nam-Hyung

    2015-06-01

    Ataxia-telangiectasia mutated (ATM) is critical for the DNA damage response, cell cycle checkpoints, and apoptosis. Significant effort has focused on elucidating the relationship between ATM and other nuclear signal transducers; however, little is known about the connection between ATM and oocyte meiotic maturation. We investigated the function of ATM in porcine oocytes. ATM was expressed at all stages of oocyte maturation and localized predominantly in the nucleus. Furthermore, the ATM-specific inhibitor KU-55933 blocked porcine oocyte maturation, reducing the percentages of oocytes that underwent germinal vesicle breakdown (GVBD) and first polar body extrusion. KU-55933 also decreased the expression of DNA damage-related genes (breast cancer 1, budding uninhibited by benzimidazoles 1, and P53) and reduced the mRNA and protein levels of AKT and other cell cycle-regulated genes that are predominantly expressed during G2/M phase, including bone morphogenetic protein 15, growth differentiation factor 9, cell division cycle protein 2, cyclinB1, and AKT. KU-55933 treatment decreased the developmental potential of blastocysts following parthenogenetic activation and increased the level of apoptosis. Together, these data suggested that ATM influenced the meiotic and cytoplasmic maturation of porcine oocytes, potentially by decreasing their sensitivity to DNA strand breaks, stimulating the AKT pathway, and/or altering the expression of other maternal genes. © 2015 International Federation for Cell Biology.

  10. Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families.

    Science.gov (United States)

    Renault, Anne-Laure; Mebirouk, Noura; Cavaciuti, Eve; Le Gal, Dorothée; Lecarpentier, Julie; d'Enghien, Catherine Dubois; Laugé, Anthony; Dondon, Marie-Gabrielle; Labbé, Martine; Lesca, Gaetan; Leroux, Dominique; Gladieff, Laurence; Adenis, Claude; Faivre, Laurence; Gilbert-Dussardier, Brigitte; Lortholary, Alain; Fricker, Jean-Pierre; Dahan, Karin; Bay, Jacques-Olivier; Longy, Michel; Buecher, Bruno; Janin, Nicolas; Zattara, Hélène; Berthet, Pascaline; Combès, Audrey; Coupier, Isabelle; Hall, Janet; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Lesueur, Fabienne

    2017-10-01

    Recent studies have linked constitutive telomere length (TL) to aging-related diseases including cancer at different sites. ATM participates in the signaling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. The goal of this study was to investigate whether carriage of an ATM mutation and TL interplay to modify cancer risk in ataxia-telangiectasia (A-T) families.The study population consisted of 284 heterozygous ATM mutation carriers (HetAT) and 174 non-carriers (non-HetAT) from 103 A-T families. Forty-eight HetAT and 14 non-HetAT individuals had cancer, among them 25 HetAT and 6 non-HetAT were diagnosed after blood sample collection. We measured mean TL using a quantitative PCR assay and genotyped seven single-nucleotide polymorphisms (SNPs) recurrently associated with TL in large population-based studies.HetAT individuals were at increased risk of cancer (OR = 2.3, 95%CI = 1.2-4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95%CI = 1.2-7.1, P = 0.02), in comparison to their non-HetAT relatives. HetAT individuals had longer telomeres than non-HetAT individuals (P = 0.0008) but TL was not associated with cancer risk, and no significant interaction was observed between ATM mutation status and TL. Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women.Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers. TL measurement alone is not a good marker for predicting cancer risk in A-T families. © The Author 2017. Published by Oxford University Press.

  11. Ataxia telangiectasia mutated (ATM) interacts with p400 ATPase for an efficient DNA damage response.

    Science.gov (United States)

    Smith, Rebecca J; Savoian, Matthew S; Weber, Lauren E; Park, Jeong Hyeon

    2016-11-04

    Ataxia telangiectasia mutated (ATM) and TRRAP proteins belong to the phosphatidylinositol 3-kinase-related kinase family and are involved in DNA damage repair and chromatin remodeling. ATM is a checkpoint kinase that is recruited to sites of DNA double-strand breaks where it phosphorylates a diverse range of proteins that are part of the chromatin and DNA repair machinery. As an integral subunit of the TRRAP-TIP60 complexes, p400 ATPase is a chromatin remodeler that is also targeted to DNA double-strand break sites. While it is understood that DNA binding transcriptional activators recruit p400 ATPase into a regulatory region of the promoter, how p400 recognises and moves to DNA double-strand break sites is far less clear. Here we investigate a possibility whether ATM serves as a shuttle to deliver p400 to break sites. Our data indicate that p400 co-immunoprecipitates with ATM independently of DNA damage state and that the N-terminal domain of p400 is vital for this interaction. Heterologous expression studies using Sf9 cells revealed that the ATM-p400 complex can be reconstituted without other mammalian bridging proteins. Overexpression of ATM-interacting p400 regions in U2OS cells induced dominant negative effects including the inhibition of both DNA damage repair and cell proliferation. Consistent with the dominant negative effect, the stable expression of an N-terminal p400 fragment showed a decrease in the association of p400 with ATM, but did not alter the association of p400 with TRRAP. Taken together, our findings suggest that a protein-protein interaction between ATM and p400 ATPase occurs independently of DNA damage and contributes to efficient DNA damage response and repair.

  12. Ataxia Telangiectasia-Mutated (ATMPolymorphisms and Risk of Lung Cancer in a Chinese Population

    Directory of Open Access Journals (Sweden)

    Ajay A. Myneni

    2017-06-01

    Full Text Available BackgroundThe ataxia telangiectasia-mutated (ATM gene has a key role in DNA repair including activation and stabilization of p53, which implicates the importance of ATM polymorphisms in the development of cancer. This study aims to investigate the association of two ATM single-nucleotide polymorphisms (SNPs with lung cancer, as well as their potential interaction with p53 gene and other known risk factors of lung cancer.MethodsA population-based case–control study was conducted in Taiyuan city, China with 399 cases and 466 controls matched on the distribution of age and sex of cases. The two ATM gene SNPs, ATMrs227060 and ATMrs228589 as well as p53 gene SNP, p53rs1042522 were genotyped using Sequenom platform. Unconditional logistic regression models were used to estimate crude and adjusted odds ratios (aOR and 95% confidence intervals (CIs. Adjusted models controlled for age, sex, and smoking status.ResultsThe study showed that TT genotype of ATMrs227060 (aOR = 1.58, 95% CI: 1.06–2.35 and AA genotype of ATMrs228589 were significantly associated with lung cancer (aOR = 1.50, 95% CI: 1.08–2.08 in a recessive model. Additionally, carrying variant genotypes of ATMrs227060 (TT, ATMrs228589 (AA, and p53rs1042522 (CC concomitantly was associated with much higher risk (aOR = 3.68, 95% CI: 1.43–9.45 of lung cancer than carrying variant genotypes of any one of the above three SNPs. We also found multiplicative and additive interaction between tea drinking and ATMrs227060 in association with lung cancer.ConclusionThis study indicates that ATM gene variants might be associated with development of lung cancer in Chinese population. These results need to be validated in larger and different population samples.

  13. Ataxia-telangiectasia: future prospects

    Directory of Open Access Journals (Sweden)

    Chaudhary MW

    2014-09-01

    Full Text Available Mohammed Wajid Chaudhary, Raidah Saleem Al-Baradie Pediatric Neurology, Neurosciences Centre, King Fahad Specialist Hospital, Dammam, Kingdom of Saudi Arabia Abstract: Ataxia-telangiectasia (A-T is an autosomal recessive multi-system disorder caused by mutation in the ataxia-telangiectasia mutated gene (ATM. ATM is a large serine/threonine protein kinase, a member of the phosphoinositide 3-kinase-related protein kinase (PIKK family whose best-studied function is as master controller of signal transduction for the DNA damage response (DDR in the event of double strand breaks (DSBs. The DDR rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell-cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence. DSBs can be generated by exposure to ionizing radiation (IR or various chemical compounds, such as topoisomerase inhibitors, or can be part of programmed generation and repair of DSBs via cellular enzymes needed for the generation of the antibody repertoire as well as the maturation of germ cells. AT patients have immunodeficiency, and are sterile with gonadal dysgenesis as a result of defect in meiotic recombination. In the cells of nervous system ATM has additional role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Moderate levels of ATM are associated with prolonged lifespan through resistance to oxidative stress. ATM inhibitors are being viewed as potential radiosensitizers as part of cancer radiotherapy. Though there is no cure for the disease at present, glucocorticoids have been shown to induce alternate splicing site in the gene for ATM partly restoring its activity, but their most effective timing in the disease natural history is not yet known. Gene therapy is promising but large size of the gene makes it technically difficult

  14. Radiosensitivity in ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Lavin, M.F.; Khanna, K.K.; Watters, D.

    1998-01-01

    Full text: Radiosensitivity is a major hallmark of the human genetic disorder ataxia-telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vitro after exposure of patients to therapeutic thought to be the major factor contculture. Clearly an understanding of the nature of the molecular defect in ataxia-telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia-telangiectasia? As outlined above since radiosensitivity is a universal characteristic of A-T understanding the mechanism of action of ATM will provide additional information or radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense c

  15. Radiosensitivity in ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Lavin, M.F. [Royal Brisbane Hospital, QLD (Australia). Queensland Institute of Medical Research and The Department of Surgery; Khanna, K.K.; Watters, D. [Royal Brisbane Hospital, QLD (Australia). Queensland Institute of Medical Research

    1998-12-31

    Full text: Radiosensitivity is a major hallmark of the human genetic disorder ataxia-telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vitro after exposure of patients to therapeutic thought to be the major factor contculture. Clearly an understanding of the nature of the molecular defect in ataxia-telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia-telangiectasia? As outlined above since radiosensitivity is a universal characteristic of A-T understanding the mechanism of action of ATM will provide additional information or radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense c

  16. MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated

    Czech Academy of Sciences Publication Activity Database

    Smida, M.; de la Cruz, F.F.; Kerzendorfer, C.; Uras, I.Z.; Mair, B.; Mazouzi, A.; Suchánková, Tereza; Konopka, T.; Katz, A.M.; Paz, K.; Nagy-Bojarszky, K.; Muellner, M.K.; Bago-Horvath, Z.; Haura, E.B.; Loizou, J.I.; Nijman, S.M.B.

    2016-01-01

    Roč. 7, DEC2016 (2016), č. článku 13701. ISSN 2041-1723 Institutional support: RVO:68081707 Keywords : breast-cancer * insulin -resistance * missense mutations Subject RIV: BO - Biophysics Impact factor: 12.124, year: 2016

  17. [Ataxia telangiectasia: review of 13 new cases].

    Science.gov (United States)

    Valbuena, O; Póo, P; Campistol, J; Vernet, A; Fernández-Alvarez, E; Sierra, I; Gean, E

    1996-01-01

    We report the review of 13 patients who were diagnosed of ataxia telangiectasia before 6 years of age. All of them manifested cerebelous ataxia, oculocutaneus telangiectasias (11), sinopulmonary infections (9), dystonia (9), oculomotor apraxia (9) and Burkitt linfoma (1). We analyse the most common presentation of the disease in early stages and the complementary studies performed. The prompt diagnosis allow us a better control of infections, malignant process and finally the possibility of genetic counseling.

  18. Two Novel Mutations Associated With Ataxia-Telangiectasia Identified Using an Ion AmpliSeq Inherited Disease Panel

    Directory of Open Access Journals (Sweden)

    Maria V. Kuznetsova

    2017-10-01

    Full Text Available Ataxia-telangiectasia (A-T, or Louis-Bar syndrome, is a rare neurodegenerative disorder associated with immunodeficiency. For families with at least one affected child, timely A-T genotyping during any subsequent pregnancy allows the parents to make an informed decision about whether to continue to term when the fetus is affected. Mutations in the ATM gene, which is 150 kb long, give rise to A-T; more than 600 pathogenic variants in ATM have been characterized since 1990 and new mutations continue to be discovered annually. Therefore, limiting genetic screening to previously known SNPs by PCR or hybridization with microarrays may not identify the specific pathogenic genotype in ATM for a given A-T family. However, recent developments in next-generation sequencing technology offer prompt high-throughput full-length sequencing of genomic fragments of interest. This allows the identification of the whole spectrum of mutations in a gene, including any novel ones. We report two A-T families with affected children and current pregnancies. Both families are consanguineous and originate from Caucasian regions of Russia and Azerbaijan. Before our study, no ATM mutations had been identified in the older children of these families. We used ion semiconductor sequencing and an Ion AmpliSeq™ Inherited Disease Panel to perform complete ATM gene sequencing in a single member of each family. Then we compared the experimentally determined genotype with the affected/normal phenotype distribution in the whole family to provide unambiguous evidence of pathogenic mutations responsible for A-T. A single novel SNP was allocated to each family. In the first case, we found a mononucleotide deletion, and in the second, a mononucleotide insertion. Both mutations lead to truncation of the ATM protein product. Identification of the pathogenic mutation in each family was performed in a timely fashion, allowing the fetuses to be tested and diagnosed. The parents chose to

  19. Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells

    Energy Technology Data Exchange (ETDEWEB)

    Kinoshita, Taisuke [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Nagamatsu, Go, E-mail: gonag@sc.itc.keio.ac.jp [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012 (Japan); Kosaka, Takeo [Department of Urology, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Takubo, Keiyo [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan); Hotta, Akitsu [Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012 (Japan); Department of Reprogramming Science, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto (Japan); Ellis, James [Ontario Human iPS Cell Facility, Molecular Genetics, University of Toronto, Developmental and Stem Cell Biology, SickKids, Toronto, Canada MG1L7 (Canada); Suda, Toshio, E-mail: sudato@sc.itc.keio.ac.jp [Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo 160-8582 (Japan)

    2011-04-08

    Highlights: {yields} iPS cells were induced with a fluorescence monitoring system. {yields} ATM-deficient tail-tip fibroblasts exhibited quite a low reprogramming efficiency. {yields} iPS cells obtained from ATM-deficient cells had pluripotent cell characteristics. {yields} ATM-deficient iPS cells had abnormal chromosomes, which were accumulated in culture. -- Abstract: During cell division, one of the major features of somatic cell reprogramming by defined factors, cells are potentially exposed to DNA damage. Inactivation of the tumor suppressor gene p53 raised reprogramming efficiency but resulted in an increased number of abnormal chromosomes in established iPS cells. Ataxia-telangiectasia mutated (ATM), which is critical in the cellular response to DNA double-strand breaks, may also play an important role during reprogramming. To clarify the function of ATM in somatic cell reprogramming, we investigated reprogramming in ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs). Although reprogramming efficiency was greatly reduced in ATM-KO TTFs, ATM-KO iPS cells were successfully generated and showed the same proliferation activity as WT iPS cells. ATM-KO iPS cells had a gene expression profile similar to ES cells and WT iPS cells, and had the capacity to differentiate into all three germ layers. On the other hand, ATM-KO iPS cells accumulated abnormal genome structures upon continuous passages. Even with the abnormal karyotype, ATM-KO iPS cells retained pluripotent cell characteristics for at least 20 passages. These data indicate that ATM does participate in the reprogramming process, although its role is not essential.

  20. Ataxia-telangiectasia mutated (ATM) deficiency decreases reprogramming efficiency and leads to genomic instability in iPS cells

    International Nuclear Information System (INIS)

    Kinoshita, Taisuke; Nagamatsu, Go; Kosaka, Takeo; Takubo, Keiyo; Hotta, Akitsu; Ellis, James; Suda, Toshio

    2011-01-01

    Highlights: → iPS cells were induced with a fluorescence monitoring system. → ATM-deficient tail-tip fibroblasts exhibited quite a low reprogramming efficiency. → iPS cells obtained from ATM-deficient cells had pluripotent cell characteristics. → ATM-deficient iPS cells had abnormal chromosomes, which were accumulated in culture. -- Abstract: During cell division, one of the major features of somatic cell reprogramming by defined factors, cells are potentially exposed to DNA damage. Inactivation of the tumor suppressor gene p53 raised reprogramming efficiency but resulted in an increased number of abnormal chromosomes in established iPS cells. Ataxia-telangiectasia mutated (ATM), which is critical in the cellular response to DNA double-strand breaks, may also play an important role during reprogramming. To clarify the function of ATM in somatic cell reprogramming, we investigated reprogramming in ATM-deficient (ATM-KO) tail-tip fibroblasts (TTFs). Although reprogramming efficiency was greatly reduced in ATM-KO TTFs, ATM-KO iPS cells were successfully generated and showed the same proliferation activity as WT iPS cells. ATM-KO iPS cells had a gene expression profile similar to ES cells and WT iPS cells, and had the capacity to differentiate into all three germ layers. On the other hand, ATM-KO iPS cells accumulated abnormal genome structures upon continuous passages. Even with the abnormal karyotype, ATM-KO iPS cells retained pluripotent cell characteristics for at least 20 passages. These data indicate that ATM does participate in the reprogramming process, although its role is not essential.

  1. Motor pathway degeneration in young ataxia telangiectasia patients: A diffusion tractography study

    Directory of Open Access Journals (Sweden)

    Ishani Sahama

    2015-01-01

    Conclusions: Whole tract analysis of the corticomotor, corticospinal and somatosensory pathways in ataxia telangiectasia showed significant white matter degeneration along the entire length of motor circuits, highlighting that ataxia–telangiectasia gene mutation impacts the cerebellum and multiple other motor circuits in young patients.

  2. Cutaneous granulomatosis and combined immunodeficiency revealing Ataxia-Telangiectasia: a case report

    OpenAIRE

    Folgori, Laura; Scarselli, Alessia; Angelino, Giulia; Ferrari, Francesca; Antoccia, Antonio; Chessa, Luciana; Finocchi, Andrea

    2010-01-01

    Abstract Ataxia-telangiectasia (A-T) is a complex multisystem disorder characterized by progressive neurological impairment, variable immunodeficiency and oculo-cutaneous telangiectasia. A-T is a member of chromosomal breakage syndromes and it is caused by a mutation in the ataxia-telangiectasia mutated (ATM) gene. Because of a wide clinical heterogeneity, A-T is often difficult to diagnose in children. We report an unusual case of a 3-year-old boy affected by A-T who presented exclusively wi...

  3. Brain glucose metabolism in adults with ataxia-telangiectasia and their asymptomatic relatives.

    Science.gov (United States)

    Volkow, Nora D; Tomasi, Dardo; Wang, Gene-Jack; Studentsova, Yana; Margus, Brad; Crawford, Thomas O

    2014-06-01

    Ataxia-telangiectasia is a recessive genetic disorder (ATM is the mutated gene) of childhood with severe motor impairments and whereas homozygotes manifest the disorder, heterozygotes are asymptomatic. Structural brain imaging and post-mortem studies in individuals with ataxia-telangiectasia have reported cerebellar atrophy; but abnormalities of motor control characteristic of extrapyramidal dysfunction suggest impairment of broader motor networks. Here, we investigated possible dysfunction in other brain areas in individuals with ataxia-telangiectasia and tested for brain changes in asymptomatic relatives to assess if heterozygocity affects brain function. We used positron emission tomography and (18)F-fluorodeoxyglucose to measure brain glucose metabolism (quantified as µmol/100 g/min), which serves as a marker of brain function, in 10 adults with ataxia-telangiectasia, 19 non-affected adult relatives (12 siblings, seven parents) and 29 age-matched healthy controls. Statistical parametric mapping and region of interest analyses were used to compare individuals with ataxia-telangiectasia, asymptomatic relatives, and unrelated controls. We found that participants with ataxia-telangiectasia had lower metabolism in cerebellar hemispheres (14%, P brain stimulation. Our finding of decreased metabolism in vermis and hippocampus of asymptomatic relatives suggests that heterozygocity influences the function of these brain regions. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.

  4. Genetic and cellular features of ataxia telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, A M.R.; Byrd, P J; McConville, C M; Thacker, S [Birmingham Univ. (United Kingdom). CRC Dept. of Cancer Studies

    1994-01-01

    Ataxia telangiectasia (AT) is a developmental disorder in which many organ systems are affected. The children are recognized by a progressive cerebellar deterioration. The gene for AT has now been localized to a region of chromosome 11q22-23 of no more than 3Mb in size and its product appears to be involved directly or indirectly in some form of DNA recombination. Patients and their cells are unusually sensitive to ionizing radiation and various radiometric drugs. Observations on the progressive nature of the disorder, with loss of selected cells or failure to develop normally, might be compatible with the pathological effect of an inability to correctly regulate apoptosis in some cell lineages. While this is an intriguing speculation, there is, at present, no evidence for such a defect in AT. (author).

  5. Complementation analysis of ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Jaspers, N.G.; Painter, R.B.; Paterson, M.C.; Kidson, C.; Inoue, T.

    1985-01-01

    In a number of laboratories genetic analysis of ataxia-telangiectasia (AT) has been performed by studying the expression of the AT phenotype in fused somatic cells or mixtures of cell-free extracts from different patients. Complementation of the defective response to ionizing radiation was observed frequently, considering four different parameters for radiosensitivity in AT. The combined results from studies on cultured fibroblasts or lymphoblastoid cells from 17 unrelated families revealed the presence of at least four and possibly nine complementation groups. These findings suggest that there is an extensive genetic heterogeneity in AT. More extensive studies are needed for an integration of these data and to provide a set of genetically characterized cell strains for future research of the AT genetic defect

  6. Cell biological study on ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Ohta, Shigeru; Katsura, Tadahiko; Shimada, Morimi; Shima, Akihiro; Chishiro, Hiroko; Kasahara, Yoshitaka.

    1985-01-01

    Diagnosis of ataxia-telangiectasia (AT) has largely been dependent on the clinical findings such as cerebellar ataxia, telangiectasia, and immunological deficiency. However, diagnosis of AT by these ordinary criteria is sometimes not sufficient because of the lack of immunological abnormalities. We examined three cases of AT by ordinary clinical criteria and also by X-ray sensitivity of cultured skin fibroblasts. Case 1, a 9-year-old boy, revealed typical clinical features of AT. However, he had no abnormality in serum IgA or IgE. Case 2, a 10-year-old boy, showed decreased serum IgA level. Case 3, a 19-year-old female, had typical clinical features of AT with normal serum IgA, and developed papillary adenocarcinoma of thyroid which was surgically removed. Fibroblast strains derived from these three cases of AT and from the parents of Case 3 were examined with regard to X-ray sensitivity. Three fibroblast strains derived from AT patients (AT homozygotes) showed remarkable hypersensitivity to X-ray. Fibroblast strains derived from the parents (AT heterozygotes) of Case 3, however, showed normal X-ray sensitivity. Recently, AT fibroblasts have been known to show hypersensitivity also to some mutagen like neocarzinostazin as reported by Shiloh et al. Fibroblasts from Case 3 revealed hypersensitivity to neocarzinostazin. However, the sensitivity of the strains from AT heterozygotes (the parents of Case 3) showed no apparent difference from that of control cells. The assay system for mutagen is quite unstable and proper conditioning of the seeding cell number is important for the carrier detection. However, the diagnosis of AT homozygotes was definitely established by X-ray irradiation to cultured fibroblasts from patients. (author)

  7. Clinical and genetic features of ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Bundey, S.

    1994-01-01

    There are several variants of ataxia-telangiectasia (A-T): classical A-T with marked radiation sensitivity; classical A-T with intermediate levels of radiation sensitivity; mild A-T with intermediate levels of radiation sensitivity; A-T without telangiectasia; A-T without oculomoto apraxia; and A-T with microcephaly. These disorders are probably caused by different allelic mutations, because affected sibs resemble the index patients, and because there is an association of certain haplo-types of 11q22-23 with specific phenotypes. The Nijmegen Breakage Syndrome, with its lack of ataxia, seems on clinical grounds to be a different disorder. Although A-T is almost always inherited as an autosomal recessive, there are some unusual features; an unexpectedly low parental consanguinity rate, an incidence in sibs that is < 0.25, and occurrence of disease in many different races and in the offspring of mixed race unions. Moreover, looking at haplotypes from 63 UK patients, there is a remarkably low incidence of homozygosity. An autosomal recessive condition that is deficient in parental consanguinity, and in homozygosity for the region around the gene, can be explained by J.H. Edwards' hypothesis that homozygosity for alleles at a neighbouring locus are lethal early in embryogenesis. Other possible mechanisms to explain the unusual genetic features are discussed. (author)

  8. Ataxia telangiectasia: LET dependence of cellular inactivation

    International Nuclear Information System (INIS)

    Blakely, E.A.; Tobias, C.A.

    1984-01-01

    Human Ataxia telangiectasia cells (AT 2SF line) have been irradiated in vitro under aerobic and hypoxic conditions with heavy-ion beams accelerated at the Berkeley Bevalac as a part of a study to characterize the radiation responses of genetically sensitive and resistant cell lines to high LET radiations. Results from track-segment exposures to neon, silicon, argon and iron ion beams accelerated to initial energies of from 225 to 670 MeV/amu provided an LET range between 30 to 1,000 KeV/μm. The data indicate: (1) The sensitivity of AT cells increases with increasing LET, similar to resistant human lines (e.g., T-1 cells). However, due to efficient repair, T-1 cells are more resistant than AT cells at LET values below 200 keV/μm; (2) Maximum cell kill occurs for both lines at 100-200 keV/μm; at higher LET the sensitivity of the two lines approach each other; (3) There is only small variation in the sensitivity of AT cells to particles of various atomic numbers at the same LET; differences are more pronounced in the LET domain between 50 and 200 keV/μm; and (4) AT cells have slightly lower OER values than T-1 cells in the range of LET studied below 200 keV/μm

  9. No evidence for association of ataxia-telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer

    International Nuclear Information System (INIS)

    Spurdle, Amanda B; Hopper, John L; Chen, Xiaoqing; McCredie, Margaret RE; Giles, Graham G; Newman, Beth; Chenevix-Trench, Georgia; Khanna, KumKum

    2002-01-01

    There is evidence that certain mutations in the double-strand break repair pathway ataxia-telangiectasia mutated gene act in a dominant-negative manner to increase the risk of breast cancer. There are also some reports to suggest that the amino acid substitution variants T2119C Ser707Pro and C3161G Pro1054Arg may be associated with breast cancer risk. We investigate the breast cancer risk associated with these two nonconservative amino acid substitution variants using a large Australian population-based case–control study. The polymorphisms were genotyped in more than 1300 cases and 600 controls using 5' exonuclease assays. Case–control analyses and genotype distributions were compared by logistic regression. The 2119C variant was rare, occurring at frequencies of 1.4 and 1.3% in cases and controls, respectively (P = 0.8). There was no difference in genotype distribution between cases and controls (P = 0.8), and the TC genotype was not associated with increased risk of breast cancer (adjusted odds ratio = 1.08, 95% confidence interval = 0.59–1.97, P = 0.8). Similarly, the 3161G variant was no more common in cases than in controls (2.9% versus 2.2%, P = 0.2), there was no difference in genotype distribution between cases and controls (P = 0.1), and the CG genotype was not associated with an increased risk of breast cancer (adjusted odds ratio = 1.30, 95% confidence interval = 0.85–1.98, P = 0.2). This lack of evidence for an association persisted within groups defined by the family history of breast cancer or by age. The 2119C and 3161G amino acid substitution variants are not associated with moderate or high risks of breast cancer in Australian women

  10. Pulmonary function in adolescents with ataxia telangiectasia.

    Science.gov (United States)

    McGrath-Morrow, Sharon; Lefton-Greif, Maureen; Rosquist, Karen; Crawford, Thomas; Kelly, Amber; Zeitlin, Pamela; Carson, Kathryn A; Lederman, Howard M

    2008-01-01

    Pulmonary complications are common in adolescents with ataxia telangiectasia (A-T), however objective measurements of lung function may be difficult to obtain because of underlying bulbar weakness, tremors, and difficulty coordinating voluntary respiratory maneuvers. To increase the reliability of pulmonary testing, minor adjustments were made to stabilize the head and to minimize leaks in the system. Fifteen A-T adolescents completed lung volume measurements by helium dilution. To assess for reproducibility of spirometry testing, 10 A-T adolescents performed spirometry on three separate occasions. Total lung capacity (TLC) was normal or just mildly decreased in 12/15 adolescents tested. TLC correlated positively with functional residual capacity (FRC), a measurement independent of patient effort (R2=0.71). The majority of individuals had residual volumes (RV) greater than 120% predicted (10/15) and slow vital capacities (VC) less than 70% predicted (9/15). By spirometry, force vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1) values were reproducible in the 10 individuals who underwent testing on three separate occasions (R=0.97 and 0.96 respectively). Seven of the 10 adolescents had FEV1/FVC ratios>90%. Lung volume measurements from A-T adolescents revealed near normal TLC values with increased RV and decreased VC values. These findings indicate a decreased ability to expire to residual volume rather then a restrictive defect. Spirometry was also found to be reproducible in A-T adolescents suggesting that spirometry testing may be useful for tracking changes in pulmonary function over time in this population. Copyright (c) 2007 Wiley-Liss, Inc.

  11. Cutaneous granulomatosis and combined immunodeficiency revealing Ataxia-Telangiectasia: a case report

    Directory of Open Access Journals (Sweden)

    Antoccia Antonio

    2010-04-01

    Full Text Available Abstract Ataxia-telangiectasia (A-T is a complex multisystem disorder characterized by progressive neurological impairment, variable immunodeficiency and oculo-cutaneous telangiectasia. A-T is a member of chromosomal breakage syndromes and it is caused by a mutation in the ataxia-telangiectasia mutated (ATM gene. Because of a wide clinical heterogeneity, A-T is often difficult to diagnose in children. We report an unusual case of a 3-year-old boy affected by A-T who presented exclusively with extensive cutaneous granulomatosis and severe combined immunodeficiency, without neurological abnormalities, at the time of diagnosis. This case clearly emphasizes the variable presentation of A-T syndrome and highlights the difficulties in the early diagnosis of A-T. A-T should be considered in children with evidence of combined humoral and cellular immunodeficiency associated with unexplained skin granulomatous lesions, even in the absence of the classic features of this syndrome.

  12. Screening for Ataxia-Telangiectasia Mutations in a Population-Based Sample of Women with Early-Onset Breast Cancer

    Science.gov (United States)

    1999-09-01

    and xeroderma pigmentosum in Britain. Cancer Res 1988;48:2929-32. 18 13. Stankovic T, Kidd AMJ, Sutcliffe A, McGuire GM, Robinson P, Weber P, et al...nested-PCR products of ATM nucleotide po - Nonsense and Missense Mutations with Indirect Effects sitions 500-1191 from cDNAs of AT113LA, AT140LA, and

  13. Bladder Wall Telangiectasia in a Patient with Ataxia-Telangiectasia and How to Manage?

    Directory of Open Access Journals (Sweden)

    Fatma Deniz Aygün

    2015-01-01

    Full Text Available Ataxia-telangiectasia (A-T is a rare neurodegenerative, inherited disease causing severe morbidity. Oculocutaneous telangiectasias are almost constant findings among the affected cases as telangiectasia is considered the main clinical finding for diagnosis. Vascular abnormalities in organs have been reported infrequently but bladder wall telangiectasias are extremely rare. We aimed to report recurrent hemorrhage from bladder wall telangiectasia in a 9-year-old boy with A-T who had received intravenous cyclophosphamide for non-Hodgkin’s lymphoma. Since A-T patients are known to be more susceptible to chemical agents, we suggested that possibly cyclophosphamide was the drug which induced bladder wall injury in this patient.

  14. Case Report: Neuro-Imaging Findings in Ataxia Telangiectasia

    Directory of Open Access Journals (Sweden)

    Farhad Mahvelati

    2004-06-01

    Full Text Available Ataxia Telangiectasia (AT is an autosomal recessive inherited disorder in which cutaneous and scleral Telangiectasia, cerebellar ataxia and immunodeficiency occur. There is a high incidence of development of malignant tumors, mainly lymphomas. Cerebellar atrophy is the most prominent abnormality and is shown better by magnetic resonance imaging (MRI than CT-Scan. Intracranial hemorrhage occurs rarely. We report a 7 years old boy who admitted for recurrent pulmonary infections. His examination showed ataxic gait with decreased deep tendon reflexes in lower extremities. He had telangiectasia in the eyes and his speech was slurred and difficult. Brain MRI showed cerebellar atrophy with diffuse hyperintensity in white matter, most prominent in occipital region, which was suggestive of leukodystrophy. This white matter change was not reported before in AT.

  15. MicroRNA-223 Enhances Radiation Sensitivity of U87MG Cells In Vitro and In Vivo by Targeting Ataxia Telangiectasia Mutated

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Liping; Zhu, Ji [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zaorsky, Nicholas G. [Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Deng, Yun [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Wu, Xingzhong [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Liu, Yong [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Liu, Fangqi; Cai, Guoxiang; Gu, Weilie [Department of Colorectal Cancer, Fudan University, Shanghai Cancer Center, Shanghai (China); Shen, Lijun [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zhang, Zhen, E-mail: zhenzhang6@hotmail.com [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China)

    2014-03-15

    Purpose: Ataxia telangiectasia mutated (ATM) protein is important in the DNA damage response because it repairs radiation-induced damage in cancers. We examined the effect of microRNA-223 (miR-223), a regulator of ATM expression, on radiation sensitivity of cancer cells. Methods and Materials: Human embryonic kidney 293 T (293T) cells were infected with pLL3.7-miR-223 plasmid to generate the pLL3.7-miR-223 and -empty virus (EV) lentivirus (miR-223 and EV). A dual luciferase assay in which the reporter contained wild-type 3′ untranslated region (UTR) of ATM was performed. U87MG cells were infected with miR-223 or EV to establish the overexpressed stable cell lines (U87-223 or U87-EV, respectively). Cells were irradiated in vitro, and dose enhancement ratios at 2 Gy (DER{sub 2}) were calculated. Hind legs of BALB/c athymic mice were injected with U87-223 or U87-EV cells; after 2 weeks, half of the tumors were irradiated. Tumor volumes were tracked for a total of 5 weeks. Results: The dual luciferase reporter assay showed a significant reduction in luciferase activity of 293T cells cotransfected with miR-223 and the ATM 3′UTR compared to that in EV control. Overexpression of miR-223 in U87MG cells showed that ATM expression was significantly downregulated in the U87-223 cells compared to that in U87-EV (ATM/β-actin mRNA 1.0 vs 1.5, P<.05). U87-223 cells were hypersensitive to radiation compared to U87-EV cells in vitro (DER{sub 2} = 1.32, P<.01). Mice injected with miR-223-expressing tumors had almost the same tumors after 3 weeks (1.5 cm{sup 3} vs 1.7 cm{sup 3}). However, irradiation significantly decreased tumor size in miR-223-expressing tumors compared to those in controls (0.033 cm{sup 3} vs 0.829 cm{sup 3}). Conclusions: miR-223 overexpression downregulates ATM expression and sensitizes U87 cells to radiation in vitro and in vivo. MicroRNA-223 may be a novel cancer-targeting therapy, although its cancer- and patient-specific roles are

  16. Glutamine deprivation induces interleukin-8 expression in ataxia telangiectasia fibroblasts.

    Science.gov (United States)

    Kim, Min-Hyun; Kim, Aryung; Yu, Ji Hoon; Lim, Joo Weon; Kim, Hyeyoung

    2014-05-01

    To investigate whether glutamine deprivation induces expression of inflammatory cytokine interleukin-8 (IL-8) by determining NF-κB activity and levels of oxidative indices (ROS, reactive oxygen species; hydrogen peroxide; GSH, glutathione) in fibroblasts isolated from patients with ataxia telangiectasia (A-T). We used A-T fibroblasts stably transfected with empty vector (Mock) or with human full-length ataxia telangiectasia mutated (ATM) cDNA (YZ5) and mouse embryonic fibroblasts (MEFs) transiently transfected with ATM small interfering RNA (siRNA) or with non-specific control siRNA. The cells were cultured with or without glutamine or GSH. ROS levels were determined using a fluorescence reader and confocal microscopy. IL-8 or murine IL-8 homolog, keratinocyte chemoattractant (KC), and hydrogen peroxide levels in the medium were determined by enzyme-linked immunosorbent assay and colorimetric assay. GSH level was assessed by enzymatic assay, while IL-8 (KC) mRNA level was measured by reverse transcription-polymerase chain reaction (RT-PCR) and/or quantitative real-time PCR. NF-κB DNA-binding activity was determined by electrophoretic mobility shift assay. Catalase activity and ATM protein levels were determined by O2 generation and Western blotting. While glutamine deprivation induced IL-8 expression and increased NF-κB DNA-binding activity in Mock cells, both processes were decreased by treatment of cells with glutamine or GSH or both glutamine and GSH. Glutamine deprivation had no effect on IL-8 expression or NF-κB DNA-binding activity in YZ5 cells. Glutamine-deprived Mock cells had higher oxidative stress indices (increases in ROS and hydrogen peroxide, reduction in GSH) than glutamine-deprived YZ5 cells. In Mock cells, glutamine deprivation-induced oxidative stress indices were suppressed by treatment with glutamine or GSH or both glutamine and GSH. GSH levels and catalase activity were lower in Mock cells than YZ5 cells. MEFs transfected with ATM siRNA and

  17. DNA-repair synthesis in ataxia telangiectasia lymphoblastoid cells

    Energy Technology Data Exchange (ETDEWEB)

    Ford, M.D.; Houldsworth, J.; Lavin, M.F. (Queensland Univ., Brisbane (Australia). Dept. of Biochemistry)

    1981-12-01

    The ability of a number of Epstein-Barr virus-transformed lymphoblastoid cells from ataxia telangiectasia (AT) patients to repair ..gamma..-radiation damage to DNA was determined. All of these AT cells were previously shown to be hypersensitive to ..gamma..-radiation. Two methods were used to determine DNA-repair synthesis: isopycnic gradient analysis and a method employing hydroxyurea to inhibit semiconservative DNA synthesis. Control, AT heterozygote and AT homozygote cells were demonstrated to have similar capacities for repair of radiation damage to DNA. In addition at high radiation doses (10-40 krad) the extent of inhibition of DNA synthesis was similar in the different cell types.

  18. Atm reactivation reverses ataxia telangiectasia phenotypes in vivo.

    Science.gov (United States)

    Di Siena, Sara; Campolo, Federica; Gimmelli, Roberto; Di Pietro, Chiara; Marazziti, Daniela; Dolci, Susanna; Lenzi, Andrea; Nussenzweig, Andre; Pellegrini, Manuela

    2018-02-22

    Hereditary deficiencies in DNA damage signaling are invariably associated with cancer predisposition, immunodeficiency, radiation sensitivity, gonadal abnormalities, premature aging, and tissue degeneration. ATM kinase has been established as a central player in DNA double-strand break repair and its deficiency causes ataxia telangiectasia, a rare, multi-system disease with no cure. So ATM represents a highly attractive target for the development of novel types of gene therapy or transplantation strategies. Atm tamoxifen-inducible mouse models were generated to explore whether Atm reconstitution is able to restore Atm function in an Atm-deficient background. Body weight, immunodeficiency, spermatogenesis, and radioresistance were recovered in transgenic mice within 1 month from Atm induction. Notably, life span was doubled after Atm restoration, mice were protected from thymoma and no cerebellar defects were observed. Atm signaling was functional after DNA damage in vivo and in vitro. In summary, we propose a new Atm mouse model to investigate novel therapeutic strategies for ATM activation in ataxia telangiectasia disease.

  19. DNA strand breakage repair in ataxia telangiectasia fibroblast-like cells

    Energy Technology Data Exchange (ETDEWEB)

    Vincent, Jr, R A; Sheridan, III, R B; Huang, P C [Johns Hopkins Univ., Baltimore, Md. (USA). Dept. of Environmental and Biophysical Sciences

    1975-12-01

    Human diploid fibroblast-like cells derived from four patients with the genetic disease ataxia telangiectasia and from two non-mutant donors were examined for the repair of x-ray induced strand breaks in DNA. The ataxia telangiectasia cultures showed no significant differences from the non-mutant cultures in the kinetics and extent of strand repair. This suggests that the increased spontaneous and x-ray induced chromatid aberrations observed in ataxia telangiectasia cells are not caused by a defect in the repair of single strand breaks as might be suspected from a general model of aberration production.

  20. ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia

    Directory of Open Access Journals (Sweden)

    Jayesh M. Bhatt

    2015-12-01

    Full Text Available Ataxia telangiectasia (A-T is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document.

  1. Characterization of glioma stem cells through multiple stem cell markers and their specific sensitization to double-strand break-inducing agents by pharmacological inhibition of ataxia telangiectasia mutated protein.

    Science.gov (United States)

    Raso, Alessandro; Vecchio, Donatella; Cappelli, Enrico; Ropolo, Monica; Poggi, Alessandro; Nozza, Paolo; Biassoni, Roberto; Mascelli, Samantha; Capra, Valeria; Kalfas, Fotios; Severi, Paolo; Frosina, Guido

    2012-09-01

    Previous studies have shown that tumor-driving glioma stem cells (GSC) may promote radio-resistance by constitutive activation of the DNA damage response started by the ataxia telangiectasia mutated (ATM) protein. We have investigated whether GSC may be specifically sensitized to ionizing radiation by inhibiting the DNA damage response. Two grade IV glioma cell lines (BORRU and DR177) were characterized for a number of immunocytochemical, karyotypic, proliferative and differentiative parameters. In particular, the expression of a panel of nine stem cell markers was quantified by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry. Overall, BORRU and DR177 displayed pronounced and poor stem phenotypes, respectively. In order to improve the therapeutic efficacy of radiation on GSC, the cells were preincubated with a nontoxic concentration of the ATM inhibitors KU-55933 and KU-60019 and then irradiated. BORRU cells were sensitized to radiation and radio-mimetic chemicals by ATM inhibitors whereas DR177 were protected under the same conditions. No sensitization was observed after cell differentiation or to drugs unable to induce double-strand breaks (DSB), indicating that ATM inhibitors specifically sensitize glioma cells possessing stem phenotype to DSB-inducing agents. In conclusion, pharmacological inhibition of ATM may specifically sensitize GSC to DSB-inducing agents while sparing nonstem cells. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

  2. Ataxia-telangiectasia: the pattern of cerebellar atrophy on MRI

    International Nuclear Information System (INIS)

    Tavani, F.; Zimmerman, R.A.; Gatti, R.; Bingham, P.; Berry, G.T.; Sullivan, K.

    2003-01-01

    We describe MRI of the brain in 19 patients with ataxia-telangiectasia (AT) and correlate the appearances with the degree of neurologic deficit. We examined 10 male and nine female patients; 17 were aged between 2 and 12 years (mean 8 years) but a woman and her brother were 35 and 38 years old, and had a variant of AT. Ataxia was the first recognized sign of the disease in every patient. We detected the following patterns of cerebellar atrophy: in the youngest patient, aged 2 years, the study was normal; in the five next youngest patients 3-7 years of age, the lateral cerebellum and superior vermis showed the earliest changes of atrophy; and all but one of the other patients had moderate to marked diffuse atrophy of vermis and cerebellar hemispheres. There were 12 patients aged 9 years and above; one, who was normal, was 9 years old. The five patients who at the time of examination were unable to walk all had diffuse atrophy involving both vermis and cerebellar hemispheres. (orig.)

  3. CT and MR imaging of splenic leiomyoma in a child with ataxia telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Coskun, M. [Dept. of Radiology, Hacettepe University Hospital, Ankara (Turkey); Aydingoez, Ue. [Dept. of Radiology, Hacettepe University Hospital, Ankara (Turkey); Tacal, T. [Dept. of Radiology, Hacettepe University Hospital, Ankara (Turkey); Ariyuerek, M. [Dept. of Radiology, Hacettepe University Hospital, Ankara (Turkey); Demirkazik, F. [Dept. of Radiology, Hacettepe University Hospital, Ankara (Turkey); Oguzkurt, L. [Dept. of Radiology, Hacettepe University Hospital, Ankara (Turkey)

    1995-02-01

    Computed tomographic and magnetic resonance imaging findings of a splenic leiomyoma in an 8-year-old boy with ataxia telangiectasia are presented. This is the first reported case of a splenic leiomyoma in the literature. (orig.)

  4. CT and MR imaging of splenic leiomyoma in a child with ataxia telangiectasia

    International Nuclear Information System (INIS)

    Coskun, M.; Aydingoez, Ue.; Tacal, T.; Ariyuerek, M.; Demirkazik, F.; Oguzkurt, L.

    1995-01-01

    Computed tomographic and magnetic resonance imaging findings of a splenic leiomyoma in an 8-year-old boy with ataxia telangiectasia are presented. This is the first reported case of a splenic leiomyoma in the literature. (orig.)

  5. Neurodegeneration in ataxia-telangiectasia: Multiple roles of ATM kinase in cellular homeostasis.

    Science.gov (United States)

    Choy, Kay Rui; Watters, Dianne J

    2018-01-01

    Ataxia-telangiectasia (A-T) is characterized by neuronal degeneration, cancer, diabetes, immune deficiency, and increased sensitivity to ionizing radiation. A-T is attributed to the deficiency of the protein kinase coded by the ATM (ataxia-telangiectasia mutated) gene. ATM is a sensor of DNA double-strand breaks (DSBs) and signals to cell cycle checkpoints and the DNA repair machinery. ATM phosphorylates numerous substrates and activates many cell-signaling pathways. There has been considerable debate about whether a defective DNA damage response is causative of the neurological aspects of the disease. In proliferating cells, ATM is localized mainly in the nucleus; however, in postmitotic cells such as neurons, ATM is mostly cytoplasmic. Recent studies reveal an increasing number of roles for ATM in the cytoplasm, including activation by oxidative stress. ATM associates with organelles including mitochondria and peroxisomes, both sources of reactive oxygen species (ROS), which have been implicated in neurodegenerative diseases and aging. ATM is also associated with synaptic vesicles and has a role in regulating cellular homeostasis and autophagy. The cytoplasmic roles of ATM provide a new perspective on the neurodegenerative process in A-T. This review will examine the expanding roles of ATM in cellular homeostasis and relate these functions to the complex A-T phenotype. Developmental Dynamics 247:33-46, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. The ATM gene and the radiobiology of ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Jorgensen, T.J.; Shiloh, Y.

    1996-01-01

    Ataxia-telangiectasia (A-T) is the classic human genetic disease involving severe ionizing radiation sensitivity and as such has been intensely studied by radiation biologists over the years. Unlike its counterpart for UV light sensitivity -xeroderma pigmentosum - A-T has no obvious DNA repair defect; and there has been much speculation as to the mechanism underlying the altered radioresponses associated with this disease. The gene defective in A-T (ATM) has recently been cloned, and its primary coding sequence determined. The primary sequence of the ATM protein suggests that it has some regulatory functions related to cellular radioresponse and maintenance of genomic stability, and shares these functions with a growing family of other proteins in various organisms. At this juncture it is appropriate to review our current knowledge about the radiobiology of A-T and reflect on the possible radiobiological mechanisms that are suggested by the ATM gene itself. This article will attempt briefly to review current knowledge about the radiobiology of A-T and to introduce new speculations about underlying radiobiological mechanisms that are suggested by the primary amino acid sequence of the predicted ATM gene product. (Author)

  7. Defect in radiation signal transduction in ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Lavin, M.F.

    1994-01-01

    Exposure of mammalian cells to ionizing radiation causes a delay in progression through the cycle at several checkpoints. Cells from patients with ataxia-telangiectasia (A-T) ignore these checkpoint controls postirradiation. The tumour suppressor gene product p53 plays a key role at the G 1 /S checkpoint preventing the progression of cells into S phase. The induction of p53 by radiation is reduced and/or delayed in A-T cells, which appears to account for the failure of delay at the G 1 /S checkpoint. We have investigated further this defect in radiation signal transduction in A-T. While the p53 response was defective after radiation, agents that interfered with cell cycle progression such as mimosine, aphidicolin and deprivation of serum led to a normal p53 response in A-T cells. None of these agents caused breaks in DNA, as determined by pulse-field gel electrophoresis, in order to elicit the response. Since this pathway is mediated by protein kinases, we investigated the activity of several of these enzymes in control and A-T cells. Ca +2 -dependent and -independent protein kinase C activities were increased by radiation to the same extent in the two cell types, a variety of serine/threonine protein kinase activities were approximately the same and anti-tyrosine antibodies failed to reveal any differences in protein phosphorylation between A-T and control cells. (author)

  8. Human iPSC-Derived Cerebellar Neurons from a Patient with Ataxia-Telangiectasia Reveal Disrupted Gene Regulatory Networks

    Directory of Open Access Journals (Sweden)

    Sam P. Nayler

    2017-10-01

    Full Text Available Ataxia-telangiectasia (A-T is a rare genetic disorder caused by loss of function of the ataxia-telangiectasia-mutated kinase and is characterized by a predisposition to cancer, pulmonary disease, immune deficiency and progressive degeneration of the cerebellum. As animal models do not faithfully recapitulate the neurological aspects, it remains unclear whether cerebellar degeneration is a neurodevelopmental or neurodegenerative phenotype. To address the necessity for a human model, we first assessed a previously published protocol for the ability to generate cerebellar neuronal cells, finding it gave rise to a population of precursors highly enriched for markers of the early hindbrain such as EN1 and GBX2, and later more mature cerebellar markers including PTF1α, MATH1, HOXB4, ZIC3, PAX6, and TUJ1. RNA sequencing was used to classify differentiated cerebellar neurons generated from integration-free A-T and control induced pluripotent stem cells. Comparison of RNA sequencing data with datasets from the Allen Brain Atlas reveals in vitro-derived cerebellar neurons are transcriptionally similar to discrete regions of the human cerebellum, and most closely resemble the cerebellum at 22 weeks post-conception. We show that patient-derived cerebellar neurons exhibit disrupted gene regulatory networks associated with synaptic vesicle dynamics and oxidative stress, offering the first molecular insights into early cerebellar pathogenesis of ataxia-telangiectasia.

  9. Ataxia Telangiectasia - A Report of a case in Port Harcourt

    African Journals Online (AJOL)

    TNHJOURNALPH

    ocularand cutaneous telangiectasia, and a predisposition to ... complications because early management with monitoring of lung ... Blymphoid malignancy and hypersensitivity to ionizing radiation. 4 Data on the prevalence of A-T in Nigeria is limited. Few cases of A-T have been reported in Nigeria. 5 The prevalence.

  10. Ataxia telangiectasia derived iPS cells show preserved x-ray sensitivity and decreased chromosomal instability

    OpenAIRE

    Fukawatase, Yoshihiro; Toyoda, Masashi; Okamura, Kohji; Nakamura, Ken-ichi; Nakabayashi, Kazuhiko; Takada, Shuji; Yamazaki-Inoue, Mayu; Masuda, Akira; Nasu, Michiyo; Hata, Kenichiro; Hanaoka, Kazunori; Higuchi, Akon; Takubo, Kaiyo; Umezawa, Akihiro

    2014-01-01

    Ataxia telangiectasia is a neurodegenerative inherited disease with chromosomal instability and hypersensitivity to ionizing radiation. iPS cells lacking ATM (AT-iPS cells) exhibited hypersensitivity to X-ray irradiation, one of the characteristics of the disease. While parental ataxia telangiectasia cells exhibited significant chromosomal abnormalities, AT-iPS cells did not show any chromosomal instability in vitro for at least 80 passages (560 days). Whole exome analysis also showed a compa...

  11. The role of the neuro-astro-vascular unit in the etiology of Ataxia Telangiectasia

    Directory of Open Access Journals (Sweden)

    Leenoy eMeshulam

    2012-09-01

    Full Text Available The growing recognition that brain pathologies do not affect neurons only but rather are, to a large extent, pathologies of glial cells as well as of the vasculature opens to new perspectives in our understanding of genetic disorders of the CNS. To validate the role of the neuron-glial-vascular unit in the etiology of genome instability disorders, we report about cell death and morphological aspects of neuro-glia networks and the associated vasculature in a mouse model of Ataxia Telangiectasia (A-T, a human genetic disorder that induces severe motor impairment. We found that AT-mutated protein deficiency was consistent with aberrant astrocytic morphology and alterations of the vasculature, often accompanied by reactive gliosis. Interestingly similar findings could also be reported in the case of other genetic disorders. These observations bolster the notion that astrocyte-specific pathologies, hampered vascularization and astrocyte-endothelium interactions in the CNS could play a crucial role in the etiology of genome instability brain disorders and could underlie neurodegeneration.

  12. Establishment of cell lines derived from ataxia telangiectasia and xeroderma pigmentosum patients with high radiation sensitivity

    International Nuclear Information System (INIS)

    Hashimoto, Tomoko; Furuyama, Jun-ichi; Nakano, Yoshiro; Owada, M. Koji; Kakunaga, Takeo

    1986-01-01

    Four human fibroblast cell lines, three of which were derived from a patient with ataxia telangiectasia and the other from a patient with xeroderma pigmentosum, were established after transfection with cloned SV40 DNA. These 4 cell lines showed some phenotypes characteristic of neoplastically transformed cells, and had a human karyotype with heteromorphisms identical to those of the parental fibroblasts. Their sensitivity to the cytotoxic effects of γ-rays or ultraviolet irradiation was as high as those of their parental fibroblasts. (Auth.)

  13. Imaging study of lymphoreticular tumor development in ataxia-telangiectasia and Nijmegen breakage syndrome

    International Nuclear Information System (INIS)

    Martinez-Leon, M. I.; Ceres-Ruiz, L.; Cuesta, M. A.; Garcia-Martin, F. J.

    2003-01-01

    Ataxia-telangiectasia (AT), or Louis-Bar syndrome, is an autosomal recessive illness characterized by progressive cerebellar ataxia, oculo-cutaneous telangiectasia, immunodeficiency combined with susceptibility to sinopulmonary infections and high incidence of neoplastic development. Nijmegen breakage syndrome (NBS) is a variant of AT, is also an autosomal recessive illness that presents cerebellar ataxia, as well as combined immunodeficiency and a tendency toward tumor development. Contrary to Louis-Bar syndrome, it doesn't present telangiectasia and exhibits a characteristics phenotype (short stature, bird-like face and microcephaly). Both entities are classified as syndrome of chromosomal instability or chromosomal fragility, a group which also includes Bloom syndrome and Fanconi anemia. All of these show an increase in the frequency of neoplastic pathologies, mainly lymphoid tumors. We present three patients,two with AT and one with NBS, who developed different lymphoma types in the course of the illness. We highlight the most outstanding aspects from a clinical-radiological point of view. (Author) 17 refs

  14. Murine scid cells complement ataxia-telangiectasia cells and show a normal port-irradiation response of DNA synthesis

    International Nuclear Information System (INIS)

    Komatsu, K.; Yoshida, M.; Okumura, Y.

    1993-01-01

    The murine severe combined immunodeficient mutation (scid) is characterized by a lack of both B and T cells, due to a deficit in lymphoid variable-(diversity)-joining (V(D)J) rearrangement. Scid cells are highly sensitive to both radiation-induced killing and chromosomal aberrations. Significantly reduced D 0 and n values were demonstrated in scid cells and were similar to ataxia-telangiectasia (AT) cells (a unique human disease conferring whole body radiosensitivity). However, the kinetics of DNA synthesis after irradiation were different between the two cell types. In contrast with the radioresistant DNA synthesis of AT cells, DNA synthesis of scid cells was markedly inhibited after irradiation. The existence of different mutations was also supported by evidence of complementation in somatic cell hybrids between scid cells and AT cells. Results indicate that the radiobiological character of scid is similar to AT but is presumably caused by different mechanisms. (author)

  15. Gastric outlet obstruction due to adenocarcinoma in a patient with Ataxia-Telangiectasia syndrome: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Hammond Sue

    2009-03-01

    Full Text Available Abstract Background Ataxia-Telangiectasia syndrome is characterized by progressive cerebellar dysfunction, conjuctival and cutaneous telangiectasias, severe immune deficiencies, premature aging and predisposition to cancer. Clinical and radiographic evaluation for malignancy in ataxia-telangiectasia patients is usually atypical, leading to delays in diagnosis. Case presentation We report the case of a 20 year old ataxia-telangiectasia patient with gastric adenocarcinoma that presented as complete gastric outlet obstruction. Conclusion A literature search of adenocarcinoma associated with ataxia-telangiectasia revealed 6 cases. All patients presented with non-specific gastrointestinal complaints suggestive of ulcer disease. Although there was no correlation between immunoglobulin levels and development of gastric adenocarcinoma, the presence of chronic gastritis and intestinal metaplasia seem to lead to the development of gastric adenocarcinoma. One should consider adenocarcinoma in any patient with ataxia-telangiectasia who presents with non-specific gastrointestinal complaints, since this can lead to earlier diagnosis.

  16. Role of chromatin structure modulation by the histone deacetylase inhibitor trichostatin A on the radio-sensitivity of ataxia telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Meschini, Roberta, E-mail: meschini@unitus.it; Morucci, Elisa; Berni, Andrea; Lopez-Martinez, Wilner; Palitti, Fabrizio

    2015-07-15

    Highlights: • Role of chromatin compaction on chromosomal instability. • Reduced radiation-induced clastogenicity in Ataxia telangiectasia cell lines. • Histone tails hyperacetylation reduces heterochromatin content favouring DSBs repair. - Abstract: At present, a lot is known about biochemical aspects of double strand breaks (DBS) repair but how chromatin structure affects this process and the sensitivity of DNA to DSB induction is still an unresolved question. Ataxia telangiectasia (A-T) patients are characterised by very high sensitivity to DSB-inducing agents such as ionising radiation. This radiosensitivity is revealed with an enhancement of chromosomal instability as a consequence of defective DNA repair for a small fraction of breaks located in the heterochromatin, where they are less accessible. Besides, recently it has been reported that Ataxia Telangiectasia Mutated (ATM) mediated signalling modifies chromatin structure. In order to study the impact of chromatin compaction on the chromosomal instability of A-T cells, the response to trichostatin-A, an histone deacetylase inhibitor, in normal and A-T lymphoblastoid cell lines was investigated testing its effect on chromosomal aberrations, cell cycle progression, DNA damage and repair after exposure to X-rays. The results suggest that the response to both trichostatin-A pre- and continuous treatments is independent of the presence of either functional or mutated ATM protein, as the reduction of chromosomal damage was found also in the wild-type cell line. The presence of trichostatin-A before exposure to X-rays could give rise to prompt DNA repair functioning on chromatin structure already in an open conformation. Differently, trichostatin-A post-treatment causing hyperacetylation of histone tails and reducing the heterochromatic DNA content might diminish the requirement for ATM and favour DSBs repair reducing chromosomal damage only in A-T cells. This fact could suggest that trichostatin-A post

  17. Excision of gamma-ray induced thymine lesions by preparations from ataxia telangiectasia fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Remsen, J F; Cerutti, P A [Florida Univ., Gainesville (USA). Inst. of Food and Agricultural Sciences; Florida Univ., Gainesville (USA). Dept. of Biochemistry)

    1977-04-01

    The capacity of whole cell sonicates of skin fibroblasts of normal individuals and patients with the autosomal recessive disease Ataxia telangiectasia (AT) to remove aerobic gamma-ray products of the 5,6-dihydroxydihydrothymine type (tsub(O/sub 2/)sup(..gamma..)) from exogenous DNA substrates was investigated. All four AT strains (AT CRL 1312, AT CRL 1343, AT GM 367, AT 4BI) possessed normal capabilities to excise tsub(O/sub 2/)sup(..gamma..) from irradiated bacteriophage DNA and irradiated chromatin isolated from normal and AT-skin fibroblasts.

  18. A novel pathogenic variant in an Iranian Ataxia telangiectasia family revealed by next-generation sequencing followed by in silico analysis.

    Science.gov (United States)

    Tabatabaiefar, Mohammad Amin; Alipour, Paria; Pourahmadiyan, Azam; Fattahi, Najmeh; Shariati, Laleh; Golchin, Neda; Mohammadi-Asl, Javad

    2017-08-15

    Ataxia telangiectasia (A-T) is a neurodegenerative autosomal recessive disorder with the main characteristics of progressive cerebellar degeneration, sensitivity to ionizing radiation, immunodeficiency, telangiectasia, premature aging, recurrent sinopulmonary infections, and increased risk of malignancy, especially of lymphoid origin. Ataxia Telangiectasia Mutated gene, ATM, as a causative gene for the A-T disorder, encodes the ATM protein, which plays an important role in the activation of cell-cycle checkpoints and initiation of DNA repair in response to DNA damage. Targeted next-generation sequencing (NGS) was performed on an Iranian 5-year-old boy presented with truncal and limb ataxia, telangiectasia of the eye, Hodgkin lymphoma, hyper pigmentation, total alopecia, hepatomegaly, and dysarthria. Sanger sequencing was used to confirm the candidate pathogenic variants. Computational docking was done using the HEX software to examine how this change affects the interactions of ATM with the upstream and downstream proteins. Three different variants were identified comprising two homozygous SNPs and one novel homozygous frameshift variant (c.80468047delTA, p.Thr2682ThrfsX5), which creates a stop codon in exon 57 leaving the protein truncated at its C-terminal portion. Therefore, the activation and phosphorylation of target proteins are lost. Moreover, the HEX software confirmed that the mutated protein lost its interaction with upstream and downstream proteins. The variant was classified as pathogenic based on the American College of Medical Genetics and Genomics guideline. This study expands the spectrum of ATM pathogenic variants in Iran and demonstrates the utility of targeted NGS in genetic diagnostics. Copyright © 2017. Published by Elsevier B.V.

  19. DNA-mediated gene transfer into ataxia-telangiectasia cells

    International Nuclear Information System (INIS)

    Crescenzi, M.; Pulciani, S.; Carbonari, M.; Tedesco, L.; Russo, G.; Gaetano, C.; Fiorilli, M.

    1986-01-01

    The complete description of the genetic lesion(s) underlying the AT mutation might, therefore, highlight not only a DNA-repair pathwa, but also an important aspect of the physiology of lymphocytes. DNA-mediated gene transfer into eukaryotic cells has proved a powerful tool for the molecular cloning of certain mammalian genes. The possibility to clone a given gene using this technology depends, basically, on the availability of a selectable marker associated with the expression of the transfected gene in the recipient cell. Recently, a human DNA repair gene has been cloned in CHO mutant cells by taking advantage of the increased resistance to ultraviolet radiation of the transformants. As a preliminary step toward the molecular cloning of the AT gene(s), the authors have attempted to confer radioresistance to AT cells by transfection with normal human DNA

  20. Sugammadex reversal of rocuronium-induced neuromuscular block in a patient with ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Kang, E.; Jung, J.W.

    2015-01-01

    A 17-year-old adolescent with ataxia-telangiectasia was scheduled to have laparoscopic colectomy for a resection of colon cancer. He had symptoms and signs of dyspnea, generalized dystonia, dysmetria, ataxia, and telangiectasia on the orbit. General anesthesia was performed, and rocuronium 30 mg was administered for muscle relaxation. Deep neuromuscular block (post-tetanic count: 0-8) was maintained for 95 minutes without additional rocuronium. On completion of surgery, sugammadex 80 mg was injected and train-of-four ratio was 0.93 at 210 seconds after administration. The tracheal tube was removed 5 min after the end of surgery. He recovered full spontaneous respiration and voluntary movements within 1 minute after extubation. After the surgery, he transferred to the intensive care unit and discharged 14 days after the surgery without any concrete problem. The reversal of rocuronium induced neuromuscular block by sugammadex was fast, complete, and recovered to the initial preoperative level of neuromuscular function in this patient. (author)

  1. Ataxia Telangiectasia

    Science.gov (United States)

    ... is the measurement of "fetal proteins," or serum alpha-fetoprotein , in the blood. These are proteins that are ... than 95 percent) have elevated levels of serum alpha-fetoprotein. When other causes of elevations of alpha-fetoprotein ...

  2. Ataxia Telangiectasia

    Science.gov (United States)

    ... the hair, difficulty swallowing, and delayed physical and sexual development. Children with A-T usually have normal or ... the hair, difficulty swallowing, and delayed physical and sexual development. Children with A-T usually have normal or ...

  3. Small Molecules Targeting Ataxia Telangiectasia and Rad3-Related (ATR) Kinase: An Emerging way to Enhance Existing Cancer Therapy

    Czech Academy of Sciences Publication Activity Database

    Andrs, M.; Korábečný, J.; Nepovimova, E.; Jun, D.; Hodný, Zdeněk; Kuca, K.

    2016-01-01

    Roč. 16, č. 3 (2016), s. 200-208 ISSN 1568-0096 Institutional support: RVO:68378050 Keywords : Ataxia telangiectasia and Rad3-related kinase (ATR) * cancer * chemosensitization * DNA damage response * phosphatidylinositol 3-kinase-related protein kinases (PIKK) * radiosensitization * synthetic lethality Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.992, year: 2016

  4. Stable radioresistance in ataxia-telangiectasia cells containing DNA from normal human cells

    International Nuclear Information System (INIS)

    Kapp, L.N.; Painter, R.B.

    1989-01-01

    SV40-transformed ataxia-telangiectasia (AT) cells were transfected with a cosmid containing a normal human DNA library and selectable marker, the neo gene, which endows successfully transformed mammalian cells with resistance to the antibiotic G418. Cells from this line were irradiated with 50 Gy of X-rays and fused with non-transfected AT cells. Among the G418-resistant colonies recovered was one stably resistant to radiation. Resistance to ionizing radiation of both primary transfectant line and its fusion derivative was intermediate between that of AT cells and normal cells, as assayed by colony-forming ability and measurement of radiation-induced G 2 chromatic aberrations; both cell lines retained AT-like radioresistant DNA synthesis. Results suggest that, because radioresistance in transfected cells was not as great as in normal human cells, two hallmarks of AT, radiosensitivity and radioresistant DNA synthesis, may still be the result of a single defective AT gene. (author)

  5. Cellular and molecular response to irradiation in ataxia telangiectasia and in Fanconi's anemia

    International Nuclear Information System (INIS)

    Ridet, A.; Guillouf, C.; Duchaud, E.; Moustacchi, E.; Rosselli, F.

    1997-01-01

    Ataxia telangiectasia (AT) and Fanconi anemia (FA) are recessive genetic diseases featuring chromosomal instability, increased predisposition to cancer and in vitro hypersensitivity to ionizing radiation (AT) or DNA cross-linking agents (FA). Moreover, an in vivo hypersensitivity to γ-rays exposure was reported in both syndromes. Cellular response to irradiation includes growth arrest (cell cycle modification) and cell death (by apoptosis or necrosis). Since it is generally accepted that apoptosis modulates cellular sensitivity to genotoxic stress, it was of interest to investigate the contribution of apoptosis in determining FA and AT responses to DNA Damaging Agents. The results support the contention that the in vivo hypersensitivity to radiation in these syndromes is not related to a higher rate of apoptotic cells but could be to a higher necrotic response triggering inflammatory reactions in the patients affected by this syndromes. (authors)

  6. Cellular and molecular response to irradiation in ataxia telangiectasia and in Fanconi`s anemia

    Energy Technology Data Exchange (ETDEWEB)

    Ridet, A.; Guillouf, C.; Duchaud, E.; Moustacchi, E.; Rosselli, F. [Institut Curie-Recherche, UMR 218, CNRS, 75 - Paris (France)

    1997-03-01

    Ataxia telangiectasia (AT) and Fanconi anemia (FA) are recessive genetic diseases featuring chromosomal instability, increased predisposition to cancer and in vitro hypersensitivity to ionizing radiation (AT) or DNA cross-linking agents (FA). Moreover, an in vivo hypersensitivity to {gamma}-rays exposure was reported in both syndromes. Cellular response to irradiation includes growth arrest (cell cycle modification) and cell death (by apoptosis or necrosis). Since it is generally accepted that apoptosis modulates cellular sensitivity to genotoxic stress, it was of interest to investigate the contribution of apoptosis in determining FA and AT responses to DNA Damaging Agents. The results support the contention that the in vivo hypersensitivity to radiation in these syndromes is not related to a higher rate of apoptotic cells but could be to a higher necrotic response triggering inflammatory reactions in the patients affected by this syndromes. (authors)

  7. Cell and Molecular Biology of Ataxia Telangiectasia Heterozygous Human Mammary Epithelial Cells Irradiated in Culture

    Science.gov (United States)

    Richmond, Robert C.

    2001-01-01

    Autologous isolates of cell types from obligate heterozygotes with the autosomal disorder ataxia-telangiectasia (A-T)were used to begin a tissue culture model for assessing pathways of radiation-induced cancer formation in this target tissue. This was done by establishing cultures of stromal fibroblasts and long-term growth human mammary epithelial cells (HMEC) in standard 2-dimensional tissue culture in order to establish expression of markers detailing early steps of carcinogenesis. The presumptive breast cancer susceptibility of A-T heterozygotes as a sequel to damage caused by ionizing radiation provided reason to study expression of markers in irradiated HMEC. Findings from our study with HMEC have included determination of differences in specific protein expression amongst growth phase (e.g., log vs stationary) and growth progression (e.g., pass 7 vs pass 9), as well as differences in morphologic markers within populations of irradiated HMEC (e.g., development of multinucleated cells).

  8. NAD+ Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair.

    Science.gov (United States)

    Fang, Evandro Fei; Kassahun, Henok; Croteau, Deborah L; Scheibye-Knudsen, Morten; Marosi, Krisztina; Lu, Huiming; Shamanna, Raghavendra A; Kalyanasundaram, Sumana; Bollineni, Ravi Chand; Wilson, Mark A; Iser, Wendy B; Wollman, Bradley N; Morevati, Marya; Li, Jun; Kerr, Jesse S; Lu, Qiping; Waltz, Tyler B; Tian, Jane; Sinclair, David A; Mattson, Mark P; Nilsen, Hilde; Bohr, Vilhelm A

    2016-10-11

    Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD + , and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD + reduce the severity of A-T neuropathology, normalize neuromuscular function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD + also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial dysfunction through nuclear DNA damage-induced nuclear-mitochondrial signaling, and demonstrates that they are important pathophysiological determinants in premature aging of A-T, pointing to therapeutic interventions. Published by Elsevier Inc.

  9. Imaging study of lymphoreticular tumor development in ataxia-telangiectasia and Nijmegen breakage syndrome; Estudio por imagen del desarrollo de tumores linforreticulares en la ataxia telangiectasia y el sindrome de Nijmegen

    Energy Technology Data Exchange (ETDEWEB)

    Martinez-Leon, M. I.; Ceres-Ruiz, L.; Cuesta, M. A.; Garcia-Martin, F. J. [Hospital Materno-Infantil C.H.U. Carlos Haya. Malaga (Spain)

    2003-07-01

    Ataxia-telangiectasia (AT), or Louis-Bar syndrome, is an autosomal recessive illness characterized by progressive cerebellar ataxia, oculo-cutaneous telangiectasia, immunodeficiency combined with susceptibility to sinopulmonary infections and high incidence of neoplastic development. Nijmegen breakage syndrome (NBS) is a variant of AT, is also an autosomal recessive illness that presents cerebellar ataxia, as well as combined immunodeficiency and a tendency toward tumor development. Contrary to Louis-Bar syndrome, it doesn't present telangiectasia and exhibits a characteristics phenotype (short stature, bird-like face and microcephaly). Both entities are classified as syndrome of chromosomal instability or chromosomal fragility, a group which also includes Bloom syndrome and Fanconi anemia. All of these show an increase in the frequency of neoplastic pathologies, mainly lymphoid tumors. We present three patients,two with AT and one with NBS, who developed different lymphoma types in the course of the illness. We highlight the most outstanding aspects from a clinical-radiological point of view. (Author) 17 refs.

  10. Body composition, muscle strength and hormonal status in patients with ataxia telangiectasia: a cohort study.

    Science.gov (United States)

    Pommerening, H; van Dullemen, S; Kieslich, M; Schubert, R; Zielen, S; Voss, S

    2015-12-09

    Ataxia-telangiectasia (A-T) is a devastating human autosomal recessive disorder that causes progressive cerebellar ataxia, immunodeficiency, premature aging, chromosomal instability and increased cancer risk. Affected patients show growth failure, poor weight gain, low body mass index (BMI), myopenia and increased fatigue during adolescence. The prevalence of alterations in body composition, muscle strength and hormonal status has not been well described in classical A-T patients. Additionally, no current guidelines are available for the assessment and management of these changes. We analyzed body composition, manual muscle strength and hormonal status in 25 A-T patients and 26 age-matched, healthy controls. Bioelectrical impedance analysis (BIA) was performed to evaluate the body composition, fat-free mass (FFM), body cell mass (BCM), extracellular matrix (ECM), phase angle (PhA), fat mass (FM) and ECM to BCM ratio. Manual muscle strength was measured using a hydraulic hand dynamometer. The BMI, FFM and PhA were significantly lower in A-T patients than in controls (BMI 16.56 ± 3.52 kg/m(2) vs. 19.86 ± 3.54 kg/m(2); Z-Score: -1.24 ± 1.29 vs. 0.05 ± 0.92, p body composition, characterized by depleted BMI, PhA and BCM; by the need to sit in a wheelchair; by altered hormone levels; and by poor muscle strength, is a major factor underlying disease progression and increased fatigue in A-T patients. ClinicalTrials.gov NCT02345200.

  11. Effect of caffeine on γ-ray induced G2 delay in ataxia telangiectasia

    International Nuclear Information System (INIS)

    Bates, P.R.; Lavin, M.F.

    1985-01-01

    Exposure of normal control and ataxia-telangiectasia (A-T) lymphoblastoid cell lines to ionizing radiation gives rise to an increase in the proportion of G2 phase cells. The size and extent of the G2 phase block is greater in A-T cells than in normal cells. Caffeine has a similar overall effect in control and A-T cell lines in reducing the G2 arrest observed after ionizing radiation. While the proportion of cells accumulated in G2 in A-T cells is considerably greater than in controls, addition of caffeine at the time of maximal G2 block brings about a return of G2 phase cell numbers to unirradiated values in 3 hours in both cell types. In normal control cells the caffeine-mediated decrease in G2 cells is reflected by an increase in mitotic cells. These mitotic cells have a higher frequency of chromosome aberrations compared to cells harvested in the absence of caffeine. Similarly in A-T cells addition of caffeine to irradiated cultures, delayed in G2 phase, increased the number of mitotic cells and the frequency of chromosome aberrations. (author)

  12. Radiation-induced chromosome aberrations and cell killing in normal human fibroblasts and ataxia telangiectasia fibroblasts

    International Nuclear Information System (INIS)

    Kawata, T.; Saito, M.; Uno, T.; Ito, H.; Shigematsu, N.

    2003-01-01

    Full text: When cells are held in a non-dividing state (G0) after irradiation, an enhanced survival can be observed compared to that of immediate plating. A change of survival depending on post irradiation condition is known to be repair of potentially lethal damage (RPLD). The effects of confluent holding recovery (24-h incubation following irradiation) on chromosome aberrations in normal human fibroblasts (AG1522) and ataxia telangiectasia fibroblasts (GM02052C) were examined. A chemical-induced premature chromosome condensation (PCC) technique with fluorescent in situ hybridization (FISH) was applied to study chromosome aberrations in G2 and M-phase. Results from cell survival showed that the capacity for potentially lethal damage repair was normal in AG1522 cells but very little in GM02052C cells. The frequency of chromosome aberrations in AG1522 cells decreased when cells were allowed to repair for 24-h. Especially complex type exchanges were found to decrease markedly at high doses (4Gy and 6Gy). However, the frequency of chromosome aberrations including complex type exchanges showed little decrease in GM02052C cells. Confluent holding can effectively reduce chromosome aberrations, especially complex type exchanges in normal cells

  13. Impaired recovery and mutagenic SOS-like responses in ataxia telangiectasia cells

    Energy Technology Data Exchange (ETDEWEB)

    Hilgers, G. (Universite Libre de Bruxelles (Belgium) Rijksuniversiteit Leiden (Netherlands)); Abrahams, P.J. (Rijksuniversiteit Leiden (Netherlands)); Chen, Y.Q. (Universite Libre de Bruxelles (Belgium)); Schouten, R. (Rijksuniversiteit Leiden (Netherlands)); Cornelis, J.J. (Universite Libre de Bruxelles (Belgium) Institut Pasteur, 75 - Paris (France)); Lowe, J.E. (Sussex Univ., Brighton (UK)); Eb, A.J. van der (Rijksuniversiteit Leiden (Netherlands)); Rommelaere, J. (Universite Libre de Bruxelles (Belgium) Institut Pasteur, 75 - Paris (France))

    1989-01-01

    Radiosensitive fibroblasts from patients with ataxia telangiectasia (AT) were studied for their proficiency in two putative eukaryotic SOS-like responses, namely the enhanced reactivation (ER) and enhanced mutagenesis of damaged viruses infecting pre-irradiated versus mock-treated cells. A previous report indicated that, unlike normal human cells, a line of AT fibroblasts (AT5BIVA) could not be induced to express ER of damaged parvovirus H-1, a single-stranded DNA virus, by UV- or X-irradiation. In the present study, AT5BIVA fibroblasts were also distinguished from normal cells by the inability of the former to achieve enhanced mutagenesis of damaged H-1 virus upon cell UV-irradiation. In contrast, dose-response and time-course experiments revealed normal levels of ER of Herpes simplex virus 1, a double-stranded DNA virus, in X- or UV-irradiated AT5BIVA cells. Taken together, these data point to a possible deficiency of AT cells in a conditioned mutagenic process that contributes to a greater extent to the recovery of damaged single-stranded than double-stranded DNA. Such a defect may concern the replication of damaged DNA or the generation of signals promoting the latter process and may be related to the lack of radiation-induced delay that is typical of AT cell DNA synthesis. (author).

  14. Impaired recovery and mutagenic SOS-like responses in ataxia telangiectasia cells

    International Nuclear Information System (INIS)

    Hilgers, G.; Abrahams, P.J.; Chen, Y.Q.; Schouten, R.; Cornelis, J.J.; Lowe, J.E.; Eb, A.J. van der; Rommelaere, J.

    1989-01-01

    Radiosensitive fibroblasts from patients with ataxia telangiectasia (AT) were studied for their proficiency in two putative eukaryotic SOS-like responses, namely the enhanced reactivation (ER) and enhanced mutagenesis of damaged viruses infecting pre-irradiated versus mock-treated cells. A previous report indicated that, unlike normal human cells, a line of AT fibroblasts (AT5BIVA) could not be induced to express ER of damaged parvovirus H-1, a single-stranded DNA virus, by UV- or X-irradiation. In the present study, AT5BIVA fibroblasts were also distinguished from normal cells by the inability of the former to achieve enhanced mutagenesis of damaged H-1 virus upon cell UV-irradiation. In contrast, dose-response and time-course experiments revealed normal levels of ER of Herpes simplex virus 1, a double-stranded DNA virus, in X- or UV-irradiated AT5BIVA cells. Taken together, these data point to a possible deficiency of AT cells in a conditioned mutagenic process that contributes to a greater extent to the recovery of damaged single-stranded than double-stranded DNA. Such a defect may concern the replication of damaged DNA or the generation of signals promoting the latter process and may be related to the lack of radiation-induced delay that is typical of AT cell DNA synthesis. (author)

  15. Effects of hyperthermia and ionizing radiation in normal and ataxia telangiectasia human fibroblast lines

    International Nuclear Information System (INIS)

    Mitchel, R.E.J.; Chan, A.; Smith, B.P.; Child, S.D.; Paterson, M.C.

    1984-01-01

    The effects of 45 0 C hyperthermia and γ radiation have been studied in three normal human fibroblast lines (GM38, GM730, WI38) and compared to the effects in two lines derived from patients with the hereditary disease ataxia telangiectasia (AR3BI, AT5BI). All lines, both normal and γ-sensitive AT, showed a similar resistance to killing by heat alone, suggesting that the defect responsible for the increased radiation sensitivity in AT lines does not confer increased heat sensitivity. Shouldered survival curves were obtained in each case indicating the ability to accumulate sublethal heat damage. All normal and AT cell lines exhibited increased resistance to the lethal effects of heat in response to a thermal stress, indicating that the defect that causes radiosensitivity in AT cell lines does not prevent the induction of thermotolerance. It was hypothesized that in normal cells, this heat treatment inactivates the process which is already defective in AT lines, and that this process may be required for the proper rejoining of double-strand breaks produced during the repair of other radiation-induced lesions

  16. Identification of 4 ataxia telangiectasia cell lines hypersensitive to. gamma. -irradiation but not to hydrogen peroxide

    Energy Technology Data Exchange (ETDEWEB)

    Cantoni, O.; Sestili, P.; Santoro, M.P.; Tannoia, M.C.; Cattabeni, F. (Universita degli Studi di Urbino (Italy). Istituto di Farmacologia e Farmacognosia and Centro di Farmacologia Oncologia Sperimentale); Novelli, G.; Dallapiccola, B. (Universit degli Studi di Urbino (Italy). Cattedra di Genetica); Fiorilli, M. (Universita di Roma ' La Sapienze' (Italy). Cattedra di Allergologia e Immunologia Clinica)

    1989-09-01

    The effct of hydrogen peroxide on the rate of semi-conservative DNA synthesis in ataxia telangiectasia (AT) and normal human lymphoblastoid cells was investigated. The rate of DNA synthesis in AT cells was not depressed to a lesser extent than in normal cells, as might have been expected since H{sub 2O2} is a radiomimetic agent. On the contrary, 4 AT cell lines displayed a higher sensitivity to the inhibitory effect of H{sub 2O2} on DNA synthesis than 2 normal cell lines. Comparable levels of cytotoxicity were detected in cell vaibility studies. Furthermore, neither the level of DNA breakage produced by H{sub 2O2}, nor the rate of repair of these lesions was signigicantly different in normal and AT cells. Together, these results indicate that the AT cell lines utilized in this study are not hypersensitive to the oxidant. It is suggested that H-2-O-2 may not induce lethality via the direct ation of the hydroxyl radical (OH). (Author). 20 refs.; 3 figs.; 1 tab.

  17. Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families

    Science.gov (United States)

    Janin, N; Andrieu, N; Ossian, K; Laugé, A; Croquette, M-F; Griscelli, C; Debré, M; Bressac-de-Paillerets, B; Aurias, A; Stoppa-Lyonnet, D

    1999-01-01

    Epidemiological studies in ataxia telangiectasia (AT) families have suggested that AT heterozygotes could have an increased cancer risk, especially breast cancer (BC) in women. It has also been suggested that an increased sensibility of AT heterozygotes to the effect of ionizing radiation could be responsible for the increased BC risk. BC relative risk (RR) estimation in AT heterozygotes within families ascertained through AT children is presented here. Family data collected included demographic characteristics, occurrence of cancers, past radiation exposures and blood samples. DNA samples were studied using seven ATM linked microsatellites markers allowing AT haplotypes reconstitution. The relative risk of BC was assessed using French estimated incidence rates. A significant increase risk of BC is found among obligate ATM heterozygotes with a point estimate of 3.32 (P = 0.002). BC relative risk calculated according to age is significantly increased among the obligate ATM heterozygotes female relatives with an age ≤ 44 years (RR = 4.55, P = 0.005). The BC relative risk is statistically borderline among the obligate ATM heterozygote female relatives with an age ≥ 45 years (RR = 2.48, P = 0.08). The estimated BC relative risk among ATM heterozygotes is consistent with previously published data. However, the increased risk is only a little higher than classical reproductive risk factors and similar to the risk associated with a first-degree relative affected by BC. © 1999 Cancer Research Campaign PMID:10362113

  18. Identification of ataxia telangiectasia heterozygotes by flow cytometric analysis of X-ray damage

    International Nuclear Information System (INIS)

    Rudolph, N.S.

    1989-01-01

    Flow cytometry was used to identify heterozygotes for the autosomal recessive DNA-repair deficiency disease ataxia telangiectasia (AT). Confluent G 0 /G 1 fibroblasts from 4 homozygotes (at/at), 5 obligate heterozygates (at/+) and 7 presumed normal (+/+) were X-irradiated with 200 Rad and subcultured immediately in medium containing 5-bromodeoxyuridine (BrdU). Cells were harvested 72 h later and stained with fluoresceinated anti-BrdU antibody to identify cells that had entered S phase. They were counterstained with propidium iodide to measure total DNA content. On the basis of relative release from G 0 /G 1 , the at/+ strains as a group were distinguished from both the presumed +/+ strains and at/at strains, although the individual values for some strains did show overlap between genotypes. When 10 cell strains were coded and analyzed in 'blind' experiments, all 4 heterozygotes were correctly assigned. By a similar assay in which exponentially growing cultures were pulsed briefly with BrdU 8 h after irradiation with 400 Rad and then harvested immediately, presumed +/+ cells as a group could be distinguished from at/at cells but not from at/- cells. This combination of assays assists in the identification of all 3 AT genotypes. This should be of both basic and diagnostic use, particularly in families known to segregate AT. (author). 37 refs.; 3 figs.; 5 tabs

  19. Phospho-SMC1 in-Cell ELISA based Detection of Ataxia Telangiectasia

    Directory of Open Access Journals (Sweden)

    Majid Zaki dizaji

    2016-12-01

    Full Text Available BackgroundAtaxia telangiectasia (A-T is a common genetically inherited cause of early childhood-onset ataxia. The infrequency of this disease, vast phenotype variation, disorders with features similar to those of A-T, and lack of definite laboratory test, make diagnosis difficult.  In addition, there is no rapid reliable laboratory method for identifying A-T heterozygotes, who susceptible to ionizing radiation (IR, atherosclerosis, diabetes, and cancers. We used SMC1pSer966 (pSMC1 in-cell colorimetric ELISA to diagnosis and screen in A-T families.Materials and Methods: With informed consent, 2cc peripheral blood was collected from the 15 A-T patients, their parents, and 24 healthy controls with no family history of malignancy, diabetes, and atherosclerosis. Extracted peripheral blood mononuclear cells (PBMCs were cultured in poly-L-Lysine treated 96-well plate with density of 70,000 cells per well. SMC1 phosphorylation was evaluated with cell-based ELISA kit 1 hour after 5 Gy IR and the pSMC1data normalized with Glyceraldehyde-3-phosphate dehydrogenase (GAPDH.Results: SMC1 phosphorylation was significantly low in A-T`s PBMC (mean + standard deviation [SD]: 0.075 + 0.034 in comparison to carriers (mean + SD: 0.190 + 0.060 and healthy controls (mean + SD: 0.312 +0.081, but unluckily could only discriminate A-T patients (Area Under the Curve -receiver operating characteristic [AUC-ROC]: 1.00, 1.00-1.00. This method in spite of rapidness and simplicity showed poor imprecision (22.49% coefficient of variation [CV] for intraday imprecision.Conclusion: It seems pSMC1 assessment by in-cell ELISA can be used for detection of A-T patients, but it may not sensitive enough for identification of carriers. This ELISA test is very simple, rapid, and requires less than 2cc blood. Thus it may be proposed for the early differential diagnosis of A-T as an alternative method.

  20. Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency.

    Science.gov (United States)

    Gul, Ersin; Sayar, Esra Hazar; Gungor, Bilgi; Eroglu, Fehime Kara; Surucu, Naz; Keles, Sevgi; Guner, Sukru Nail; Findik, Siddika; Alpdundar, Esin; Ayanoglu, Ihsan Cihan; Kayaoglu, Basak; Geckin, Busra Nur; Sanli, Hatice Asena; Kahraman, Tamer; Yakicier, Cengiz; Muftuoglu, Meltem; Oguz, Berna; Cagdas Ayvaz, Deniz Nazire; Gursel, Ihsan; Ozen, Seza; Reisli, Ismail; Gursel, Mayda

    2017-11-16

    Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. Type I and III IFN signatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed from the accumulation of DNA in the cytoplasm of AT and Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-α. Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights

  1. Gamma-ray induced inhibition of DNA synthesis in ataxia telangiectasia fibroblasts is a function of excision repair capacity

    International Nuclear Information System (INIS)

    Smith, P.J.; Paterson, M.C.

    1980-01-01

    The extent of the deficiency in γ-ray induced DNA repair synthesis in an ataxia telangiectasia (AT) human fibroblast strain was found to show no oxygen enhancement, consistent with a defect in the repair of base damage. Repair deficiency, but not repair proficiency, in AT cells was accompanied by a lack of inhibition of DNA synthesis by either γ-rays or the radiomimetic drug bleomycin. Experiments with 4-nitroquinoline 1-oxide indicated that lack of inhibition was specific for radiogenic-type damage. Thus excision repair, perhaps by DNA strand incision or chromatin modification, appears to halt replicon initiation in irradiated repair proficient cells whereas in repair defective AT strains this putatively important biological function is inoperative

  2. Effects of radiation therapy for Hodgkin's disease in a child with ataxia telangiectasia: a clinical, biological and pathologic study

    International Nuclear Information System (INIS)

    Pritchard, J.; Sandland, M.R.; Breatnach, F.B.; Pincott, J.R.; Cox, R.; Husband, P.

    1982-01-01

    Stage I lymphocyte-predominant Hodgkin's disease was diagnosed in a 44-month-old girl. Although immune deficiency was suspected and IgA deficiency demonstrated, the diagnosis of an ataxia-telangiectasia (AT)-like syndrome was not confirmed until eight weeks later when results of studies on the radiosensitivity of cultured skin fibroblasts were available. The child had none of the usual physical stigmata of AT. Severe acute radiation damage followed the treatment of this child with standard doses of radiation therapy. Clinical, pathologic, and radiobiologic correlations are drawn. The diagnosis of a malignant lymphoma disorder in children under the age of five should alert clinicians to the possibility of immune deficiency and, even in the absence of classical physical signs, to AT in particular. Suggestions for the management of future similar cases are put forward

  3. The production and repair of double strand breaks in cells from normal humans and patients with ataxia telangiectasia

    International Nuclear Information System (INIS)

    Lehman, A.R.; Stevens, S.

    1977-01-01

    The production and repair of double strand breaks induced by γ-rays in the DNA of human fibroblasts have been measured by sedimentation in sucrose gradients under non-denaturing conditions. Unirradiated DNA formed a rapidly sedimenting gel. Low doses of radiation released freely sedimenting DNA molecules from this gel. Higher doses reduced the rate of sedimentation of the free DNA due to the introduction of double strand breaks. The breakage efficiency was 1 break/1.3x10 10 daltons of DNA/krad. Postirradiation incubation after a high dose of radiation resulted in an increase in molecular weight of the free DNA molecules, and after a low dose the rapidly-sedimenting gel was reformed. These data suggest that double strand breaks are repaired in human fibroblasts. No significant differences were found between fibroblasts from two normal donors and four patients with the radiosensitive disorder, ataxia telangiectasia, in either the production or repair of double strand breaks

  4. Lack of effect of inhibitors of DNA synthesis/repair on the ionizing radiation-induced chromosomal damage in G[sub 2] stage of ataxia telangiectasia cells

    Energy Technology Data Exchange (ETDEWEB)

    Antoccia, A. (Univ. ' La Sapienza' , Rome (Italy). Dipt. di Genetica e Biologia Molecolare); Palitti, F.; Raggi, T. (Univ. del Tuscia, Viterbo (Italy). Dipt. di Agrobiologia ed Agrochimica); Catena, C. (ENEA, Casaccia (Italy). Centro Ricerche Energia); Tanzarella, C. (Rome Univ. 3 (Italy). Dipt. di Biologia)

    1994-09-01

    The relationship between the repair processes occurring at the G[sub 2] phase of the cell cycle and cytogenetic damage in ataxia telangiectasia (AT) cells was studied. Lymphoblastoid cells derived from normal, heterozygote AT (HzAT) and three AT patients were exposed to X-rays or fission neutrons and post-treated with inhibitors of DNA synthesis/repair, such as inhibitors of DNA polymerases [alpha], [sigma] and [epsilon] (cytosine arabinoside, ara-C; aphidicolin, APC; buthylphenyl-guanine, BuPdG) or ribonucleotide reductase (hydroxyurea HU). A strong increase of radiation-induced chromosomal aberrations was observed in normal and HzAT cells post-treated with ara-C, APC and HU, but not in the presence of BuPdG. No enhancing effect was observed in cells derived from AT patients, except for HU post-irradiation treatment. These results suggest that the enzymes that can be inhibited by these agents are not directly involved in the repair of radiation damage induced in G[sub 2] cells from AT patients, indicating that probably the AT cells that we used lack the capability to transform the primary DNA lesions into reparable products, or that AT cells might contain a mutated form of DNA polymerase resistant to the inhibitors. (author).

  5. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy.

    Science.gov (United States)

    Corbett, Mark A; Bellows, Susannah T; Li, Melody; Carroll, Renée; Micallef, Silvana; Carvill, Gemma L; Myers, Candace T; Howell, Katherine B; Maljevic, Snezana; Lerche, Holger; Gazina, Elena V; Mefford, Heather C; Bahlo, Melanie; Berkovic, Samuel F; Petrou, Steven; Scheffer, Ingrid E; Gecz, Jozef

    2016-11-08

    To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations. A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes. The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G>A; p.Arg297Gln) in a girl with EE, ataxia, and tremor. A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders. © 2016 American Academy of Neurology.

  6. Ionizing radiation-induced phosphorylation of RPA p34 is deficient in ataxia telangiectasia and reduced in aged normal fibroblasts

    International Nuclear Information System (INIS)

    Xinbo Cheng; Nge Cheong; Ya Wang; Iliakis, George

    1996-01-01

    Replication protein A (RPA, also called human single stranded DNA binding protein, hSSB) is a trimeric, multifunctional protein complex involved in DNA replication, DNA repair and recombination. Phosphorylation of RPA p34 subunit is observed after exposure of cells to radiation and other DNA damaging agents, which implicates the protein not only in repair but also in the regulation of replication on damaged DNA template. Here, we show that the phosphorylation observed in RPA p34 after exposure to ionizing radiation, X- or γ-rays, is reduced and occurs later in primary fibroblasts from patients suffering from ataxia telangiectasia (AT), as compared to normal fibroblasts. We also show that in primary normal human fibroblasts, radiation-induced phosphorylation of RPA p34 is 'age'-dependent and decreases significantly as cultures senesce. Radiation-induced phosphorylation of RPA p34 is nearly absent in non-cycling cells, while the expression of p21 cip1/waf1/sdi1 remains inducible. The results demonstrate a growth-stage and culture-age dependency in radiation-induced RPA p34 phosphorylation, and suggest the operation of a signal transduction pathway that is inactivated in senescing or quiescent fibroblasts and defective in AT cells

  7. Ataxia-telangiectasia cells are not uniformly deficient in poly(ADP-ribose) synthesis following X-irradiation

    International Nuclear Information System (INIS)

    Zwelling, L.A.; Kerrigan, D.; Mattern, M.R.

    1983-01-01

    The synthesis of poly(adenosine diphosphoribose [poly(ADP-R)] follows the DNA strand breakage produced by a number of physical and chemical agents, including X-radiation, and may be important for repair of several types of DNA damage. The reduction or abolition of its synthesis following X-irradiation might explain the enhanced sensitivity of ataxia-telangiectasia (A-T) cells to X-ray. We have examined 8 lines of human fibroblasts (including 4 A-T lines) for stimulation of the synthesis of poly(ADP-R) by X-irradiation. Similar amounts of X-ray-stimulated synthesis of poly(ADP-R) were detected in 4 lines of A-T fibroblasts, and in fibrolasts from a xeroderma pigmentosum (XP) patient, a Fanconi's anemia (FA) patient and 2 normal patients. 6 lines of human lymphoblastoid lines were also examined for X-ray-stimulated poly(ADP-R) synthesis. 4 A-T lines displayed an unusually high synthesis of poly(ADP-R) in unirradiated cells compared with 2 normal lines. (orig./AJ)

  8. Ataxia-telangiectasia cells are not uniformly deficient in poly(ADP-ribose) synthesis following X-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Zwelling, L.A.; Kerrigan, D. (National Cancer Inst., Bethesda, MD (USA). Lab. of Molecular Pharmacology); Mattern, M.R. (National Cancer Inst., Bethesda, MD (USA). Lab. of Molecular Carcinogenesis)

    1983-04-01

    The synthesis of poly(adenosine diphosphoribose (poly(ADP-R)) follows the DNA strand breakage produced by a number of physical and chemical agents, including X-radiation, and may be important for repair of several types of DNA damage. The reduction or abolition of its synthesis following X-irradiation might explain the enhanced sensitivity of ataxia-telangiectasia (A-T) cells to X-ray. We have examined 8 lines of human fibroblasts (including 4 A-T lines) for stimulation of the synthesis of poly(ADP-R) by X-irradiation. Similar amounts of X-ray-stimulated synthesis of poly(ADP-R) were detected in 4 lines of A-T fibroblasts, and in fibrolasts from a xeroderma pigmentosum (XP) patient, a Fanconi's anemia (FA) patient and 2 normal patients. 6 lines of human lymphoblastoid lines were also examined for X-ray-stimulated poly(ADP-R) synthesis. 4 A-T lines displayed an unusually high synthesis of poly(ADP-R) in unirradiated cells compared with 2 normal lines.

  9. Patients with an inherited syndrome characterized by immunodeficiency, microcephaly, and chromosomal instability: genetic relationship to ataxia telangiectasia

    International Nuclear Information System (INIS)

    Jaspers, N.G.; Taalman, R.D.; Baan, C.

    1988-01-01

    Fibroblast cultures from six unrelated patients having a familial type of immunodeficiency combined with microcephaly, developmental delay, and chromosomal instability were studied with respect to their response to ionizing radiation. The cells from five of them resembled those from individuals with ataxia telangiectasia (AT) in that they were two to three times more radiosensitive on the basis of clonogenic cell survival. In addition, after exposure to either X-rays or bleomycin, they showed an inhibition of DNA replication that was less pronounced than that in normal cells and characteristic of AT fibroblasts. However, the patients are clinically very different from AT patients, not showing any signs of neurocutaneous symptoms. Genetic complementation studies in fused cells, with the radioresistant DNA synthesis used as a marker, showed that the patients' cells could complement representatives of all presently known AT complementation groups. Furthermore, they were shown to constitute a genetically heterogeneous group as well. It is concluded that these patients are similar to AT patients with respect to cytological parameters. The clinical differences between these patients and AT patients are a reflection of genetic heterogeneity. The data indicate that the patients suffer from a chromosome-instability syndrome that is distinct from AT

  10. Nutritional status of patients with ataxia-telangiectasia: A case for early and ongoing nutrition support and intervention.

    Science.gov (United States)

    Ross, Lynda J; Capra, Sandra; Baguley, Brenton; Sinclair, Kate; Munro, Kate; Lewindon, Peter; Lavin, Martin

    2015-08-01

    Ataxia-telangiectasia (A-T) is a rare genomic syndrome resulting in severe disability. Chronic childhood disorders can profoundly influence growth and development. Nutrition-related issues in A-T are not well described, and there are no nutritional guidelines. This study investigated the nutrition-related characteristics and behaviours of Australian A-T patients attending a national clinic. A cross-sectional analysis of 13 A-T patients (nine females; aged: 4-23 years): nutritional status was assessed by anthropometric and body cell mass (BCM) calculations. Parents reported their child's diet history and physical and behavioural factors that affect nutrition including fatigue and need for assistance. Ten (77%) had short stature (height for age z scores nutritional barriers as chronic tiredness and the need for care giver assistance with meals. This study confirms profound malnutrition in Australian A-T patients. Poor intakes and diet quality suggest the need for early nutrition intervention. Ongoing support for families and early discussions on tube feeding are required to address changing needs in childhood and likely nutritional decline into adulthood. A prospective study is required to assess feasibility and effectiveness of nutrition interventions in young people with A-T. © 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  11. Normal rejoining of DNA strand breaks in ataxia telangiectasia fibroblast lines after low x-ray exposure

    International Nuclear Information System (INIS)

    Hariharan, P.V.; Eleczko, S.; Smith, B.P.; Paterson, M.C.

    1981-01-01

    The alkaline elution method was used to measure the enzymatic repair of x-ray-induced DNA strand breaks in skin fibroblasts derived from human subjects afflicted with ataxia telangiectasia (AT). Monolayer cultures of normal control and AT cell lines were exposed acutely to moderately lethal (250-rad) and highly lethal (1250-rad) doses of 250-kV x rays under aerobic conditions. Upon receiving 250 rad, the control fibroblasts from a clinically normal donor rejoined all detectable single-strand breaks (plus alkali-labile bonds) within 30 to 60 min of incubation. When challenged with 1250 rad the kinetics of strand rejoining by the normal control cells were biphasic. For both exposures, no significant difference in either the rate or the extent of strand rejoining was detected between the normal cell line (GM38) and three mutant cell lines (AT2BE, AT3BI, AT4BI) belonging to the three known genetic complementation groups in AT. It would thus appear that the enhanced radiosensitivity of cultured AT cells does not stem from faulty rejoining of radiogenic DNA strand breaks

  12. The rate of DNA synthesis in normal human and ataxia telangiectasia cells after exposure to X-irradiation

    International Nuclear Information System (INIS)

    Wit, J. de; Bootsma, D.; Jaspers, N.G.J.; Rijksverdedigingsorganisatie TNO, Rijswijk

    1981-01-01

    The rate of DNA synthesis was studied in normal cell strains and in strains from patients suffering from the inherited disorder ataxia telangiectasia (AT). After exposure to relatively low doses of oxic X-rays (0- 4 krad) DNA synthesis was depressed in AT cell strains to a significantly lesser extent than in normal cells. This response was observed in both an excision-deficient and an excision-proficient strain. In contrast, there was no difference in DNA-synthesis inhibition between AT and normal cells after UV exposure. After X-irradiation of cells from patients with xeroderma pigmentosum, both complementation group A and XP variants, the observed rate of DNA synthesis was equal to that in normal cells. An exception was the strain XP3BR which has been shown to be X-ray-sensitive. This strain exhibited diminished DNA synthesis inhibition after X-ray doses below 1 krad. These data suggest a relationship between hypersensitivity to X-rays and diminished depression of DNA synthesis. (orig.)

  13. Abnormal levels of UV-induced unscheduled DNA synthesis in ataxia telangiectasia cells after exposure to ionizing radiation

    International Nuclear Information System (INIS)

    Jaspers, N.G.J.; Nederlandse Centrale Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek, Rijswijk. Medical Biological Lab.); Bootsma, D.

    1982-01-01

    In cultured cells from normal individuals and from patients having ataxia telangiectasia (AT) the rate of unscheduled DNA synthesis (UDS) induced by UV light was investigated by autoradiography. The number of grains in 6 different AT cell strains was similar to that observed in normal cells. Exposure of normal cells to doses of X-rays up to 20 krad had no influence on the rate of UV-induced UDS. In contrast, the UV-induced UDS was significantly modified in AT cells by treatment with X-rays. In AT cell strains that were reported to have reduced levels of γ-ray-induced repair DNA synthesis ('excision-deficient' AT cells) the effect of X-rays on UV-induced UDS was inhibitory, whereas UV-induced UDS was stimulated by X-ray exposure in 'excision-proficient' AT cell strains. Different UV and X-ray dose-response relationships were seen in the two categories of AT cell strains. (orig./AJ)

  14. Identification of 4 ataxia telangiectasia cell lines hypersensitive to γ-irradiation but not to hydrogen peroxide

    International Nuclear Information System (INIS)

    Cantoni, O.; Sestili, P.; Santoro, M.P.; Tannoia, M.C.; Cattabeni, F.; Novelli, G.; Dallapiccola, B.; Fiorilli, M.

    1989-01-01

    The effct of hydrogen peroxide on the rate of semi-conservative DNA synthesis in ataxia telangiectasia (AT) and normal human lymphoblastoid cells was investigated. The rate of DNA synthesis in AT cells was not depressed to a lesser extent than in normal cells, as might have been expected since H 2O2 is a radiomimetic agent. On the contrary, 4 AT cell lines displayed a higher sensitivity to the inhibitory effect of H 2O2 on DNA synthesis than 2 normal cell lines. Comparable levels of cytotoxicity were detected in cell vaibility studies. Furthermore, neither the level of DNA breakage produced by H 2O2 , nor the rate of repair of these lesions was signigicantly different in normal and AT cells. Together, these results indicate that the AT cell lines utilized in this study are not hypersensitive to the oxidant. It is suggested that H-2-O-2 may not induce lethality via the direct ation of the hydroxyl radical (OH). (Author). 20 refs.; 3 figs.; 1 tab

  15. The effect of caffeine on X-ray-induced mitotic delay in normal human and ataxia-telangiectasia fibroblasts

    International Nuclear Information System (INIS)

    Zampetti-Bosseler, F.; Scott, D.

    1985-01-01

    The authors previously showed that radiation-sensitive fibroblasts from ataxia-telangiectasia (A-T) patients sustain less G 2 delay after X-irradiation than normal fibroblasts. Caffeine is known to reduce the amount of X-ray-induced delay in various mammalian cell types. It is proposed that A-T cells have an altered chromatin structure, similar to that of caffeine-treated normal cells and that this results in a failure of A-T cells to delay their progression through the cell cycle to allow time for DNA repair. The authors now show that caffeine treatment after X-irradiation reduces G 2 delay in both A-T and normal cells. The authors confirm the results previously obtained on lymphocytes that caffeine potentiates the chromosome-damaging effects of X-rays in both A-T and normal fibroblasts. These and other data suggest that the radiation responses of A-T cells and of caffeine-treated normal cells are caused by different mechanisms. (Auth.)

  16. Kinetics of chromatid aberrations in G2 ataxia-telangiectasia cells exposed to X-rays and ara A

    International Nuclear Information System (INIS)

    Mozdarani, Hossein; Bryant, P.E.

    1989-01-01

    The cytogenetic effects of X-rays alone or in combination with 9-β-D-arabinofuranosyladenine (ara A) were studied in an immortalized fibroblastic line of ataxia-telangiectasia (A-T) cells. It is postulated that the kinetics of disappearance (rejoining) of chromatid deletions with postirradiation incubation time reflects the underlying repair of dsb, and is inhibited by ara A. The rejoining kinetics for deletions in A-T was similar to that found in a previous study of normal human fibroblasts (Mozdarani and Bryant 1987). The number of deletions in X-irradiated A-T cells at 1.5 h before fixation was found to be higher by a factor of approximately 2 than that found previously in normals, indicating that in A-T a higher rate of conversion of dsb into chromatid deletions occurs. The frequency of exchanges induced in G2 A-T cells was similarly enhanced but, unlike the situation in normal cells, ara A was found to cause only a slight increase in this frequency. (author)

  17. Prenatal diagnosis of ataxia-telangiectasia and Nijmegen Breakage Syndrome by the assay of radioresistant DNA synthesis

    International Nuclear Information System (INIS)

    Kleijer, W.J.; Kraan, M. van der; Los, F.J.; Jaspers, N.G.J.

    1994-01-01

    Prenatal diagnosis was performed in 16 pregnancies at risk of ataxia-telangiectasia (A-T) or Nijmegen Breakage Syndrome (NBS). Radioresistant DNA synthesis (RDS) was investigated in cultured chorionic villus (CV) cells and/or amniotic fluid (AF) cells. In four pregnancies, an affected foetus was diagnosed with increased RDS in cultured CV cells. In three of the four cases confirmation of the diagnosis was obtained by analysis of AF cells and/or skin fibroblasts from the foetus cultured after termination of the pregnancy; in the fourth case a fibroblast culture from the aborted foetus failed. In one case, only AF cells could be analysed in a late stage of pregnancy; pregnancy was terminated due to intermediate/equivocal results but the foetus fibroblasts showed normal RDS. Normal RDS was demonstrated in the other 11 pregnancies at 25% risk either by analysis of CB cells (nine cases) or of AF cells (two cases). In some cases the (normal) results on the CV cells were corroborated by subsequent analysis of Af cells. The results suggest that RDS analysis of CV cells allows reliable prenatal diagnosis of A-T/NBS. However, amniocentesis may be necessary to confirm normal results on CV cells if the foetus is female (because of the risk of maternal cell contamination) or in the rare case of equivocal results. (author)

  18. Comparison of Selected Parameters of Redox Homeostasis in Patients with Ataxia-Telangiectasia and Nijmegen Breakage Syndrome

    Directory of Open Access Journals (Sweden)

    Barbara Pietrucha

    2017-01-01

    Full Text Available This study compared the antioxidant status and major lipophilic antioxidants in patients with ataxia-telangiectasia (AT and Nijmegen breakage syndrome (NBS. Total antioxidant status (TAS, total oxidant status (TOS, oxidative stress index (OSI, and concentrations of coenzyme Q10 (CoQ10 and vitamins A and E were estimated in the plasma of 22 patients with AT, 12 children with NBS, and the healthy controls. In AT patients, TAS (median 261.7 μmol/L was statistically lower but TOS (496.8 μmol/L was significantly elevated in comparison with the healthy group (312.7 μmol/L and 311.2 μmol/L, resp.. Tocopherol (0.8 μg/mL and CoQ10 (0.1 μg/mL were reduced in AT patients versus control (1.4 μg/mL and 0.3 μg/mL, resp.. NBS patients also displayed statistically lower TAS levels (290.3 μmol/L, while TOS (404.8 μmol/L was comparable to the controls. We found that in NBS patients retinol concentration (0.1 μg/mL was highly elevated and CoQ10 (0.1 μg/mL was significantly lower in comparison with those in the healthy group. Our study confirms disturbances in redox homeostasis in AT and NBS patients and indicates a need for diagnosing oxidative stress in those cases as a potential disease biomarker. Decreased CoQ10 concentration found in NBS and AT indicates a need for possible supplementation.

  19. Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

    Directory of Open Access Journals (Sweden)

    Mateusz Maciejczyk

    2017-04-01

    Full Text Available Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T, Bloom syndrome (BS and Nijmegen breakage syndrome (NBS are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4, oxidised low-density lipoprotein (ox-LDL or Poly (ADP-ribose polymerases (PARP. Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS, and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model.

  20. Abnormal regulation of DNA replication and increased lethality in ataxia telangiectasia cells exposed to carcinogenic agents

    International Nuclear Information System (INIS)

    Jaspers, N.G.; de Wit, J.; Regulski, M.R.; Bootsma, D.

    1982-01-01

    The effect of different carcinogenic agents on the rate of semiconservative DNA replication in normal and ataxia telangiectasis (AT) cells was investigated. The rate of DNA synthesis in all AT cell strains tested was depressed to a significantly lesser extent than in normal cells after exposure to X-rays under oxia or hypoxia or to bleomycin, agents to which AT cells are hypersensitive. In contrast, inhibition of DNA replication in normal human and AT cells was similar after treatment with some DNA-methylating agents or mitomycin C. Colony-forming ability of AT cells treated with these agents was not different from normal cells. Treatment with 4-nitroquinoline 1-oxide elicited a variable response in both AT and normal cell strains. In some strains, including those shown to be hypersensitive to the drug by other workers, the inhibition of DNA synthesis was more pronounced than in other cell strains, but no significant difference between AT and normal cells could be detected. The rejoining of DNA strand breaks induced by X-rays, measured by DNA elution techniques, occurred within l2 hr after treatment and could not be correlated with the difference in DNA synthesis inhibition in AT and normal cells. After low doses of X-rays, AT cells rejoined single-strand breaks slightly more slowly than did normal cells. The rate of DNA replication in X-irradiation AT and normal cells was not affected by nicotinamide, an inhibitor of poly(adenosine diphosphate ribose) synthesis. These data indicate that the diminished inhibition of DNA replication in carcinogen-treated AT cells (a) is a general characteristic of all AT cell strains, (b) correlates with AT cellular hypersensitivity, (c) is not directly caused by the bulk of the DNA strand breaks produced by carcinogenic agents, and (d) is not based on differences in the induction of poly(adenosine diphosphate ribose) synthesis between X-irradiated AT and normal cells

  1. Rejoining of DNA double-strand breaks in human fibroblasts and its impairment in one ataxia telangiectasia and two Fanconi strains

    International Nuclear Information System (INIS)

    Coquerelle, T.M.; Weibezahn, K.F.

    1981-01-01

    Using the technique of neutral elution through polycarbonate filters as a measure of DNA length, and hence of the number of double-strand breaks incurred as a result of radiation damage, we found that normal human fibroblasts rejoin 50% of all breaks within only 3 min (37 degrees C). This fast rejoining was impaired in fibroblasts from one patient with Ataxia telangiectasia and in fibroblasts from two patients with Fanconi's anemia. Also the number of residual breaks after several hours of repair was higher than in control cells. Other cases with the same diseases were normal in their rejoining of double-strand breaks

  2. Familial study of ataxia telangiectasia. Heterozygotes identification on the basis of sensitivity of gamma-irradiated cultures to caffeine post-treatment

    Energy Technology Data Exchange (ETDEWEB)

    Pawlak, A.L.; Kotecki, M. [Polska Akademia Nauk, Poznan (Poland). Zaklad Genetyki Czlowieka; Ignatowicz, R. [Centrum Zdrowia Dziecka, Warsaw (Poland)

    1994-12-31

    The effects of caffeine (CF), {gamma}-irradiation + CF post-treatment on chromosomal aberrations were studied in lymphocyte cultures from a patient with ataxia telangiectasia (AT), his parents and brother. In the studied family both the homozygotes and the obligatory heterozygotes of AT showed increased sensitivity to CF post-treatment. Individual differences in sensitivity to {gamma}-irradiation + CF post-treatment proved to be correlated with the sensitivity of non-irradiated cells to CF treatment, but not to {gamma}-irradiation. (author). 19 refs, 1 fig., 1 tab.

  3. Familial study of ataxia telangiectasia. Heterozygotes identification on the basis of sensitivity of gamma-irradiated cultures to caffeine post-treatment

    International Nuclear Information System (INIS)

    Pawlak, A.L.; Kotecki, M.

    1994-01-01

    The effects of caffeine (CF), γ-irradiation + CF post-treatment on chromosomal aberrations were studied in lymphocyte cultures from a patient with ataxia telangiectasia (AT), his parents and brother. In the studied family both the homozygotes and the obligatory heterozygotes of AT showed increased sensitivity to CF post-treatment. Individual differences in sensitivity to γ-irradiation + CF post-treatment proved to be correlated with the sensitivity of non-irradiated cells to CF treatment, but not to γ-irradiation. (author). 19 refs, 1 fig., 1 tab

  4. ENG mutational mosaicism in a family with hereditary hemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Tørring, Pernille M; Kjeldsen, Anette D; Ousager, Lilian Bomme

    2018-01-01

    mutation using Sanger sequencing. Analyzing her DNA by NGS HHT panel sequencing when extracted from both peripheral blood leukocytes, and cheek swabs, identified the familial ENG mutation at low levels. CONCLUSION: We provide evidence of ENG mutational mosaicism in an individual presenting with clinical...

  5. Selected missense mutations impair frataxin processing in Friedreich ataxia.

    Science.gov (United States)

    Clark, Elisia; Butler, Jill S; Isaacs, Charles J; Napierala, Marek; Lynch, David R

    2017-08-01

    Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing. Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing. Coimmunoprecipitation was performed to study the interaction between FXN and mitochondrial processing peptidase. A proteasome inhibitor was used to model traditional therapeutic strategies. In addition, clinical profiles of subjects with and without point mutations were compared in a large natural history study. FXN I 154F and FXN G 130V missense mutations decrease FXN 81-210 levels compared with FXN WT , FXN R 165C , and FXN W 155R , but do not block its association with mitochondria. FXN I 154F and FXN G 130V also impair FXN maturation and enhance the binding between FXN 42-210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN 81-210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXN G 130V . Finally, clinical data from patients with FXN G 130V and FXN I 154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia. These data suggest that the effects on processing associated with FXN G 130V and FXN I 154F mutations lead to higher levels of partially processed FXN, which may contribute to the milder clinical phenotypes in these patients.

  6. The response of normal and ataxia-telangiectasia human fibroblasts to the lethal effects of far, mid and near ultraviolet radiations

    International Nuclear Information System (INIS)

    Keyse, S.M.; McAleer, M.A.; Davies, D.J.G.; Moss, S.H.

    1985-01-01

    The responses of two ataxia-telangiectasia (A-T) cell strains to the lethal effects of monochromatic far, mid and near ultraviolet radiations have been determined and compared with the responses of three normal human cell strains. The authors results confirm a previous observation that the A-T cell strain AT4BI is abnormally sensitive to the lethal effects of mid u.v. (313 nm) radiation. After far u.v. (254 nm) radiation the strain AT4BI exhibits a small but statistically significant increase in sensitivity compared to the normal strains. Of most interest, in terms of a mechanistic interpretation of the sensitivity of A-T strains, the survival responses of neither A-T strain tested to near u.v. (365 nm) radiation differed significantly from the mean response of the normal strains, although it is of interest that one normal strain (48BR) was found to be significantly more resistant to near u.v. radiation than any of the other strains tested. The results are discussed in terms of the possible induction of radiogenic lesions in DNA by ultraviolet radiations and the possible mechanisms of radiation sensitivity in ataxia-telangiectasia. (author)

  7. Case report of novel CACNA1A gene mutation causing episodic ataxia type 2

    Directory of Open Access Journals (Sweden)

    David Alan Isaacs

    2017-05-01

    Full Text Available Background: Episodic ataxia type 2 (OMIM 108500 is an autosomal dominant channelopathy characterized by paroxysms of ataxia, vertigo, nausea, and other neurologic symptoms. More than 50 mutations of the CACNA1A gene have been discovered in families with episodic ataxia type 2, although 30%–50% of all patients with typical episodic ataxia type 2 phenotype have no detectable mutation of the CACNA1A gene. Case: A 46-year-old Caucasian man, with a long history of bouts of imbalance, vertigo, and nausea, presented to our hospital with 2 weeks of ataxia and headache. Subsequent evaluation revealed a novel mutation in the CACNA1A gene: c.1364 G > A Arg455Gln. Acetazolamide was initiated with symptomatic improvement. Conclusion: This case report expands the list of known CACNA1A mutations associated with episodic ataxia type 2.

  8. National mutation study among Danish patients with hereditary haemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Tørring, P M; Brusgaard, K; Ousager, L B

    2014-01-01

    carry mutations in the ENG, ACVRL1 or SMAD4 genes. Here, we report on the genetic heterogeneity in the Danish national HHT population and address the prevalence of pulmonary arteriovenous malformations (PAVM). Probands of 107 apparently unrelated families received genetic testing, including sequencing...... and multiplex ligation-dependent probe amplification (MLPA) analyses of ENG, ACVRL1 and SMAD4. These 107 families included 320 patients confirmed to have HHT either clinically or genetically. In 89% of the probands (n=95), a mutation was identified. We detected 64 unique mutations of which 27 (41%) were novel....... Large deletions were identified in ENG and ACVRL1. The prevalence of PAVM was 52.3% in patients with an ENG mutation and 12.9% in the ACVRL1 mutation carriers. We diagnosed 80% of the patients clinically, fulfilling the Curaçao criteria, and those remaining were diagnosed by genetic testing...

  9. Mutations found in the Danish population causing Hereditary Hemorrhagic Telangiectasia

    DEFF Research Database (Denmark)

    Tørring, Pernille M; Brusgaard, Klaus

    2011-01-01

    University Hospital, Denmark HHT is an autosomal vascular disorder caused by mutations of either of three loci ENG, ACVLR1 or MADH4. HHT is characterised by recurrent nosebleeds, mucocutaneous telangiectases, and more severe visceral malformations. During the last decade the Danish HHT centre has...

  10. DNA-mediated gene transfer into human diploid fibroblasts derived from normal and ataxia-telangiectasia donors: parameters for DNA transfer and properties of DNA transformants

    International Nuclear Information System (INIS)

    Debenham, P.G.; Webb, M.B.T.; Masson, W.K.; Cox, R.

    1984-01-01

    An investigation was made of the feasibility of DNA-mediated gene transfer into human diploid fibroblasts derived from patients with the radiation sensitive syndrome ataxia-telangiectasia (A-T) and from a normal donor. Although they are markedly different in their growth characteristics, both normal and A-T strains give similar frequencies for DNA transfer in a model system using the recombinant plasmid pSV2-gpt. pSV2-gpt DNA transformants arise with a frequency between 10 -5 and 10 -4 per viable cell. Analysis of such transformants, although possible, is severely handicapped by the limited clonal life span of diploid human cells. Despite these problems it may be concluded that diploid human fibroblasts are competent recipients for DNA-mediated gene transfer and the putative repair deficiency of A-T does not markedly effect the efficiency of this process. (author)

  11. Excision repair in ataxia telangiectasia, Fanconi's anemia, Cockayne syndrome, and Bloom's syndrome after treatment with ultraviolet radiation and N-acetoxy-2-acetylaminofluorene

    International Nuclear Information System (INIS)

    Ahmed, F.E.; Setlow, R.B.

    1978-01-01

    Excision repair of damage due to ultraviolet radiation, N-acetoxy-2-acetylaminofluorene and a combination of both agents was studied in normal human fibroblasts and various cells from cancer prone patients (ataxia telangiectasia, Fanconi's anemia, Cockayne syndrome and Bloom's syndrome). Three methods giving similar results were used: unscheduled DNA synthesis by radioautography, photolysis of bromodeoxyuridine incorporated into parental DNA during repair, and loss of sites sensitive to an ultraviolet endonuclease. All cell lines were proficient in repair of ultraviolet and acetoxy acetylaminofluorene damage and at saturation doses of both agents repair was additive. We interpret these data as indicating that the rate limiting step in excision repair of ultraviolet and acetoxy acetylaminofluorene is different and that there are different enzyme(s) working on incision of both types of damages. (Auth.)

  12. Potentiation by caffeine of x-ray damage to cultured human skin fibroblasts from normal subjects and ataxia-telangiectasia patients

    International Nuclear Information System (INIS)

    Furcinitti, P.S.

    1983-01-01

    Caffeine was found to potentiate x-ray-induced killing of human diploid fibroblasts from a normal subject and an ataxia-telangiectasia (AT) patient when it was present at 2 mM concentration for 30 to 66 h postirradiation. The dose-modifying factor for caffeine-treated normal cells had an average value of 1.26 +- 0.13 which did not vary significantly with treatment time or x-ray dose. The dose-modifying factor for caffeine-treated AT cells was 1.12 +- 0.12 at 30 h, rose to 1.66 +- 0.17 at 41 h, and decreased to 1.31 +- 0.13 at 66 h. Thus no clear difference was observed between these two cell strains' susceptibility to postirradiation caffeine treatment

  13. [Mutations of ACVRL1 gene in a pedigree with hereditary hemorrhagic telangiectasia].

    Science.gov (United States)

    Luo, Jie-wei; Chen, Hui; Yang, Liu-qing; Zhu, Ai-lan; Wu, Yan-an; Li, Jian-wei

    2008-06-01

    To identify the activin A receptor type II-like 1 gene (ACVRL1) mutations in a Chinese family with hereditary hemorrhagic telangiectasia (HHT2). The exons 3, 7 and 8 of ACVRL1 gene of the proband and her five family members were amplified by polymerase chain reaction (PCR), and the PCR products were sequenced. The proband had obvious telangiectasis of gastric mucosa, and small arteriovenous fistula in the right kidney. All the patients in the HHT2 family had iterative epistaxis or bleeding in other sites, and had telangiectasis of nasal mucosa, tunica mucosa oris and finger tips. ACVRL1 gene analysis confirmed that there is frameshift mutation caused by deletion of G145 in exon 3 in the 4 patients, but the mutation is absent in 2 members without HHT2. The HHT2 family is caused by a 145delG mutation of ACVRL1 gene, resulting in frameshift and a new stop codon at codon 53.

  14. S phase entry causes homocysteine-induced death while ataxia telangiectasia and Rad3 related protein functions anti-apoptotically to protect neurons.

    Science.gov (United States)

    Ye, Weizhen; Blain, Stacy W

    2010-08-01

    A major phenotype seen in neurodegenerative disorders is the selective loss of neurons due to apoptotic death and evidence suggests that inappropriate re-activation of cell cycle proteins in post-mitotic neurons may be responsible. To investigate whether reactivation of the G1 cell cycle proteins and S phase entry was linked with apoptosis, we examined homocysteine-induced neuronal cell death in a rat cortical neuron tissue culture system. Hyperhomocysteinaemia is a physiological risk factor for a variety of neurodegenerative diseases, including Alzheimer's disease. We found that in response to homocysteine treatment, cyclin D1, and cyclin-dependent kinases 4 and 2 translocated to the nucleus, and p27 levels decreased. Both cyclin-dependent kinases 4 and 2 regained catalytic activity, the G1 gatekeeper retinoblastoma protein was phosphorylated and DNA synthesis was detected, suggesting transit into S phase. Double-labelling immunofluorescence showed a 95% co-localization of anti-bromodeoxyuridine labelling with apoptotic markers, demonstrating that those cells that entered S phase eventually died. Neurons could be protected from homocysteine-induced death by methods that inhibited G1 phase progression, including down-regulation of cyclin D1 expression, inhibition of cyclin-dependent kinases 4 or 2 activity by small molecule inhibitors, or use of the c-Abl kinase inhibitor, Gleevec, which blocked cyclin D and cyclin-dependent kinase 4 nuclear translocation. However, blocking cell cycle progression post G1, using DNA replication inhibitors, did not prevent apoptosis, suggesting that death was not preventable post the G1-S phase checkpoint. While homocysteine treatment caused DNA damage and activated the DNA damage response, its mechanism of action was distinct from that of more traditional DNA damaging agents, such as camptothecin, as it was p53-independent. Likewise, inhibition of the DNA damage sensors, ataxia-telangiectasia mutant and ataxia telangiectasia and Rad

  15. Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia.

    Science.gov (United States)

    Zambonin, Jessica L; Bellomo, Allison; Ben-Pazi, Hilla; Everman, David B; Frazer, Lee M; Geraghty, Michael T; Harper, Amy D; Jones, Julie R; Kamien, Benjamin; Kernohan, Kristin; Koenig, Mary Kay; Lines, Matthew; Palmer, Elizabeth Emma; Richardson, Randal; Segel, Reeval; Tarnopolsky, Mark; Vanstone, Jason R; Gibbons, Melissa; Collins, Abigail; Fogel, Brent L; Dudding-Byth, Tracy; Boycott, Kym M

    2017-06-28

    Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible. Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort. Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural

  16. Deficient expression of enhanced reactivation of parvovirus H-1 in ataxia telangiectasia cells irradiated with X-rays or u.v. light

    International Nuclear Information System (INIS)

    Gilgers, Genevieve; Chen, Y.Q.; Cornelis, J.J.; Rommelaere, Jean

    1987-01-01

    Cells of patients with ataxia telangiectasia (AT), an inherited disease characterized by a high propensity to cancer, are hypersensitive to ionizing radiation. We investigated whether the hyper-radiosensitivity of AT cells correlated with a defect in their constitutive and/or conditional ability to rescue a damaged exogenous virus. For that purpose, parvovirus H-1, a single-stranded DNA virus whose intranuclear replication mostly relies on host cell functions, was used as a probe. The survival of u.v.-or γ-irradiated H-1 was measured in X-, u.v.-or mock-irradiated human cells of normal (NB-E) or AT (AT5BIVA) origin. γ-Irradiated H-1 survived to similar extents in untreated normal and AT cell lines. Both X- and u.v.-irradiation induced normal cells to achieve an enhanced reactivation (ER) of γ- or u.v.-damaged H-1. In contrast, neither dose-effect curves nor time course revealed significant levels of ER expression after X- or u.v.-irradiation in AT5BIVA cells. Our results suggest that the impairment of ER of damaged parvoviruses may constitute a marker of the AT cell phenotype and be related to the radiosensitivity of AT cells. (author)

  17. Deficient expression of enhanced reactivation of parvovirus H-1 in ataxia telangiectasia cells irradiated with X-rays or u. v. light

    Energy Technology Data Exchange (ETDEWEB)

    Hilgers, G.; Chen, Y.Q.; Cornelis, J.J.; Rommelaere, J.

    1987-02-01

    Cells of patients with ataxia telangiectasia (AT), an inherited disease characterized by a high propensity to cancer, are hypersensitive to ionizing radiation. We investigated whether the hyper-radiosensitivity of AT cells correlated with a defect in their constitutive and/or conditional ability to rescue a damaged exogenous virus. For that purpose, parvovirus H-1, a single-stranded DNA virus whose intranuclear replication mostly relies on host cell functions, was used as a probe. The survival of u.v.- or gamma-irradiated H-1 was measured in X-, u.v.- or mock-irradiated human cells of normal (NB-E) or AT (AT5BIVA) origin. gamma-Irradiated H-1 survived to similar extents in untreated normal and AT cell lines. Both X- and u.v.-irradiation induced normal cells to achieve an enhanced reactivation (ER) of gamma- or u.v.-damaged H-1. In contrast, neither dose-effect curves nor time course revealed significant levels of ER expression after X- or u.v.-irradiation in AT5BIVA cells. Our results suggest that the impairment of ER of damaged parvoviruses may constitute a marker of the AT cell phenotype and be related to the radiosensitivity of AT cells.

  18. Enhanced radiosensitivity of cultured fibroblasts from ataxia telangiectasia heterozygotes manifested by defective colony-forming ability and reduced DNA repair replication after hypoxic γ-irradiation

    International Nuclear Information System (INIS)

    Paterson, M.C.; Anderson, A.K.; Smith, B.P.; Smith, P.J.

    1979-01-01

    We have measured the sensitivity to γ-ray inactivation of diploid skin fibroblasts cultured from 10 persons in four families with ataxia telangiectasia (AT). Persons heterozygous for AT, including parents of afflicted patients, are not as yet detectable by any specific clinical or laboratory marker but are believed to constitute a substantial portion of the middle-aged cancer population. In one AT family, fibroblast strains from both parents exhibited a colony-forming ability after hypoxic irradiation which was intermediate between that displayed by five control strains from normal children and that from the affected child. In the remaining three families, cultures from only one parent were available; one parental strain displayed an intermediate survival capacity as above, whereas the other two responded normally. The homozygous recessive strains from the five afflicted children in the four families were all equally hypersensitive to hypoxic γ-ray inactivation. The three presumed AT heterozygous strains that displayed intermediate rayiosensitivity also carried out γ-rad-induced DNA repair replication to an extent intermediate between those in normals and AT homozygotes. These findings suggest that a numerically significant, cancer-prone subpopulation of humans carrying one normal and one abnormal AT gene may also be moderately sensitive to lethal effects of hypoxic γ-rays due to a defect in the enzymatic repair of DNA

  19. Effects of X-irradiation on cell-cycle progression, induction of chromosomal aberrations and cell killing in ataxia telangiectasia (AT) fibroblasts

    International Nuclear Information System (INIS)

    Nagasawa, H.; Little, J.B.; Latt, S.A.; Lalande, M.E.

    1985-01-01

    Survival, cumulative labeling indices, chromosomal aberrations and cell-cycle distribution by flow microfluorometry (FMF) were studied in fibroblasts from normal and three ataxia telangiectasia (AT) families after X-irradiation during density-inhibition of growth and immediate release by subculture to low density. Homozygotic AT (proband) fibroblasts were very hypersensitive to cell killing by X-irradiation. Fibroblasts from AT heterozygotes (parents) were minimally hypersensitive, with D 0 's slightly lower than those for normal fibroblasts. There were three different response groups for a G 1 phase block induced by 400 rad of X-rays: (1) minimal or no G 1 block was observed in AT homozygote cell strains; (2) 10-20% of the cells were blocked in G 1 in normal cell strains; and (3) 50% or more of the cells were blocked in AT heterozygote strains. FMF profiles and cumulative labeling indices showed that homozygotic AT cells irradiated in plateau phase moved into the S-phase following subculture with no additional delay over non-irradiated controls. Homozygotic AT cells showed not only a 4-5 times higher frequency of X-ray-induced chromosomal aberrations than normal strains, but approximately 30% of these were of the chromatid-type. There were no differences in the frequency or type of X-ray-induced chromosomal aberrations between normal and heterozygotic AT cells. (orig.)

  20. Ataxia telangiectasia: un desorden multisistémico con inestabilidad cromosómica y predisposición al cáncer

    Directory of Open Access Journals (Sweden)

    M. Guzmán

    1994-12-01

    Full Text Available El síndrome de ataxia telangiectasia (A-T fue descrito por Syllaba y Henneren 1926 y redescrito en 1941 por Louis Bar (1,2. Es una entidad autosómica recesiva que afecta a hombres y mujeres en igual proporción. La expresividad del gen A-Tes variable y la incidencia familiares alta (1,2. Se ha estimado que la frecuencia de individuos homocigotos (afectados para el gen A-T, es de 1/40.000 nacidos vivos y 1% de la población general serían heterocigotos (portadores. Sin embargo, la incidencia en la población se puede incrementar ya que los homocigotos pueden tener descendencia. Es así como se estima que en la población blanca de Estados Unidos los heterocigotos podrían llegar a constituir el 1,4% de la población (2,3. Otros autores estiman una frecuencia de heterocigotos mucho más alta entre 0,68% y 7,7% de la población (4.

  1. Characteristic brain MRI findings in ataxia-neuropathy spectrum related to POLG mutation.

    Science.gov (United States)

    Henao, Adriana I; Pira, Sonia; Herrera, Diego A; Vargas, Sergio A; Montoya, Jorge; Castillo, Mauricio

    2016-02-01

    Patients with mutations in the polymerase gamma gene (POLG) may present with progressive ataxia and in such situations neuroimaging findings may suggest the diagnosis. Herein we report a patient with a POLG gene W748S homozygous mutation and characteristic lesions in the thalamus, cerebellum and inferior olivary nucleus seen on magnetic resonance imaging. © The Author(s) 2016.

  2. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia

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    Huang Lijia

    2012-09-01

    Full Text Available Abstract Background Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family. Methods and Results Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified. Conclusions ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.

  3. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy

    DEFF Research Database (Denmark)

    Winkelmann, Juliane; Lin, Ling; Schormair, Barbara

    2012-01-01

    to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21......Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT...

  4. Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism

    Science.gov (United States)

    Mandriota, Stefano J.; Valentijn, Linda J.; Lesne, Laurence; Betts, David R.; Marino, Denis; Boudal-Khoshbeen, Mary; London, Wendy B.; Rougemont, Anne-Laure; Attiyeh, Edward F.; Maris, John M.; Hogarty, Michael D.; Koster, Jan; Molenaar, Jan J.; Versteeg, Rogier

    2015-01-01

    Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma. PMID:26053094

  5. Ataxia-telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review.

    Science.gov (United States)

    Jerzak, K J; Mancuso, T; Eisen, A

    2018-04-01

    Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult population, clinical guidelines to inform physicians and genetic counsellors about optimal management in that population are lacking. In this narrative review, we describe the challenges and controversies in the management of women who are heterozygous for a pathogenic ATM variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy. Given that the lifetime risk for breast cancer in women who are heterozygous for a pathogenic ATM variant is likely greater than 25%, those women should undergo annual mammographic screening starting at least by 40 years of age. For women in this group who have a strong family history of breast cancer, earlier screening with both magnetic resonance imaging and mammography should be considered. High-quality data to inform the management of established breast cancer in carriers of pathogenic ATM variants are lacking. Although deficiency in the ATM gene product might confer sensitivity to dna-damaging pharmaceuticals such as inhibitors of poly (adp-ribose) polymerase or platinum agents, prospective clinical trials have not been conducted in the relevant patient population. Furthermore, the evidence with respect to radiation therapy is mixed; some data suggest increased toxicity, and other data suggest improved clinical benefit from radiation in women who are carriers of a pathogenic ATM variant. As in the 2017 U.S. National Comprehensive Cancer Network guidelines, we recommend high-risk imaging for women in Ontario who are heterozygous for a pathogenic ATM variant. Currently, ATM carrier status should not influence decisions about systemic or radiation therapy in the setting of an established breast cancer diagnosis.

  6. Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism

    NARCIS (Netherlands)

    Mandriota, Stefano J.; Valentijn, Linda J.; Lesne, Laurence; Betts, David R.; Marino, Denis; Boudal-Khoshbeen, Mary; London, Wendy B.; Rougemont, Anne-Laure; Attiyeh, Edward F.; Maris, John M.; Hogarty, Michael D.; Koster, Jan; Molenaar, Jan J.; Versteeg, Rogier; Ansari, Marc; Gumy-Pause, Fabienne

    2015-01-01

    Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most

  7. Delayed expression of enhanced reactivation and decreased mutagenesis of UV-irradiated adenovirus in UV-irradiated ataxia telangiectasia fibroblasts

    International Nuclear Information System (INIS)

    Bennett, C.B.; Rainbow, A.J.

    1988-01-01

    In this study the authors examined UV-enhanced reactivation (UVER) and UV-enhanced mutagenesis (UVEM) of UV-irradiated adenovirus in AT fibroblasts. UVER factors for Ad V antigen expression were significantly less than normal in AT strains tested when infection occurred immediately after UV-irradiation of cells. However, UVER factors were >1 and similar to those found for normal strains when cells were infected 24 h after UV-irradiation, indicating delay in the expression of UVER for Ad V antigen in AT cells. UV-irradiation of both normal and AT cells 24 h prior to infection also resulted in a significant increase in progeny survival for UV-irradiated Ad. In normal cells, this progeny UVER was concomitant with a significant increase in the mutation frequency for UV-irradiated virus (increase in targeted mutagenesis) suggesting existence of an inducible error-prone DNA repair mode in normal human cells. In contrast, pre-UV-irradiation of AT cells resulted in a significant decrease in the mutation frequency for UV-irradiated virus. (author)

  8. Novel Mitochondrial Homoplasmic T4216C Mutation in Iranian Patients with Friedreich Ataxia

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    M Heidari

    2010-06-01

    Full Text Available Introduction: The mitochondrial defects in Friedreich ataxia (FRDA have been reported in many researches. Friedreich ataxia is an autosomal recessive neurodegenerative disorder caused by decreased expression of the Frataxin protein. Frataxin deficiency leads to excessive free radical production and dysfunction of respiratory chain complexes. Mitochondrial DNA (mtDNA could be considered as a candidate modifier factor for FRDA disease. It prompted us to focus on the mtDNA and monitor the nucleotide changes of genome which are probably the cause of respiratory chain defects and reduced ATP generation. Methods: We searched the mitochondrial NADH dehydroganase I (ND1 gene by PCR-TTGE and DNA fragments showing abnormal banding patterns were sequenced for the identification of exact mutations. Results: In 20 patients, we detected 3 mtDNA mutations which is novel in Friedreich ataxia. T4216C mutation results in conversion of Tyrosine to Histidine in 313 amino acid locations in ND1 and bioinformatics studies show that ND1 protein loses sixth intramembrane α chain. Conclusion: Our results showed that ND1 gene mutations in FRDA samples are higher than normal controls (P<0.001. It is possible that mutations in mtDNA could constitute a predisposing factor in combination with environmental risk factors that could affect the age of onset and rate of disease progression.

  9. Pure Progressive Ataxia and Palatal Tremor (PAPT) Associated with a New Polymerase Gamma (POLG) Mutation.

    Science.gov (United States)

    Nicastro, Nicolas; Ranza, Emmanuelle; Antonarakis, Stylianos E; Horvath, Judit

    2016-12-01

    Progressive ataxia with palatal tremor (PAPT) is a syndrome caused by cerebellar and brainstem lesions involving the dentato-rubro-olivary tract and associated with hypertrophic olivary degeneration. Etiologies include acquired posterior fossa lesions (e.g. tumors, superficial siderosis, and inflammatory diseases) and genetic disorders, such as glial fibrillary acidic protein (GFAP) and polymerase gamma (POLG) mutations. We describe the case of a 52-year-old man who developed pure progressive ataxia and palatal tremor. Genetic analysis has shown that he is compound heterozygote for a known pathogenic (W748S) and a novel POLG variant (I1185N). Patients with POLG recessive mutations usually manifest a more complex clinical picture, including polyneuropathy and epilepsy; our case emphasizes the need to consider a genetic origin in a seemingly sporadic and pure PAPT.

  10. Ataxia-Telangiectasia Children's Project

    Science.gov (United States)

    ... T CURE TEAM Walt Disney World® Marathon Weekend Star Wars™ Half Marathon - The Dark Side Pittsburgh Marathon Weekend Hess Lake Run Half Marathon Super Heroes Half Marathon Run Any Race What's New Exploring the Epidemiology of A-T in ...

  11. DNA synthesis in ataxia telangiectasia

    NARCIS (Netherlands)

    N.G.J. Jaspers (Nicolaas)

    1985-01-01

    textabstractAfter the discovery that cultured cells from AT patients are hypersensitive to ionizing radiation the suggestion was made that AT-could be the 1 X-ray-analogue 1 of xeroderma pigmentosum. The latter syndrome (XP) is characterized by hypersensitivity to short-wave UV-radiation, caused by

  12. DNA synthesis in ataxia telangiectasia

    OpenAIRE

    Jaspers, Nicolaas

    1985-01-01

    textabstractAfter the discovery that cultured cells from AT patients are hypersensitive to ionizing radiation the suggestion was made that AT-could be the 1 X-ray-analogue 1 of xeroderma pigmentosum. The latter syndrome (XP) is characterized by hypersensitivity to short-wave UV-radiation, caused by a reduced ability to properly remove UV-induced DNA damage. The evidence for a DNA repair defect in AT cells is not as strong as in the case of XP (see section 2.2.5 of this thesis). Different XP p...

  13. A novel mitochondrial mutation m.8989G>C associated with neuropathy, ataxia, retinitis pigmentosa - the NARP syndrome

    DEFF Research Database (Denmark)

    Duno, Morten; Wibrand, Flemming; Baggesen, Kirsten

    2013-01-01

    mitochondrial point mutation, m.8989G>C, in a patient presenting with neuropathy, ataxia and retinitis pigmentosa constituting the classical NARP phenotype. This mutation alters the amino acid right next to canonical NARP mutation. We suggest that classic NARP syndrome relates to a defined dysfunction of p...

  14. Novel Missense Mitochondrial ND4L Gene Mutations in Friedreich's Ataxia

    Directory of Open Access Journals (Sweden)

    Mohammad Mehdi Heidari

    2011-05-01

    Full Text Available AbstractObjective(sThe mitochondrial defects in Friedreich's ataxia have been reported in many researches. Mitochondrial DNA is one of the candidates for defects in mitochondrion, and complex I is the first and one of the largest catalytic complexes of oxidative phosphorylation (OXPHOS system. Materials and MethodsWe searched the mitochondrial ND4L gene for mutations by TTGE and sequencing on 30 FRDA patients and 35 healthy controls.ResultsWe found 3 missense mutations [m.10506A>G (T13A, m.10530G>A (V21M, and m.10653G>A (A62T] in four patients whose m.10530G>A and m.10653G>A were not reported previously. In two patients, heteroplasmic m.10530G>A mutation was detected. They showed a very early ataxia syndrome. Our results showed that the number of mutations in FRDA patients was higher than that in the control cases (P= 0.0287.ConclusionAlthough this disease is due to nuclear gene mutation, the presence of these mutations might be responsible for further mitochondrial defects and the increase of the gravity of the disease. Thus, it should be considered in patients with this disorder.

  15. Novel PNKP mutation in siblings with ataxia-oculomotor apraxia type 4.

    Science.gov (United States)

    Schiess, Nicoline; Zee, David S; Siddiqui, Khurram A; Szolics, Miklos; El-Hattab, Ayman W

    The phenotypic and genetic spectrum of ataxia with oculomotor apraxia (AOA) disorders is rapidly evolving and new technologies such as genetic mapping using whole exome sequencing reveal subtle distinctions among the various subtypes. We report a novel PNKP mutation in two siblings with progressive ataxia, abnormal saccades, sensorimotor neuropathy and dystonia consistent with the AOA type 4 phenotype. Laboratory evaluation revealed hypoalbuminemia, hypercholesterolemia with elevated LDL, elevated IgE levels and normal α fetoprotein levels. Eye movement examination demonstrated a marked saccade initiation defect with profound hypometric horizontal saccades. Vertical saccades were also affected but less so. Also present were conspicuous thrusting head movements when attempting to change gaze, but rather than an apraxia these were an adaptive strategy to take advantage of an intact vestibulo-ocular reflex to carry the eyes to a new target of interest. This is demonstrated in accompanying videos.

  16. Recurrent major depression, ataxia, and cardiomyopathy: association with a novel POLG mutation?

    Directory of Open Access Journals (Sweden)

    Verhoeven WMA

    2011-05-01

    Full Text Available Willem MA Verhoeven1,2, Jos IM Egger1,3,4, Berry PH Kremer5, Boudewijn JHB de Pont1, Carlo LM Marcelis61Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, The Netherlands; 2Erasmus University Medical Centre, Department of Psychiatry, Rotterdam, The Netherlands; 3Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands; 4Donders Institute for Brain, Cognition and Behaviour, Centre for Cognition, Radboud University Nijmegen, Nijmegen, The Netherlands; 5Department of Neurology, University Medical Centre Groningen, The Netherlands; 6Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsAbstract: At present, more than 100 disease mutations in mitochondrial DNA polymerase γ (POLG have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter being associated with Parkinsonism and depressive or psychotic syndromes. In this report, a middle-aged female patient with recurrent major depression with melancholic features, slowly progressive gait instability, and dilated cardiomyopathy is described. Detailed diagnostic evaluation was performed to elucidate the supposed relationship between ataxia, cardiomyopathy, and major depression with melancholia. After extensive genetic and metabolic investigation, a nucleotide substitution c.2207 A→G in the POLG gene resulting in amino acid change Asn 736Ser in exon 13 was demonstrated. This mutation was considered to be compatible with a mitochondrial disorder and implicated in the pathophysiology of the neuropsychiatric syndrome. It is concluded that this novel POLG mutation forms the most parsimonious etiological explanation for the here-described combination of ataxia, major depression, and cardiomyopathy. Therefore, in patients with a complex neuropsychiatric

  17. ATP1A3 Mutation in Adult Rapid-Onset Ataxia.

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    Kathleen J Sweadner

    Full Text Available A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP with a similar age and speed of onset, as well as severe diseases of infancy. The patient's ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4, a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1 deletes a motif with multiple copies and is unlikely to be causative.

  18. Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.

    Science.gov (United States)

    Coutelier, Marie; Hammer, Monia B; Stevanin, Giovanni; Monin, Marie-Lorraine; Davoine, Claire-Sophie; Mochel, Fanny; Labauge, Pierre; Ewenczyk, Claire; Ding, Jinhui; Gibbs, J Raphael; Hannequin, Didier; Melki, Judith; Toutain, Annick; Laugel, Vincent; Forlani, Sylvie; Charles, Perrine; Broussolle, Emmanuel; Thobois, Stéphane; Afenjar, Alexandra; Anheim, Mathieu; Calvas, Patrick; Castelnovo, Giovanni; de Broucker, Thomas; Vidailhet, Marie; Moulignier, Antoine; Ghnassia, Robert T; Tallaksen, Chantal; Mignot, Cyril; Goizet, Cyril; Le Ber, Isabelle; Ollagnon-Roman, Elisabeth; Pouget, Jean; Brice, Alexis; Singleton, Andrew; Durr, Alexandra

    2018-05-01

    Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or

  19. Recurrent gastrointestinal hemorrhage in treatment with dasatinib in a patient showing SMAD4 mutation with acute lymphoblastic leukemia Philadelphia positive and juvenile polyposis hereditary hemorrhagic telangiectasia syndrome

    Directory of Open Access Journals (Sweden)

    Chiara Sartor

    2013-07-01

    Full Text Available We report a case of a patient affected by juvenile polyposis and hereditary hemorrhagic telangiectasia linked to a SMAD4 mutation who developed acute lymphoblastic leukemia positive for the Philadelphia chromosome translocation and with a complex karyotype. During the treatment with the tyrosine kinase inhibitor dasatinib the patient presented recurrent severe gastrointestinal hemorrhages linked to the genetic background and aggravated by thrombocytopenia.

  20. Myoclonus epilepsy and ataxia due to KCNC1 mutation

    DEFF Research Database (Denmark)

    Oliver, Karen L.; Franceschetti, Silvana; Milligan, Carol J.

    2017-01-01

    generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG–electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy...... data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant KV3.1 channels. Results: Symptoms began at between 3 and 15 years of age (median = 9.......5), with progressively severe myoclonus and rare tonic–clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed...

  1. Trovafloxacin-induced replication stress sensitizes HepG2 cells to tumor necrosis factor-alpha-induced cytotoxicity mediated by extracellular signal-regulated kinase and ataxia telangiectasia and Rad3-related

    International Nuclear Information System (INIS)

    Beggs, Kevin M.; Maiuri, Ashley R.; Fullerton, Aaron M.; Poulsen, Kyle L.; Breier, Anna B.; Ganey, Patricia E.; Roth, Robert A.

    2015-01-01

    Use of the fluoroquinolone antibiotic trovafloxacin (TVX) was restricted due to idiosyncratic, drug-induced liver injury (IDILI). Previous studies demonstrated that tumor necrosis factor-alpha (TNF) and TVX interact to cause death of hepatocytes in vitro that was associated with prolonged activation of c-Jun N-terminal kinase (JNK), activation of caspases 9 and 3, and DNA damage. The purpose of this study was to explore further the mechanism by which TVX interacts with TNF to cause cytotoxicity. Treatment with TVX caused cell cycle arrest, enhanced expression of p21 and impaired proliferation, but cell death only occurred after cotreatment with TVX and TNF. Cell death involved activation of extracellular signal-related kinase (ERK), which in turn activated caspase 3 and ataxia telangiectasia and Rad3-related (ATR), both of which contributed to cytotoxicity. Cotreatment of HepG2 cells with TVX and TNF caused double-strand breaks in DNA, and ERK contributed to this effect. Inhibition of caspase activity abolished the DNA strand breaks. The data suggest a complex interaction of TVX and TNF in which TVX causes replication stress, and the downstream effects are exacerbated by TNF, leading to hepatocellular death. These results raise the possibility that IDILI from TVX results from MAPK and ATR activation in hepatocytes initiated by interaction of cytokine signaling with drug-induced replication stress

  2. Comparative human cellular radiosensitivity: I. The effect of SV40 transformation and immortalisation on the gamma-irradiation survival of skin derived fibroblasts from normal individuals and from ataxia-telangiectasia patients and heterozygotes.

    Science.gov (United States)

    Arlett, C F; Green, M H; Priestley, A; Harcourt, S A; Mayne, L V

    1988-12-01

    We have compared cell killing following 60Co gamma irradiation in 22 primary human fibroblast strains, nine SV40-immortalized human fibroblast lines and seven SV40-transformed pre-crisis human fibroblast cultures. We have examined material from normal individuals, from ataxia-telangiectasia (A-T) patients and from A-T heterozygotes. We have confirmed the greater sensitivity of A-T derived cells to gamma radiation. The distinction between A-T and normal cells is maintained in cells immortalized by SV40 virus but the immortal cells are more gamma radiation resistant than the corresponding primary fibroblasts. Cells transformed by plasmids (pSV3gpt and pSV3neo) expressing SV40 T-antigen, both pre- and post-crisis, show this increased resistance, indicating that it is expression of SV40 T-antigen, rather than immortalization per se which is responsible for the change. We use D0, obtained from a straight line fit, and D, estimated from a multitarget curve, as parameters to compare radiosensitivity. We suggest that both have their advantages; D0 is perhaps more reproducible, but D is more realistic when comparing shouldered and non-shouldered data.

  3. First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy

    NARCIS (Netherlands)

    Smets, Katrien; Duarri, Anna; Deconinck, Tine; Ceulemans, Berten; van de Warrenburg, Bart P.; Zuechner, Stephan; Gonzalez, Michael Anthony; Schuele, Rebecca; Synofzik, Matthis; Van der Aa, Nathalie; De Jonghe, Peter; Verbeek, Dineke S.; Baets, Jonathan

    2015-01-01

    Background: Identification of the first de novo mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) in a patient with complex early onset cerebellar ataxia in order to expand the genetic and phenotypic spectrum. Methods: Whole exome sequencing in a cerebellar ataxia

  4. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency.

    Science.gov (United States)

    Lagier-Tourenne, Clotilde; Tazir, Meriem; López, Luis Carlos; Quinzii, Catarina M; Assoum, Mirna; Drouot, Nathalie; Busso, Cleverson; Makri, Samira; Ali-Pacha, Lamia; Benhassine, Traki; Anheim, Mathieu; Lynch, David R; Thibault, Christelle; Plewniak, Frédéric; Bianchetti, Laurent; Tranchant, Christine; Poch, Olivier; DiMauro, Salvatore; Mandel, Jean-Louis; Barros, Mario H; Hirano, Michio; Koenig, Michel

    2008-03-01

    Muscle coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ(10) biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ(10) deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ(10) in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ(10) biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.

  5. Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.

    Science.gov (United States)

    Shaibani, Aziz; Wong, Lee-Jun; Wei Zhang, Victor; Lewis, Richard Alan; Shinawi, Marwan

    2015-01-01

    Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.

  6. Capillary electrophoresis fragment analysis and clone sequencing in detection of dynamic mutations of spinocerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Yuan-yuan CHEN

    2018-04-01

    Full Text Available Objective To estimate the accuracy and stability of capillary electrophoresis fragment analysis and clone sequencing in detecting dynamic mutations of spinocerebellar ataxia (SCA. Methods Capillary electrophoresis fragment analysis and clone sequencing were used in detecting trinucleotide repeated sequence of 14 SCA patients (3 cases of SCA2, 2 cases of SCA7, 7 cases of SCA8 and 2 cases of SCA17. Results Capillary electrophoresis fragment analysis of 3 SCA2 cases showed the expanded cytosine-adenine-guanine (CAG repeats were 31, 30 and 32, and the copy numbers of 3 clone sequencing for 3 colonies in each case were 37/40/40, 37/38/39 and 38/39/40 respectively. Capillary electrophoresis fragment analysis of 2 SCA7 cases showed the expanded CAG repeats were 57 and 34, and the copy numbers of repeats were 69, 74, 75 in 3 colonies of one case, and was 45 in the other case. For the 7 SCA8 cases with the expanded cytosine-thymine-adenine (CTA/cytosine-thymine-guanine (CTG repeats of 99, 111, 104, 92, 89, 104 and 75, the results of clone sequencing were 97, 116, 104, 90, 90, 102 and 76 respectively. For 2 SCA17 cases with the short/expanded CAG repeats of 37/50 and 36/45, the results of clone sequencing were 51/50/52 and 45/44 for 3 and 2 colonies. Conclusions Although the higher mobility of polymerase chain reaction (PCR products containing dynamic mutation in the capillary electrophoresis fragment analysis might cause the deviation for analysis of copy numbers, the deviation was predictable and the results were repeatable. The clone sequencing results showed obvious instability, especially for SCA2 and SCA7 genes, which might owing to their simple CAG repeats. Consequently, clone sequencing is not suited for detection of dynamic mutation, not to mention the quantitative criteria of dynamic mutation sequencing. DOI: 10.3969/j.issn.1672-6731.2018.03.008

  7. A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia.

    Science.gov (United States)

    Vicario, Mattia; Zanni, Ginevra; Vallese, Francesca; Santorelli, Filippo; Grinzato, Alessandro; Cieri, Domenico; Berto, Paola; Frizzarin, Martina; Lopreiato, Raffaele; Zonta, Francesco; Ferro, Stefania; Sandre, Michele; Marin, Oriano; Ruzzene, Maria; Bertini, Enrico; Zanotti, Giuseppe; Brini, Marisa; Calì, Tito; Carafoli, Ernesto

    2018-04-12

    The fine regulation of intracellular calcium is fundamental for all eukaryotic cells. In neurons, Ca 2+ oscillations govern the synaptic development, the release of neurotransmitters and the expression of several genes. Alterations of Ca 2+ homeostasis were found to play a pivotal role in neurodegenerative progression. The maintenance of proper Ca 2+ signaling in neurons demands the continuous activity of Ca 2+ pumps and exchangers to guarantee physiological cytosolic concentration of the cation. The plasma membrane Ca 2+ ATPases (PMCA pumps) play a key role in the regulation of Ca 2+ handling in selected sub-plasma membrane microdomains. Among the four basic PMCA pump isoforms existing in mammals, isoforms 2 and 3 are particularly enriched in the nervous system. In humans, genetic mutations in the PMCA2 gene in association with cadherin 23 mutations have been linked to hearing loss phenotypes, while those occurring in the PMCA3 gene were associated with X-linked congenital cerebellar ataxias. Here we describe a novel missense mutation (V1143F) in the calmodulin binding domain (CaM-BD) of the PMCA2 protein. The mutant pump was present in a patient showing congenital cerebellar ataxia but no overt signs of deafness, in line with the absence of mutations in the cadherin 23 gene. Biochemical and molecular dynamics studies on the mutated PMCA2 have revealed that the V1143F substitution alters the binding of calmodulin to the CaM-BD leading to impaired Ca 2+ ejection. Copyright © 2018. Published by Elsevier Inc.

  8. Hereditary spastic paraplegia with cerebellar ataxia: a complex phenotype associated with a new SPG4 gene mutation

    DEFF Research Database (Denmark)

    Nielsen, Jørgen Erik; Johnson, B; Koefoed, Pernille

    2004-01-01

    Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria......, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked...... in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance...

  9. Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed.

    Directory of Open Access Journals (Sweden)

    Oliver P Forman

    Full Text Available Spinocerebellar ataxia (SCA in the Parson Russell Terrier (PRT dog breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain, was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans.

  10. The mammalian mid-pachytene checkpoint: meiotic arrest in spermatocytes with a mutation in Atm alone or in combination with a Trp53 (p53) or Cdkn1a (p21/cip1) mutation

    NARCIS (Netherlands)

    Ashley, T.; Westphal, C.; Plug-de Maggio, A.; de rooij, D. G.

    2004-01-01

    ATM, the protein product of the gene mutated in the human autosomal recessive disorder ataxia telangiectasia, is involved in detection of double strand breaks (DSBs) and is a key component of the damage surveillance network of cell cycle proteins. In somatic cells ATM phosphorylates many other

  11. A Novel TTBK2 De Novo Mutation in a Danish Family with Early-Onset Spinocerebellar Ataxia

    DEFF Research Database (Denmark)

    Lindquist, Suzanne Granhøj; Møller, Lisbeth Birk; Dali, Christine I.

    2017-01-01

    Spinocerebellar ataxia type 11 (SCA11) is rare and has previously been described in four families worldwide. We report a Danish family with onset of symptoms in early childhood and affected family members in two generations. The proband, a Danish female born in 1968, and family members were...... examined. Exome sequencing was performed and a “movement disorders” gene panel consisting of approximately 200 genes was used for filtering, while Sanger sequencing was used for subsequent testing for the mutation in the family. Onset of symptoms in affected family members was in early childhood. A novel...... delineates the phenotypic spectrum of the rare SCA11 disease. In contrast to previously reported cases, onset of symptoms was in early childhood and the mutation was de novo in the proband....

  12. A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Zamba-Papanicolaou Eleni

    2008-04-01

    Full Text Available Abstract Background Senataxin (chromosome 9q34 was recently identified as the causative gene for an autosomal recessive form of Ataxia (ARCA, termed as Ataxia with Oculomotor Apraxia, type 2 (AOA2 and characterized by generalized incoordination, cerebellar atrophy, peripheral neuropathy, "oculomotor apraxia" and increased alpha-fetoprotein (AFP. Here, we report a novel Senataxin mutation in a Cypriot ARCA family. Methods We studied several Cypriot autosomal recessive cerebellar ataxia (ARCA families for linkage to known ARCA gene loci. We linked one family (909 to the SETX locus on chromosome 9q34 and screened the proband for mutations by direct sequencing. Results Sequence analysis revealed a novel c.5308_5311delGAGA mutation in exon 11 of the SETX gene. The mutation has not been detected in 204 control chromosomes from the Cypriot population, the remaining Cypriot ARCA families and 37 Cypriot sporadic cerebellar ataxia patients. Conclusion We identified a novel SETX homozygous c.5308_5311delGAGA mutation that co-segregates with ARCA with cerebellar atrophy and raised AFP.

  13. A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.

    Science.gov (United States)

    Tsoi, Ho; Yu, Allen C S; Chen, Zhefan S; Ng, Nelson K N; Chan, Anne Y Y; Yuen, Liz Y P; Abrigo, Jill M; Tsang, Suk Ying; Tsui, Stephen K W; Tong, Tony M F; Lo, Ivan F M; Lam, Stephen T S; Mok, Vincent C T; Wong, Lawrence K S; Ngo, Jacky C K; Lau, Kwok-Fai; Chan, Ting-Fung; Chan, H Y Edwin

    2014-09-01

    Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume. Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis. This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  14. A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD machinery.

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    Kaisa Kyöstilä

    Full Text Available Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (p(raw = 1.1x10(-7, p(genome = 7.5x10(-4. Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L, revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER-associated protein degradation (ERAD machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD-mediated neurodegenerative

  15. Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.

    Science.gov (United States)

    Hu, Hao; Matter, Michelle L; Issa-Jahns, Lina; Jijiwa, Mayumi; Kraemer, Nadine; Musante, Luciana; de la Vega, Michelle; Ninnemann, Olaf; Schindler, Detlev; Damatova, Natalia; Eirich, Katharina; Sifringer, Marco; Schrötter, Sandra; Eickholt, Britta J; van den Heuvel, Lambert; Casamina, Chanel; Stoltenburg-Didinger, Gisela; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Kaindl, Angela M

    2014-12-01

    To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.

  16. Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

    Science.gov (United States)

    Hu, Hao; Matter, Michelle L; Issa-Jahns, Lina; Jijiwa, Mayumi; Kraemer, Nadine; Musante, Luciana; de la Vega, Michelle; Ninnemann, Olaf; Schindler, Detlev; Damatova, Natalia; Eirich, Katharina; Sifringer, Marco; Schrötter, Sandra; Eickholt, Britta J; van den Heuvel, Lambert; Casamina, Chanel; Stoltenburg-Didinger, Gisela; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Kaindl, Angela M

    2014-01-01

    Objective To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). Methods We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. Results In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. Interpretation We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease. PMID:25574476

  17. Compound Heterozygous Inheritance of Mutations in Coenzyme Q8A Results in Autosomal Recessive Cerebellar Ataxia and Coenzyme Q10 Deficiency in a Female Sib-Pair.

    Science.gov (United States)

    Jacobsen, Jessie C; Whitford, Whitney; Swan, Brendan; Taylor, Juliet; Love, Donald R; Hill, Rosamund; Molyneux, Sarah; George, Peter M; Mackay, Richard; Robertson, Stephen P; Snell, Russell G; Lehnert, Klaus

    2017-11-21

    Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ 10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q 10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ 10, and the siblings were subsequently established on a therapeutic dose of CoQ 10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.

  18. Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome

    NARCIS (Netherlands)

    Thomas, Anna C.; Williams, Hywel; Setó-Salvia, Núria; Bacchelli, Chiara; Jenkins, Dagan; O'Sullivan, Mary; Mengrelis, Konstantinos; Ishida, Miho; Ocaka, Louise; Chanudet, Estelle; James, Chela; Lescai, Francesco; Anderson, Glenn; Morrogh, Deborah; Ryten, Mina; Duncan, Andrew J.; Pai, Yun Jin; Saraiva, Jorge M.; Ramos, Fabiana; Farren, Bernadette; Saunders, Dawn; Vernay, Bertrand; Gissen, Paul; Straatmaan-Iwanowska, Anna; Baas, Frank; Wood, Nicholas W.; Hersheson, Joshua; Houlden, Henry; Hurst, Jane; Scott, Richard; Bitner-Glindzicz, Maria; Moore, Gudrun E.; Sousa, Sérgio B.; Stanier, Philip

    2014-01-01

    Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three

  19. Recurrent major depression, ataxia, and cardiomyopathy : association with a novel POLG mutation?

    NARCIS (Netherlands)

    Verhoeven, Willem M. A.; Egger, Jos I. M.; Kremer, Berry P. H.; de Pont, Boudewijn J. H. B.; Marcelis, Carlo L. M.

    2011-01-01

    At present, more than 100 disease mutations in mitochondrial DNA polymerase gamma (POLG) have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter being

  20. Recurrent major depression, ataxia, and cardiomyopathy: Association with a novel POLG mutation?

    NARCIS (Netherlands)

    W.M.A. Verhoeven (Wim); J.I.M. Egger (Jos); H.P.H. Kremer (Berry); B.J.H.B. de Pont (Boudewijn J.H.B.); C.L.M. Marcelis (Carlo)

    2011-01-01

    textabstractAt present, more than 100 disease mutations in mitochondrial DNA polymerase γ (POLG) have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter

  1. Spinocerebellar ataxias Ataxias espinocerebelares

    Directory of Open Access Journals (Sweden)

    Hélio A.G. Teive

    2009-12-01

    Full Text Available Spinocerebellar ataxias (SCAs constitute a heterogeneous group of neurodegenerative diseases characterized by progressive cerebellar ataxia in association with some or all of the following conditions: ophthalmoplegia, pyramidal signs, movement disorders, pigmentary retinopathy, peripheral neuropathy, cognitive dysfunction and dementia. OBJECTIVE: To carry out a clinical and genetic review of the main types of SCA. METHOD: The review was based on a search of the PUBMED and OMIM databases. RESULTS: Thirty types of SCAs are currently known, and 16 genes associated with the disease have been identified. The most common types are SCA type 3, or Machado-Joseph disease, SCA type 10 and SCA types 7, 2, 1 and 6. SCAs are genotypically and phenotypically very heterogeneous. A clinical algorithm can be used to distinguish between the different types of SCAs. CONCLUSIONS: Detailed clinical neurological examination of SCA patients can be of great help when assessing them, and the information thus gained can be used in an algorithm to screen patients before molecular tests to investigate the correct etiology of the disease are requested.As ataxias espinocerebelares (AECs compreendem um grupo heterogeneo de enfermidades neurodegenerativas, que se caracterizam pela presença de ataxia cerebelar progressiva, associada de forma variada com oftalmoplegia, sinais piramidais, distúrbios do movimento, retinopatia pigmentar, neuropatia periférica, disfunção cognitiva e demência. OBJETIVO: Realizar uma revisão clínico-genética dos principais tipos de AECs. MÉTODO: A revisão foi realizada através da pesquisa pelo sistema do PUBMED e do OMIM. RESULTADOS: Na atualidade existem cerca de 30 tipos de AECs, com a descoberta de 16 genes. Os tipos mais comuns são a AEC tipo 3, ou doença de Machado-Joseph, a AEC tipo 10, e as AECs tipo 7, 2 1, e 6. As AECs apresentam grande heterogeneidade genotípica e fenotípica. Pode-se utilizar um algoritmo clínico para a

  2. Whole-Exome Sequencing Identifies Homozygous AFG3L2 Mutations in a Spastic Ataxia-Neuropathy Syndrome Linked to Mitochondrial m-AAA Proteases

    Science.gov (United States)

    Martinelli, Paola; Cherukuri, Praveen F.; Teer, Jamie K.; Hansen, Nancy F.; Cruz, Pedro; Mullikin for the NISC Comparative Sequencing Program, James C.; Blakesley, Robert W.; Golas, Gretchen; Kwan, Justin; Sandler, Anthony; Fuentes Fajardo, Karin; Markello, Thomas; Tifft, Cynthia; Blackstone, Craig; Rugarli, Elena I.; Langer, Thomas; Gahl, William A.; Toro, Camilo

    2011-01-01

    We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2Y616C complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other “mitochondrial” features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias. PMID:22022284

  3. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.

    Directory of Open Access Journals (Sweden)

    Tyler Mark Pierson

    2011-10-01

    Full Text Available We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7. Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28, a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2(Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2(Y616C complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other "mitochondrial" features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.

  4. The ovarian DNA damage repair response is induced prior to phosphoramide mustard-induced follicle depletion, and ataxia telangiectasia mutated inhibition prevents PM-induced follicle depletion

    Energy Technology Data Exchange (ETDEWEB)

    Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    2016-02-01

    Phosphoramide mustard (PM) is an ovotoxic metabolite of cyclophosphamide and destroys primordial and primary follicles potentially by DNA damage induction. The temporal pattern by which PM induces DNA damage and initiation of the ovarian response to DNA damage has not yet been well characterized. This study investigated DNA damage initiation, the DNA repair response, as well as induction of follicular demise using a neonatal rat ovarian culture system. Additionally, to delineate specific mechanisms involved in the ovarian response to PM exposure, utility was made of PKC delta (PKCδ) deficient mice as well as an ATM inhibitor (KU 55933; AI). Fisher 344 PND4 rat ovaries were cultured for 12, 24, 48 or 96 h in medium containing DMSO ± 60 μM PM or KU 55933 (48 h; 10 nM). PM-induced activation of DNA damage repair genes was observed as early as 12 h post-exposure. ATM, PARP1, E2F7, P73 and CASP3 abundance were increased but RAD51 and BCL2 protein decreased after 96 h of PM exposure. PKCδ deficiency reduced numbers of all follicular stages, but did not have an additive impact on PM-induced ovotoxicity. ATM inhibition protected all follicle stages from PM-induced depletion. In conclusion, the ovarian DNA damage repair response is active post-PM exposure, supporting that DNA damage contributes to PM-induced ovotoxicity. - Highlights: • PM exposure induces DNA damage repair gene expression. • Inhibition of ATM prevented PM-induced follicle depletion. • PKCδ deficiency did not impact PM-induced ovotoxicity.

  5. Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation

    DEFF Research Database (Denmark)

    Gatei, Magtouf; Sloper, Katie; Sørensen, Claus Storgaard

    2003-01-01

    . In mammalian cells, evidence has been presented that Chk1 is devoted to the ATR signaling pathway and is modified by ATR in response to replication inhibition and UV-induced damage, whereas Chk2 functions primarily through ATM in response to ionizing radiation (IR), suggesting that Chk2 and Chk1 might have...

  6. Hereditary haemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, A D; Vase, P; Green, A

    1999-01-01

    Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by telangiectatic lesions. The disease manifestations are variable and include epistaxis, gastrointestinal bleeding, pulmonary arteriovenous malformations and cerebral arteriovenous malformations. Early...

  7. A Disease Mutation Causing Episodic Ataxia Type I in the S1 Links Directly to the Voltage Sensor and the Selectivity Filter in Kv Channels.

    Science.gov (United States)

    Petitjean, Dimitri; Kalstrup, Tanja; Zhao, Juan; Blunck, Rikard

    2015-09-02

    The mutation F184C in Kv1.1 leads to development of episodic ataxia type I (EA1). Although the mutation has been said to alter activation kinetics and to lower expression, we show here that the underlying molecular mechanisms may be more complex. Although F184 is positioned in the "peripheral" S1 helix, it occupies a central position in the 3D fold. We show in cut-open oocyte voltage-clamp recordings of gating and ionic currents of the Shaker Kv channel expressed in Xenopus oocytes that F184 not only interacts directly with the gating charges of the S4, but also creates a functional link to the selectivity filter of the neighboring subunit. This link leads to impaired fast and slow inactivation. The effect on fast inactivation is of an allosteric nature considering that fast inactivation is caused by a linked cytosolic ball peptide. The extensive effects of F184C provide a new mechanism underlying EA. Episodic ataxia (EA) is an inherited disease that leads to occasional loss of motor control in combination with variable other symptoms such as vertigo or migraine. EA type I (EA1), studied here, is caused by mutations in a voltage-gated potassium channel that contributes to the generation of electrical signals in the brain. The mechanism by which mutations in voltage-gated potassium channels lead to EA is still unknown and there is no consistent pharmacological treatment. By studying in detail one disease-causing mutation in Kv1.1, we describe a novel molecular mechanism distinct from mechanisms described previously. This mechanism contributes to the understanding of potassium channel function in general and might lead to a better understanding of how EA develops. Copyright © 2015 the authors 0270-6474/15/3512198-09$15.00/0.

  8. Dysphonia and vocal fold telangiectasia in hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Chang, Joseph; Yung, Katherine C

    2014-11-01

    This case report is the first documentation of dysphonia and vocal fold telangiectasia as a complication of hereditary hemorrhagic telangiectasia (HHT). Case report of a 40-year-old man with HHT presenting with 2 years of worsening hoarseness. Hoarseness corresponded with a period of anticoagulation. Endoscopy revealed vocal fold scarring, vocal fold telangiectasias, and plica ventricular is suggestive of previous submucosal vocal fold hemorrhage and subsequent counterproductive compensation with ventricular phonation. Hereditary hemorrhagic telangiectasia may present as dysphonia with vocal fold telangiectasias and place patients at risk of vocal fold hemorrhage. © The Author(s) 2014.

  9. Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays.

    Science.gov (United States)

    H'mida-Ben Brahim, D; M'zahem, A; Assoum, M; Bouhlal, Y; Fattori, F; Anheim, M; Ali-Pacha, L; Ferrat, F; Chaouch, M; Lagier-Tourenne, C; Drouot, N; Thibaut, C; Benhassine, T; Sifi, Y; Stoppa-Lyonnet, D; N'Guyen, K; Poujet, J; Hamri, A; Hentati, F; Amouri, R; Santorelli, F M; Tazir, M; Koenig, M

    2011-01-01

    The diagnosis of rare inherited diseases is becoming more and more complex as an increasing number of clinical conditions appear to be genetically heterogeneous. Multigenic inheritance also applies to the autosomal recessive progressive cerebellar ataxias (ARCAs), for which 14 genes have been identified and more are expected to be discovered. We used homozygosity mapping as a guide for identification of the defective locus in patients with ARCA born from consanguineous parents. Patients from 97 families were analyzed with GeneChip Mapping 10K or 50K SNP Affymetrix microarrays. We identified six families homozygous for regions containing the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) gene, two families homozygous for the ataxia-telangiectasia gene (ATM), two families homozygous for the ataxia with oculomotor apraxia type 1 (AOA1) gene, and one family homozygous for the AOA type 2 (AOA2) gene. Upon direct gene testing, we were able to identify a disease-related mutation in all families but one of the two kindred homozygous at the ATM locus. Although linkage analyses pointed to a single locus on chromosome 11q22.1-q23.1 for this family, clinical features, normal levels of serum alpha-foetoprotein as well as absence of mutations in the ATM gene rather suggest the existence of an additional ARCA-related gene in that interval. While the use of homozygosity mapping was very effective at pointing to the correct gene, it also suggests that the majority of patients harbor mutations either in the genes of the rare forms of ARCA or in genes yet to be identified.

  10. A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations.

    Science.gov (United States)

    Calì, Tito; Lopreiato, Raffaele; Shimony, Joshua; Vineyard, Marisa; Frizzarin, Martina; Zanni, Ginevra; Zanotti, Giuseppe; Brini, Marisa; Shinawi, Marwan; Carafoli, Ernesto

    2015-06-26

    The particular importance of Ca(2+) signaling to neurons demands its precise regulation within their cytoplasm. Isoform 3 of the plasma membrane Ca(2+) ATPase (the PMCA3 pump), which is highly expressed in brain and cerebellum, plays an important role in the regulation of neuronal Ca(2+). A genetic defect of the PMCA3 pump has been described in one family with X-linked congenital cerebellar ataxia. Here we describe a novel mutation in the ATP2B3 gene in a patient with global developmental delay, generalized hypotonia and cerebellar ataxia. The mutation (a R482H replacement) impairs the Ca(2+) ejection function of the pump. It reduces the ability of the pump expressed in model cells to control Ca(2+) transients generated by cell stimulation and impairs its Ca(2+) extrusion function under conditions of low resting cytosolic Ca(2+) as well. In silico analysis of the structural effect of the mutation suggests a reduced stabilization of the portion of the pump surrounding the mutated residue in the Ca(2+)-bound state. The patient also carries two missense mutations in LAMA1, encoding laminin subunit 1α. On the basis of the family pedigree of the patient, the presence of both PMCA3 and laminin subunit 1α mutations appears to be necessary for the development of the disease. Considering the observed defect in cellular Ca(2+) homeostasis and the previous finding that PMCAs act as digenic modulators in Ca(2+)-linked pathologies, the PMCA3 dysfunction along with LAMA1 mutations could act synergistically to cause the neurological phenotype. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations*

    Science.gov (United States)

    Calì, Tito; Lopreiato, Raffaele; Shimony, Joshua; Vineyard, Marisa; Frizzarin, Martina; Zanni, Ginevra; Zanotti, Giuseppe; Brini, Marisa; Shinawi, Marwan; Carafoli, Ernesto

    2015-01-01

    The particular importance of Ca2+ signaling to neurons demands its precise regulation within their cytoplasm. Isoform 3 of the plasma membrane Ca2+ ATPase (the PMCA3 pump), which is highly expressed in brain and cerebellum, plays an important role in the regulation of neuronal Ca2+. A genetic defect of the PMCA3 pump has been described in one family with X-linked congenital cerebellar ataxia. Here we describe a novel mutation in the ATP2B3 gene in a patient with global developmental delay, generalized hypotonia and cerebellar ataxia. The mutation (a R482H replacement) impairs the Ca2+ ejection function of the pump. It reduces the ability of the pump expressed in model cells to control Ca2+ transients generated by cell stimulation and impairs its Ca2+ extrusion function under conditions of low resting cytosolic Ca2+ as well. In silico analysis of the structural effect of the mutation suggests a reduced stabilization of the portion of the pump surrounding the mutated residue in the Ca2+-bound state. The patient also carries two missense mutations in LAMA1, encoding laminin subunit 1α. On the basis of the family pedigree of the patient, the presence of both PMCA3 and laminin subunit 1α mutations appears to be necessary for the development of the disease. Considering the observed defect in cellular Ca2+ homeostasis and the previous finding that PMCAs act as digenic modulators in Ca2+-linked pathologies, the PMCA3 dysfunction along with LAMA1 mutations could act synergistically to cause the neurological phenotype. PMID:25953895

  12. Imaging of Hereditary Hemorrhagic Telangiectasia

    International Nuclear Information System (INIS)

    Carette, Marie-France; Nedelcu, Cosmina; Tassart, Marc; Grange, Jean-Didier; Wislez, Marie; Khalil, Antoine

    2009-01-01

    This pictorial review is based on our experience of the follow-up of 120 patients at our multidisciplinary center for hereditary hemorrhagic telangiectasia (HHT). Rendu-Osler-Weber disease or HHT is a multiorgan autosomal dominant disorder with high penetrance, characterized by epistaxis, mucocutaneous telangiectasis, and visceral arteriovenous malformations (AVMs). The research on gene mutations is fundamental and family screening by clinical examination, chest X-ray, research of pulmonary shunting, and abdominal color Doppler sonography is absolutely necessary. The angioarchitecture of pulmonary AVMs can be studied by unenhanced multidetector computed tomography; however, all other explorations of liver, digestive bowels, or brain require administration of contrast media. Magnetic resonance angiography is helpful for central nervous system screening, in particular for the spinal cord, but also for pulmonary, hepatic, and pelvic AVMs. Knowledge of the multiorgan involvement of HHT, mechanism of complications, and radiologic findings is fundamental for the correct management of these patients.

  13. Juvenile Leigh syndrome, optic atrophy, ataxia, dystonia, and epilepsy due to T14487C mutation in the mtDNA-ND6 gene: a mitochondrial syndrome presenting from birth to adolescence.

    Science.gov (United States)

    Leshinsky-Silver, Esther; Shuvalov, Ruslan; Inbar, Shani; Cohen, Sarit; Lev, Dorit; Lerman-Sagie, Tally

    2011-04-01

    An increasing number of reports describe mutations in mitochondrial DNA coding regions, especially in mitochondrial DNA- encoded nicotinamide adenine dinucleotide dehydrogenase subunit genes of the respiratory chain complex I, as causing early-onset Leigh syndrome. The authors report the molecular findings in a 24-year-old patient with juvenile-onset Leigh syndrome presenting with optic atrophy, ataxia dystonia, and epilepsy. A brain magnetic resonance imaging revealed bilateral basal ganglia and thalamic hypointensities, and a magnetic resonance spectroscopy revealed an increased lactate peak. The authors identified a T14487C change causing M63V substitution in the mitochondrial ND6 gene. The mutation was heteroplasmic in muscle and blood samples, with different mutation loads, and was absent in the patient's mother's urine and blood samples. They suggest that the T14487C mtDNA mutation should be analyzed in Leigh syndrome, presenting with optic atrophy, ataxia, dystonia, and epilepsy, regardless of age.

  14. A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia

    Science.gov (United States)

    Coutelier, Marie; Blesneac, Iulia; Monteil, Arnaud; Monin, Marie-Lorraine; Ando, Kunie; Mundwiller, Emeline; Brusco, Alfredo; Le Ber, Isabelle; Anheim, Mathieu; Castrioto, Anna; Duyckaerts, Charles; Brice, Alexis; Durr, Alexandra; Lory, Philippe; Stevanin, Giovanni

    2015-01-01

    Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs. PMID:26456284

  15. Huntington's disease-like and ataxia syndromes: identification of a family with a de novo SCA17/TBP mutation

    DEFF Research Database (Denmark)

    Bech, Sara; Petersen, Thor; Nørremølle, Anne

    2010-01-01

    The autosomal dominant spinocerebellar ataxias, commonly referred to as SCAs, are clinically and genetically heterogeneous neurodegenerative disorders. Twenty-eight genetic subtypes have been identified, of which 7 are caused by expansion of a CAG trinucleotide repeat that encodes a polyglutamine....... The patient's mother and father both carried normal range repeats, 38/38 and 33/39 respectively. Analysis of the repeat structures revealed that the expansion had occurred upon expansion of the longer paternal allele. We conclude that, however rare, SCA17 must be considered as a cause of Huntington's disease...

  16. Polysomnographic and neurometabolic features may mark preclinical autosomal dominant cerebellar ataxia, deafness, and narcolepsy due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.

    Science.gov (United States)

    Moghadam, Keivan Kaveh; Pizza, Fabio; Tonon, Caterina; Lodi, Raffaele; Carelli, Valerio; Poli, Francesca; Franceschini, Christian; Barboni, Piero; Seri, Marco; Ferrari, Simona; La Morgia, Chiara; Testa, Claudia; Cornelio, Ferdinando; Liguori, Rocco; Winkelmann, Juliane; Lin, Ling; Mignot, Emmanuel; Plazzi, Giuseppe

    2014-05-01

    We aimed to report the clinical picture of two asymptomatic daughters of a patient with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1. Clinical assessment based on history, neurologic examination, sleep recordings, neurophysiologic neuroimaging, and genetic tests was performed. History and neurologic examination in both subjects were unremarkable. Genetic analysis disclosed in both the paternally-inherited heterozygous point mutation in the DNMT1 gene. Sleep recordings found sleep-onset rapid eye movement periods (SOREMPs) and proton magnetic resonance spectroscopy (MRS) revealed increased cerebellar myoinositol (mI) in both subjects. Auditory and ophthalmologic investigations as well as structural brain magnetic resonance imaging (MRI) scans revealed no abnormalities. The two asymptomatic carriers of the heterozygous DNMT1 mutation for ADCA-DN, a late-onset neurodegenerative disease, presented with SOREMPs associated with an increase of mI in the brain, a marker of glial cell activity and density characteristic of early stages of neurodegenerative diseases. Therefore, SOREMPs may precede the clinical picture of ADCA-DN as an early polysomnographic marker of central nervous system involvement detected by MRS. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. The ataxia related G1107D mutation of the plasma membrane Ca2+ ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process.

    Science.gov (United States)

    Calì, Tito; Frizzarin, Martina; Luoni, Laura; Zonta, Francesco; Pantano, Sergio; Cruz, Carlos; Bonza, Maria Cristina; Bertipaglia, Ilenia; Ruzzene, Maria; De Michelis, Maria Ida; Damiano, Nunzio; Marin, Oriano; Zanni, Ginevra; Zanotti, Giuseppe; Brini, Marisa; Lopreiato, Raffaele; Carafoli, Ernesto

    2017-01-01

    The plasma membrane Ca 2+ ATPases (PMCA pumps) have a long, cytosolic C-terminal regulatory region where a calmodulin-binding domain (CaM-BD) is located. Under basal conditions (low Ca 2+ ), the C-terminal tail of the pump interacts with autoinhibitory sites proximal to the active center of the enzyme. In activating conditions (i.e., high Ca 2+ ), Ca 2+ -bound CaM displaces the C-terminal tail from the autoinhibitory sites, restoring activity. We have recently identified a G1107D replacement within the CaM-BD of isoform 3 of the PMCA pump in a family affected by X-linked congenital cerebellar ataxia. Here, we investigate the effects of the G1107D replacement on the interplay of the mutated CaM-BD with both CaM and the pump core, by combining computational, biochemical and functional approaches. We provide evidence that the affinity of the isolated mutated CaM-BD for CaM is significantly reduced with respect to the wild type (wt) counterpart, and that the ability of CaM to activate the pump in vitro is thus decreased. Multiscale simulations support the conclusions on the detrimental effect of the mutation, indicating reduced stability of the CaM binding. We further show that the G1107D replacement impairs the autoinhibition mechanism of the PMCA3 pump as well, as the introduction of a negative charge perturbs the contacts between the CaM-BD and the pump core. Thus, the mutation affects both the ability of the pump to optimally transport Ca 2+ in the activated state, and the autoinhibition mechanism in its resting state. Copyright © 2016. Published by Elsevier B.V.

  18. Risk for Sporadic Breast Cancer in Ataxia Telangiectasia Heterozygotes

    Science.gov (United States)

    2001-08-01

    cervix , kidney and colon cancer ) and 1 large benign ovarian tumour (serous cystadenoma), DNp73 was specifically upregulated 3 to 78-fold in 10...solos, alliances and feuds among family members. This article is in press in Biochimica and Biophysica Acta Reviews on Cancer . Appendix: manuscript...role in carcinogenesis, no related genes were known for HPV -mediated cancers (23). However, the adenovirus E4orf6 20 years. In 1997, two novel family

  19. Mutation in the kv3.3 voltage-gated potassium channel causing spinocerebellar ataxia 13 disrupts sound-localization mechanisms.

    Directory of Open Access Journals (Sweden)

    John C Middlebrooks

    Full Text Available Normal sound localization requires precise comparisons of sound timing and pressure levels between the two ears. The primary localization cues are interaural time differences, ITD, and interaural level differences, ILD. Voltage-gated potassium channels, including Kv3.3, are highly expressed in the auditory brainstem and are thought to underlie the exquisite temporal precision and rapid spike rates that characterize brainstem binaural pathways. An autosomal dominant mutation in the gene encoding Kv3.3 has been demonstrated in a large Filipino kindred manifesting as spinocerebellar ataxia type 13 (SCA13. This kindred provides a rare opportunity to test in vivo the importance of a specific channel subunit for human hearing. Here, we demonstrate psychophysically that individuals with the mutant allele exhibit profound deficits in both ITD and ILD sensitivity, despite showing no obvious impairment in pure-tone sensitivity with either ear. Surprisingly, several individuals exhibited the auditory deficits even though they were pre-symptomatic for SCA13. We would expect that impairments of binaural processing as great as those observed in this family would result in prominent deficits in localization of sound sources and in loss of the "spatial release from masking" that aids in understanding speech in the presence of competing sounds.

  20. A Case of Ataxia with Isolated Vitamin E Deficiency Initially Diagnosed as Friedreich’s Ataxia

    Directory of Open Access Journals (Sweden)

    Michael Bonello

    2016-01-01

    Full Text Available Ataxia with isolated vitamin E deficiency (AVED is a rare autosomal recessive condition that is caused by a mutation in the alpha tocopherol transfer protein gene. It is almost indistinguishable clinically from Friedreich’s ataxia but with appropriate treatment its devastating neurological features can be prevented. Patients can present with a progressive cerebellar ataxia, pyramidal spasticity, and evidence of a neuropathy with absent deep tendon reflexes. It is important to screen for this condition on initial evaluation of a young patient presenting with progressive ataxia and it should be considered in patients with a long standing ataxia without any diagnosis in view of the potential therapeutics and genetic counselling. In this case report we present a patient who was initially diagnosed with Friedreich’s ataxia but was later found to have AVED.

  1. Germline mutations in BMP9 are not identified in a series of Danish and French patients with hereditary hemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Tørring, P. M.; Dupuis-Girod, S.; Giraud, S

    2016-01-01

    undiscovered HHT causative genes. A new vascular-anomaly syndrome caused by mutations in BMP9 has recently been published. Three patients suspected of HHT, with familial nose bleedings and dermal manifestations not characteristic for HHT, were described. Although, it was concluded that these patients probably...

  2. Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients.

    LENUS (Irish Health Repository)

    Anheim, M

    2009-10-01

    Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg\\/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg\\/l, P = 0.0004; itself higher than the normal level (3.4 microg\\/l, range from 0.5 to 17.2 microg\\/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg\\/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia

  3. Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients.

    Science.gov (United States)

    Anheim, M; Monga, B; Fleury, M; Charles, P; Barbot, C; Salih, M; Delaunoy, J P; Fritsch, M; Arning, L; Synofzik, M; Schöls, L; Sequeiros, J; Goizet, C; Marelli, C; Le Ber, I; Koht, J; Gazulla, J; De Bleecker, J; Mukhtar, M; Drouot, N; Ali-Pacha, L; Benhassine, T; Chbicheb, M; M'Zahem, A; Hamri, A; Chabrol, B; Pouget, J; Murphy, R; Watanabe, M; Coutinho, P; Tazir, M; Durr, A; Brice, A; Tranchant, C; Koenig, M

    2009-10-01

    Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia

  4. Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA in a large group of Brazilian patients Freqüência das mutações que causam ataxia espinocerebelar (SCA1, SCA2, MJD/SCA3 e DRPLA em um grupo numeroso de pacientes Brasileiros

    Directory of Open Access Journals (Sweden)

    Iscia Lopes-Cendesi

    1997-09-01

    Full Text Available Spinocerebellar ataxia type 1 (SCA1, spinocerebellar ataxia type 2 (SCA2 and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3 are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, dentatorubropallidoluysian atrophy (DRPLA is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39%, 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3% of all patients; and 6 % in the dominantly inherited SCAs. We identified the SCA2 mutation in 6% of all families and in 9% of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30 % of all patients; and in the 44% of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.Ataxia espinocerebelar tipo 1 (SCA1, ataxia espinocerebelar tipo 2 (SCA2 e doença de Machado-Joseph ou ataxia espinocerebelar tipo 3 (MJD/SCA3 são três formas de ataxia espinocerebelar (SCA que apresentam herança genética autossômica dominante. Nessas três doenças foi encontrada uma expansão instável de trinucleotídeo CAG localizada na região codificadora dos

  5. Clinical features of Hereditary Haemorrhagic Telangiectasia

    NARCIS (Netherlands)

    Hosman, A.E.

    2017-01-01

    Hereditary Haemorrhagic Telangiectasia (HHT), also known as Rendu-Osler-Weber disease (ROW), is an autosomal dominant disease with multi-systemic vascular dysplasia characterized by mucocutaneous telangiectasia, arteriovenous malformations and recurrent spontaneous epistaxis (nosebleeds). Most cases

  6. Ataxia Telangiectasia–Mutated Gene Polymorphisms and Acute Normal Tissue Injuries in Cancer Patients After Radiation Therapy: A Systematic Review and Meta-analysis

    International Nuclear Information System (INIS)

    Dong, Lihua; Cui, Jingkun; Tang, Fengjiao; Cong, Xiaofeng; Han, Fujun

    2015-01-01

    Purpose: Studies of the association between ataxia telangiectasia–mutated (ATM) gene polymorphisms and acute radiation injuries are often small in sample size, and the results are inconsistent. We conducted the first meta-analysis to provide a systematic review of published findings. Methods and Materials: Publications were identified by searching PubMed up to April 25, 2014. Primary meta-analysis was performed for all acute radiation injuries, and subgroup meta-analyses were based on clinical endpoint. The influence of sample size and radiation injury incidence on genetic effects was estimated in sensitivity analyses. Power calculations were also conducted. Results: The meta-analysis was conducted on the ATM polymorphism rs1801516, including 5 studies with 1588 participants. For all studies, the cut-off for differentiating cases from controls was grade 2 acute radiation injuries. The primary meta-analysis showed a significant association with overall acute radiation injuries (allelic model: odds ratio = 1.33, 95% confidence interval: 1.04-1.71). Subgroup analyses detected an association between the rs1801516 polymorphism and a significant increase in urinary and lower gastrointestinal injuries and an increase in skin injury that was not statistically significant. There was no between-study heterogeneity in any meta-analyses. In the sensitivity analyses, small studies did not show larger effects than large studies. In addition, studies with high incidence of acute radiation injuries showed larger effects than studies with low incidence. Power calculations revealed that the statistical power of the primary meta-analysis was borderline, whereas there was adequate power for the subgroup analysis of studies with high incidence of acute radiation injuries. Conclusions: Our meta-analysis showed a consistency of the results from the overall and subgroup analyses. We also showed that the genetic effect of the rs1801516 polymorphism on acute radiation injuries was

  7. Fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Hoem, Gry; Koht, Jeanette

    2017-10-31

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a hereditary neurodegenerative disorder caused by a mutation on the X chromosome. The major signs and symptoms are tremor, ataxia and parkinsonism. Up to one in 2 000 persons over 50 years of age will develop the syndrome. There is reason to believe that too few individuals in Norway undergo testing for this condition.

  8. Friedreich's ataxia mimicking hereditary motor and sensory neuropathy.

    Science.gov (United States)

    Panas, Marios; Kalfakis, Nikolaos; Karadima, Georgia; Davaki, Panagiota; Vassilopoulos, Demetris

    2002-11-01

    Four patients from three unrelated families, with clinical and electrophysiological findings compatible with the diagnosis of hereditary motor and sensory neuropathy, are presented. The molecular analysis showed that the affected individuals were homozygous for the mutation in the X25 gene, characteristic of Friedreich's ataxia. These patients seem to represent a form of Friedreich's ataxia mimicking Charcot-Marie-Tooth disease.

  9. Ataxia crónica en pediatría

    Directory of Open Access Journals (Sweden)

    Ricardo Erazo Torricelli

    2013-09-01

    Full Text Available Las ataxias crónicas constituyen un grupo heterogéneo de enfermedades, que afectan al niño a diferentes edades. Así las formas congénitas, generalmente no progresivas, se observan desde los primeros meses de vida y se expresan por hipotonía y retraso motor, mucho antes de que la ataxia se haga evidente. La resonancia magnética cerebral puede ser diagnóstica en algunos cuadros, como ocurre con el síndrome de Joubert. El grupo de ataxias hereditarias progresivas, en constante expansión, suelen comenzar después del período del lactante. Los signos clínicos destacables son la apraxia ocular y la inestabilidad de la marcha que pueden asociarse a telangiectasias oculocutáneas (ataxia-telangiectasia o a neuropatía sensitiva (ataxia de Friedreich. En esta revisión se describen en forma sucinta las ataxias congénitas y en forma más detallada las causas principales de ataxias hereditarias progresivas autosómicas recesivas, autosómicas dominantes y mitocondriales. Se destaca la importancia del estudio genético, que es la clave para lograr el diagnóstico en la mayoría de estas enfermedades. Aunque aún no hay tratamiento para la mayoría de las ataxias hereditarias progresivas, algunas sí lo tienen, como la enfermedad de Refsum, déficit de vitamina E, déficit de Coenzima Q10, por lo cual el diagnóstico en estos casos es aún más relevante. En la actualidad, el diagnóstico de los cuadros de ataxia hereditaria del niño aún no tratable es fundamental para lograr un manejo adecuado, determinar un pronóstico preciso y dar a la familia un consejo genético oportuno.

  10. Vertical transmission of macular telangiectasia type 2.

    Science.gov (United States)

    Delaere, Lien; Spielberg, Leigh; Leys, Anita M

    2012-01-01

    The purpose of this study was to report vertical transmission of macular telangiectasia type 2 and type 2 diabetes mellitus in 3 families. In this retrospective interventional case series, the charts of patients with inherited macular telangiectasia type 2 were reviewed. A large spectrum of presentations of macular telangiectasia type 2 was observed and has been studied with different techniques including best-corrected visual acuity, microperimetry, confocal blue reflectance fundus autofluorescence, fluorescein angiography, and time domain and spectral domain optical coherence tomography. Vertical transmission of macular telangiectasia type 2 and associated type 2 diabetes mellitus is described in 3 families. Symptomatic as well as asymptomatic eyes with macular telangiectasia type 2 were identified. In 2 families, a mother and son experienced visual loss and were diagnosed with macular telangiectasia type 2. All 4 patients had type 2 diabetes. Diabetic retinopathy was observed in one mother and her son. In the third family, the index patient was diagnosed macular telangiectasia type 2 after complaints of metamorphopsia. She and her family members had type 2 diabetes mellitus, and further screening of her family revealed familial macular telangiectasia type 2. None of the patients were treated for macular telangiectasia type 2. Macular telangiectasia type 2 may be more common than previously assumed, as vision can remain preserved and patients may go undiagnosed. Screening of family members is indicated, and detection of mild anomalies is possible using fundus autofluorescence and spectral domain optical coherence tomography.

  11. Mitochondrial recessive ataxia syndrome mimicking dominant spinocerebellar ataxia.

    Science.gov (United States)

    Palin, Eino J H; Hakonen, Anna H; Korpela, Mari; Paetau, Anders; Suomalainen, Anu

    2012-04-15

    We studied the genetic background of a family with SCA, showing dominant inheritance and anticipation. Muscle histology, POLG1 gene sequence, neuropathology and mitochondrial DNA analyses in a mother and a son showed typical findings for a mitochondrial disorder, and both were shown to be homozygous for a recessive POLG1 mutation, underlying mitochondrial recessive ataxia syndrome, MIRAS. The healthy father was a heterozygous carrier for the same mutation. Recessively inherited MIRAS mutations should be tested in dominantly inherited SCAs cases of unknown cause, as the high carrier frequency of MIRAS may result in two independent introductions of the mutant allele in the family and thereby mimic dominant inheritance. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Clinical neurogenetics: friedreich ataxia.

    Science.gov (United States)

    Collins, Abigail

    2013-11-01

    Friedreich ataxia is the most common autosomal recessive ataxia. It is a progressive neurodegenerative disorder, typically with onset before 20 years of age. Signs and symptoms include progressive ataxia, ascending weakness and ascending loss of vibration and joint position senses, pes cavus, scoliosis, cardiomyopathy, and arrhythmias. There are no disease-modifying medications to either slow or halt the progression of the disease, but research investigating therapies to increase endogenous frataxin production and decrease the downstream consequences of disrupted iron homeostasis is ongoing. Clinical trials of promising medications are underway, and the treatment era of Friedreich ataxia is beginning. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. Ataxia with Vitamin E Deficiency in Norway

    Directory of Open Access Journals (Sweden)

    Areej Elkamil

    2015-01-01

    Full Text Available Objective Ataxia with vitamin E deficiency (AVED is a rare autosomal recessive neurological disorder which usually starts in childhood. The clinical presentation is very similar to Friedreich ataxia, most patients have progressive truncal and extremity ataxia, areflexia, positive Babinski sign, dysarthria and sensory neuropathy. Methods We made an inquiry to our colleagues in Norway, we included information from a prevalence study published southern Norway and added data from our own known case. Results A newly published prevalence study of hereditary ataxias (total of 171 subjects found only one subject with AVED in Southeast Norway. We describe two more patients, one from the Central part and one from the Northern part of Norway. All 3 cases had age of onset in early childhood (age of 4–5 years and all experienced gait ataxia and dysarthria. The genetic testing confirmed that they had pathogenic mutations in the α-tocopherol transfer protein gene (TTPA. All were carriers of the non-sense c.400C > T mutation, one was homozygous for that mutation and the others were compound heterozygous, either with c.358G > A or c.513_514insTT. The homozygous carrier was by far the most severely affected case. Conclusions We estimate the occurrence of AVED in Norway to be at least 0.6 per million inhabitants. We emphasize that all patients who develop ataxia in childhood should be routinely tested for AVED to make an early diagnosis for initiating treatment with high dose vitamin E to avoid severe neurological deficits.

  14. Frontal ataxia in childhood.

    NARCIS (Netherlands)

    Erasmus, C.E.; Beems, T.; Rotteveel, J.J.

    2004-01-01

    Frontal ataxia may be the result of a unilateral frontal lesion. In this report three cases are presented with ataxia due to right frontal lesions. One case concerns a boy presenting with an unsteady gait and titubation of the trunk, mimicking developmental disequilibrium and with complex partial

  15. Phenotype variability and early onset ataxia symptoms in spinocerebellar ataxia type 7: comparison and correlation with other spinocerebellar ataxias

    Directory of Open Access Journals (Sweden)

    Marcus Vinicius Cristino de Albuquerque

    2015-01-01

    Full Text Available The spinocerebellar ataxias (SCA are a group of neurodegenerative disorders characterized by heterogeneous clinical presentation. Spinocerebellar ataxia type 7 (SCA7 is caused by an abnormal CAG repeat expansion and includes cerebellar signs associated with visual loss and ophthalmoplegia. Marked anticipation and dynamic mutation is observed in SCA7. Moreover, phenotype variability and very early onset of symptoms may occur. In this article, a large series of Brazilian patients with different SCA subtypes was evaluated, and we compared the age of onset of SCA7 with other SCA. From the 26 patients with SCA7, 4 manifested their symptoms before 10-year-old. Also, occasionally the parents may have the onset of symptoms after their children. In conclusion, our study highlights the genetic anticipation phenomenon that occurs in SCA7 families. Patients with very early onset ataxia in the context of a remarkable family history, must be considered and tested for SCA7.

  16. Exome Capture Reveals ZNF423 and CEP164 Mutations, Linking Renal Ciliopathies to DNA Damage Response Signaling

    Czech Academy of Sciences Publication Activity Database

    Chaki, M.; Airik, R.; Ghosh, A.K.; Giles, R.H.; Bryja, Vítězslav

    2012-01-01

    Roč. 150, č. 3 (2012), s. 533-548 ISSN 0092-8674 Institutional support: RVO:68081707 Keywords : MULTIPOINT LINKAGE ANALYSIS * POLYCYSTIC KIDNEY -DISEASE * ATAXIA-TELANGIECTASIA Subject RIV: BO - Biophysics Impact factor: 31.957, year: 2012

  17. Characterizing POLG ataxia: clinics, electrophysiology and imaging.

    Science.gov (United States)

    Synofzik, Matthis; Srulijes, Karin; Godau, Jana; Berg, Daniela; Schöls, Ludger

    2012-12-01

    Mutations in the mitochondrial DNA polymerase gamma (POLG) cause a highly pleomorphic disease spectrum, and reports about their frequencies in ataxia populations yield equivocal results. This leads to uncertainties about the role of POLG genetics in the workup of patients with unexplained ataxia. A comprehensive characterization of POLG-associated ataxia (POLG-A) will help guide genetic diagnostics and advance our understanding of the disease processes underlying POLG-A. Thirteen patients with POLG-A were assessed by standardized clinical investigation, nerve conduction studies, motor-evoked potentials, magnetic resonance imaging (MRI) and transcranial sonography (TCS). The findings were compared with 13 matched patients with Friedreich's ataxia (FA). In addition to the well-known POLG-associated features of chronic external ophthalmoplegia (100 %), areflexia to the lower extremity (100 %), impaired vibration sense (100 %), bilateral ptosis (69 %) and epilepsy (38 %), also hyperkinetic movement disorders were frequent in POLG-A patients, including chorea (31 %), dystonia (31 %) and myoclonus (23 %). Similar to FA, polyneuropathy was of sensory axonal type (100 %). In contrast to FA, none of the POLG-A patients showed impaired central motor conduction. TCS demonstrated less enlargement of the fourth ventricle and more diffuse cerebellar hyperechogenicity in POLG-A. Corresponding to TCS, MRI revealed no or only mild cerebellar atrophy in most POLG-A patients (85 %). POLG ataxia presents with the clinical characteristics of both afferent and cerebellar ataxia. Cerebellar alterations diffusely involve various parts of the cerebellum, yet cerebellar atrophy is generally mild. POLG-A presents with a high load of distinct non-ataxia features, namely, sensory neuropathy, external ophthalmoplegia, ptosis, epilepsy and/or hyperkinetic movement disorders. Involvement of the corticospinal tract, however, is rare.

  18. Speech in spinocerebellar ataxia.

    Science.gov (United States)

    Schalling, Ellika; Hartelius, Lena

    2013-12-01

    Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominant cerebellar ataxias clinically characterized by progressive ataxia, dysarthria and a range of other concomitant neurological symptoms. Only a few studies include detailed characterization of speech symptoms in SCA. Speech symptoms in SCA resemble ataxic dysarthria but symptoms related to phonation may be more prominent. One study to date has shown an association between differences in speech and voice symptoms related to genotype. More studies of speech and voice phenotypes are motivated, to possibly aid in clinical diagnosis. In addition, instrumental speech analysis has been demonstrated to be a reliable measure that may be used to monitor disease progression or therapy outcomes in possible future pharmacological treatments. Intervention by speech and language pathologists should go beyond assessment. Clinical guidelines for management of speech, communication and swallowing need to be developed for individuals with progressive cerebellar ataxia. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Frontal ataxia in childhood.

    OpenAIRE

    Erasmus, C.E.; Beems, T.; Rotteveel, J.J.

    2004-01-01

    Frontal ataxia may be the result of a unilateral frontal lesion. In this report three cases are presented with ataxia due to right frontal lesions. One case concerns a boy presenting with an unsteady gait and titubation of the trunk, mimicking developmental disequilibrium and with complex partial seizures. It proved to be caused by a small right-sided cavernoma in the middle frontal gyrus. After surgical intervention the symptoms and the seizures disappeared. Two subsequent cases concern teen...

  20. Spinocerebellar ataxia-10 with paranoid schizophrenia

    Directory of Open Access Journals (Sweden)

    Bhavesh Trikamji

    2015-01-01

    Full Text Available Spino-cerebellar ataxia type 10 (SCA10 is an autosomal dominant disorder that is characterized by cerebellar ataxia, seizures and nystagmus with a fragmented pursuit. Schizophrenia has been reported with SCAs 1 and 2 yet in SCA 10, psychiatric manifestations are uncommon. We report a Hispanic family involving a father and his four children with SCA10 genetic mutation. Two of his children, a 20-year-old female and a 23-year-old male, presented with gradually progressive spino-cerebellar ataxia and paranoid schizophrenia. Neurological examination revealed ocular dysmetria, dysdiadokinesia, impaired finger-to-nose exam, gait ataxia and hyperreflexia in both the cases. Additionally, they had a history of psychosis with destructive behavior, depression and paranoid delusions with auditory hallucinations. Serology and CSF studies were unremarkable and MRI brain revealed cerebellar volume loss. Ultimately, a test for ATAXIN-10 mutation was positive thus confirming the diagnosis of SCA10 in father and his four children. We now endeavor to investigate the association between schizophrenia and SCA10.

  1. [A sporadic case of episodic ataxia with nystagmus (EA-2)].

    Science.gov (United States)

    Namekawa, M; Takiyama, Y; Ueno, N; Nishizawa, M

    1998-05-01

    A 39-year-old man with episodic ataxia with nystagmus (EA-2) was reported. He showed intermittent cerebellar dysfunction, i.e., ataxia, nystagmus, dysarthria and vertigo, since he was 10 years old. Although this attack lasted for several hours, he was normal with exception of interictal nystagmus. His parents and sister showed no episodic ataxia. We ruled out the diseases, which may cause episodic ataxia, such as multiple sclerosis, vascular disorders, metabolic disorders and congenital anomalies. He was released from the attack by treatment with acetazolamide. EA-2 has been associated with mutations in the alpha 1A-voltage dependent calcium channel gene (CACNL1A4), which is also affected in familial hemiplegic migraine (FMH) and spinocerebellar ataxia type 6 (SCA6). In EA-2, frame-shift mutation leading to premature stop and splice-site mutation leading to truncated, non-functional channel protein have been reported. However, our patient did not have the mutations in the CACNL1A4 gene that were previously reported. In addition, our patient did not have an expanded CAG allele in the CACNL1A4 gene which is responsible for SCA6. Further examination is required to address whether a new mutation exists in the CACNL1A4 gene in our patient.

  2. Frontal ataxia in childhood.

    Science.gov (United States)

    Erasmus, C E; Beems, T; Rotteveel, J J

    2004-12-01

    Frontal ataxia may be the result of a unilateral frontal lesion. In this report three cases are presented with ataxia due to right frontal lesions. One case concerns a boy presenting with an unsteady gait and titubation of the trunk, mimicking developmental disequilibrium and with complex partial seizures. It proved to be caused by a small right-sided cavernoma in the middle frontal gyrus. After surgical intervention the symptoms and the seizures disappeared. Two subsequent cases concern teenage patients presenting with headache after an ENT infection and on physical examination mild dysmetric function of the upper limbs and slight disequilibrium, due to right-sided frontal lobe abscesses. After neurosurgical and antibiotic therapy the symptoms were relieved. The frontal origin of ataxia should be considered in children presenting with a "cerebellar syndrome". Frontal gait disorders consist of a clinical pattern of different gait disorders. The syndrome has been mentioned in the literature under different names. Our patients show signs compatible with the term frontal disequilibrium, a clinical pattern of frontal gait disorder. This assumes walking problems characterized by loss of control of motor planning, leading to imbalance. Remarkably, frontal ataxia may mimic developmental delay as demonstrated in the first case and may be the leading mild symptom in extensive frontal lobe damage as demonstrated by the two other cases. We suppose that frontal ataxia is the result of a disturbance in the cerebellar-frontal circuitries and an impairment of executive and planning functions of the basal ganglia-frontal lobe circuitry.

  3. Splenic Involvement in Hereditary Hemorrhagic Telangiectasia

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    Susumu Takamatsu

    2016-01-01

    Full Text Available A 33-year-old man who presented with prolonged epigastric pain was referred to our hospital. He had experienced recurrent epistaxis and had a family history of hereditary hemorrhagic telangiectasia. Computed tomography and magnetic resonance imaging revealed splenomegaly and a 9 cm hypervascular mass in his spleen. Computed tomography also showed a pulmonary arteriovenous malformation and heterogeneous enhancement of the liver parenchyma, suggesting the presence of arteriosystemic shunts and telangiectases. Based on these findings, the patient was definitely diagnosed with hereditary hemorrhagic telangiectasia according to Curaçao criteria. He underwent splenectomy, and his symptoms disappeared after surgery. Pathological examination of the resected specimen revealed that the hypervascular lesion of the spleen was not a tumor but was composed of abnormal vessels associated with hereditary hemorrhagic telangiectasia. Symptomatic splenic involvement may be a rare manifestation of hereditary hemorrhagic telangiectasia but can be revealed by imaging modalities.

  4. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era

    Directory of Open Access Journals (Sweden)

    Jamie eMcDonald

    2015-01-01

    Full Text Available Hereditary hemorrhagic telangiectasia (HHT is a vascular dysplasia characterized by telangiectases and arteriovenous malformations (AVMs in particular locations described in consensus clinical diagnostic criteria published in 2000. Two genes in the transforming growth factor-beta (TGF-β signaling pathway, ENG and ACVRL1, were discovered almost two decades ago, and mutations in these genes have been reported to cause up to 85% of HHT. In our experience, approximately 96% of individuals with HHT have a mutation in these two genes, when published (Curaçao diagnostic criteria for HHT are strictly applied. More recently, two additional genes in the same pathway, SMAD4 and GDF2, have been identified in a much smaller number of patients with a similar or overlapping phenotype to HHT. Yet families still exist with compelling evidence of a hereditary telangiectasia disorder, but no identifiable mutation in a known gene. Recent availability of whole exome and genome testing has created new opportunities to facilitate gene discovery, identify genetic modifiers to explain clinical variability, and potentially define an increased spectrum of hereditary telangiectasia disorders. An expanded approach to molecular diagnostics for inherited telangiectasia disorders that incorporates a multi-gene next generation sequencing (NGS HHT panel is proposed.

  5. Friedreich's ataxia and other hereditary ataxias in Greece: an 18-year perspective.

    Science.gov (United States)

    Koutsis, Georgios; Kladi, Athina; Karadima, Georgia; Houlden, Henry; Wood, Nicholas W; Christodoulou, Kyproula; Panas, Marios

    2014-01-15

    Limited data exist on the spectrum of heredoataxias in Greece, including the prevalence and phenotype of Friedreich's ataxia (FRDA) and the prevalence and subtypes of dominant spinocerebellar ataxias (SCAs). We analyzed clinically and investigated genetically for FRDA and triplet-repeat expansion SCAs a consecutive series of 186 patients with suspected heredoataxia referred to Athens over 18 years. For prevalence estimates we included patients with molecular diagnosis from Cyprus that were absent from the Athens cohort. The minimum prevalence of FRDA was ~0.9/100,000, with clusters of high prevalence in Aegean islands. FRDA was diagnosed in 73 probands. The genotypic and phenotypic spectrum of FRDA was similar to other populations, with one patient compound heterozygote for a known point mutation in FXN (Asn146Lys). Undiagnosed recessive ataxias included FRDA-like and spastic ataxias. The minimum prevalence of dominant SCAs was ~0.7/100,000. SCA1 (4), SCA7 (4), SCA2, SCA6, and SCA17 (1 each) probands were identified. A molecular diagnosis was reached in 31% of dominant cases. Undiagnosed dominant patients included a majority of type III autosomal dominant cerebellar ataxias. FRDA is the commonest heredoataxia in the Greek population with prevalence towards the lower end of other European populations. Dominant SCAs are almost as prevalent. SCA1, SCA2, SCA6, SCA7 and SCA17 patients complete the spectrum of cases with a specific molecular diagnosis. © 2013.

  6. Hereditary spastic paraplegia with cerebellar ataxia

    DEFF Research Database (Denmark)

    Nielsen, J E; Johnsen, B; Koefoed, P

    2004-01-01

    Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria......, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked...... in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance...

  7. Spinocerebellar ataxia 36 (SCA36): «Costa da Morte ataxia».

    Science.gov (United States)

    Arias, M; García-Murias, M; Sobrido, M J

    To describe the history of the discovery of SCA36 and review knowledge of this entity, which is currently the most prevalent hereditary ataxia in Galicia (Spain) owing to a founder effect. SCA36 is an autosomal dominant hereditary ataxia with late onset and slow progression. It presents with cerebellar ataxia, sensorineural hearing loss, and discrete motor neuron impairment (tongue atrophy with denervation, discrete pyramidal signs). SCA36 was first described in Japan (Asida River ataxia) and in Galicia(Costa da Morte ataxia). The condition is caused by a genetic mutation (intronic hexanucleotide repeat expansion) in the NOP56 gene on the short arm of chromosome 20 (20p13). Magnetic resonance image study initially shows cerebellar vermian atrophy that subsequently extends to the rest of the cerebellum and finally to the pontomedullary region of the brainstem without producing white matter lesions. Peripheral nerve conduction velocities are normal, and sensorimotor evoked potential studies show delayed conduction of stimuli to lower limbs. In patients with hearing loss, audiometric studies show a drop of >40dB in frequencies exceeding 2,500Hz. Auditory evoked potential studies may also show lack of waves I and II. Costa da Morte ataxia or SCA36 is the most prevalent SCA in the Spanish region of Galicia. Given the region's history of high rates of emigration, new cases may be diagnosed in numerous countries, especially in Latin America. Genetic studies are now available to patients and asymptomatic carriers. Since many people are at risk for this disease, we will continue our investigations aimed at elucidating the underlying pathogenic molecular mechanisms and discovering effective treatment. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia

    Science.gov (United States)

    Baeyens, Nicolas; Larrivée, Bruno; Ola, Roxana; Hayward-Piatkowskyi, Brielle; Dubrac, Alexandre; Huang, Billy; Ross, Tyler D.; Coon, Brian G.; Min, Elizabeth; Tsarfati, Maya; Tong, Haibin; Eichmann, Anne

    2016-01-01

    Morphogenesis of the vascular system is strongly modulated by mechanical forces from blood flow. Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal-dominant disease in which arteriovenous malformations and telangiectasias accumulate with age. Most cases are linked to heterozygous mutations in Alk1 or Endoglin, receptors for bone morphogenetic proteins (BMPs) 9 and 10. Evidence suggests that a second hit results in clonal expansion of endothelial cells to form lesions with poor mural cell coverage that spontaneously rupture and bleed. We now report that fluid shear stress potentiates BMPs to activate Alk1 signaling, which correlates with enhanced association of Alk1 and endoglin. Alk1 is required for BMP9 and flow responses, whereas endoglin is only required for enhancement by flow. This pathway mediates both inhibition of endothelial proliferation and recruitment of mural cells; thus, its loss blocks flow-induced vascular stabilization. Identification of Alk1 signaling as a convergence point for flow and soluble ligands provides a molecular mechanism for development of HHT lesions. PMID:27646277

  9. Avances en el tratamiento de las ataxias crónicas

    Directory of Open Access Journals (Sweden)

    María Celeste Buompadre

    2013-09-01

    Full Text Available Las ataxias crónicas cerebelosas autosómicas recesivas constituyen el grupo más amplio de ataxias hereditarias, con presentación principalmente en la edad pediátrica, se caracterizan por degeneración o desarrollo anormal del cerebelo y de la médula espinal. Hasta el momento el tratamiento etiológico está disponible sólo para algunas formas: aquellas con defecto metabólico conocido como la abetalipoproteinemia, la ataxia con deficiencia de vitamina E y la xantomatosis cerebrotendinosa. En estas entidades la modificación de la dieta, el suplemento con vitaminas E y A principalmente y la administración de ácido quenodexocicólico pueden cambiar el curso de la enfermedad. En la mayoría de los otros tipos de ataxia el tratamiento es solo de soporte, como por ejemplo el uso de antioxidantes y quelantes del hierro en la ataxia de Friederich con el objetivo de disminuir los depósitos de hierro mitocondriales, de corticoides en la ataxia telangiectasia y de ubiquinona /coenzima Q10 en la ataxia por deficiencia de coenzima Q-10. Si bien hasta el momento ningún tratamiento es curativo para la mayoría de las ataxias crónicas autosómico recesivas, el diagnóstico precoz de estas entidades se asocia con una mejor respuesta a las diferentes drogas.

  10. The use of muscle biopsy in the diagnosis of undefined ataxia with cerebellar atrophy in children.

    Science.gov (United States)

    Terracciano, Alessandra; Renaldo, Florence; Zanni, Ginevra; D'Amico, Adele; Pastore, Anna; Barresi, Sabina; Valente, Enza Maria; Piemonte, Fiorella; Tozzi, Giulia; Carrozzo, Rosalba; Valeriani, Massimiliano; Boldrini, Renata; Mercuri, Eugenio; Santorelli, Filippo Maria; Bertini, Enrico

    2012-05-01

    Childhood cerebellar ataxias, and particularly congenital ataxias, are heterogeneous disorders and several remain undefined. We performed a muscle biopsy in patients with congenital ataxia and children with later onset undefined ataxia having neuroimaging evidence of cerebellar atrophy. Significant reduced levels of Coenzyme Q10 (COQ10) were found in the skeletal muscle of 9 out of 34 patients that were consecutively screened. A mutation in the ADCK3/Coq8 gene (R347X) was identified in a female patient with ataxia, seizures and markedly reduced COQ10 levels. In a 2.5-years-old male patient with non syndromic congenital ataxia and autophagic vacuoles in the muscle biopsy we identified a homozygous nonsense mutation R111X mutation in SIL1 gene, leading to early diagnosis of Marinesco-Sjogren syndrome. We think that muscle biopsy is a valuable procedure to improve diagnostic assesement in children with congenital ataxia or other undefined forms of later onset childhood ataxia associated to cerebellar atrophy at MRI. Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  11. Sleep disorders in cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    José L. Pedroso

    2011-04-01

    Full Text Available Cerebellar ataxias comprise a wide range of etiologies leading to central nervous system-related motor and non-motor symptoms. Recently, a large body of evidence has demonstrated a high frequency of non-motor manifestations in cerebellar ataxias, specially in autosomal dominant spinocerebellar ataxias (SCA. Among these non-motor dysfunctions, sleep disorders have been recognized, although still under or even misdiagnosed. In this review, we highlight the main sleep disorders related to cerebellar ataxias focusing on REM sleep behavior disorder (RBD, restless legs syndrome (RLS, periodic limb movement in sleep (PLMS, excessive daytime sleepiness (EDS, insomnia and sleep apnea.

  12. Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome.

    OpenAIRE

    Cross, J. H.; Arora, R.; Heckemann, R. A.; Gunny, R.; Chong, K.; Carr, L.; Baldeweg, T.; Differ, A. M.; Lench, N.; Varadkar, S.; Sirimanna, T.; Wassmer, E.; Hulton, S. A.; Ognjanovic, M.; Ramesh, V.

    2013-01-01

    Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities.

  13. Genetics Home Reference: hereditary hemorrhagic telangiectasia

    Science.gov (United States)

    ... Central OMIM: JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic ... 10.1097/GIM.0b013e3182136d32. Review. Citation on PubMed McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead ...

  14. Hereditary hemorrhagic telangiectasia clinical and molecular genetics

    NARCIS (Netherlands)

    Letteboer, T.G.W.

    2010-01-01

    Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber (ROW) syndrome is an autosomal dominant disease characterized by vascular malformations in multiple organ systems. HHT has an age-related penetrance and variable clinical expression. The clinical symptoms are caused by direct

  15. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.

    Science.gov (United States)

    Moreira, Maria-Céu; Klur, Sandra; Watanabe, Mitsunori; Németh, Andrea H; Le Ber, Isabelle; Moniz, José-Carlos; Tranchant, Christine; Aubourg, Patrick; Tazir, Meriem; Schöls, Lüdger; Pandolfo, Massimo; Schulz, Jörg B; Pouget, Jean; Calvas, Patrick; Shizuka-Ikeda, Masami; Shoji, Mikio; Tanaka, Makoto; Izatt, Louise; Shaw, Christopher E; M'Zahem, Abderrahim; Dunne, Eimear; Bomont, Pascale; Benhassine, Traki; Bouslam, Naïma; Stevanin, Giovanni; Brice, Alexis; Guimarães, João; Mendonça, Pedro; Barbot, Clara; Coutinho, Paula; Sequeiros, Jorge; Dürr, Alexandra; Warter, Jean-Marie; Koenig, Michel

    2004-03-01

    Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination.

  16. The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers.

    Science.gov (United States)

    Weigelt, Britta; Bi, Rui; Kumar, Rahul; Blecua, Pedro; Mandelker, Diana L; Geyer, Felipe C; Pareja, Fresia; James, Paul A; Couch, Fergus J; Eccles, Diana M; Blows, Fiona; Pharoah, Paul; Li, Anqi; Selenica, Pier; Lim, Raymond S; Jayakumaran, Gowtham; Waddell, Nic; Shen, Ronglai; Norton, Larry; Wen, Hannah Y; Powell, Simon N; Riaz, Nadeem; Robson, Mark E; Reis-Filho, Jorge S; Chenevix-Trench, Georgia

    2018-02-28

    Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.

  17. Purkinje Cell Signaling Deficits in Animal Models of Ataxia

    Directory of Open Access Journals (Sweden)

    Eriola Hoxha

    2018-04-01

    Full Text Available Purkinje cell (PC dysfunction or degeneration is the most frequent finding in animal models with ataxic symptoms. Mutations affecting intrinsic membrane properties can lead to ataxia by altering the firing rate of PCs or their firing pattern. However, the relationship between specific firing alterations and motor symptoms is not yet clear, and in some cases PC dysfunction precedes the onset of ataxic signs. Moreover, a great variety of ionic and synaptic mechanisms can affect PC signaling, resulting in different features of motor dysfunction. Mutations affecting Na+ channels (NaV1.1, NaV1.6, NaVβ4, Fgf14 or Rer1 reduce the firing rate of PCs, mainly via an impairment of the Na+ resurgent current. Mutations that reduce Kv3 currents limit the firing rate frequency range. Mutations of Kv1 channels act mainly on inhibitory interneurons, generating excessive GABAergic signaling onto PCs, resulting in episodic ataxia. Kv4.3 mutations are responsible for a complex syndrome with several neurologic dysfunctions including ataxia. Mutations of either Cav or BK channels have similar consequences, consisting in a disruption of the firing pattern of PCs, with loss of precision, leading to ataxia. Another category of pathogenic mechanisms of ataxia regards alterations of synaptic signals arriving at the PC. At the parallel fiber (PF-PC synapse, mutations of glutamate delta-2 (GluD2 or its ligand Crbl1 are responsible for the loss of synaptic contacts, abolishment of long-term depression (LTD and motor deficits. At the same synapse, a correct function of metabotropic glutamate receptor 1 (mGlu1 receptors is necessary to avoid ataxia. Failure of climbing fiber (CF maturation and establishment of PC mono-innervation occurs in a great number of mutant mice, including mGlu1 and its transduction pathway, GluD2, semaphorins and their receptors. All these models have in common the alteration of PC output signals, due to a variety of mechanisms affecting incoming

  18. Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia.

    Science.gov (United States)

    Hamza, Wahiba; Ali Pacha, Lamia; Hamadouche, Tarik; Muller, Jean; Drouot, Nathalie; Ferrat, Farida; Makri, Samira; Chaouch, Malika; Tazir, Meriem; Koenig, Michel; Benhassine, Traki

    2015-06-12

    Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with great genetic and phenotypic heterogeneity, over 30 genes/loci have been associated with more than 20 different clinical forms of ARCA. Genetic heterogeneity combined with highly variable clinical expression of the cerebellar symptoms and overlapping features complicate furthermore the etiological diagnosis of ARCA. The determination of the most frequent mutations and corresponding ataxias, as well as particular features specific to a population, are mandatory to facilitate and speed up the diagnosis process, especially when an appropriate treatment is available. We explored 166 patients (115 families) refered to the neurology units of Algiers central hospitals (Algeria) with a cerebellar ataxia phenotype segregating as an autosomal recessive pattern of inheritance. Genomic DNA was extracted from peripheral blood samples and mutational screening was performed by PCR and direct sequencing or by targeted genomic capture and massive parallel sequencing of 57 genes associated with inherited cerebellar ataxia phenotypes. In this work we report the clinical and molecular results obtained on a large cohort of Algerian patients (110 patients/76 families) with genetically determined autosomal recessive ataxia, representing 9 different types of ARCA and 23 different mutations, including 6 novel ones. The five most common ARCA in this cohort were Friedreich ataxia, ataxia with isolated vitamin E deficiency, ataxia with oculomotor apraxia type 2, autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with oculomotor apraxia type 1. We report here a large cohort of patients with genetically determined autosomal recessive ataxia and the first study of the genetic context of ARCA in Algeria. This study showed that in Algerian patients, the two most common types of ataxia (Friedreich ataxia and ataxia with isolated vitamin E deficiency) coexist with forms that may be

  19. Autosomal dominant hereditary ataxia in Sri Lanka

    OpenAIRE

    Sumathipala, Dulika S; Abeysekera, Gayan S; Jayasekara, Rohan W; Tallaksen, Chantal ME; Dissanayake, Vajira HW

    2013-01-01

    Background Spinocerebellar ataxias (SCA) are a group of hereditary neurodegenerative disorders. Prevalence of SCA subtypes differ worldwide. Autosomal dominant ataxias are the commonest types of inherited ataxias seen in Sri Lanka. The aim of the study is to determine the genetic etiology of patients with autosomal dominant ataxia in Sri Lanka and to describe the clinical features of each genetic subtype. Methods ...

  20. NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair

    DEFF Research Database (Denmark)

    Fang, Evandro Fei; Kassahun, Henok; Croteau, Deborah L

    2016-01-01

    and neurodegeneration in A-T patients is unclear. Here we report and examine the significance of increased PARylation, low NAD(+), and mitochondrial dysfunction in ATM-deficient neurons, mice, and worms. Treatments that replenish intracellular NAD(+) reduce the severity of A-T neuropathology, normalize neuromuscular...... function, delay memory loss, and extend lifespan in both animal models. Mechanistically, treatments that increase intracellular NAD(+) also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy. This work links two major theories on aging, DNA damage accumulation, and mitochondrial...

  1. Cellular and molecular studies on ataxia-telangiectasia lymphoblastoid cell lines

    International Nuclear Information System (INIS)

    Fiorilli, M.; Crescenzi, M.; Carbonari, M.; Russo, G.; Businco, L.; Aiuti, F.

    1985-01-01

    We have examined several AT-related lesions in lymphoblastoid cell lines (LCLs) derived from AT patients. Diminished sensitivity to gamma-irradiation was found in six of seven AT-LCLs. A seventh line, from a patient with apparently normal T-cell immunity, responded normally following radiation. Constitutive proteins from exponentially growing AT-LCLs were assessed by SDS-PAGE analysis and did not differ significantly from normals. IgM synthesis was also normal except for one AT-LCL that contained native IgM molecules of different sizes, corresponding to the presence of pentamers and oligomers. Analysis under reducing conditions showed normal-sized secretory mu-chains. Finally, we examined mRNAs corresponding to two oncogenes, c-myc and c-myb, in AT and normal LCLs and found marked overproduction of c-myc in one AT-LCL (i.e., ATL6). The latter findings suggest that AT cells might be prone to aberrantly express cellular oncogenes as a result of chromosomal instability and consequent transposition of oncogenes

  2. Research on Potential Biomarkers in Hereditary Haemorrhagic Telangiectasia

    Directory of Open Access Journals (Sweden)

    Luisa Maria Botella

    2015-03-01

    Full Text Available Hereditary Hemorrhagic Telangiectasia (HHT is a genetically heterogeneous disorder, involving mutations in two predominant genes known as Endoglin (ENG; HHT1 and Activin receptor like kinase 1 (ACVRL1/ALK1; HHT2, as well as in some less frequent genes, such as MADH4/SMAD4 (JP-HHT or BMP9/GDF2 (HHT5. The diagnosis of HHT patients currently remains at the clinical level, according to the Curaçao criteria, whereas the molecular diagnosis is used to confirm or rule out suspected HHT cases, especially when a well characterized index case is present in the family or in an isolated population. Unfortunately, many suspected patients do not present a clear HHT diagnosis or do not show pathogenic mutations in HHT genes, prompting the need to investigate additional biomarkers of the disease. Here, several HHT biomarkers and novel methodological approaches developed during the last years will be reviewed. On one hand, products detected in plasma or serum samples: soluble proteins (VEGF, TGF-β1, soluble endoglin, angiopoietin-2 and microRNA variants (miR-27a, miR-205, miR-210. On the other hand, differential HHT gene expression fingerprinting, Next Generation Sequencing (NGS of a panel of genes involved in HHT, and infrared spectroscopy combined with Artificial Neural Network (ANN patterns will also be reviewed. All these biomarkers might help to improve and refine HHT diagnosis by distinguishing from the non-HHT population.

  3. Deep Brain Stimulation for Tremor Associated with Underlying Ataxia Syndromes: A Case Series and Discussion of Issues

    Directory of Open Access Journals (Sweden)

    Genko Oyama

    2014-07-01

    Full Text Available Background: Deep brain stimulation (DBS has been utilized to treat various symptoms in patients suffering from movement disorders such as Parkinson's disease, dystonia, and essential tremor. Though ataxia syndromes have not been formally or frequently addressed with DBS, there are patients with ataxia and associated medication refractory tremor or dystonia who may potentially benefit from therapy.Methods: A retrospective database review was performed, searching for cases of ataxia where tremor and/or dystonia were addressed by utilizing DBS at the University of Florida Center for Movement Disorders and Neurorestoration between 2008 and 2011. Five patients were found who had DBS implantation to address either medication refractory tremor or dystonia. The patient's underlying diagnoses included spinocerebellar ataxia type 2 (SCA2, fragile X associated tremor ataxia syndrome (FXTAS, a case of idiopathic ataxia (ataxia not otherwise specified [NOS], spinocerebellar ataxia type 17 (SCA17, and a senataxin mutation (SETX.Results: DBS improved medication refractory tremor in the SCA2 and the ataxia NOS patients. The outcome for the FXTAS patient was poor. DBS improved dystonia in the SCA17 and SETX patients, although dystonia did not improve in the lower extremities of the SCA17 patient. All patients reported a transient gait dysfunction postoperatively, and there were no reports of improvement in ataxia‐related symptoms.Discussion: DBS may be an option to treat tremor, inclusive of dystonic tremor in patients with underlying ataxia; however, gait and other symptoms may possibly be worsened.Erratum published on July 27, 2016

  4. Ataxia with oculomotor apraxia type 2: a clinical and genetic study of 19 patients.

    Science.gov (United States)

    Tazir, M; Ali-Pacha, L; M'Zahem, A; Delaunoy, J P; Fritsch, M; Nouioua, S; Benhassine, T; Assami, S; Grid, D; Vallat, J M; Hamri, A; Koenig, M

    2009-03-15

    Ataxia with oculo-motor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia (ARCA) caused by mutations in the senataxin gene (SETX). We analysed the phenotypic spectrum of 19 AOA2 patients with mutations in SETX, which seems to be the third most frequent form of ARCA in Algeria after Freidreich ataxia and Ataxia with vitamin E deficiency. In AOA2 patients, the mean age at onset for all families was in the second decade. Cerebellar ataxia was progressive, slowly leading to disability which was aggravated by axonal polyneuropathy present in almost all the patients. Mean disease duration until wheelchair was around 20 years. Oculo-motor apraxia (OMA) was present in 32% of the patients while convergent strabismus was present in 37%. Strabismus is therefore also very suggestive of AOA2 when associated with ataxia and polyneuropathy even in the absence of OMA. Cerebellar atrophy was more severe in the eldest patients; however it may also be an early sign since it was present in the youngest and paucisymptomatic patients. The initial sign was gait ataxia in all but two patients who presented with head tremor and writer cramp, respectively. Serum alpha-fetoprotein, which was elevated in all tested patients, was a good marker to suggest molecular studies of the SETX gene.

  5. Adult onset sporadic ataxias: a diagnostic challenge

    Directory of Open Access Journals (Sweden)

    Orlando Graziani Povoas Barsottini

    2014-03-01

    Full Text Available Patients with adult onset non-familial progressive ataxia are classified in sporadic ataxia group. There are several disease categories that may manifest with sporadic ataxia: toxic causes, immune-mediated ataxias, vitamin deficiency, infectious diseases, degenerative disorders and even genetic conditions. Considering heterogeneity in the clinical spectrum of sporadic ataxias, the correct diagnosis remains a clinical challenge. In this review, the different disease categories that lead to sporadic ataxia with adult onset are discussed with special emphasis on their clinical and neuroimaging features, and diagnostic criteria.

  6. Very early disease manifestations of macular telangiectasia type 2

    NARCIS (Netherlands)

    Issa, P.C.; Heeren, T.F.C.; Kupitz, E.H.; Holz, F.G.; Berendschot, T.T.J.M.

    Background: To report very early morphologic and functional alterations in patients with macular telangiectasia type 2. Methods: Patients with asymmetric disease manifestations, in whom retinal alterations characteristic for macular telangiectasia type 2 were present in one but not in the apparently

  7. Brain abscesses and hereditary hemorrhagic telangiectasia

    International Nuclear Information System (INIS)

    Vives, Daniel A.; Bauni, Carlos E.; Mendoza, Monica E.

    2003-01-01

    Rendu-Osler-Weber disease or Hereditary Hemorrhagic Telangiectasia (HHT) is a generalized familial angiodysplastic disorder. The neurological manifestations of this entity are due to Central Nervous System vascular lesions or to complications of other visceral lesions such as pulmonary arteriovenous fistulae. This report describes two patients (males, 40 and 61 years old), with brain abscesses associated with HHT. The CT, MRI and Angiographic findings as well as the therapeutic approach are analyzed. Patients with brain abscess of unknown origin must be evaluated for the presence of lung vascular malformation in association with HHT. (author)

  8. Genetics of Hereditary Ataxia in Scottish Terriers.

    Science.gov (United States)

    Urkasemsin, G; Nielsen, D M; Singleton, A; Arepalli, S; Hernandez, D; Agler, C; Olby, N J

    2017-07-01

    Scottish Terriers have a high incidence of juvenile onset hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex and causing slowly progressive cerebellar dysfunction. To identify chromosomal regions associated with hereditary ataxia in Scottish Terriers. One hundred and fifty-three Scottish Terriers were recruited through the Scottish Terrier Club of America. Prospective study. Dogs were classified as affected if they had slowly progressive cerebellar signs. When possible, magnetic resonance imaging and histopathological evaluation of the brain were completed as diagnostic aids. To identify genomic regions connected with the disease, genome-wide mapping was performed using both linkage- and association-based approaches. Pedigree evaluation and homozygosity mapping were also performed to examine mode of inheritance and to investigate the region of interest, respectively. Linkage and genome-wide association studies in a cohort of Scottish Terriers both identified a region on CFA X strongly associated with the disease trait. Homozygosity mapping revealed a 4 Mb region of interest. Pedigree evaluation failed to identify the possible mode of inheritance due to the lack of complete litter information. This finding suggests that further genetic investigation of the potential region of interest on CFA X should be considered in order to identify the causal mutation as well as develop a genetic test to eliminate the disease from this breed. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  9. ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2).

    Science.gov (United States)

    Jiang, Y; Chen, H-C; Su, X; Thompson, P A; Liu, X; Do, K-A; Wierda, W; Keating, M J; Plunkett, W

    2016-09-02

    Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22-23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

  10. Maculopathy and spinocerebellar ataxia type 1

    DEFF Research Database (Denmark)

    Lebranchu, Pierre; Le Meur, Guylène; Magot, Armelle

    2013-01-01

    Autosomal dominant cerebellar ataxia is a rare heterogeneous group of diseases characterized by cerebellar symptoms, often associated with other multisystemic signs. Mild optic neuropathy has been associated with spinocerebellar ataxia type 1 (SCA1), but macular dysfunction has been reported...

  11. Ataxias and Cerebellar or Spinocerebellar Degeneration

    Science.gov (United States)

    ... and conducts a broad range of basic and clinical research on cerebellar and spinocerebellar degeneration, including work aimed at finding the cause(s) of ataxias and ways to ... Publications Definition Ataxia ...

  12. Falls and cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    I. V. Damulin

    2015-01-01

    Full Text Available The paper considers the main causes of falls. Whatever their cause is, falls may lead to severe maladjustment in everyday life. In nearly 1 out of 10 cases, they are accompanied by severe injuries, including fractures (most commonly those of the proximal femur and humerus, hands, pelvic bones, and vertebrae, subdural hematoma, and severe soft tissue and head injuries. This process is emphasized to be multifactorial. Particular emphasis is laid on the involvement of the cerebellum and its associations, which may be accompanied by falls. This is clinically manifested mainly by gait disorders. Walking is a result of an interaction of three related functions (locomotion, maintenance of balance and adaptive reactions. In addition to synergies related to locomotion and balance maintenance, standing at rest and walking are influenced bythe following factors: postural and environmental information (proprioceptive, vestibular, and visual, the capacity to interpret and integrate this information, the ability of the musculoskeletal system to make movements, and the capability to optimally modulate these movements in view of the specific situation and the ability to choose and adapt synergy in terms of external factors and the capacities and purposes of an individual. The clinical signs of damage to the cerebellum and its associations are considered in detail. These structures are emphasized to be involved not only in movements, but also in cognitive functions. The major symptoms that permit cerebellar dysfunction to be diagnosed are given. Symptoms in cerebellar injuries are generally most pronounced when suddenly changing the direction of movements or attempting to start walking immediately after a dramatic rise. The magnitude of ataxia also increases in a patient who tries to decrease the step size. Falling tendencies or bending to one side (in other symptoms characteristic of cerebellar diseases suggest injury of the corresponding

  13. Evidence-based management of epistaxis in hereditary haemorrhagic telangiectasia.

    Science.gov (United States)

    Syed, I; Sunkaraneni, V S

    2015-05-01

    There are currently no guidelines in the UK for the specific management of hereditary haemorrhagic telangiectasia related epistaxis. The authors aimed to review the literature and provide an algorithm for the management of hereditary haemorrhagic telangiectasia related epistaxis. The Medline and Embase databases were interrogated on 15 November 2013 using the search items 'hereditary haemorrhagic telangiectasia' (title), 'epistaxis' (title) and 'treatment' (title and abstract), and limiting the search to articles published in English. A total of 46 publications were identified, comprising 1 systematic review, 2 randomised, controlled trials, 27 case series, 9 case reports, 4 questionnaire studies and 3 in vitro studies. There is a lack of high-level evidence for the use of many of the available treatments for the specific management of epistaxis in hereditary haemorrhagic telangiectasia. Current management should be based on a multidisciplinary team approach involving both a hereditary haemorrhagic telangiectasia physician and an ENT surgeon, especially when systemic therapy is being considered. The suggested treatment algorithm considers that the severity of epistaxis merits intervention at different levels of the treatment ladder. The patient should be assessed using a reproducible validated assessment tool, for example an epistaxis severity score, to guide treatment. More research is required, particularly in the investigation of topical agents targeting the development and fragility of telangiectasiae in hereditary haemorrhagic telangiectasia.

  14. Allelic Dropout in the ENG Gene, Affecting the Results of Genetic Testing in Hereditary Hemorrhagic Telangiectasia

    DEFF Research Database (Denmark)

    Tørring, Pernille M; Kjeldsen, A.D.; Ousager, L.B.

    2012-01-01

    Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder with three disease-causing genes identified to date: ENG, ACVRL1, and SMAD4. We report an HHT patient with allelic dropout that on routine sequence analysis for a known mutation in the family (c.817......-3T>G in ENG) initially seemed to be homozygous for the mutation. Aim: To explore the possibility of allelic dropout causing a false result in this patient. Methods: Mutation analysis of additional family members was performed and haplotype analysis carried out. New primers were designed to reveal...... the presence of a possible sequence variant, which could explain the presumed allelic dropout. Results: Allelic dropout caused by a six-nucleotide duplication close to the standard reverse primer was the assumed cause of a false homozygous diagnosis. Conclusion: Sequence variants outside of the primer regions...

  15. Movement disorders in hereditary ataxias.

    Science.gov (United States)

    Garcia Ruiz, Pedro J; Mayo, David; Hernandez, Jaime; Cantarero, Susana; Ayuso, Carmen

    2002-10-15

    Movement disorders are well known features of some dominant hereditary ataxias (HA), specially SCA3/Machado-Joseph disease and dentatorubropallidolusyan atrophy. However, little is known about the existence and classification of movement disorders in other dominant and recessive ataxias. We prospectively studied the presence of movement disorders in patients referred for HA over the last 3 years. Only those patients with a confirmed family history of ataxia were included. We studied 84 cases of HA, including 46 cases of recessive and 38 cases of dominant HA. Thirty out of 46 cases of recessive HA could be classified as: Friedreich ataxia (FA), 29 cases; vitamin E deficiency, 1 case. Twenty-three out of 38 cases of dominant HA could be classified as: SCA 2, 4 cases; SCA 3, 8 cases; SCA 6, 4 cases; SCA 7, 6 cases and SCA 8, 1 case. We observed movement disorders in 20/38 (52%) patients with dominant HA and 25/46 (54%) cases with recessive HA, including 16 patients (16/29) with FA. In general, postural tremor was the most frequent observed movement disorder (27 cases), followed by dystonia (22 cases). Five patients had akinetic rigid syndrome, and in 13 cases, several movement disorders coexisted. Movement disorders are frequent findings in HA, not only in dominant HA but also in recessive HA. Copyright 2002 Elsevier Science B.V.

  16. Language Impairment in Cerebellar Ataxia

    NARCIS (Netherlands)

    van Gaalen, Judith; de Swart, Bert J. M.; Oostveen, Judith; Knuijt, Simone; van de Warrenburg, Bart P. C.; Kremer, Berry (H. ) P. H.

    Background: Several studies have suggested that language impairment can be observed in patients with cerebellar pathology. The aim of this study was to investigate language performance in patients with spinocerebellar ataxia type 6 (SCA6). Methods: We assessed speech and language in 29 SCA6 patients

  17. Speech Prosody in Cerebellar Ataxia

    Science.gov (United States)

    Casper, Maureen A.; Raphael, Lawrence J.; Harris, Katherine S.; Geibel, Jennifer M.

    2007-01-01

    Persons with cerebellar ataxia exhibit changes in physical coordination and speech and voice production. Previously, these alterations of speech and voice production were described primarily via perceptual coordinates. In this study, the spatial-temporal properties of syllable production were examined in 12 speakers, six of whom were healthy…

  18. Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT).

    Science.gov (United States)

    Zarrabeitia, Roberto; Fariñas-Álvarez, Concepción; Santibáñez, Miguel; Señaris, Blanca; Fontalba, Ana; Botella, Luisa María; Parra, José Antonio

    2017-01-23

    There are very few studies about general quality of life parameters, standards for the description of health status and comparison with general population data on patients with Hereditary hemorrhagic telangiectasia (HHT), a rare disease in which epistaxis is a cardinal symptom. To assess the quality of life in a population of Spanish patients with HHT and compare it with the general population. Between January 1 st 2005 and December 31 st 2013, 187 adult patients diagnosed with HHT who were admitted to the HHT Unit of the Hospital Sierrallana, completed on their first visit, the EuroQol 5D-3L (five dimensions and three levels) quality of life descriptive test and the visual analog scale (VAS). The numerical social index value was also determined and the subjective effect of the nasal epistaxis on their quality of life was estimated classified as mild, moderate or severe. Patients with HHT had greater problems than the general population in the five dimensions of the EuroQol 5D-3L, particularly considering pain/discomfort and anxiety/depression. In the VAS and the social index value, patients with HHT also scored lower than the general population, particularly older patients, males, and patients with HHT2. They also had values similar to those of populations with chronic illnesses. The subjective perception of the severity of epistaxis correlated strongly with the VAS and social index values. The quality of life of patients with HHT, estimated using the EuroQol 5D-3L scale, is affected across all dimensions. The scores are similar to those seen in cases of other chronic diseases. Older patients, males and the carriers of the ACVRL1 mutation generally have worse scores on these scales. The VAS and the social index value are index that correlate well with the severity of the clinical symptoms associated mainly with epistaxis.

  19. CLINICAL APPROACH TO HEREDITARY HEMORRHAGIC TELANGIECTASIA

    Directory of Open Access Journals (Sweden)

    Mary Hachmeriyan

    2013-11-01

    Full Text Available Background: Hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber disease is a rare syndrome, inherited as an autosomal dominant trait with incidence of 1/10000. The clinical manifestations are due to vascular malformations and predisposition to hemorrhages in different organs, the leading symptom being recurrent epistaxis. If diagnosed with HHT, the patient and his relatives and especially children have to be screened for occult vascular malformations.Case report: A 30 years old woman was treated for cerebral stroke, epistaxis, anemia, arterio-venous malformations for over 6 months. Only at this point she was diagnosed with HHT, after noticing the typical mucosal changes. Focused family history revealed symptoms of HHT in her only child, her father, aunt and two cousins The child was screened for occult vascular malformations – attainment of the nasal mucosa, lungs, gastrointestinal system, liver and brain. Pulmonary and gastrointestinal arterio-venous malformations were proven.Conclusion: Any case of recurrent epistaxis should be evaluated for HHT. After confirmation of the diagnosis every patient and close relatives have to be screened for attainment of other organs and followed up in order to prevent severe life threatening complications.

  20. Recurrent Ataxia in Children and Adolescents.

    Science.gov (United States)

    Salman, Michael S; Klassen, Samantha F; Johnston, Janine L

    2017-07-01

    Recurrent ataxia is encountered infrequently in clinical pediatric neurology practise and presents with diagnostic challenges. It is caused by several disorders. Our aims were to describe the epidemiology and clinical features in children with recurrent ataxia. A retrospective review was undertaken in 185 children with chronic ataxia, who presented during 1991 to 2008. Several databases were searched to ensure optimum ascertainment. Patients with brain tumors or isolated disorders of the peripheral nerves or vestibular system were excluded. Recurrent ataxia was reported in 21 patients. Their age range was between 6 and 32.75 years (males=12). The crude period prevalence rate for the 18-year study period was 7.44/100,000. Eight patients had episodic ataxia and seven had inflammatory and metabolic disorders. In the rest the etiology was unknown. Many patients presented with ataxia, dizziness, and vertigo. The frequency and duration of the ataxic episodes varied from several per day to one every few months. Other clinical features included developmental delay and seizures. Neuroimaging in episodic ataxia was normal and abnormal in inflammatory or metabolic disorders. Acetazolamide provided symptomatic relief in patients with episodic ataxia, while steroids were beneficial in patients with an inflammatory etiology. One child with a metabolic disorder died. Recurrent ataxia is an uncommon presentation in children and mortality is rare. Genetic, metabolic, and inflammatory disorders should be considered in these patients. Neuroimaging is essential. Acetazolamide in selected patients provides good symptomatic relief.

  1. In children with Friedreich ataxia, muscle and ataxia parameters are associated

    NARCIS (Netherlands)

    Sival, Deborah A.; Pouwels, Maria E.; van Brederode, Agnes; Maurits, Natasha M.; Verschuuren - Bemelmans, Corien C.; Brunt, Ewout R.; Sarvaas, Gideon J. Du Marchie; Verbeek, Renate J.; Brouwer, Oebele F.; van der Hoeven, Johannes H.

    Aim In children with Friedreich ataxia (FRDA), ataxia is assessed using the surrogate marker the International Cooperative Ataxia Rating Scale (ICARS). We aimed to determine whether ICARS scores in children with FRDA are confounded by muscle weakness. Method In 12 children with FRDA (10 males, two

  2. Genetics Home Reference: ataxia with vitamin E deficiency

    Science.gov (United States)

    ... Conditions Ataxia with vitamin E deficiency Ataxia with vitamin E deficiency Printable PDF Open All Close All Enable ... view the expand/collapse boxes. Description Ataxia with vitamin E deficiency is a disorder that impairs the body's ...

  3. Genetics Home Reference: X-linked sideroblastic anemia and ataxia

    Science.gov (United States)

    ... linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open All Close All ... the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare condition characterized by ...

  4. Diode laser for the treatment of telangiectasias following hemangioma involution.

    Science.gov (United States)

    Cerrati, Eric W; O, Teresa M; Chung, Hoyun; Waner, Milton

    2015-02-01

    Infantile hemangiomas are well known for their rapid growth during the first 6 to 9 months of life, followed by a spontaneous but slow involution. The standard of care is to treat these lesions at an early age with propranolol to expedite the involution process; however, surgery still remains an active component in the management. Medical treatment with propranolol or natural involution will often result in residual telangiectasias. We evaluated the efficacy of using a diode laser as a treatment for telangiectasias following cervicofacial infantile hemangioma involution. Case series with chart review. Tertiary care hospital and practice specializing in the care of vascular anomalies. Twenty patients, aged 4 months to 11 years (average 2.69 years), underwent treatment with a 532-nm diode laser to treat the residual telangiectasias following hemangioma involution. All procedures were performed in the operating room. To assess the efficacy, we independently evaluated pre- and posttreatment digital photographs and ranked them on a 0- to 4-point scale (0 = no change and 4 = complete response). Adverse reactions were also recorded. The telangiectasias showed considerable improvement following treatment. In more than half of the patients treated, the affected area demonstrated a complete response. No adverse reactions were noted. A 532-nm diode laser effectively treats the remaining telangiectasias following hemangioma involution. Whether used independently or in conjunction with other treatment modalities, the diode laser should be part of the surgical armamentarium when treating infantile hemangiomas. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.

  5. Progression of Dysphagia in Spinocerebellar Ataxia Type 6.

    Science.gov (United States)

    Isono, Chiharu; Hirano, Makito; Sakamoto, Hikaru; Ueno, Shuichi; Kusunoki, Susumu; Nakamura, Yusaku

    2017-06-01

    Spinocerebellar ataxia type 6 (SCA6), an autosomal dominant triplet repeat disease, predominantly affects the cerebellum with a late onset and generally good prognosis. Dysphagia is commonly associated with the outcomes of neurodegenerative diseases such as SCA6. Although the characteristics of dysphagia have been rarely reported in SCA6, our previous study indicated that dysphagia is generally milder in SCA6 than in SCA3, another inherited ataxia with multisystem involvement. However, abnormalities in the pharyngeal phase in SCA6 were indistinguishable from those in SCA3, with no explainable reason. To determine the reason, we repeatedly performed videofluoroscopic examinations (VF) in 14 patients with SCA6. The results showed that the gross progression of dysphagia was apparently slow, but four patients had progressive dysphagia at an early disease stage; dysphagia began within 10 years from the onset of ataxia and rapidly progressed. A common clinical feature of the four patients was a significantly older age at the onset of ataxia (74.0 vs. 60.3 years), associated with significantly shorter triplet repeats. This finding surprisingly indicated that patients who had shorter repeats and thereby later onset and potentially better prognoses were at risk for dysphagia-associated problems. Ischemic changes, homozygous mutation, and diabetes mellitus as well as aging might have contributed to the observed progressive dysphagia. We found that conventionally monitored somatosensory evoked potentials at least partly reflected progressive dysphagia. Despite the small study group, our findings suggest that clinicians should carefully monitor dysphagia in patients with SCA6 who are older at disease onset (>60 years).

  6. Ataxias agudas en la infancia

    Directory of Open Access Journals (Sweden)

    Yaline Betancourt Fursow

    2013-09-01

    Full Text Available La ataxia cerebelosa aguda infantil (ACAI es la forma más frecuente de complicación neurológica por el virus de la varicela.Descritas dentro del grupo de las cerebelitis agudas. Los objetivos de este estudio fueron: evaluar la presentación clínica, manejo y seguimiento de niños hospitalizados con ACAI en un hospital pediátrico terciario donde la inmunización para varicela no está disponible (parte I y describir los diagnósticos diferenciales de la cerebelitis aguda (parte II. Estudiamos 95 pacientes. Los criterios diagnósticos de ataxia aguda se basaron en: pérdida aguda de la coordinación o dificultad para la marcha con o sin nistagmo asociado y duración menor de 48 horas, en un niño previamente sano. Estos criterios se cumplían en todos los casos valorados, excepto en las ataxias secundarias a ingesta de tóxicos, en los que la duración debía ser menor de 24 horas para su inclusión en el estudio. Se registraron los datos en una historia clínica pediátrica y neurológica. Entre los pacientes inmunosuprimidos la incidencia mayor fue la complicación por varicela. La mayoría de los pacientes fueron varones. El rango de edad fue la preescolar, 5 años . El intervalo entre la presentación del rash y el ingreso fue de 1 a 3 días. El estudio de LCR se practicó en 59.5% de los casos. La TAC y la resonancia magnética cerebral (RM presentaron edema en el 33.3%. El aciclovir endovenoso fue utilizado en 23 pacientes; pero no hubo diferencias significativas en las manifestaciones clínicas y seguimiento entre tratados y no tratados. La ataxia fue la primera manifestación clínica. La estadía hospitalaria fue de 4 días (rango: 2-11 días.

  7. Hereditary haemorrhagic telangiectasia: a cause of preventable morbidity and mortality.

    LENUS (Irish Health Repository)

    Brady, A P

    2012-01-31

    Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition whose effects are mediated through deficient blood vessel formation and regeneration, with multisystem involvement. Patients are usually aware of resulting skin telangiectasia and epistaxis, but are also exposed to dangers posed by occult vascular malformations in other organs. About 15-35% of HHT patients have pulmonary AVMs (PAVMs), 10% have cerebral AVMs (CAVMs), 25-33% suffer significant GI blood loss from GI tract telangiectasia, and an unknown but high percentage have liver involvement. In total, 10% of affected individuals die prematurely or suffer major disability from HHT, largely because of bleeding from CAVMs and PAVMs, or paradoxical embolization through PAVMs. Screening for and early intervention to treat occult PAVMs and CAVMs can largely eliminate these risks, and should be undertaken in a specialist centre. The National HHT Center in The Mercy University Hospital in Cork is the referral centre for HHT screening in Ireland.

  8. [Hereditary hemorrhagic telangiectasia presenting with hematuria and severe anemia].

    Science.gov (United States)

    Paz, A; Goren, E; Segal, M

    1995-07-01

    A patient with hereditary hemorrhagic telangiectasia was admitted with hematuria and severe anemia after mild recurrent episodes of epistaxis. Telangiectasias were found in the skin and buccal and nasal mucosa. No defect in the coagulation mechanism was found; thrombocyte count and function were normal. On cystoscopy, tortuous engorged vessels, some actively bleeding, were seen in the trigonal mucosa. Biopsy showed enlarged vessels in the lamina propria. Electrocoagulation of the bleeding vessels stopped hematuria, but 6 months later it recurred. This time Nd-YAG laser was used to stop the bleeding after electrocoagulation was ineffective.

  9. Cerebellar ataxia of early onset

    International Nuclear Information System (INIS)

    Yamashita, Sumimasa; Miyake, Shota; Yamada, Michiko; Iwamoto, Hiroko; Yamada, Kazuhiko.

    1989-01-01

    Eight cases of childhood cerebellar ataxia were reported. All these cases showed chronic cerebellar ataxia with early onset, and the other diseases of cerebellum such as infections, neoplasms and storage diseases were excluded by clinical symptoms and laboratory findings including blood counts, blood chemistry, lactate, pyruvate, ceruloplasmine, urinalysis, serum immunoglobulins, amino acid analysis in blood and urine, CSF analysis, leukocyte lysosomal enzymes, MCV, EMG, EEG and brain X-CT. Two pairs of siblings were included in this study. The clinical diagnosis were cerebellar type (5), spinocerebellar type (1), one Marinesco-Sjoegren syndrome and undetermined type (1). The age of onset was 1 to 5 years. The chief complaint was motor developmental delay in 6 cases; among them 5 patients could walk alone at the ages of 2 to 3 years'. Mental retardation was observed in 7 cases and epilepsy in 2. TRH was effective in 5 cases. The MRI study revealed that the area of medial sagittal slice of the cerebellum was reduced significantly in all cases and also that of pons was reduced in 5 cases. Different from typical adult onset spinocerebellar degenerations, most of the present cases have achieved slow developmental milestones and the clinical course was not progressive. Genetic factors are suspected in the pathogenesis of this disease in some cases. (author)

  10. Two in one: report of a patient with spinocerebellar ataxia types 2 and 10.

    Science.gov (United States)

    Kapur, Sachin S; Goldman, Jennifer G

    2012-09-01

    To report a rare case of the coexistence of 2 spinocerebellar ataxia (SCA) mutations in a single patient. Case report. University hospital, Movement Disorders Center. A 54-year-old man of Mexican, American Indian, and French descent with an 11-year history of gait and limb ataxia. Findings of clinical examination, magnetic resonance imaging, and video electroencephalographic monitoring. Neurologic history revealed a gradually progressive gait and limb ataxia along with muscle cramps and sensory symptoms in his distal extremities; examination revealed executive dysfunction, dysarthria, ataxia, and sensory neuronopathy. Episodes of loss of awareness were reported, but electroencephalograms were negative. Brain imaging demonstrated severe cerebellar and brainstem atrophy. Genetic evaluation of the case revealed mutations in both the SCA2 and SCA10 genes. Our patient has a unique combination of genetic mutations for 2 different SCAs, types 2 and 10, which to our knowledge, has not been previously reported. His clinical phenotype is largely consistent with SCA2, but his possible seizures and Mexican heritage suggest influences of SCA10.

  11. Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage.

    Science.gov (United States)

    Quek, Hazel; Luff, John; Cheung, KaGeen; Kozlov, Sergei; Gatei, Magtouf; Lee, C Soon; Bellingham, Mark C; Noakes, Peter G; Lim, Yi Chieh; Barnett, Nigel L; Dingwall, Steven; Wolvetang, Ernst; Mashimo, Tomoji; Roberts, Tara L; Lavin, Martin F

    2017-04-01

    Mutations in the ataxia-telangiectasia (A-T)-mutated ( ATM ) gene give rise to the human genetic disorder A-T, characterized by immunodeficiency, cancer predisposition, and neurodegeneration. Whereas a series of animal models recapitulate much of the A-T phenotype, they fail to present with ataxia or neurodegeneration. We describe here the generation of an Atm missense mutant [amino acid change of leucine (L) to proline (P) at position 2262 (L2262P)] rat by intracytoplasmic injection (ICSI) of mutant sperm into oocytes. Atm -mutant rats ( Atm L2262P/L2262P ) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with Atm +/+ Whereas these rats did not show cerebellar atrophy, they succumbed to hind-limb paralysis (45%), and the remainder developed tumors. Closer examination revealed the presence of both dsDNA and ssDNA in the cytoplasm of cells in the hippocampus, cerebellum, and spinal cord of Atm L2262P/L2262P rats. Significantly increased levels of IFN-β and IL-1β in all 3 tissues were indicative of DNA damage induction of the type 1 IFN response. This was further supported by NF-κB activation, as evidenced by p65 phosphorylation (P65) and translocation to the nucleus in the spinal cord and parahippocampus. Other evidence of neuroinflammation in the brain and spinal cord was the loss of motor neurons and the presence of increased activation of microglia. These data provide support for a proinflammatory phenotype that is manifested in the Atm mutant rat as hind-limb paralysis. This mutant represents a useful model to investigate the importance of neuroinflammation in A-T. © Society for Leukocyte Biology.

  12. SNP Analysis and Whole Exome Sequencing: Their Application in the Analysis of a Consanguineous Pedigree Segregating Ataxia

    Directory of Open Access Journals (Sweden)

    Sarah L. Nickerson

    2015-10-01

    Full Text Available Autosomal recessive cerebellar ataxia encompasses a large and heterogeneous group of neurodegenerative disorders. We employed single nucleotide polymorphism (SNP analysis and whole exome sequencing to investigate a consanguineous Maori pedigree segregating ataxia. We identified a novel mutation in exon 10 of the SACS gene: c.7962T>G p.(Tyr2654*, establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS. Our findings expand both the genetic and phenotypic spectrum of this rare disorder, and highlight the value of high-density SNP analysis and whole exome sequencing as powerful and cost-effective tools in the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.

  13. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, A D; Kjeldsen, J

    2000-01-01

    Gastrointestinal bleeding occurs in a number of patients with hereditary hemorrhagic telangiectasia (HHT) and may lead to a high transfusion need. The aim of this study was to estimate the occurrence and severity of gastrointestinal bleeding in a geographically well defined HHT population....

  14. Molecular profiling of appendiceal epithelial tumors using massively parallel sequencing to identify somatic mutations.

    Science.gov (United States)

    Liu, Xiaoying; Mody, Kabir; de Abreu, Francine B; Pipas, J Marc; Peterson, Jason D; Gallagher, Torrey L; Suriawinata, Arief A; Ripple, Gregory H; Hourdequin, Kathryn C; Smith, Kerrington D; Barth, Richard J; Colacchio, Thomas A; Tsapakos, Michael J; Zaki, Bassem I; Gardner, Timothy B; Gordon, Stuart R; Amos, Christopher I; Wells, Wendy A; Tsongalis, Gregory J

    2014-07-01

    Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2. Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer. A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes. Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts

  15. Toxic agents causing cerebellar ataxias.

    Science.gov (United States)

    Manto, Mario

    2012-01-01

    The cerebellum is particularly vulnerable to intoxication and poisoning, especially so the cerebellar cortex and Purkinje neurons. In humans, the most common cause of a toxic lesion to the cerebellar circuitry is alcohol related, but the cerebellum is also a main target of drug exposure (such as anticonvulsants, antineoplastics, lithium salts, calcineurin inhibitors), drug abuse and addiction (such as cocaine, heroin, phencyclidine), and environmental toxins (such as mercury, lead, manganese, toluene/benzene derivatives). Although data for the prevalence and incidence of cerebellar lesions related to intoxication and poisoning are still unknown in many cases, clinicians should keep in mind the list of agents that may cause cerebellar deficits, since toxin-induced cerebellar ataxias are not rare in daily practice. Moreover, the patient's status may require immediate therapies when the intoxication is life-threatening. 2012 Elsevier B.V. All rights reserved.

  16. Aspectos moleculares das ataxias espinocerebelares autossomicas recessivas

    OpenAIRE

    Flavia Chagas Costa

    2000-01-01

    Resumo: As ataxias espinocerebelares (ABC) formam um grupo heterogêneo de doenças degenerativas que envolvem o sistema nervoso central. Esse grupo se caracteriza clinicamente por apresentar disfunção cerebelar manifestada por ataxia de marcha, incoordenação e disartria. Nos casos familiares, o padrão de herança é variável, podendo ser compatível com herança autossômica dominante (HAD) ou herança autossômica recessiva (HAR). Para as ataxias espinocerebelares com HAR existem três lócus identifi...

  17. Acute Cerebellar Ataxia Induced by Nivolumab

    Science.gov (United States)

    Kawamura, Reina; Nagata, Eiichiro; Mukai, Masako; Ohnuki, Yoichi; Matsuzaki, Tomohiko; Ohiwa, Kana; Nakagawa, Tomoki; Kohno, Mitsutomo; Masuda, Ryota; Iwazaki, Masayuki; Takizawa, Shunya

    2017-01-01

    A 54-year-old woman with adenocarcinoma of the lung and lymph node metastasis experienced nystagmus and cerebellar ataxia 2 weeks after initiating nivolumab therapy. An evaluation for several autoimmune-related antibodies and paraneoplastic syndrome yielded negative results. We eventually diagnosed the patient with nivolumab-induced acute cerebellar ataxia, after excluding other potential conditions. Her ataxic gait and nystagmus resolved shortly after intravenous steroid pulse therapy followed by the administration of decreasing doses of oral steroids. Nivolumab, an immune checkpoint inhibitor, is known to induce various neurological adverse events. However, this is the first report of acute cerebellar ataxia associated with nivolumab treatment. PMID:29249765

  18. Genetic testing for clinically suspected spinocerebellar ataxias ...

    Indian Academy of Sciences (India)

    Mahesh

    Research Article. Genetic ... Melbourne, Australia and Department of Animal Science, School of Life .... The patients were assessed according to the International Cooperative Ataxia Rating ..... The Indian Journal of Medical Research 126(5):.

  19. Acute Cerebellar Ataxia Induced by Nivolumab

    OpenAIRE

    Kawamura, Reina; Nagata, Eiichiro; Mukai, Masako; Ohnuki, Yoichi; Matsuzaki, Tomohiko; Ohiwa, Kana; Nakagawa, Tomoki; Kohno, Mitsutomo; Masuda, Ryota; Iwazaki, Masayuki; Takizawa, Shunya

    2017-01-01

    A 54-year-old woman with adenocarcinoma of the lung and lymph node metastasis experienced nystagmus and cerebellar ataxia 2 weeks after initiating nivolumab therapy. An evaluation for several autoimmune-related antibodies and paraneoplastic syndrome yielded negative results. We eventually diagnosed the patient with nivolumab-induced acute cerebellar ataxia, after excluding other potential conditions. Her ataxic gait and nystagmus resolved shortly after intravenous steroid pulse therapy follow...

  20. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.

    Science.gov (United States)

    Coutelier, Marie; Coarelli, Giulia; Monin, Marie-Lorraine; Konop, Juliette; Davoine, Claire-Sophie; Tesson, Christelle; Valter, Rémi; Anheim, Mathieu; Behin, Anthony; Castelnovo, Giovanni; Charles, Perrine; David, Albert; Ewenczyk, Claire; Fradin, Mélanie; Goizet, Cyril; Hannequin, Didier; Labauge, Pierre; Riant, Florence; Sarda, Pierre; Sznajer, Yves; Tison, François; Ullmann, Urielle; Van Maldergem, Lionel; Mochel, Fanny; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra

    2017-06-01

    Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar

  1. Small-molecule inhibitors of Ataxia Telangiectasia and Rad3 related kinase (ATR) sensitize lymphoma cells to UVA radiation

    DEFF Research Database (Denmark)

    Biskup, Edyta; Naym, David Gram; Gniadecki, Robert

    2016-01-01

    inhibited by small molecule antagonists VE-821, VE-822 or Chir-124, or by small interfering RNAs (siRNAs). Cell cycle and viability were assessed by flow cytometry. RESULTS: Small molecule inhibitors of ATR and Chk1 potently sensitized all cell lines to PUVA and, importantly, also to UVA, which by itself...... did not cause apoptotic response. VE-821/2 blocked ATR pathway activation and released the cells from the G2/M block caused by UVA and PUVA, but did not affect apoptosis caused by other chemotherapeutics (etoposide, gemcitabine, doxorubicine) or by hydrogen peroxide. Knockdown of ATR and Chk1 with si......RNA also blocked the ATR pathway and released the cells from G2/M block but did not sensitize the cells to UVA as observed with the small molecule inhibitors. The latter suggested that the synergism between VE-821/2 or Chir-124 and UVA was not solely caused by specific blocking of ATR kinase but also ATR...

  2. Endoplasmic reticulum quality control is involved in the mechanism of endoglin-mediated hereditary haemorrhagic telangiectasia.

    Directory of Open Access Journals (Sweden)

    Bassam R Ali

    Full Text Available Hereditary haemorrhagic telangiectasia (HHT is an autosomal dominant genetic condition affecting the vascular system and is characterised by epistaxis, arteriovenous malformations and mucocutaneous and gastrointestinal telangiectases. This disorder affects approximately 1 in 8,000 people worldwide. Significant morbidity is associated with this condition in affected individuals, and anaemia can be a consequence of repeated haemorrhages from telangiectasia in the gut and nose. In the majority of the cases reported, the condition is caused by mutations in either ACVRL1 or endoglin genes, which encode components of the TGF-beta signalling pathway. Numerous missense mutations in endoglin have been reported as causative defects for HHT but the exact underlying cellular mechanisms caused by these mutations have not been fully established despite data supporting a role for the endoplasmic reticulum (ER quality control machinery. For this reason, we examined the subcellular trafficking of twenty-five endoglin disease-causing missense mutations. The mutant proteins were expressed in HeLa and HEK293 cell lines, and their subcellular localizations were established by confocal fluorescence microscopy alongside the analysis of their N-glycosylation profiles. ER quality control was found to be responsible in eight (L32R, V49F, C53R, V125D, A160D, P165L, I271N and A308D out of eleven mutants located on the orphan extracellular domain in addition to two (C363Y and C382W out of thirteen mutants in the Zona Pellucida (ZP domain. In addition, a single intracellular domain missense mutant was examined and found to traffic predominantly to the plasma membrane. These findings support the notion of the involvement of the ER's quality control in the mechanism of a significant number, but not all, missense endoglin mutants found in HHT type 1 patients. Other mechanisms including loss of interactions with signalling partners as well as adverse effects on functional

  3. [Hereditary haemorrhagic telangiectasia diagnosed in connection with a traffic accident].

    Science.gov (United States)

    Sivapalan, Pradeesh; Demény, Ann Kathrin; Almind, Merete; Kjeldsen, Anette Drøhse

    2014-02-17

    Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by vascular dysplasia and haemorrhage. It is manifested by mucocutaneous telangiec-tases and arteriovenous malformations in organs such as lungs, liver and brain. We present a case of HHT. A 16-year-old patient with a history of recurrent epistaxis was admitted to the local hospital with chest pain and desaturation. A CT scan revealed pulmonary arteriovenous malformations.

  4. Current concepts in the treatment of hereditary ataxias

    Directory of Open Access Journals (Sweden)

    Pedro Braga Neto

    2016-03-01

    Full Text Available ABSTRACT Hereditary ataxias (HA represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.

  5. Clinical features of Friedreich's ataxia: classical and atypical phenotypes.

    Science.gov (United States)

    Parkinson, Michael H; Boesch, Sylvia; Nachbauer, Wolfgang; Mariotti, Caterina; Giunti, Paola

    2013-08-01

    One hundred and fifty years since Nikolaus Friedreich's first description of the degenerative ataxic syndrome which bears his name, his description remains at the core of the classical clinical phenotype of gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia, eye movement abnormalities, scoliosis, foot deformities, cardiomyopathy and diabetes. Onset is typically around puberty with slow progression and shortened life-span often related to cardiac complications. Inheritance is autosomal recessive with the vast majority of cases showing an unstable intronic GAA expansion in both alleles of the frataxin gene on chromosome 9q13. A small number of cases are caused by a compound heterozygous expansion with a point mutation or deletion. Understanding of the underlying molecular biology has enabled identification of atypical phenotypes with late onset, or atypical features such as retained reflexes. Late-onset cases tend to have slower progression and are associated with smaller GAA expansions. Early-onset cases tend to have more rapid progression and a higher frequency of non-neurological features such as diabetes, cardiomyopathy, scoliosis and pes cavus. Compound heterozygotes, including those with large deletions, often have atypical features. In this paper, we review the classical and atypical clinical phenotypes of Friedreich's ataxia. © 2013 International Society for Neurochemistry.

  6. Generation of spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cell line SCA3.A11

    DEFF Research Database (Denmark)

    Hansen, Susanne Kofoed; Borland, Helena; Hasholt, Lis Frydenreich

    2016-01-01

    Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a CAG-repeat expanding mutation in ATXN3. We generated induced pluripotent stem cells (iPSCs) from a SCA3 patient by electroporation of dermal fibroblasts with episomal plasmids encoding L-MYC, LIN28...

  7. Genetics Home Reference: neuropathy, ataxia, and retinitis pigmentosa

    Science.gov (United States)

    ... Twitter Home Health Conditions NARP Neuropathy, ataxia, and retinitis pigmentosa Printable PDF Open All Close All Enable Javascript ... the expand/collapse boxes. Description Neuropathy, ataxia, and retinitis pigmentosa ( NARP ) is a condition that causes a variety ...

  8. Friedreich's ataxia cardiomyopathy: case based discussion and management issues.

    LENUS (Irish Health Repository)

    Hanley, A

    2010-04-01

    Cardiac involvement is common in Friedreich\\'s Ataxia and is a common cause of premature death. Evidence regarding treatment of congestive heart failure in patients with Friedreich\\'s Ataxia is lacking. The case of a 31-year-old male with advanced Friedreich\\'s Ataxia who presented with an acute diarrhoeal illness and features of acute heart failure is discussed. We then review the reported cardiac manifestations of Friedreich\\'s Ataxia and discuss management options.

  9. Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics

    Directory of Open Access Journals (Sweden)

    Fujioka Shinsuke

    2011-05-01

    Full Text Available Abstract Type I autosomal dominant cerebellar ataxia (ADCA is a type of spinocerebellar ataxia (SCA characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA. Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical

  10. Clinical neurogenetics: autosomal dominant spinocerebellar ataxia.

    Science.gov (United States)

    Shakkottai, Vikram G; Fogel, Brent L

    2013-11-01

    The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Juvenil polypose-syndrom og hereditær hæmoragisk telangiektasi hos en patient med SMAD4-mutation

    DEFF Research Database (Denmark)

    Jelsig, Anne Marie; Tørring, Pernille Mathiesen; Wikman, Friedrik

    2014-01-01

    Germ line mutations in SMAD4 can cause both juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia syndrome. In this case we present a 37-year-old man with a frameshift mutation in SMAD4. The patient had multiple polyps in the gastrointestinal tract and was diagnosed with colon ca...... cancer at the age of 21 and gastro-oesophageal junction cancer at the age of 37. Furthermore the patient had telangiectasias and recurrent epistaxis....

  12. Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

    Directory of Open Access Journals (Sweden)

    Yubin Wang

    2016-06-01

    Full Text Available A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1, which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.

  13. Diversity of ARSACS mutations in French-Canadians.

    Science.gov (United States)

    Thiffault, I; Dicaire, M J; Tetreault, M; Huang, K N; Demers-Lamarche, J; Bernard, G; Duquette, A; Larivière, R; Gehring, K; Montpetit, A; McPherson, P S; Richter, A; Montermini, L; Mercier, J; Mitchell, G A; Dupré, N; Prévost, C; Bouchard, J P; Mathieu, J; Brais, B

    2013-01-01

    The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

  14. Treatment of Hereditary Hemorrhagic Telangiectasia-Related Epistaxis.

    Science.gov (United States)

    Sautter, Nathan B; Smith, Timothy L

    2016-06-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an incidence of 1:5000. Recurrent, spontaneous epistaxis is the most common presenting symptom. Severity of epistaxis varies widely, from mild, self-limited nosebleeds to severe, life-threatening nasal hemorrhage. Treatment of HHT-related epistaxis presents a challenge to the otolaryngologist due to the recurrent, persistent nature of epistaxis often requiring multiple treatments. Treatment modalities range from conservative topical therapies to more aggressive surgical treatments. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Efficiency of laser treatment in patients with hereditary hemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Jørgensen, Gita; Lange, Bibi; Wanscher, Jens Højberg

    2011-01-01

    Earlier studies have shown the effect of laser treatment on epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT). At the present time, only very few prospective trials have been performed, and many studies are based on patients' subjective assessment of the severity of epistaxis....... This prospective study measures the objective effect of laser treatment in HHT patients with mild to moderate epistaxis. We introduce an objective measure to assess the severity of epistaxis: the bleeding time (BT). Before and after treatment, the quality of life, as measured by the patient, was assessed...

  16. Hepatic telangiectasia in Osler's disease treated with arterial embolization

    Energy Technology Data Exchange (ETDEWEB)

    Goethlin, J H; Nordgard, K; Jonsson, K; Nyman, U

    1982-02-01

    Hepatic hereditary telangiectasia in 2 females was treated with hepatic artery embolization. In one patient both peripheral and central arterial occlusion was performed; the patient died of massive gastro-intestinal bleeding 2 months later. Autopsy showed extensive regions with necrosis in the right liver lobe. In the next patient only central occlusion of the right hepatic artery was performed and the arterio-venous shunting in the left liver lobe left remaining. After a long reconvalescence period the patient recovered completely. It is advocated to centrally occlude only that hepatic artery supplying the most affected parts of the liver in Osler's disease. Thus extensive necrosis with possible ensuing death may be avoided.

  17. Hyper-radiation sensitivity of murine scid mutation and mapping of the human homologue HYRC1 gene

    International Nuclear Information System (INIS)

    Komatsu, Kenshi; Ohta, Tohru; Niikawa, Norio; Okumura, Yutaka; Kubota, Nobuo.

    1994-01-01

    The murine severe combined immunodeficient mutation (scid) is characterized by a lack of both B and T cells, due to a defect in lymphoid variable-(diversity)-joining(V(D)J) rearrangement. Scid cells are highly sensitive to both radiation-induced killing and chromosomal aberrations. Present experiments also demonstrated the high sensitivity of scid cells to killing, because of a deficient repair of double strand breaks(DSB). Scid cells can repair only 60% of radiation-induced DSB for 3 hours, while normal cells repair 85% of the DSB. Significantly reduced Do and n values were obtained from survival curves of scid cells and were similar to ataxia-telangiectasia(AT) cells (a unique human disease conferring whole body radiosensitivity). However, the kinetics of DNA synthesis after irradiation were different between the two cell types. In contrast with the radioresistant DNA synthesis of AT cells, DNA synthesis of scid cells was markedly inhibited after irradiation. The existence of different mutations was also supported by evidence of complementation in somatic cell hybrids between scid cells and AT cells. Using these hybrid cells, fragments of human chromosome 8 were introduced into scid cells HPRT mutant via X-irradiation and somatic cell fusion. The resulting hybrid clones contained human DNA fragment(s) which complemented the hyper-radiosensitivity of the scid cells. Alu-PCR products from these hybrids were used for chromosome painting using the technique of chromosome in situ suppression hybridization, allowing assignment of the human HYRC1 (hyper-radiosensitivity of murine scid mutation, complementing 1) gene, a candidate for a V(D)J recombinant gene, to human chromosome 8q11. (author)

  18. Influence of inhibitors of poly(ADP-ribose) polymerase on DNA repair, chromosomal alterations, and mutations

    Energy Technology Data Exchange (ETDEWEB)

    Natarajan, A.T.; van Zeeland, A.A.; Zwanenburg, T.S.

    1983-01-01

    The influence of inhibitors of poly(ADP-ribose) polymerase such as 3-aminobenzamide (3AB) and benzamide (B) on the spontaneously occurring as well as mutagen induced chromosomal aberrations, sister chromatid exchanges (SCEs) and point mutations has been studied. In addition, the influence of 3AB on DNA repair was measured following treatment with physical and chemical mutagens. Post treatment of X-irradiated mammalian cells with 3AB increases the frequencies of induced chromosomal aberrations by a factor of 2 to 3. 3AB, when present in the medium containing bromodeoxyuridine(BrdUrd) during two cell cycles, increases the frequencies of SCEs in Chinese hamster ovary cells (CHO) in a concentration dependent manner leading to about a 10-fold increase at 10 mM concentration. The extent of increase in the frequencies of SCEs due to 1 mM 3AB in several human cell lines has been studied, including those derived from patients suffering from genetic diseases such as ataxia telangiectasia (A-T), Fanconi's anemia (FA), and Huntington's chorea. None of these syndromes showed any increased response when compared to normal cells. 3AB, however, increased the frequencies of spontaneously occurring chromosomal aberrations in A-T and FA cells. 3AB does not influence the frequencies of SCEs induced by UV or mitomycin C (MMC) in CHO cells. However, it increases the frequencies of SCEs induced by ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS). Under the conditions in which 3AB increases the frequencies of spontaneously occurring as well as induced SCEs, it does not increase the frequencies of point mutations in hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus. 3AB does not influence the amount of repair replication following dimethylsulphate (DMS) treatment of human fibroblasts, or UV irradiated human lymphocytes.

  19. Spinocerebellar ataxias in Venezuela: genetic epidemiology and their most likely ethnic descent.

    Science.gov (United States)

    Paradisi, Irene; Ikonomu, Vassiliki; Arias, Sergio

    2016-03-01

    Dominantly inherited ataxias (spinocerebellar ataxias, SCAs) are a genetically heterogeneous group of neurologic diseases characterized by progressive cerebellar and spinal tract degeneration with ataxia and other signs, common to all known subtypes. Several types are relatively frequent worldwide, but in several countries, one specific SCA may show a higher prevalence owing to founder phenomena. In Venezuela, genetic epidemiological features of SCAs have been assessed during the last 30 years; mutations in ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), ATXN8 (SCA8), ATXN10 (SCA10), TBP (SCA17) and ATN1 (dentatorubral pallidoluysian atrophy, DRPLA) loci were searched among 115 independent families. SCA7 was the most frequent subtype (26.6%), followed by SCA3 (25.0%), SCA2 (21.9%), SCA1 (17.2%), SCA10 (4.7%) and DRPLA (3.1%); in 43% of the families, the subtype remained unidentified. SCA7 mutations displayed strong geographic aggregation in two independent founder foci, and SCA1 showed a very remote founder effect for a subset of families. SCA10 families were scattered across the country, but all had an identical in-phase haplotype carried also by Mexican, Brazilian and Sioux patients, supporting a very old common Amerindian origin. Prevalence for dominant SCAs in Venezuela was estimated as 1:25 000 nuclear families, provenances of which are either Caucasoid, African or Amerindian.

  20. Xeroderma pigmentosum complementation group F: A rare cause of cerebellar ataxia with chorea.

    Science.gov (United States)

    Carré, G; Marelli, C; Anheim, M; Geny, C; Renaud, M; Rezvani, H R; Koenig, M; Guissart, C; Tranchant, C

    2017-05-15

    The complementation group F of Xeroderma pigmentosum (XP-F) is rare in the Caucasian population, and usually devoid of neurological symptoms. We report two cases, both Caucasian, who exhibited progressive cerebellar ataxia, chorea, a mild subcortical frontal cognitive impairment, and in one case severe polyneuropathy. Brain MRI demonstrated cerebellar (2/2) and cortical (1/2) atrophy. Both patients had only mild sunburn sensitivity and no skin cancer. Mini-exome sequencing approach revealed in ERCC4, two heterozygous mutations, one of which was never described (c.580-584+1delCCAAGG, exon 3), in the first case, and an already reported homozygous mutation, in the second case. These cases emphasize that XP-F is a rare cause of recessive cerebellar ataxia and can in some cases clinically mimic Huntington's disease due to chorea and executive impairment. The association of ataxia, chorea, and sun hypersensitivity are major guidance for the diagnosis, which should not be missed, in order to prevent skin neoplastic complications. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Familial cosegregation of manic-depressive illness and a form of hereditary cerebellar ataxia

    Energy Technology Data Exchange (ETDEWEB)

    Piqueras, J.F.; Santos, J.; Puertollano, R. [Universidad Autonoma, Madrid (Spain)] [and others

    1995-06-19

    We report on a Spanish family with co-occurrence of manic-depression and a form of hereditary cerebellar ataxia. All affected individuals in the second generation showed cerebellar ataxia and manic-depression simultaneously. Since anticipation has been described in both disorders and the pattern of segregation may be autosomal as well as X-linked, we have searched for a possible involvement of two candidate genes which are located either on an autosome (SCA1) or on the X-chromosome (GABRA3). We concluded that expansion of trinucleotide repeats at SCA1 gene cannot be considered as a disease-causing mutation, and this gene should be initially discarded. 19 refs., 3 figs.

  2. Activation of ATM by DNA Damaging Agents

    National Research Council Canada - National Science Library

    Kurz, Ebba U; Lees-Miller, Susan P

    2004-01-01

    Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase that acts as a master switch controlling the cell cycle in response to ionizing radiation-induced DNA double-strand breaks (DSBs...

  3. Activation of ATM by DNA Damaging Agents

    National Research Council Canada - National Science Library

    Kurz, Ebba U; Lees-Miller, Susan P

    2005-01-01

    Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase that acts as a master switch controlling the cell cycle in response to ionizing radiation-induced DNA double-strand breaks (DSBs...

  4. Further Delineation of the Clinical Phenotype of Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome Type 4

    Directory of Open Access Journals (Sweden)

    Saud Alsahli

    2018-02-01

    Full Text Available Background: Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ is a heterogeneous group of genetic disorders that have been grouped by shared clinical features; all of these features are transmitted via an autosomal recessive mechanism. Four variants of this syndrome have been identified so far, and each one differs in terms of both clinical and genotypical features. CAMRQ4 is a rare genetic disorder characterized by mental retardation, ataxia or an inability to walk, dysarthria and, in some patients, quadrupedal gait. Methods: We investigated three Saudi families with CAMRQ4. Blood samples were collected from the affected patients, their parents, and healthy siblings. DNA was extracted from whole blood, and whole-exome sequencing was performed. Findings were confirmed by segregation analysis, which was performed on other family members. Results: Thus far, 17 patients have been affected by CAMRQ4. Genetic analysis of all patients, including our current patients, showed a mutation in the aminophospholipid transporter, class I, type 8A, member 2 gene ( ATP8A2 . A series of common phenotypical features have been reported in these patients, with few exceptions. Ataxia, mental retardation, and hypotonia were present in all patients, consanguinity in 90% and abnormal movements in 50%. Moreover, 40% achieved ambulation at least once in their lifetime, 40% had microcephaly, whereas 30% were mute. Magnetic resonance imaging (MRI of the brain was normal in 60% of patients. Conclusions: We described the largest cohort of patients with CAMRQ4 syndrome and identified three novel mutations. CAMRQ4 syndrome should be suspected in patients presenting with ataxia, intellectual disability, hypotonia, microcephaly, choreoathetoid movements, ophthalmoplegia, and global developmental delay, even if brain MRI appears normal.

  5. Further Delineation of the Clinical Phenotype of Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome Type 4.

    Science.gov (United States)

    Alsahli, Saud; Alrifai, Muhammad Talal; Al Tala, Saeed; Mutairi, Fuad Al; Alfadhel, Majid

    2018-01-01

    Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a heterogeneous group of genetic disorders that have been grouped by shared clinical features; all of these features are transmitted via an autosomal recessive mechanism. Four variants of this syndrome have been identified so far, and each one differs in terms of both clinical and genotypical features. CAMRQ4 is a rare genetic disorder characterized by mental retardation, ataxia or an inability to walk, dysarthria and, in some patients, quadrupedal gait. We investigated three Saudi families with CAMRQ4. Blood samples were collected from the affected patients, their parents, and healthy siblings. DNA was extracted from whole blood, and whole-exome sequencing was performed. Findings were confirmed by segregation analysis, which was performed on other family members. Thus far, 17 patients have been affected by CAMRQ4. Genetic analysis of all patients, including our current patients, showed a mutation in the aminophospholipid transporter, class I, type 8A, member 2 gene ( ATP8A2 ). A series of common phenotypical features have been reported in these patients, with few exceptions. Ataxia, mental retardation, and hypotonia were present in all patients, consanguinity in 90% and abnormal movements in 50%. Moreover, 40% achieved ambulation at least once in their lifetime, 40% had microcephaly, whereas 30% were mute. Magnetic resonance imaging (MRI) of the brain was normal in 60% of patients. We described the largest cohort of patients with CAMRQ4 syndrome and identified three novel mutations. CAMRQ4 syndrome should be suspected in patients presenting with ataxia, intellectual disability, hypotonia, microcephaly, choreoathetoid movements, ophthalmoplegia, and global developmental delay, even if brain MRI appears normal.

  6. Living with hereditary haemorrhagic telangiectasia: coping and psychological distress - a cross-sectional study.

    Science.gov (United States)

    Geirdal, Amy Østertun; Dheyauldeen, Sinan; Bachmann-Harildstad, Gregor; Heimdal, Ketil

    2013-02-01

    The purpose of this study was to examine the relationship between coping strategies measured by Coping Orientation to Problems Experienced Scale (COPE) and psychological distress measured by Hospital Anxiety and Depression Scale (HADS) and Becks Hopelessness Scale (BHS) in individuals living with Hereditary hemorrhagic telangiectasia (HHT) and to examine if coping strategies might have a mediating role between experienced illness and psychological distress. HHT is mainly caused by mutations in the ENG- or ALK1-genes and associated with a shorter life span. 90% of patients have recurrent nosebleeds. 66 individuals affected of HHT participated in this cross-sectional study, completing questions due to demographic variables, Experience of illness, COPE, BHS and HADS. X(2) test, bivariate correlations with Pearson r and hierarchical multiple regression were used using PASW 18. Experience of illness made the highest variance in anxiety, depression and hopelessness and the coping strategy "behavioral disengagement" seems to have a mediating role between nose bleedings, being afraid of complications, satisfied with life and psychological distress. Experience of illness is of big importance in psychological distress in individuals affected of HHT, and behavioral disengagement explained the actual relationship between experience of illness and psychological distress.

  7. PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia.

    Science.gov (United States)

    Ola, Roxana; Dubrac, Alexandre; Han, Jinah; Zhang, Feng; Fang, Jennifer S; Larrivée, Bruno; Lee, Monica; Urarte, Ana A; Kraehling, Jan R; Genet, Gael; Hirschi, Karen K; Sessa, William C; Canals, Francesc V; Graupera, Mariona; Yan, Minhong; Young, Lawrence H; Oh, Paul S; Eichmann, Anne

    2016-11-29

    Activin receptor-like kinase 1 (ALK1) is an endothelial serine-threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.

  8. Investigation of Exon 1 in FXN Gene in Patients with Clinical Symptomatic of Friedreich Ataxia

    Directory of Open Access Journals (Sweden)

    Naseroleslami M

    2013-01-01

    Full Text Available Background and Objectives: Friedreich’s ataxia (FRDA is an autosomal recessive disorder that is typically associated with dysarthria, muscle weakness, spasticity in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense. Approximately two-thirds of these patients suffer from cardiomyopathy and more than 30% have diabetes mellitus. Individuals with FRDA have identifiable mutations in the FXN gene. The most common type of mutation which is observed on both alleles in more than 98% of patients is an expansion of a GAA triplet-repeat in intron of FXN gene. Approximately 2% of individuals with FRDA are compound heterozygotes, who have a GAA expansion in the disease-causing range in one FXN allele and an inactivating FXN mutation in another allele. Aim of the present study was to investigate exon 1 in FRDA gene in patients with clinical symptoms of Friedreich’s Ataxia that have not GAA triplet-repeat expansion in intron 1 of FXN gene.Methods: In this study, exon 1 in 5 patients suspected of FRDA analyzed using PCR and sequencing. Results: An A to G transition at nucleotide number 815284, in exon 1 was observed in all patients. Conclusion: The results of this study showed that disease-causing homozygous mutations could be because of consanguinity marriage in Iran. Therefore, sequencing of all exons of the gene is necessary.

  9. Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2

    Directory of Open Access Journals (Sweden)

    Jijun eWan

    2011-09-01

    Full Text Available Episodic ataxia (EA syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. Episodic ataxia type 2 (EA2, the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4-40kb in EA2. In 47 subjects with EA (26 with EA2-like features who tested negative for mutations in the known EA genes, we used Multiplex Ligation-dependent Probe Amplification (MLPA to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.

  10. Fragile X syndrome and fragile X-associated tremor ataxia syndrome.

    Science.gov (United States)

    Hall, Deborah A; Berry-Kravis, Elizabeth

    2018-01-01

    Fragile X-associated disorders encompass several conditions, which are caused by expansion mutations in the fragile X mental retardation 1 (FMR1) gene. Fragile X syndrome is the most common inherited etiology of intellectual disability and results from a full mutation or >200 CGG repeats in FMR1. It is associated with developmental delay, autism spectrum disorder, and seizures. Fragile X-associated tremor/ataxia syndrome is a progressive neurodegenerative disease that occurs in premutation carriers of 55-200 CGG repeats in FMR1 and is characterized by kinetic tremor, gait ataxia, parkinsonism, executive dysfunction, and neuropathy. Fragile X-associated primary ovarian insufficiency also occurs in premutation carrier women and manifests with infertility and early menopause. The diseases constituting fragile X-associated disorders differ mechanistically, due to the distinct molecular properties of premutation versus full mutations. Fragile X syndrome occurs when there is a lack of fragile X mental retardation protein (FMRP) due to FMR1 methylation and silencing. In fragile X-associated tremor ataxia syndrome, a toxic gain of function is postulated with the production of excess CGG repeat-containing FMR1 mRNA, abnormal translation of the repeat sequence leading to production of polyglycine, polyalanine, and other polypeptides and to outright deficits in translation leading to reduced FMRP at larger premutation sizes. The changes in underlying brain chemistry due to FMR1 mutations have led to therapeutic studies in these disorders, with some progress being made in fragile X syndrome. This paper also summarizes indications for testing, genetic counseling issues, and what the future holds for these disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. From mild ataxia to huntington disease phenocopy: the multiple faces of spinocerebellar ataxia 17.

    Science.gov (United States)

    Koutsis, Georgios; Panas, Marios; Paraskevas, George P; Bougea, Anastasia M; Kladi, Athina; Karadima, Georgia; Kapaki, Elisabeth

    2014-01-01

    Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family.

  12. From Mild Ataxia to Huntington Disease Phenocopy: The Multiple Faces of Spinocerebellar Ataxia 17

    Directory of Open Access Journals (Sweden)

    Georgios Koutsis

    2014-01-01

    Full Text Available Introduction. Spinocerebellar ataxia 17 (SCA 17 is a rare autosomal dominant cerebellar ataxia (ADCA caused by a CAG/CAA expansion in the TBP gene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed. Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms. Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family.

  13. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)

    DEFF Research Database (Denmark)

    Shovlin, C L; Guttmacher, A E; Buscarini, E

    2000-01-01

    Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous ma...... in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years....... of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot...

  14. Treatment for ataxia in multiple sclerosis.

    Science.gov (United States)

    Mills, R J; Yap, L; Young, C A

    2007-01-24

    Disabling tremor or ataxia is common in multiple sclerosis (MS) and up to 80% of patients experience tremor or ataxia at some point during their disease. A variety of treatments are available, ranging from pharmacotherapy or stereotactic neurosurgery to neurorehabilitation. To assess the efficacy and tolerability of both pharmacological and non-pharmacologic treatments of ataxia in patients with MS. The following electronic resources were searched: Cochrane MS Group trials register (June 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2006), National Health Service National Research Register (NRR) including the Medical Research Council Clinical Trials Directory (Issue 2, 2006), MEDLINE (January 1996 to June 2006), and EMBASE (Jan 1988 to June 2006). Manual searches of bibliographies of relevant articles, pertinent medical and neurology journals and abstract books of major neurology and MS conferences (2001-2006) were also performed. Direct communication with experts and drug companies was sought. Blinded, randomised trials which were either placebo-controlled or which compared two or more treatments were included. Trials testing pharmacological agents must have had both participant and assessor blinding. Trials testing surgical interventions or effects of physiotherapy, where participants could not have been blinded to the treatment, must have had independent assessors who were blinded to the treatment. Cross-over trials were included. Three independent reviewers extracted data and the findings of the trials were summarised. A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed. Ten randomised controlled trials met the inclusion criteria. Six placebo-controlled studies (pharmacotherapy) and four comparative studies (one stereotactic neurosurgery and three neurorehabilitation) were reviewed. No standardised outcome measures were used across the studies. In

  15. Video game-based coordinative training improves ataxia in children with degenerative ataxia.

    Science.gov (United States)

    Ilg, Winfried; Schatton, Cornelia; Schicks, Julia; Giese, Martin A; Schöls, Ludger; Synofzik, Matthis

    2012-11-13

    Degenerative ataxias in children present a rare condition where effective treatments are lacking. Intensive coordinative training based on physiotherapeutic exercises improves degenerative ataxia in adults, but such exercises have drawbacks for children, often including a lack of motivation for high-frequent physiotherapy. Recently developed whole-body controlled video game technology might present a novel treatment strategy for highly interactive and motivational coordinative training for children with degenerative ataxias. We examined the effectiveness of an 8-week coordinative training for 10 children with progressive spinocerebellar ataxia. Training was based on 3 Microsoft Xbox Kinect video games particularly suitable to exercise whole-body coordination and dynamic balance. Training was started with a laboratory-based 2-week training phase and followed by 6 weeks training in children's home environment. Rater-blinded assessments were performed 2 weeks before laboratory-based training, immediately prior to and after the laboratory-based training period, as well as after home training. These assessments allowed for an intraindividual control design, where performance changes with and without training were compared. Ataxia symptoms were significantly reduced (decrease in Scale for the Assessment and Rating of Ataxia score, p = 0.0078) and balance capacities improved (dynamic gait index, p = 0.04) after intervention. Quantitative movement analysis revealed improvements in gait (lateral sway: p = 0.01; step length variability: p = 0.01) and in goal-directed leg placement (p = 0.03). Despite progressive cerebellar degeneration, children are able to improve motor performance by intensive coordination training. Directed training of whole-body controlled video games might present a highly motivational, cost-efficient, and home-based rehabilitation strategy to train dynamic balance and interaction with dynamic environments in a large variety of young-onset neurologic

  16. Terapia alternativa para microvarizes e telangiectasias com uso de agulha Alternative therapy for microvarices and telangiectasias with use of needle

    Directory of Open Access Journals (Sweden)

    Raimundo Rosendo de Oliveira

    2007-03-01

    Full Text Available CONTEXTO: O desenvolvimento de terapia alternativa à convencional para a destruição de microvarizes e telangiectasias sem o uso de produtos químicos tem como objetivo reduzir os efeitos colaterais, faz uso de agulha para lise mecânica dos vasos e tem como modelo experimental galinhas da linhagem Lohmann Brown. OBJETIVO: Elaborar uma nova técnica, desenvolvendo um tratamento alternativo, sem uso de produtos químicos, objetivando a redução dos efeitos colaterais. MÉTODOS: Foram utilizadas 30 galinhas da linhagem Lohmann Brown, sendo que 15 foram submetidas ao método convencional de tratamento de microvarizes e telangiectasias (grupo-controle e as outras 15 receberam o tratamento experimental proposto (grupo experimental. O grupo experimental foi tratado com agulha de lise vascular, percorrendo todo o trajeto dos vasos escolhidos em punções escalonadas até que todo o vaso ser atingido. O grupo-controle foi tratado com oleato de monoetanolamina e glicose a 50%, puncionando-se o vaso com agulha 13 x 3 mm e injetando-se, em média, 0,3 mL da solução em cada vaso. RESULTADOS: Dos 50 vasos tratados no grupo experimental, dois apresentaram recidiva total, cinco apresentaram recidiva parcial, e 43 apresentaram destruição (lise satisfatória; enquanto que, no grupo-controle, dos 51 vasos tratados, quatro apresentaram recidiva total, 12, recidiva parcial, 22, destruição satisfatória, e em 13 ocorreu endurecimento de trajeto. CONCLUSÃO: O presente estudo demonstrou que o método experimental proposto, com uso de agulha de lise vascular, possui mais eficiência no tratamento de microvarizes se comparado com o método convencional, devido à redução das recidivas e à ausência de hipercromia de trajeto endurecido.BACKGROUND: The development of an alternative to the conventional therapy for microvarices and telangiectasias without using chemical products aims at reducing side effects, using a needle for mechanical lysis of vessels. It

  17. Cerebellar ataxia by enhanced Cav2.1 currents is alleviated by Ca2+-dependent K-channel activators in Cacna1aS218l mutant mice

    NARCIS (Netherlands)

    Z. Gao (Zhenyu); B. Todorov (Boyan); C.F. Barrett (Curtis); S. van Dorp (Stijn); M.D. Ferrari (Michel); M. Dichgans (Martin); C.I. de Zeeuw (Chris); F.E. Hoebeek (Freek)

    2012-01-01

    textabstractMutations in the CACNA1A gene are associated with neurological disorders, such as ataxia, hemiplegic migraine, and epilepsy. These mutations affect the pore-forming α1A-subunit of CaV2.1 channels and thereby either decrease or increase neuronal Ca2+ influx. A decreased CaV2.1-mediated

  18. Exome Sequencing and Linkage Analysis Identified Novel Candidate Genes in Recessive Intellectual Disability Associated with Ataxia.

    Science.gov (United States)

    Jazayeri, Roshanak; Hu, Hao; Fattahi, Zohreh; Musante, Luciana; Abedini, Seyedeh Sedigheh; Hosseini, Masoumeh; Wienker, Thomas F; Ropers, Hans Hilger; Najmabadi, Hossein; Kahrizi, Kimia

    2015-10-01

    Intellectual disability (ID) is a neuro-developmental disorder which causes considerable socio-economic problems. Some ID individuals are also affected by ataxia, and the condition includes different mutations affecting several genes. We used whole exome sequencing (WES) in combination with homozygosity mapping (HM) to identify the genetic defects in five consanguineous families among our cohort study, with two affected children with ID and ataxia as major clinical symptoms. We identified three novel candidate genes, RIPPLY1, MRPL10, SNX14, and a new mutation in known gene SURF1. All are autosomal genes, except RIPPLY1, which is located on the X chromosome. Two are housekeeping genes, implicated in transcription and translation regulation and intracellular trafficking, and two encode mitochondrial proteins. The pathogenesis of these variants was evaluated by mutation classification, bioinformatic methods, review of medical and biological relevance, co-segregation studies in the particular family, and a normal population study. Linkage analysis and exome sequencing of a small number of affected family members is a powerful new technique which can be used to decrease the number of candidate genes in heterogenic disorders such as ID, and may even identify the responsible gene(s).

  19. Ataxia caused by amiodarone in older people.

    Science.gov (United States)

    Hindle, J V; Ibrahim, Amin; Ramaraj, Radhakrishnan

    2008-05-01

    Amiodarone is recommended for the cardioversion of atrial fibrillation and prevention of paroxysmal atrial fibrillation in patients with structural heart disease, coronary artery disease or left ventricular dysfunction. It has well-recognised side-effects on the skin, lungs, liver, thyroid and eyes. Neurological side-effects, including ataxia and neuropathy, also occur, and may be more prevalent in older patients. These side-effects are reversible after cessation of amiodarone. Monitoring of amiodarone therapy should include assessment of the central and peripheral nervous system especially in older patients.

  20. Compound mitochondrial DNA mutations in a neurological patient ...

    Indian Academy of Sciences (India)

    Compound mitochondrial DNA mutations in a neurological patient with ataxia, myoclonus and deafness. Ji Hoon Park, Bo Ram Yoon, Hye Jin Kim, Phil Hyu Lee, Byung-Ok Choi and Ki Wha Chung. J. Genet. 93, 173–177. Table 1. Variations from the whole mtDNA sequence in the AMDF patient. Mutation. Report. Locus/ ...

  1. Ataxia rating scales are age-dependent in healthy children

    NARCIS (Netherlands)

    Brandsma, Rick; Spits, Anne H.; Kuiper, Marieke J.; Lunsing, Roelinka J.; Burger, Huibert; Kremer, Hubertus P.; Sival, Deborah A.

    AIM: To investigate ataxia rating scales in children for reliability and the effect of age and sex. METHOD: Three independent neuropaediatric observers cross-sectionally scored a set of paediatric ataxia rating scales in a group of 52 healthy children (26 males, 26 females) aged 4 to 16 years (mean

  2. CT and MR imaging of acute cerebellar ataxia

    International Nuclear Information System (INIS)

    Shoji, H.; Hirai, S.; Ishikawa, K.; Aramaki, M.; Sato, Y.; Abe, T.; Kojima, K.

    1991-01-01

    An adult female showed mild cerebellar ataxia and CSF pleocytosis following an acute infection of the upper respiratory tract, and was diagnosed as having acute cerebellar ataxia (ACA). CT and MR appearances in the acute stage revealed moderate swelling of the cerebellum and bilaterally increased signal intensity in the cerebellar cortex. (orig.)

  3. Ataxia rating scales are age-dependent in healthy children

    NARCIS (Netherlands)

    Brandsma, Rick; Spits, Anne H.; Kuiper, Marieke J.; Lunsing, Roelinka J.; Burger, Huibert; Kremer, Hubertus P.; Sival, Deborah A.; Barisic, N.; Baxter, P.; Brankovic-Sreckovic, V.; Calabrò, G. E.; Catsman-Berrevoets, C.; de Coo, Ifm; Craiu, D.; Dan, B.; Gburek-Augustat, J.; Kammoun-Feki, F.; Kennedy, C.; Mancini, F.; Mirabelli-Badenier, M.; Nemeth, A.; Newton, R.; Poll-The, B. T.; Steinlin, M.; Synofzik, M.; Topcu, M.; Triki, C.; Valente, E. M.

    2014-01-01

    To investigate ataxia rating scales in children for reliability and the effect of age and sex. Three independent neuropaediatric observers cross-sectionally scored a set of paediatric ataxia rating scales in a group of 52 healthy children (26 males, 26 females) aged 4 to 16 years (mean age 10y 5mo

  4. Cognitive Functions in Ataxia with Oculomotor Apraxia Type 2

    Directory of Open Access Journals (Sweden)

    Péter eKlivényi

    2012-08-01

    Full Text Available Background: Ataxia with oculomotor apraxia type 2 (AOA2 is characterized by cerebellar atrophy, peripheral neuropathy, oculomotor apraxia, and elevated serum alpha-fetoprotein levels. The disease is caused by a recessive mutation in the senataxin gene. Since it is a very rare cerebellar disorder, no detailed examination of cognitive functions in AOA2 has been published to date. The aim of the present study was to investigate the neuropsychological profile of a 54-year-old patient with AOA2. Methods: A broad range of neuropsychological examination protocol was administered including the following domains: short-term, working- and episodic- memories, executive functions, implicit sequence learning, and the temporal parameters of speech. Results: The performance on the Listening Span, Letter Fluency, Serial Reaction Time Task and pause ratio in speech was 2 or more standard deviations (SD lower compared to controls, and 1 SD lower on Backward Digit Span, Semantic Fluency, articulation rate and speech tempo. Conclusions: These findings indicate that the pathogenesis of the cerebrocerebellar circuit in AOA2 is responsible for the weaker coordination of complex cognitive functions such as working memory, executive functions, speech and sequence learning.

  5. Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia

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    Emmanuelle eTillet

    2015-01-01

    Full Text Available Rendu-Osler-Weber syndrome, also known as hereditary hemorrhagic telangiectasia (HHT, is an autosomal dominant vascular disorder. Three genes are causally related to HHT: the ENG gene encoding endoglin, a co-receptor of the TGFß family (HHT1, the ACVRL1 gene encoding ALK1 (activin receptor-like kinase 1, a type I receptor of the TGFß family (HHT2, and the SMAD4 gene, encoding a transcription factor critical for this signaling pathway. Bone morphogenetic proteins (BMPs are growth factors of the TGFß family. Among them, BMP9 and BMP10 have been shown to bind directly with high affinity to ALK1 and endoglin, and BMP9 mutations have recently been linked to a vascular-anomaly syndrome that has phenotypic overlap with HHT. BMP9 and BMP10 are both circulating cytokines in blood, and the current working model is that BMP9 and BMP10 maintain a quiescent endothelial state that is dependent on the level of ALK1/endoglin activation on endothelial cells. In accordance with this model, to explain the etiology of HHT we hypothesize that a deficient BMP9/BMP10/ALK1/endoglin pathway may lead to re-activation of angiogenesis or a greater sensitivity to an angiogenic stimulus. Resulting endothelial hyperproliferation and hypermigration may lead to vasodilatation and formation of arteriovenous malformation (AVM. HHT would thus result from a defect in the angiogenic balance. This review will focus on the emerging role played by BMP9 and BMP10 in the development of this disease and the therapeutic approaches that this opens.

  6. Bevacizumab: an option for refractory epistaxis in hereditary haemorrhagic telangiectasia.

    Science.gov (United States)

    Amann, Arno; Steiner, Normann; Gunsilius, Eberhard

    2015-08-01

    Recurrent epistaxis in hereditary haemorrhagic telangiectasia (HHT) patients significantly decreases their quality of life. Treatment in therapy refractory patients is limited although various options have been tested so far. Herein, one patient is described that was treated for HHT for over 20 years with only intermediate benefits. As epistaxis duration and frequency increased continuously, bevacizumab 5 mg/kg was administered every 2 weeks. During the time of treatment (six doses) and up to 3 month afterwards clinical symptoms, blood pressure, cardiac output, pulmonary arterial hypertension (PAH), bleeding duration and frequency were assessed as criteria for treatment benefit. Duration and frequency of epistaxis decreased immediately after the first application resulting in reduced need of blood transfusions. After completion of six cycles, a further decrease in frequency and duration of bleeding was noted. Cardiac output and PAH decreased or remained stable, respectively, during time and after treatment. No increase in blood pressure could be found but a significant increase in heart rate was experienced after completion of all six applications. Unfortunately, the patient died due to a cerebral abscess. Bevacizumab led to an improvement of HHT related epistaxis, refractory to other treatments.

  7. Automatic telangiectasia analysis in dermoscopy images using adaptive critic design.

    Science.gov (United States)

    Cheng, B; Stanley, R J; Stoecker, W V; Hinton, K

    2012-11-01

    Telangiectasia, tiny skin vessels, are important dermoscopy structures used to discriminate basal cell carcinoma (BCC) from benign skin lesions. This research builds off of previously developed image analysis techniques to identify vessels automatically to discriminate benign lesions from BCCs. A biologically inspired reinforcement learning approach is investigated in an adaptive critic design framework to apply action-dependent heuristic dynamic programming (ADHDP) for discrimination based on computed features using different skin lesion contrast variations to promote the discrimination process. Lesion discrimination results for ADHDP are compared with multilayer perception backpropagation artificial neural networks. This study uses a data set of 498 dermoscopy skin lesion images of 263 BCCs and 226 competitive benign images as the input sets. This data set is extended from previous research [Cheng et al., Skin Research and Technology, 2011, 17: 278]. Experimental results yielded a diagnostic accuracy as high as 84.6% using the ADHDP approach, providing an 8.03% improvement over a standard multilayer perception method. We have chosen BCC detection rather than vessel detection as the endpoint. Although vessel detection is inherently easier, BCC detection has potential direct clinical applications. Small BCCs are detectable early by dermoscopy and potentially detectable by the automated methods described in this research. © 2011 John Wiley & Sons A/S.

  8. An epistaxis severity score for hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Hoag, Jeffrey B; Terry, Peter; Mitchell, Sally; Reh, Douglas; Merlo, Christian A

    2010-04-01

    Hereditary hemorrhagic telangiectasia (HHT)-related epistaxis leads to alterations in social functioning and quality of life. Although more than 95% experience epistaxis, there is considerable variability of severity. Because no standardized method exists to measure epistaxis severity, the purpose of this study was to determine factors associated with patient-reported severity to develop a severity score. Prospective, survey-based study. HHT care providers and a focus group of patients were interviewed to determine epistaxis-associated factors. From this, an electronic survey was developed and administered to patients with HHT. Descriptive analyses were performed with calculations of means and medians for continuous and proportions for categorical variables. Multiple ordinal logistic and linear regression models were developed to determine risk factors for epistaxis severity. Nine hundred respondents from 21 countries were included. Eight hundred fifty-five (95%) subjects reported epistaxis. The mean (standard deviation) age was 52.1 (13.9) years, and 61.4% were female. Independently associated risk factors for self-reported epistaxis severity included epistaxis frequency (odds ratio [OR] 1.57), duration (OR 2.17), intensity (OR 2.45), need for transfusion (OR 2.74), anemia (OR 1.44), and aggressiveness of treatment required (OR 1.53, P epistaxis severity in patients with HHT include frequency, duration, and intensity of episodes; invasiveness of prior therapy required to stop epistaxis; anemia; and the need for blood transfusion. From these factors, an epistaxis severity score will be presented.

  9. An evaluation of the severity and progression of epistaxis in hereditary hemorrhagic telangiectasia 1 versus hereditary hemorrhagic telangiectasia 2.

    Science.gov (United States)

    Hunter, Benjamin N; Timmins, Benjamin H; McDonald, Jamie; Whitehead, Kevin J; Ward, P Daniel; Wilson, Kevin F

    2016-04-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia whose hallmark symptom is spontaneous recurrent epistaxis. Two major genetic subtypes of this syndrome are HHT1 and HHT2. Severity of epistaxis ranges from occasional low-volume bleeding to frequent large-volume hemorrhage. This study evaluated the severity and progression of epistaxis in HHT1 versus HHT2. Retrospective cohort study. A retrospective chart review was performed for 183 genotyped HHT patients seen at our center from 2010 to 2013. Data collected included epistaxis severity score (ESS), age of epistaxis onset, number and type of treatments, age at which treatments were sought, complete blood count values, ferritin, number of telangiectases, blood transfusions, iron therapy history, and patient demographics. 115 subjects with HHT2 were compared to 68 with HHT1. Subjects with HHT2 had a higher ESS compared to HHT1 (P = .043) and a later age of onset of epistaxis (P = .005). HHT2 subjects were more likely to use oral iron (P = .032) and were more likely to seek interventions to control their epistaxis (P = .029). HHT2 is associated with more severe epistaxis and a subsequent higher rate of interventions, requiring more aggressive therapy as compared to HHT1. 4. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

  10. Ataxia cerebelar aguda na criança Acute cerebellar ataxia in children

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    Valeriana Moura Ribeiro

    1968-03-01

    Full Text Available São relatados os casos de 6 crianças com ataxia cerebelar aguda. Admitem os autores a presença de um fator etiológico de caráter viral comum a todos êles, discutindo os mecanismos patogênicos com base nos casos da literatura. A evolução foi favorável em todos os pacientes, com regressão completa da sintomatologia, dentro do período de 6 a 60 dias.Clinical observations of 6 children with acute cerebellar ataxia and respective laboratorial data are reported. Considerations are made in order to support the hypothesis of involving virus. The evolution of the disorder was a nonfatal one and the patients regained normal cerebellar function within a period of 6 to 60 days.

  11. Identification of IFRD1 variant in a Han Chinese family with autosomal dominant hereditary spastic paraplegia associated with peripheral neuropathy and ataxia.

    Science.gov (United States)

    Lin, Pengfei; Zhang, Dong; Xu, Guangrun; Yan, Chuanzhu

    2018-04-01

    Spinocerebellar ataxias (SCAs) are a group of autosomal dominant, clinically heterogeneous neurodegenerative disorders. SCA18 is a rare autosomal dominant sensory/motor neuropathy with ataxia (OMIM#607458) associated with a single missense variant c.514 A>G in the interferon related developmental regulator 1 (IFRD1) gene previously reported in a five-generation American family of Irish origin. However, to date, there have been no other reports of the IFRD1 mutation to confirm its role in SCA. Here, we report a Han Chinese family with SCA18; the family members presented with a slowly progressing gait ataxia, pyramidal tract signs, and peripheral neuropathy. We identified a missense variant (c.514 A>G, p.I172V) in IFRD1 gene in the family using targeted next-generation sequencing and Sanger direct sequencing with specific primers. Our results suggest that the IFRD1 gene may be the causative allele for SCA18.

  12. An Immunotherapeutic Approach to the Treatment and Prevention of Breast Cancer, Based on Epidermal Growth Factor Receptor Variant, Type III

    Science.gov (United States)

    1999-05-01

    clofibrate [CLF] for 3-60 days to induce hepatic hyperplasia, and 4-chloro-6-(2,3 xylidino)-2-pyrimidinyl-thio(N-ß-hydroxyethyl) acetamide [BR931] for 10...XIV List of Abbreviations aa Amino Acid ABs Alveolar Buds ABC ATP-Binding Cassette Ad Adenovirus APC Antigen Presenting Cell AT Ataxia...Telangiectasia ATCC American Type Culture Collection ATM Ataxia Telangiectasia, Mutated BCA Bicinchoninic Acid BDC Bile Duct Carcinomas BrdU

  13. Ataxia espinocerebelar tipo 6: relato de caso

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    Bianca Simone Zeigelboim

    2014-10-01

    Full Text Available O objetivo deste estudo foi verificar as alterações vestibulococleares observadas em um caso de ataxia espinocerebelar tipo 6. O caso foi encaminhado do Hospital de Clínicas para o Laboratório de Otoneurologia de uma Instituição de Ensino e foi submetido aos seguintes procedimentos: anamnese, inspeção otológica, avaliações audiológica e vestibular. O caso retrata uma paciente com diagnóstico genético de ataxia espinocerebelar tipo 6, do sexo feminino, com 57 anos de idade, que referiu desequilíbrio à marcha com tendência a queda para a esquerda, disartria e disfonia. Na avaliação audiológica apresentou configuração audiométrica descendente a partir da frequência de 4kHz e curva timpanométrica do tipo "A" com presença dos reflexos estapedianos bilateralmente. No exame vestibular observou-se na pesquisa da vertigem posicional presença de nistagmo vertical inferior e oblíquo, espontâneo e semiespontâneo múltiplo com características centrais (ausência de latência, paroxismo, fatigabilidade e vertigem, nistagmooptocinético abolido e hiporreflexia à prova calórica. Constataram-se alterações labirínticas que indicaram afecção do sistema vestibular central evidenciando-se a importância dessa avaliação. A existência da possível relação entre os achados com os sintomas vestibulares apresentados pela paciente apontou a relevância do exame labiríntico neste tipo de ataxia uma vez que a presença do nistagmo vertical inferior demonstrou ser frequente neste tipo de patologia.

  14. Ataxia heredo-degenerativa associada a hipoacusia

    Directory of Open Access Journals (Sweden)

    José Antonio Levy

    1964-06-01

    Full Text Available São estudados três irmãos, respectivamente com 16, 8 e 6 anos de idade, todos do sexo masculino, com ataxia heredo-degenerativa associada, em dois dêles, a hipoacusia. Nos antecedentes há referência a moléstia semelhante em um avô e um tio-avô. É discutido o diagnóstico diferencial com a moléstia de Pièrre Marie, a doença de Charcot-Marie-Tooth, a síndrome de Refsum e a neurite intersticial hipertrófica, sendo acentuada a semelhança dos casos estudados com a moléstia de Friedreich. São feitos comentários à associação da doença de Friedreich com distúrbios da audição.

  15. Research progress of spinocerebellar ataxia type 1

    Directory of Open Access Journals (Sweden)

    Lin-wei ZHANG

    2014-05-01

    Full Text Available Spinocerebellar ataxia type 1 (SCA1 is a kind of autosomal dominant genetic neurodegenerative disorder. To date, the pathogenesis of SCA1 remains unclear. Studies in numerous SCA1 experimental models, including transgenic mice, transgenic drosophila and induced pluripotent stem cells, have shown that phosphorylation of S776 in mutant ataxin-1, molecular chaperones, ubiquitin-proteasome system and down-regulation of several components of RAS-MAPK-MSK1 pathway may involve in the pathogenesis of SCA1. In this review, the clinical and pathological features of SCA1, and the latest advances of pathogenesis, model systems and therapeutic exploration will be briefly summarized. doi: 10.3969/j.issn.1672-6731.2014.05.017

  16. The fragile x-associated tremor and ataxia syndrome (FXTAS A síndrome de tremor e ataxia associada ao X frágil (FXTAS

    Directory of Open Access Journals (Sweden)

    Leonardo Pires Capelli

    2010-10-01

    Full Text Available FXTAS (Fragile X-associated tremor and ataxia syndrome is a late- onset neurodegenerative disorder affecting mainly men, over 50 years of age, who are carriers of the FMR1 gene premutation. The full mutation of this gene causes the fragile X syndrome (FXS, the most common cause of inherited mental retardation. Individuals affected by FXTAS generally present intention tremor and gait ataxia that might be associated to specific radiological and/or neuropathological signs. Other features commonly observed are parkinsonism, cognitive decline, peripheral neuropathy and autonomic dysfunction. Nearly a decade after its clinical characterization, FXTAS is poorly recognized in Brazil. Here we present a review of the current knowledge on the clinical, genetic and diagnostic aspects of the disease.A FXTAS (síndrome de tremor e ataxia associada ao X frágil é uma doença neurodegenerativa de início tardio que afeta principalmente homens acima dos 50 anos de idade, portadores de pré-mutação do gene FMR1. A mutação completa desse gene é responsável pela síndrome do cromossomo X frágil (SXF, a causa mais comum de deficiência mental herdada. Indivíduos afetados pela FXTAS geralmente apresentam tremor de intenção e ataxia de marcha que podem estar associados a sinais radiológicos ou neuropatológicos específicos. Outras características comumente observadas são parkinsonismo, declínio cognitivo, neuropatia periférica e disfunções autonômicas. Quase uma década após sua caracterização clínica, a FXTAS é mal conhecida por médicos no Brasil. Esta revisão apresenta o conhecimento atual sobre os aspectos clínicos, genéticos e diagnósticos da síndrome.

  17. The effect of piracetam on ataxia: clinical observations in a group of autosomal dominant cerebellar ataxia patients.

    Science.gov (United States)

    Ince Gunal, D; Agan, K; Afsar, N; Borucu, D; Us, O

    2008-04-01

    Autosomal dominant cerebellar ataxias are clinically and genetically heterogeneous neurodegenerative disorders. There is no known treatment to prevent neuronal cell death in these disorders. Current treatment is purely symptomatic; ataxia is one of the most disabling symptoms and represents the main therapeutic challenge. A previous case report suggesting benefit from administration of high dose piracetam inspired the present study of the efficacy of this agent in patients with cerebellar ataxia. Piracetam is a low molecular weight derivative of gamma-aminobutyric acid. Although little is known of its mode of action, its efficacy has been documented in a wide range of clinical indications, such as cognitive disorders, dementia, vertigo and dyslexia, as well as cortical myoclonus. The present report investigated the role of high dose piracetam in patients with cerebellar ataxia. Eight patients with autosomal dominant cerebellar ataxia were given intravenous piracetam 60 g/day by a structured protocol for 14 days. The baseline and end-of-the study evaluations were based on the International Cooperative Ataxia Rating Scale. Statistical analysis demonstrated a significant improvement in the patients' total score (P = 0.018) and a subscale analysis showed statistical significance for only the posture and gait disturbances item (P = 0.018). This study is providing good clinical observation in favour of high dose piracetam infusion to reduce the disability of the patients by improving their gait ataxia.

  18. Spontaneous shaker rat mutant - a new model for X-linked tremor/ataxia.

    Science.gov (United States)

    Figueroa, Karla P; Paul, Sharan; Calì, Tito; Lopreiato, Raffaele; Karan, Sukanya; Frizzarin, Martina; Ames, Darren; Zanni, Ginevra; Brini, Marisa; Dansithong, Warunee; Milash, Brett; Scoles, Daniel R; Carafoli, Ernesto; Pulst, Stefan M

    2016-05-01

    The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca(2+) transporting, plasma membrane 3 (Atp2b3) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3(R35C) function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes. © 2016. Published by The Company of Biologists Ltd.

  19. Spontaneous shaker rat mutant – a new model for X-linked tremor/ataxia

    Directory of Open Access Journals (Sweden)

    Karla P. Figueroa

    2016-05-01

    Full Text Available The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF/Brown Norwegian (BN F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm. In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R to cysteine (C change at codon 35 of the ATPase, Ca2+ transporting, plasma membrane 3 (Atp2b3 gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes.

  20. Spontaneous shaker rat mutant – a new model for X-linked tremor/ataxia

    Science.gov (United States)

    Figueroa, Karla P.; Paul, Sharan; Calì, Tito; Lopreiato, Raffaele; Karan, Sukanya; Frizzarin, Martina; Ames, Darren; Zanni, Ginevra; Brini, Marisa; Dansithong, Warunee; Milash, Brett; Scoles, Daniel R.; Carafoli, Ernesto; Pulst, Stefan M.

    2016-01-01

    ABSTRACT The shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca2+ transporting, plasma membrane 3 (Atp2b3) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes. PMID:27013529

  1. Genetics Home Reference: autosomal dominant cerebellar ataxia, deafness, and narcolepsy

    Science.gov (United States)

    ... may help regulate nerve cell (neuron) maturation and specialization (differentiation), the ability of neurons to move (migrate) ... Ataxia Foundation National Sleep Foundation University of Kansas Medical Center Resource List: Deafness and Hard of Hearing ...

  2. Efavirenz as a cause of ataxia in children

    African Journals Online (AJOL)

    more side-effects of these drugs. We report ... negative; however, a CT scan of her brain was suggestive of possible ... posterior fossa structures revealed a normal brain. .... reported dizziness, ataxia, insomnia, bad dreams and hallucinations.

  3. Seasonal ataxia: a case report of a disappearing disease

    African Journals Online (AJOL)

    Seasonal ataxia: a case report of a disappearing disease. Adebiyi Ayoade ... ological profiles of the disease. ... low serum albumin levels [8] act as a potentiating factor to trigger the ... 65% neutrophils, 25% lymphocytes,eosinophils 5% and.

  4. Dyspnea with anemia turned out to be a case of hereditary hemorrhagic telangiectasia

    Directory of Open Access Journals (Sweden)

    Amitabha Sengupta

    2013-01-01

    Full Text Available Hereditary hemorrhagic telangiectasia (HHT is a rare autosomal dominant inherited disorder of the vascular system. It can be asymptomatic but when symptomatic most common presentation being epistaxis. It can involve any organs of the body like lungs, skin, liver brain, GI mucosa etc. We are reporting a case of HHT presented to us with dyspnea and severe anemia. He had arteriovenous malformations of different visceral organs and telangiectasia of skin along with presence of similar history in first-degree relatives.

  5. Gerstmann's syndrome and unilateral optic ataxia in the emergency department

    Science.gov (United States)

    Barbosa, Breno José Alencar Pires; de Brito, Marcelo Houat; Rodrigues, Júlia Chartouni; Kubota, Gabriel Taricani; Parmera, Jacy Bezerra

    2017-01-01

    ABSTRACT. A 75-year-old right-handed woman presented to the emergency department with simultanagnosia and right unilateral optic ataxia. Moreover, the patient had agraphia, acalculia, digital agnosia and right-left disorientation, consistent with complete Gerstmann's syndrome. This case highlights the concurrence of Gerstmann's syndrome and unilateral optic ataxia in the acute phase of a left middle cerebral artery stroke. PMID:29354229

  6. Gerstmann's syndrome and unilateral optic ataxia in the emergency department

    Directory of Open Access Journals (Sweden)

    Breno José Alencar Pires Barbosa

    Full Text Available ABSTRACT. A 75-year-old right-handed woman presented to the emergency department with simultanagnosia and right unilateral optic ataxia. Moreover, the patient had agraphia, acalculia, digital agnosia and right-left disorientation, consistent with complete Gerstmann's syndrome. This case highlights the concurrence of Gerstmann's syndrome and unilateral optic ataxia in the acute phase of a left middle cerebral artery stroke.

  7. Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes.

    Science.gov (United States)

    Vogel, Adam P; Folker, Joanne; Poole, Matthew L

    2014-10-28

    Hereditary ataxia syndromes can result in significant speech impairment, a symptom thought to be responsive to treatment. The type of speech impairment most commonly reported in hereditary ataxias is dysarthria. Dysarthria is a collective term referring to a group of movement disorders affecting the muscular control of speech. Dysarthria affects the ability of individuals to communicate and to participate in society. This in turn reduces quality of life. Given the harmful impact of speech disorder on a person's functioning, treatment of speech impairment in these conditions is important and evidence-based interventions are needed. To assess the effects of interventions for speech disorder in adults and children with Friedreich ataxia and other hereditary ataxias. On 14 October 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, CINAHL Plus, PsycINFO, Education Resources Information Center (ERIC), Linguistics and Language Behavior Abstracts (LLBA), Dissertation Abstracts and trials registries. We checked all references in the identified trials to identify any additional published data. We considered for inclusion randomised controlled trials (RCTs) or quasi-RCTs that compared treatments for hereditary ataxias with no treatment, placebo or another treatment or combination of treatments, where investigators measured speech production. Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias of included studies using the standard methodological procedures expected by The Cochrane Collaboration. The review authors collected information on adverse effects from included studies. We did not conduct a meta-analysis as no two studies utilised the same assessment procedures within the same treatment. Fourteen clinical trials, involving 721 participants, met the criteria for inclusion in the review. Thirteen studies compared a pharmaceutical treatment with placebo (or a

  8. Comparison of. gamma. i-irradiation-induced accumulation of ataxia telangiesctasia and control cells in G sub 2 phase

    Energy Technology Data Exchange (ETDEWEB)

    Bates, P.R. (Royal Brisbane Hospital, Herston (Australia)); Lavin, M.F. (Queensland Inst. of Medical Research, Brisbane (Australia))

    1989-09-01

    Recent reports from a number of laboratories have linked radiosensitivity in ataxia telangiectasia (AT) to a large and prolonged block of some cells in G{sub 2} phase. Previous results from this laboratory, largely with one Epstein-Barr virus-transformed A-T lymphoblastoid cell line, presented evidence for a dramatic increase in the number of cells in G{sub 2} phase over controls during a 24 h period post irradiation. We describe here a study of the effect of {gamma}-radiation on G{sub 2} phase delay in several A-T cell lines. Based on previous results with several cell lines 24 h post irradiation was selected as the optimum time to discriminate between G{sub 2} phase delay in control and A-T cells. All A-T homozygotes showed a signigicantly greater number of cells in G{sub 2} phase, 24 h post irradiation, than observed in controls. A more prolonged delay in G{sub 2} phase after irradiation was seen in different A-T cell types that included lymphoblastoid cells, fibroblasts and SV40-transformed fibroblasts. At the radiation dose used it was not possibel to distinguish A-T heterozygotes from controls (Author). 28 refs.; 2 figs.; 1 tab.

  9. Comparison of γ i-irradiation-induced accumulation of ataxia telangiesctasia and control cells in G2 phase

    International Nuclear Information System (INIS)

    Bates, P.R.; Lavin, M.F.

    1989-01-01

    Recent reports from a number of laboratories have linked radiosensitivity in ataxia telangiectasia (AT) to a large and prolonged block of some cells in G 2 phase. Previous results from this laboratory, largely with one Epstein-Barr virus-transformed A-T lymphoblastoid cell line, presented evidence for a dramatic increase in the number of cells in G 2 phase over controls during a 24 h period post irradiation. We describe here a study of the effect of γ-radiation on G 2 phase delay in several A-T cell lines. Based on previous results with several cell lines 24 h post irradiation was selected as the optimum time to discriminate between G 2 phase delay in control and A-T cells. All A-T homozygotes showed a signigicantly greater number of cells in G 2 phase, 24 h post irradiation, than observed in controls. A more prolonged delay in G 2 phase after irradiation was seen in different A-T cell types that included lymphoblastoid cells, fibroblasts and SV40-transformed fibroblasts. At the radiation dose used it was not possibel to distinguish A-T heterozygotes from controls (Author). 28 refs.; 2 figs.; 1 tab

  10. Preliminary Study of Intravenous Amantadine Treatment for Ataxia Management in Patients with Probable Multiple System Atrophy with Predominant Cerebellar Ataxia

    Directory of Open Access Journals (Sweden)

    Jinyoung Youn

    2012-05-01

    Full Text Available Background and Purpose: Multiple system atrophy with predominant cerebellar ataxia is a disabling neurologic disease. However, effective management has not yet been established. We conducted a short-term, open-label preliminary study to assess the benefits of intravenous amantadine treatment in patients with probable multiple system atrophy with predominant cerebellar ataxia. Methods: Twenty patients (10 male, 10 female with probable multiple system atrophy with predominant cerebellar ataxia received 400 mg of amantadine by intravenous per day for 5 days. Ataxia severity was evaluated by the International Cooperative Ataxia Rating Scale before and after intravenous amantadine therapy and all subjects reported subjective improvement after intravenous amantadine treatment using a patient global impression scale. We analyzed the total and subscale scores by the ataxia scale and patient global impression scale. Results: The mean age was 57.4 years (range: 47–72 and the mean disease duration was 30.8 months (range: 11–79. The ataxia severity significantly decreased after intravenous amantadine therapy from 42.5 to 37.3 (p < 0.001. The mean patient global impression scale for improvement was 2.9 and there were no side effects of intravenous amantadine treatment observed. When we assessed responders, the duration of intravenous amantadine effect was more than 1 month in 4 subjects of 7 responders. Conclusions: Our findings suggest that intravenous amantadine treatment can be a safe management option in cerebellar ataxia, although the mechanism is unclear. Thus, further double-blind, long-term studies with a larger sample size are needed.

  11. High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Basuta, Kirin; Schneider, Andrea; Gane, Louise; Polussa, Jonathan; Woodruff, Bryan; Pretto, Dalyir; Hagerman, Randi; Tassone, Flora

    2015-09-01

    Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. © 2015 Wiley Periodicals, Inc.

  12. Treatment of Laryngeal Telangiectatic Lesions in a Patient Diagnosed with Hereditary Haemorrhagic Telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, Anette Drøhse; Printz, Trine; Slot Mehlum, Camilla

    2015-01-01

    Abstract We here present a case concerning a 69 year old female patient with Hereditary Haemorrhagic Telangiectasia (HHT). She was suffering from hoarseness due to a telangiectatic lesion on the right vocal cord. The lesion was treated with laser and the voice improved markedly, which is document...

  13. Global Gene Expression Profiling of Telangiectasial Tissue from Patients with Hereditary Haemorrhagic Telangiectasia

    DEFF Research Database (Denmark)

    Tørring, Pernille M; Larsen, Martin Jakob; Kjeldsen, Anette D

    2015-01-01

    and arteriovenous malformations in visceral organs, primarily the lungs, brain and liver. The most common symptom in HHT is epistaxis originating from nasal telangiectasia, which can be difficult to prevent and can lead to severe anaemia. The clinical manifestations of HHT are extremely variable, even within family...

  14. Splenic arteriovenous malformation manifested by thrombocytopenia in hereditary hemorrhagic telangiectasia: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Hee Jin; Choi, Jong Cheol; Oh, Jong Yeong; Cho, Jin Han; Kang, Myong Jin; Lee, Jin Hwa; Yoon, Seong Kuk; Nam, Kyeong Jin [College of Medicine, Dong-A University, Busan (Korea, Republic of)

    2008-09-15

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterized by epistaxis, telangiectases and visceral arteriovenous malformations (AVMs). The involvement of the gastrointestinal tract, liver, lung and cerebrum for HHT has been described, whereas little is known about AVMs of the spleen. We report here the radiological findings of a case of a splenic AVM manifested by thrombocytopenia in HHT.

  15. Splenic arteriovenous malformation manifested by thrombocytopenia in hereditary hemorrhagic telangiectasia: a case report

    International Nuclear Information System (INIS)

    Kwon, Hee Jin; Choi, Jong Cheol; Oh, Jong Yeong; Cho, Jin Han; Kang, Myong Jin; Lee, Jin Hwa; Yoon, Seong Kuk; Nam, Kyeong Jin

    2008-01-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterized by epistaxis, telangiectases and visceral arteriovenous malformations (AVMs). The involvement of the gastrointestinal tract, liver, lung and cerebrum for HHT has been described, whereas little is known about AVMs of the spleen. We report here the radiological findings of a case of a splenic AVM manifested by thrombocytopenia in HHT

  16. MutLα heterodimers modify the molecular phenotype of Friedreich ataxia.

    Directory of Open Access Journals (Sweden)

    Vahid Ezzatizadeh

    Full Text Available Friedreich ataxia (FRDA, the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions.To determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription.Both MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription.

  17. MutLα Heterodimers Modify the Molecular Phenotype of Friedreich Ataxia

    Science.gov (United States)

    Ezzatizadeh, Vahid; Sandi, Chiranjeevi; Sandi, Madhavi; Anjomani-Virmouni, Sara; Al-Mahdawi, Sahar; Pook, Mark A.

    2014-01-01

    Background Friedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions. Methodology/Principal Findings To determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription. Conclusions/Significance Both MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription. PMID:24971578

  18. Cerebellar Expression of the Neurotrophin Receptor p75 in Naked-Ataxia Mutant Mouse

    Directory of Open Access Journals (Sweden)

    Maryam Rahimi Balaei

    2016-01-01

    Full Text Available Spontaneous mutation in the lysosomal acid phosphatase 2 (Acp2 mouse (nax—naked-ataxia mutant mouse correlates with severe cerebellar defects including ataxia, reduced size and abnormal lobulation as well as Purkinje cell (Pc degeneration. Loss of Pcs in the nax cerebellum is compartmentalized and harmonized to the classic pattern of gene expression of the cerebellum in the wild type mouse. Usually, degeneration starts in the anterior and posterior zones and continues to the central and nodular zones of cerebellum. Studies have suggested that the p75 neurotrophin receptor (NTR plays a role in Pc degeneration; thus, in this study, we investigated the p75NTR pattern and protein expression in the cerebellum of the nax mutant mouse. Despite massive Pc degeneration that was observed in the nax mouse cerebellum, p75NTR pattern expression was similar to the HSP25 pattern in nax mice and comparable with wild type sibling cerebellum. In addition, immunoblot analysis of p75NTR protein expression did not show any significant difference between nax and wild type sibling (p > 0.5. In comparison with wild type counterparts, p75NTR pattern expression is aligned with the fundamental cytoarchitecture organization of the cerebellum and is unchanged in the nax mouse cerebellum despite the severe neurodevelopmental disorder accompanied with Pc degeneration.

  19. Complementation of radiation-sensitive Ataxia telangiectasia cells after transfection of cDNA expression libraries and cosmid clones from wildtype cells

    International Nuclear Information System (INIS)

    Fritz, E.

    1994-06-01

    In this Ph.D.-thesis, phenotypic complementation of AT-cells (AT5BIVA) by transfection of cDNA-expression-libraries was adressed: After stable transfection of cDNA-expression-libraries G418 resistant clones were selected for enhanced radioresistance by a fractionated X-ray selection. One surviving transfectant clone (clone 514) exhibited enhanced radiation resistance in dose-response experiments and further X-ray selections. Cell cycle analysis revealed complementation of untreated and irradiated 514-cells in cell cycle progression. The rate of DNA synthesis, however, is not diminished after irradiation but shows the reverse effect. A transfected cDNA-fragment (AT500-cDNA) was isolated from the genomic DNA of 514-cells and proved to be an unknown DNA sequence. A homologous sequence could be detected in genomic DNA from human cell lines, but not in DNA from other species. The cDNA-sequence could be localized to human chromosome 11. In human cells the cDNA sequence is part of two large mRNAs. 4 different cosmid clones containing high molecular genomic DNA from normal human cells could be isolated from a library, each hybridizing to the AT500-cDNA. After stable transfection into AT-cells, one cosmid-clone was able to confer enhanced radiation resistance both in X-ray selections and dose-response experiments. The results indicate that the cloned cDNA-fragment is based on an unknown gene from human chromosome 11 which partially complements the radiosensitivity and the defective cell cycle progression in AT5BIVA cells. (orig.) [de

  20. Vascular Risk Factors and Clinical Progression in Spinocerebellar Ataxias

    Directory of Open Access Journals (Sweden)

    Raymond Y. Lo

    2015-02-01

    Full Text Available Background: The contributions of vascular risk factors to spinocerebellar ataxia (SCA are not known.Methods: We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account.Results: Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. Discussion: Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression.

  1. Very Late-Onset Friedreich Ataxia with Laryngeal Dystonia

    Directory of Open Access Journals (Sweden)

    Silvia Rota

    2014-12-01

    Full Text Available Friedreich ataxia (FRDA is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, visual defects, scoliosis, pes cavus and cardiomyopathy. It is caused by a homozygous guanine-adenine-adenine (GAA trinucleotide repeat expansion in intron 1 of the frataxin gene (FXN on chromosome 9q13-q21.1. Onset is usually in the first or second decade of life; however, late-onset cases of Freidreich ataxia (LOFA, after the age of 25 years, and very late-onset cases of Freidreich ataxia (VLOFA, after the age of 40 years, have been reported. VLOFA is quite rare and usually presents a milder progression of the disease. We report the case of a 64-year-old woman affected with VLOFA whose first symptoms (balance and gait disturbances occurred at the age of 44 years. At the age of 62 years, she started complaining of a slowly progressive dysphonia showing the clinical aspects of laryngeal dystonia. Molecular analysis showed a 210- and 230-trinucleotide GAA repeat expansion in the two alleles of the FXN gene. Laryngeal dystonia has been reported only in very few cases of ataxia syndrome and never before in FRDA patients. It may represent a rare clinical manifestation of VLOFA thus confirming the high variability of the clinical spectrum of FRDA.

  2. Prevalence of spinocerebellar ataxia 36 in a US population.

    Science.gov (United States)

    Valera, Juliana M; Diaz, Tatyana; Petty, Lauren E; Quintáns, Beatriz; Yáñez, Zuleima; Boerwinkle, Eric; Muzny, Donna; Akhmedov, Dmitry; Berdeaux, Rebecca; Sobrido, Maria J; Gibbs, Richard; Lupski, James R; Geschwind, Daniel H; Perlman, Susan; Below, Jennifer E; Fogel, Brent L

    2017-08-01

    To assess the prevalence and clinical features of individuals affected by spinocerebellar ataxia 36 (SCA36) at a large tertiary referral center in the United States. A total of 577 patients with undiagnosed sporadic or familial cerebellar ataxia comprehensively evaluated at a tertiary referral ataxia center were molecularly evaluated for SCA36. Repeat primed PCR and fragment analysis were used to screen for the presence of a repeat expansion in the NOP56 gene. Fragment analysis of triplet repeat primed PCR products identified a GGCCTG hexanucleotide repeat expansion in intron 1 of NOP56 in 4 index cases. These 4 SCA36-positive families comprised 2 distinct ethnic groups: white (European) (2) and Asian (Japanese [1] and Vietnamese [1]). Individuals affected by SCA36 exhibited typical clinical features with gait ataxia and age at onset ranging between 35 and 50 years. Patients also suffered from ataxic or spastic limbs, altered reflexes, abnormal ocular movement, and cognitive impairment. In a US population, SCA36 was observed to be a rare disorder, accounting for 0.7% (4/577 index cases) of disease in a large undiagnosed ataxia cohort.

  3. Genetics Home Reference: spinocerebellar ataxia type 6

    Science.gov (United States)

    ... CaV2.1 channels play an essential role in communication between neurons in the brain. The CACNA1A gene mutations that ... calcium channels in the cell membrane impairs cell communication between neurons in the brain. Diminished cell communication leads to ...

  4. Clinical neurogenetics: fragile x-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Hall, Deborah A; O'Keefe, Joan A

    2013-11-01

    This article summarizes the clinical findings, genetics, pathophysiology, and treatment of fragile X-associated tremor ataxia syndrome. The disorder occurs from a CGG repeat (55-200) expansion in the fragile X mental retardation 1 gene. It manifests clinically in kinetic tremor, gait ataxia, and executive dysfunction, usually in older men who carry the genetic abnormality. The disorder has distinct radiographic and pathologic findings. Symptomatic treatment is beneficial in some patients. The inheritance is X-linked and family members may be at risk for other fragile X-associated disorders. This information is useful to neurologists, general practitioners, and geneticists. Copyright © 2013. Published by Elsevier Inc.

  5. Enfermedad cardiovascular en pacientes cubanos afectados por Ataxia de Friedreich.

    OpenAIRE

    Tania Cruz Mariño; Ana Luz Portelles Caminero; William Áreas Zalazar; Luís Velázquez Pérez

    2010-01-01

    Al describir la ataxia de Friedreich, Nicholaus hizo referencia a la patología cardiaca. Esta enfermedad autosómica recesiva se debe a una mutación dinámica en el gen FRDA, codificándose deficientemente la proteína Frataxina, conduciendo a estrés oxidativo y muerte celular cardiaca. La presente investigación se desarrolló con el objetivo de describir las anomalías cardiovasculares presentes en los pacientes cubanos afectados por ataxia de Friedreich. A los individuos con diagnóstico molecular...

  6. Spinocerebellar ataxia type 6: MRI of three Japanese patients

    International Nuclear Information System (INIS)

    Satoh, J.I.; Tokumoto, H.; Yukitake, M.; Matsui, M.; Kuroda, Y.; Matsuyama, Z.; Kawakami, H.; Nakamura, S.

    1998-01-01

    We describe the MRI findings in three Japanese patients with spinocerebellar ataxia type 6 (SCA6) in which a polymorphic CAG repeat was identified in the gene encoding the α 1A voltage-dependent P/Q-type Ca 2+ channel subunit (CACNL1A4). All showed slowly progressive cerebellar ataxia and mild pyramidal signs. Neuroradiologically, they had moderate cerebellar atrophy, most prominently in the superior vermis, whereas the brain stem appeared to be spared. No abnormal signal intensity was identified. (orig.)

  7. Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian breast/ovarian cancer families

    Directory of Open Access Journals (Sweden)

    Pichette Roxane

    2006-09-01

    Full Text Available Abstract Background Ataxia telangiectasia-mutated and Rad3-related (ATR is a member of the PIK-related family which plays, along with ATM, a central role in cell-cycle regulation. ATR has been shown to phosphorylate several tumor suppressors like BRCA1, CHEK1 and TP53. ATR appears as a good candidate breast cancer susceptibility gene and the current study was designed to screen for ATR germline mutations potentially involved in breast cancer predisposition. Methods ATR direct sequencing was performed using a fluorescent method while widely available programs were used for linkage disequilibrium (LD, haplotype analyses, and tagging SNP (tSNP identification. Expression analyses were carried out using real-time PCR. Results The complete sequence of all exons and flanking intronic sequences were analyzed in DNA samples from 54 individuals affected with breast cancer from non-BRCA1/2 high-risk French Canadian breast/ovarian families. Although no germline mutation has been identified in the coding region, we identified 41 sequence variants, including 16 coding variants, 3 of which are not reported in public databases. SNP haplotypes were established and tSNPs were identified in 73 healthy unrelated French Canadians, providing a valuable tool for further association studies involving the ATR gene, using large cohorts. Our analyses led to the identification of two novel alternative splice transcripts. In contrast to the transcript generated by an alternative splicing site in the intron 41, the one resulting from a deletion of 121 nucleotides in exon 33 is widely expressed, at significant but relatively low levels, in both normal and tumoral cells including normal breast and ovarian tissue. Conclusion Although no deleterious mutations were identified in the ATR gene, the current study provides an haplotype analysis of the ATR gene polymorphisms, which allowed the identification of a set of SNPs that could be used as tSNPs for large-scale association

  8. Macular telangiectasia type 2 (MacTel) in a 34-year-old patient.

    Science.gov (United States)

    Nicolai, Heleen; Wirix, Mieke; Spielberg, Leigh; Leys, Anita

    2014-09-23

    We report macular telangiectasia type 2 (MacTel) in a 34-year-old man, the youngest patient so far published with MacTel type 2. The patient presented with metamorphopsia and impaired reading ability. Diagnosis was based on bilateral abnormal macular autofluorescence, perifoveal telangiectasia with fluorescein angiographic hyperfluorescence without cystoid oedema, a small foveal avascular zone, asymmetric configuration of the foveal pit, disruptions in the inner segment/outer segment layer and hyper-reflective haze and spots in the outer nuclear layer. Although MacTel usually manifests with a slowly progressive decrease in visual acuity in the fifth to seventh decades of life, younger patients may occasionally be diagnosed with the disease. Awareness of subtle signs of the condition is essential for early diagnosis. 2014 BMJ Publishing Group Ltd.

  9. CHEK2 1100DELC germline mutation: a frequency study in hereditary breast and colon cancer Brazilian families Mutação germinativa 1100delC no gene CHEK2: estudo da frequência em famílias brasileiras com câncer de mama e cólon hereditários

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    Jamile Abud

    2012-12-01

    Full Text Available CONTEXT: CHEK2 encodes a cell cycle checkpoint kinase that plays an important role in the DNA damage repair pathway, activated mainly by ATM (Ataxia Telangiectasia Mutated in response to double-stranded DNA breaks. A germline mutation in CHEK2, 1100delC, has been described as a low penetrance allele in a significant number of families with breast and colorectal cancer in certain countries and is also associated with increased risk of contralateral breast cancer in women previously affected by the disease. About 5%-10% of all breast and colorectal cancers are associated with hereditary predisposition and its recognition is of great importance for genetic counseling and cancer risk management. OBJECTIVES: Here, we have assessed the frequency of the CHEK2 1100delC mutation in the germline of 59 unrelated Brazilian individuals with clinical criteria for the hereditary breast and colorectal cancer syndrome. METHODS: A long-range PCR strategy followed by gene sequencing was used. RESULTS: The 1100delC mutation was encountered in the germline of one (1.7% individual in this high risk cohort. This indicates that the CHEK2 1100delC is not commonly encountered in Brazilian families with multiple diagnoses of breast and colorectal cancer. CONCLUSION: These results should be confirmed in a larger series of families and further testing should be undertaken to investigate the molecular mechanisms underlying the hereditary breast and colorectal cancer phenotype.INTRODUÇÃO: CHEK2 codifica uma proteína quinase envolvida em um ponto de checagem do ciclo celular que desempenha um papel importante na via de reparação do DNA, danos ativados principalmente por ATM (Ataxia Telangiectasia Mutado em resposta a danos na dupla hélice do DNA. A mutação germinativa 1100delC no gene CHEK2 tem sido descrita como um alelo de baixa penetrância em um número significativo de famílias com câncer de mama e cólon em certos países e também está associada com risco

  10. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, A D; Møller, T R; Brusgaard, K

    2005-01-01

    BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease, characterized by a wide variety of clinical manifestations, including epistaxis, gastrointestinal (GI) bleeding, pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. HHT is a genetically...... patients had experienced more severe GI bleeding than HHT2 patients. There was no significant difference in severity of epistaxis or age at debut. Finally the mortality over a 90-month observation period was not significantly increased....

  11. Neurologic Manifestation as Initial Presentation in a Case of Hereditary Haemorrhagic Telangiectasia

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    Yeow Kwan Teo

    2010-01-01

    Full Text Available Hereditary Haemorrhagic Telangiectasia (HHT, or Osler-Weber-Rendu syndrome is an uncommon autosomal dominant multi-organ condition of vascular dysplasias. We describe a 19 year old Indian female who presented with cerebral abscess secondary to paradoxical emboli from pulmonary arteriovenous malformations (PAVMs associated with HHT. Cerebral, pulmonary, hepatic and gastrointestinal involvement can be life-threatening and it is important to have lifelong follow-ups on these patients.

  12. Friedreich's Ataxia: a review from a cardiology perspective.

    LENUS (Irish Health Repository)

    Bourke, T

    2011-12-01

    Neuromuscular disorders are not among the common causes of cardiomyopathy in the general population; however, cardiomyopathy is known to occur in several neuromuscular disorders including Friedreich\\'s Ataxia (FA). In patients with neuromuscular disorders, concomitant cardiac involvement contributes significantly to morbidity and mortality and often leads to premature death.

  13. Tremor in neurodegenerative ataxias, Huntington disease and tic disorder.

    Science.gov (United States)

    Rudzińska, M; Krawczyk, M; Wójcik-Pędziwiatr, M; Szczudlik, A; Tomaszewski, T

    2013-01-01

    Tremor is the most prevalent movement disorder, defined as rhythmic oscillations of a body part, caused by alternating or synchronic contractions of agonistic or antagonistic muscles. The aim of the study was to assess prevalence and to characterize parameters of tremor accompanying de-generative ataxias, Huntington disease (HD) and tic disorders in comparison with a control group. Forty-three patients with degenerative ataxias, 28 with HD and 26 with tic disorders together with 51 healthy controls were included in the study. For each participant, clinical and instrumental assessment (accelerometer, electromyography [EMG], graphic tablet) of hand tremor was performed. Frequency and severity of tremor were assessed in three positions: at rest (rest tremor), with hands extended (postural tremor), during the 'finger-to-nose' test and during Archimedes spiral drawing (kinetic tremor). Based on the mass load test, the type of tremor was determined as essential tremor type or enhanced physiological tremor type. The incidence of tremor in the accelerometry in patients with degenerative ataxia (50%) significantly differs from controls (10%) (p = 0.001). The dominant tremor was postural, low-intense, with 7-Hz frequency, essential tremor (23%) or other tremor type (23%), while enhanced physiological tremor was the least frequent (2%). Tremor in patients with HD and tic disorders was found in 10% and 20% of patients, respectively, similarly to the control group. Tremor was mild, postural and of essential tremor type, less frequently of enhanced physiological tremor type. No correlation between severity of tremor and severity of disease was found. The prevalence of tremor is considerably higher among patients with degenerative ataxias compared with HD, tic disorder and the control group. The most common type of tremor accompanying ataxias, HD and tic disorders is essential tremor type.

  14. Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases

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    Albano Lilian M. J.

    2001-01-01

    Full Text Available INTRODUCTION: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a early age of onset (< 20 or 25 years, b autosomal recessive inheritance, c progressive ataxia of limbs and gait, and d absence of lower limb tendon reflexes. METHODS: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia - 19 typical and 6 atypical - using a long-range PCR test. RESULTS: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68% - all typical cases. In 8 patients (32% (6 atypical and 2 typical, no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions. DISCUSSION: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion.

  15. Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

    Science.gov (United States)

    2017-09-28

    -epilepsy-intellectual Disability Syndrome Due to TUD Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to KIAA0226 Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome; Autosomal Recessive Cerebellar Ataxia With Late-onset Spasticity; Autosomal Recessive Cerebellar Ataxia Due to STUB1 Deficiency; Autosomal Recessive Cerebellar Ataxia Due to a DNA Repair Defect; Autosomal Recessive Cerebellar Ataxia - Saccadic Intrusion; Autosomal Recessive Cerebellar Ataxia - Psychomotor Retardation; Autosomal Recessive Cerebellar Ataxia - Blindness - Deafness; Autosomal Recessive Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to a Polyglutamine Anomaly; Autosomal Dominant Spinocerebellar Ataxia Due to a Point Mutation; Autosomal Dominant Spinocerebellar Ataxia Due to a Channelopathy; Autosomal Dominant Spastic Ataxia Type 1; Autosomal Dominant Spastic Ataxia; Autosomal Dominant Optic Atrophy; Ataxia-telangiectasia Variant; Ataxia-telangiectasia; Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy; Autosomal Dominant Cerebellar Ataxia Type 4; Autosomal Dominant Cerebellar Ataxia Type 3; Autosomal Dominant Cerebellar Ataxia Type 2; Autosomal Dominant Cerebellar Ataxia Type 1; Autosomal Dominant Cerebellar Ataxia; Ataxia-telangiectasia-like Disorder; Ataxia-intellectual Disability-oculomotor Apraxia-cerebellar Cysts Syndrome; Ataxia-deafness-intellectual Disability Syndrome; Ataxia With Vitamin E Deficiency; Ataxia With Dementia; Ataxia Neuropathy Spectrum; Ataxia - Tapetoretinal Degeneration; Ataxia - Photosensitivity - Short Stature; Ataxia - Pancytopenia; Ataxia - Oculomotor Apraxia Type 1; Ataxia - Hypogonadism - Choroidal Dystrophy; Ataxia - Other; Ataxia - Genetic Diagnosis - Unknown; Acquired Ataxia; Adult-onset Autosomal Recessive Cerebellar Ataxia; Alcohol Related Ataxia; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type II; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine

  16. Expression of Caytaxin protein in Cayman Ataxia mouse models correlates with phenotype severity.

    Directory of Open Access Journals (Sweden)

    Kristine M Sikora

    Full Text Available Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcay(jit (jittery and Atcay(swd (sidewinder mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcay(ji-hes (hesitant line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin's physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin's role in maintaining normal neuronal function.

  17. Characteristics of gait ataxia in δ2 glutamate receptor mutant mice, ho15J.

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    Eri Takeuchi

    Full Text Available The cerebellum plays a fundamental, but as yet poorly understood, role in the control of locomotion. Recently, mice with gene mutations or knockouts have been used to investigate various aspects of cerebellar function with regard to locomotion. Although many of the mutant mice exhibit severe gait ataxia, kinematic analyses of limb movements have been performed in only a few cases. Here, we investigated locomotion in ho15J mice that have a mutation of the δ2 glutamate receptor. The cerebellum of ho15J mice shows a severe reduction in the number of parallel fiber-Purkinje synapses compared with wild-type mice. Analysis of hindlimb kinematics during treadmill locomotion showed abnormal hindlimb movements characterized by excessive toe elevation during the swing phase, and by severe hyperflexion of the ankles in ho15J mice. The great trochanter heights in ho15J mice were lower than in wild-type mice throughout the step cycle. However, there were no significant differences in various temporal parameters between ho15J and wild-type mice. We suggest that dysfunction of the cerebellar neuronal circuits underlies the observed characteristic kinematic abnormality of hindlimb movements during locomotion of ho15J mice.

  18. New insights into the pathogenesis and therapeutics of Episodic Ataxia type 1.

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    Maria Cristina D'Adamo

    2015-08-01

    Full Text Available Episodic ataxia type 1 (EA1 is a K+ channelopathy characterized by a broad spectrum of symptoms. Generally, patients may experience constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks additional symptoms may be reported such as vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing. These episodes may be precipitated by anxiety, emotional stress, fatigue, startle response or sudden postural changes. Epilepsy is overrepresented in EA1. The disease is inherited in an autosomal dominant manner, and genetic analysis of several families has led to the discovery of a number of point mutations in the voltage-dependent K+ channel gene KCNA1 (Kv1.1, on chromosome 12p13. To date KCNA1 is the only gene known to be associated with EA1. Functional studies have shown that these mutations impair Kv1.1 channel function with variable effects on channel assembly, trafficking and biophysics. Despite the solid evidence obtained on the molecular mechanisms underlying EA1, how these cause dysfunctions within the central and peripheral nervous systems circuitries remains elusive. This review summarizes the main breakthrough findings in EA1, discusses the neurophysiological mechanisms underlying the disease, current therapies, future challenges and opens a window onto the role of Kv1.1 channels in CNS and PNS functions.

  19. A 70-year-old male with peripheral neuropathy, ataxia and antigliadin antibodies shows improvement in neuropathy, but not ataxia, after intravenous immunoglobulin and gluten-free diet

    Directory of Open Access Journals (Sweden)

    Dharshan Anandacoomaraswamy

    2008-10-01

    Full Text Available Dharshan Anandacoomaraswamy1, Jagdeesh Ullal2, Aaron I Vinik21Department of Internal Medicine, Coney Island Hospital, Brooklyn, NY, USA; 2Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USAAbstract: This is a case of a 70-year-old man with severe peripheral neuropathy, type 2 diabetes and progressively worsening cerebellar ataxia. He was found to have circulating antigliadin and antireticulin antibodies compatible with celiac disease in the absence of intestinal pathology. The peripheral neuropathy improved with a gluten-free diet, antioxidants and intravenous immunoglobulin, whereas the ataxia did not. This case illustrates the need to test for celiac disease in patients with idiopathic ataxia and peripheral neuropathy and the need for alternative therapies for ataxia. Keywords: celiac disease, peripheral neuropathy, autoimmune disease, cerebellar ataxia, type 2 diabetes

  20. [Spinocerebellar ataxia type 2 associated to pigmentary retinitis].

    Science.gov (United States)

    Jiménez-Caballero, Pedro Enrique; Serviá, Mónica

    2010-07-01

    Ocular disorders are useful in the characterisation of the different types of spinocerebellar ataxias (SCA); pigmentary retinitis is an alteration that is specifically associated to SCA type 7 and is characterised by night blindness, sensitivity to glare and progressive narrowing of the visual field. A 34-year-old woman with clinical symptoms of progressive ataxia and visual impairment secondary to pigmentary retinitis. The patient had a personal history with an autosomal dominant pattern of a similar disorder in her father and paternal grandmother. In the genetic study she presented a triplet expansion in the SCA type 2 gene. CONCLUSIONS; Although pigmentary retinitis belongs to the SCA type 7 phenotype, our patient presented this retinal disorder, as in other cases of SCA type 2. A genetic study for SCA type 2 must therefore be conducted in patients with a degenerative ataxic clinical picture and who present evidence of pigmentary retinitis.

  1. Spinocerebellar ataxia type 7: Report of an Indian family

    Directory of Open Access Journals (Sweden)

    Gurusidheshwar M Wali

    2013-01-01

    Full Text Available Spinocerebellar ataxia type 7 (SCA7 is a form of autosomal dominant cerebellar ataxia which is associated with pigmentary retinal degeneration. It is known for its world-wide rarity except in the Scandinavian countries. It is very rarely reported from India and the neighbouring Asian countries . The present report describes the neurogenetic findings of a family of SCA7, from the northern part of Karnataka in South India. It documents the wide intrafamilial phenotypic variability, which could be correlated with the CAG repeat counts and phenomenon of anticipation. Genotype phenotype correlation highlighted certain disparities in comparison with the previous studies. The report highlights the need for multiethnic population studies and the role of genetic counseling and prenatal testing in SCA7 patients.

  2. Transient cerebellopontine demyelinisation revealed by MRI in acute cerebellar ataxia

    International Nuclear Information System (INIS)

    Aufricht, C.A.; Tenner, W.; Rosenmayr, F.; Stiglbauer, R.

    1990-01-01

    An eight year old boy was admitted to our ward with a history of abrupt onset of rapidly progressive gait disorder, nausea, vertigo and vomiting. The clinical as well as the laboratory findings suggested the diagnosis of acute cerebellar ataxia. Magnetic resonance imaging (MRI), however, showed marked demyelinisation in the cerebellar region and visual evoked potentials were pathologic. After immunosuppression the patient promptly improved clinically and the lesions depicted by MRI disappeared almost completely. (orig.)

  3. A longitudinal study of the Friedreich Ataxia Impact Scale.

    Science.gov (United States)

    Tai, Geneieve; Yiu, Eppie M; Corben, Louise A; Delatycki, Martin B

    2015-05-15

    Quality of life in Friedreich ataxia (FRDA) has been explored using various generic health status measurement tools, most commonly the Short Form Health Survey Version 2 (SF-36v2). The tool did not address many specific issues related to disease impact in people with FRDA. The Friedreich Ataxia Impact Scale (FAIS) was developed to examine clinically relevant areas in FRDA. The aims of the current study were to assess the relationship between the FAIS and clinical characteristics of FRDA, as well as to determine the responsiveness of the FAIS to change over one and two years. One hundred and four individuals with FRDA, homozygous for the GAA expansion in intron 1 of FXN, completed the FAIS at baseline. Seventy individuals completed the FAIS again 12 months later and 49 completed the FAIS at 24 months. Clinical parameters and neurologic scales (Friedreich Ataxia Rating Scale (FARS)) were also recorded. The total FARS score, onset age and disease duration correlated significantly with FAIS subscales measuring symptoms and physical functioning. The physical and mental summary measures of the SF-36 V2 also correlated well with the FAIS subscales. Speech was the only subscale that demonstrated significant change over one and two years. The FAIS provides valuable insight into the perspective of individuals with FRDA on their health status, and is an important measure of morbidity. It has, however, limited responsiveness to change and its use in intervention studies is questionable. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Hereditary Hemorrhagic Telangiectasia Presenting as High Output Cardiac Failure during Pregnancy

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    Tareq Goussous

    2009-01-01

    Full Text Available High-output cardiac failure secondary to hepatic involvement is a rare complication of hereditary hemorrhagic telangiectasia (HHT. Here we report a 43-year-old woman who presented at 29 weeks gestation of her second pregnancy with complications of right-sided heart failure and preterm labor. After delivery via cesarean section, the patient was found to have intrahepatic arteriovenous malformations through non-invasive imaging. Subsequently, a family history of vascular malformations and epistaxis was elucidated and a diagnosis of HHT was made. This case is presented, along with a review of the literature and discussion of hepatic involvement in HHT with particular focus on the pregnant patient.

  5. Hereditary hemorrhagic telangiectasia: progress of diagnostic imaging and vascular therapeutic embolization

    International Nuclear Information System (INIS)

    Lu Chuan; Liu Zuoqin

    2008-01-01

    Hereditary haemorrhagic telangiectasia (HHT) is a genetic autosomal-dominant disorder characterized by the presence of epistaxis, vascular telangiectasis in mucosal and cutaneous tissues, with visceral lesions and family history. However, many specialists or radiologists are still in lack of appreciation concerning the full range of consequences in diagnosis and their family relationship resulting the poor recognition of the disease. Understanding the diagnostic imaging and therapeutic measure for HHT will be critical, because of the continuous growth and risk existance of these arteriovenous malformations arousing early diagnosis, proper treatment, adequate follow-up and screening of the family. (authors)

  6. Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14.

    Science.gov (United States)

    Ji, Jingmin; Hassler, Melanie L; Shimobayashi, Etsuko; Paka, Nagendher; Streit, Raphael; Kapfhammer, Josef P

    2014-10-01

    Spinocerebellar ataxias (SCAs) are hereditary diseases leading to Purkinje cell degeneration and cerebellar dysfunction. Most forms of SCA are caused by expansion of CAG repeats similar to other polyglutamine disorders such as Huntington's disease. In contrast, in the autosomal dominant SCA-14 the disease is caused by mutations in the protein kinase C gamma (PKCγ) gene which is a well characterized signaling molecule in cerebellar Purkinje cells. The study of SCA-14, therefore, offers the unique opportunity to reveal the molecular and pathological mechanism eventually leading to Purkinje cell dysfunction and degeneration. We have created a mouse model of SCA-14 in which PKCγ protein with a mutation found in SCA-14 is specifically expressed in cerebellar Purkinje cells. We find that in mice expressing the mutated PKCγ protein the morphology of Purkinje cells in cerebellar slice cultures is drastically altered and mimics closely the morphology seen after pharmacological PKC activation. Similar morphological abnormalities were seen in localized areas of the cerebellum of juvenile transgenic mice in vivo. In adult transgenic mice there is evidence for some localized loss of Purkinje cells but there is no overall cerebellar atrophy. Transgenic mice show a mild cerebellar ataxia revealed by testing on the rotarod and on the walking beam. Our findings provide evidence for both an increased PKCγ activity in Purkinje cells in vivo and for pathological changes typical for cerebellar disease thus linking the increased and dysregulated activity of PKCγ tightly to the development of cerebellar disease in SCA-14 and possibly also in other forms of SCA. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia.

    Science.gov (United States)

    Piguet, Françoise; de Montigny, Charline; Vaucamps, Nadège; Reutenauer, Laurence; Eisenmann, Aurélie; Puccio, Hélène

    2018-05-28

    Friedreich ataxia (FA) is a rare mitochondrial disease characterized by sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy, and diabetes, for which there is no treatment. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin-positive cells that recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, although fully dysfunctional, proprioceptive neurons can survive for many weeks without frataxin. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue of the sensory neuropathy associated with frataxin deficiency, thus establishing the pre-clinical proof of concept for the potential of gene therapy in treating FA neuropathy. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  8. Fragile X-associated tremor/ataxia syndrome: An under-recognised cause of tremor and ataxia.

    Science.gov (United States)

    Kalus, Sarah; King, John; Lui, Elaine; Gaillard, Frank

    2016-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X "premutation", defined as 55-200 CGG repeats in the 5'-untranslated region of the FMR1 gene. The FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40-45% of male and 8-16% of female premutation carriers over the age of 50. FXTAS typically presents with kinetic tremor and cerebellar ataxia. FXTAS has a classical imaging profile which, in concert with clinical manifestations and genetic testing, participates vitally in its diagnosis. The revised FXTAS diagnostic criteria include two major radiological features. The "MCP sign", referring to T2 hyperintensity in the middle cerebellar peduncle, has long been considered the radiological hallmark of FXTAS. Recently included as a major radiological criterion in the diagnosis of FXTAS is T2 hyperintensity in the splenium of the corpus callosum. Other imaging features of FXTAS include T2 hyperintensities in the pons, insula and periventricular white matter as well as generalised brain and cerebellar atrophy. FXTAS is an under-recognised and misdiagnosed entity. In patients with unexplained tremor, ataxia and cognitive decline, the presence of middle cerebellar peduncle and/or corpus callosum splenium hyperintensity should raise suspicion of FXTAS. Diagnosis of FXTAS has important implications not only for the patient but also, through genetic counselling and testing, for future generations. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Appreciating the broad clinical features of SMAD4 mutation carriers: a multi-center chart review

    OpenAIRE

    Wain, K.E.; Ellingson, M.S.; McDonald, J.; Gammon, A.; Roberts, M.; Pichurin, P.; Winship, I.; Riegert-Johnson, D.; Weitzel, J. N.; Lindor, N.M.

    2014-01-01

    Heterozygous loss-of-function (LOF) SMAD4 mutations are associated with juvenile polyposis syndrome (JP) and hereditary hemorrhagic telangiectasia (HHT). Some carriers exhibit symptoms of both conditions, leading to the name JP-HHT syndrome. Three families have been reported with connective tissue abnormalities. In order to better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. ...

  10. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia

    Directory of Open Access Journals (Sweden)

    Arvind Chaturvedi

    2011-01-01

    Full Text Available Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and vomiting along with severe vertigo, ataxia and hypertension. Neurological evaluation was normal except for the presence of vertigo and ataxia. Computerised tomography scan brain was also normal. Patient was admitted for observation and symptomatic treatment was given. Vertigo and ataxia gradually improved over 24 hours.

  11. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia.

    Science.gov (United States)

    Chaturvedi, Arvind; Dash, Hh

    2011-07-01

    Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and vomiting along with severe vertigo, ataxia and hypertension. Neurological evaluation was normal except for the presence of vertigo and ataxia. Computerised tomography scan brain was also normal. Patient was admitted for observation and symptomatic treatment was given. Vertigo and ataxia gradually improved over 24 hours.

  12. SACS gene-related autosomal recessive spastic ataxia of Charlevoix-Saguenay from South India

    Directory of Open Access Journals (Sweden)

    M Suraj Menon

    2016-01-01

    Full Text Available Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS is a neurodegenerative disorder characterized by late infantile onset spastic ataxia and other neurological features. Initially described in the Charlevoix-Saguenay region of Quebec, Canada, it is being increasingly reported from many other countries. Here, we present the case of a 20-year-old male from South India, who presented with progressive ataxia, spasticity, and peripheral neuropathy with imaging features and genetic testing suggestive of SACS gene-related ARSACS. The phenotypic variability from other cases and occurrence in a geographically distinct region is stressed upon to alert the clinicians to consider ARSACS in progressive ataxias.

  13. Abnormal brain MRI in a case of acute ataxia as the only sign of abdominal neuroblastoma

    International Nuclear Information System (INIS)

    Molla Mohammadi, M.; Karimzadeh, P.; Khatami, A.; Jadali, F.

    2010-01-01

    Ataxia is a movement disorder that may manifest an acute, intermittent, non progressive or chronic progressive course. Ataxia alone is rare as a para neoplastic sign, especially if it is due to neuroblastoma (abdominal or chest). We report an abdominal neuroblastoma in a two-year-old girl presenting with only acute ataxia and abnormal neuroimaging. Brain MRI showed abnormal signal finding in the medulla, pons, cortico spinal tract and the periventricular space. In the abdominal CT, a mass was detected in the right adrenal gland with calcification and the histopathologic examination re-vealed neuroblastoma. We suggest in children with acute ataxia, with or without opalescence-myoclonus, neuroblastoma should be considered.

  14. Multimodality imaging in macular telangiectasia 2: A clue to its pathogenesis

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    Lihteh Wu

    2015-01-01

    Full Text Available Macular telangiectasia type 2 also known as idiopathic perifoveal telangiectasia and juxtafoveolar retinal telangiectasis type 2A is an acquired bilateral neurodegenerative macular disease that manifests itself during the fifth or sixth decades of life. It is characterized by minimal dilatation of the parafoveal capillaries with graying of the retinal area involved, a lack of lipid exudation, right-angled retinal venules, refractile deposits in the superficial retina, hyperplasia of the retinal pigment epithelium, foveal atrophy, and subretinal neovascularization (SRNV. Our understanding of the disease has paralleled advances in multimodality imaging of the fundus. Optical coherence tomography (OCT images typically demonstrate the presence of intraretinal hyporeflective spaces that are usually not related to retinal thickening or fluorescein leakage. The typical fluorescein angiographic (FA finding is a deep intraretinal hyperfluorescent staining in the temporal parafoveal area. With time, the staining may involve the whole parafoveal area but does not extend to the center of the fovea. Long-term prognosis for central vision is poor, because of the development of SRNV or macular atrophy. Its pathogenesis remains unclear but multimodality imaging with FA, spectral domain OCT, adaptive optics, confocal blue reflectance and short wave fundus autofluorescence implicate Müller cells and macular pigment. Currently, there is no known treatment for this condition.

  15. Hereditary hemorrhagic telangiectasia with bilateral pulmonary vascular malformations: A case report

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    Lončarević Olivera

    2016-01-01

    Full Text Available Introduction. Hereditary hemorrhagic telangiectasia (HHT also known as Osler-Weber-Rendu syndrome is an autosomal dominant disease that occurs due to vascular dysplasia associated with the disorder in the signaling pathway of transforming growth factor β (TGF-β. The clinical consequence is a disorder of blood vessels in multiple organ systems with the existence of telangiectasia which causes dilation of capillaries and veins, are present from birth and are localized on the skin and mucosa of the mouth, respiratory, gastrointestinal and urinary tract. They can make a rupture with consequent serious bleeding that can end up with fatal outcome. Since there is a disruption of blood vessels of more than one organic system, the diagnosis is very complex and requires a multidisciplinary approach. Case report. We reported a 40-year-old female patient with a long-time evolution of problems, who was diagnosed and treated at the Clinic for Lung Diseases of the Military Medical Academy in Belgrade, Serbia, because of bilaterally pulmonary arteriovenous malformations associated with HHT. Embolization was performed in two acts, followed with normalization of clinical, radiological and functional findings with the cessation of hemoptysis, effort intolerance with a significant improvement of the quality of life. Conclusion. HHT is a rare dominant inherited multisystem disease that requires multidisciplinary approach to diagnosis and treatment. Embolization is the method of choice in the treatment of arteriovenous malformations with minor adverse effects and very satisfying therapeutic effect.

  16. Telangiectasia hemorrágica hereditária e malformações arteriovenosas pulmonares - Embolização com rolhão vascular Amplatzer Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations - Embolization with Amplatzer vascular plug

    Directory of Open Access Journals (Sweden)

    Cláudia Sofia Santos

    2009-03-01

    Full Text Available As malformações arteriovenosas pulmonares (MAVP estão associadas a telangiectasia hemorrágica hereditária em cerca de 70% dos casos, podendo cursar com complicações neurológicas graves decorrentes do embolismo paradoxal potencial. A terapêutica das malformações é realizada no sentido de prevenir estas complicações. Descreve-se o caso clínico de uma doente com duas MAVP, no contexto de telangiectasia hemorrágica hereditária,submetida a embolização com o rolhão vascular Amplatzer. Este novo dispositivo é cada vez mais utilizado nestas situações, salientando-se algumas das suas características e vantagens em relação a outras técnicas de embolização mais frequentemente utilizadas.Pulmonary arteriovenous malformations (PAVMs are associated to hereditary hemorrhagic telangiectasia in about 70% of the cases. PAVMs are associated to serious neurologic complications, secondary to inherent paradoxical embolisms. Treatment of the malformations is done to prevent these complications. The authors report a clinical case of a patient with two PAVMs, with hereditary hemorrhagic telangiectasia, who was treated by embolization with na Amplatzer vascular plug, a new device increasingly used in these situations. The authors emphasise some of its characteristics and advantages when compared with other embolization techniques most commonly used.

  17. Using the ultra-long pulse width pulsed dye laser and elliptical spot to treat resistant nasal telangiectasia.

    Science.gov (United States)

    Madan, Vishal; Ferguson, Janice

    2010-01-01

    Thick linear telangiectasia on the ala nasi and nasolabial crease can be resistant to treatment with the potassium-titanyl-phosphate (KTP) laser and the traditional round spot on a pulsed dye laser (PDL). We evaluated the efficacy of a 3 mm x 10 mm elliptical spot using the ultra-long pulse width on a Candela Vbeam(R) PDL for treatment of PDL- and KTP laser-resistant nasal telangiectasia. Nasal telangiectasia resistant to PDL (12 patients) and KTP laser (12 patients) in 18 patients were treated with a 3 mm x 10 mm elliptical spot on the ultra-long pulse pulsed dye laser (ULPDL) utilising long pulse width [595 nm, 40 ms, double pulse, 30:20 dynamic cooling device (DCD)]. Six patients had previously received treatment with both PDL and KTP laser prior to ULPDL (40 treatments, range1-4, mean 2.2). Complete clearance was seen in ten patients, and eight patients displayed more than 80% improvement after ULPDL treatment. Self-limiting purpura occurred with round spot PDL and erythema with KTP laser and ULPDL. Subtle linear furrows along the treatment sites were seen in three patients treated with the KTP laser. ULPDL treatment delivered using a 3 mm x 10 mm elliptical spot was non-purpuric and highly effective in the treatment of nasal telangiectasia resistant to KTP laser and PDL.

  18. Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age. Review of 50 consecutive patients aged 1 day-60 years

    International Nuclear Information System (INIS)

    Krings, T.; Ozanne, A.; Chng, S.M.; Alvarez, H.; Lasjaunias, P.L.; Rodesch, G.

    2005-01-01

    Hereditary haemorrhagic telangiectasia (HHT) is inherited as an autosomal dominant trait with varying penetrance and expressivity. Some of the most devastating consequences of this disease result from cerebral vascular malformations that manifest themselves in either arteriovenous fistulae (AVF), small nidus-type arteriovenous malformations (AVM) or micro-AVMs with a nidus less than 1 cm in size. The purpose of this study was to compare the phenotypes of CNS-manifestations of HHT with the age of the patient. The charts and angiographic films of 50 patients diagnosed with HHT according to the Curacao criteria were retrospectively evaluated concerning age of onset of symptoms, or, if not applicable of first consultation. The files were reviewed for clinical presentation, family and personal history, while the patients' angiograms were analysed with respect to the number of lesions (single and multiple), the location (superficial supratentorial, deep supratentorial, infratentorial, and spinal), and type of lesion (fistulous AVM, nidus-type AVM, and micro-AVM). A total of 75 central nervous system manifestations of HHT were found. Lesions included seven spinal cord AVFs that were all present in the paediatric age group (mean age: 2.2 years), 34 cerebral AV fistulae, all but two affected patients were less than 6 years (mean age 3.0). Sixteen nidus type AVMs (mean age: 23.1 years) and 18 micro-AVMs (mean age: 31.8 years) were found. HHT displays an age-related penetrance of clinical manifestations. Since members of the same family can present with completely different phenotypes of this disease there seems to be no relationship between the type of mutation and the phenotype of the disease. Since there seems to be a continuum of vascular abnormalities (from large fistulous areas to small AVMs and micro-AVMs) associated with HHT, the most likely determinating factor of the HHT phenotype is the timing of the revealing event in relation to the maturity of the vessel

  19. A new mutation in the prion protein gene: A patient with dementia and white matter changes

    NARCIS (Netherlands)

    Van Harten, B.; Van Gool, W.A.; Van Langen, I.M.; Deekman, J.M.; Meijerink, P.H.S.; Weinstein, H.C.

    2000-01-01

    The authors describe the clinical characteristics, MRI abnormalities, and molecular findings in a patient with a novel variant of a two-octarepeat insertion mutation in the prion protein gene. This patient presented with moderately progressive dementia of presenile onset and gait ataxia. MRI showed

  20. Ataxia cerebelar aguda na criança

    Directory of Open Access Journals (Sweden)

    Valeriana Moura Ribeiro

    1968-03-01

    Full Text Available São relatados os casos de 6 crianças com ataxia cerebelar aguda. Admitem os autores a presença de um fator etiológico de caráter viral comum a todos êles, discutindo os mecanismos patogênicos com base nos casos da literatura. A evolução foi favorável em todos os pacientes, com regressão completa da sintomatologia, dentro do período de 6 a 60 dias.

  1. The cardiomyopathy in Friedreich's ataxia: isotopic ventriculography and myocardial imaging with thallium-201

    International Nuclear Information System (INIS)

    Therriault, L.; Lamoureux, G.; Cote, M.; Plourde, G.; Lemieux, B.

    1984-01-01

    Myocardial scanning after the intravenous administration of Thallium 201 was used to evaluate regional myocardial perfusion in 14 patients with Friedreich's ataxia. Isotopic ventriculography was also used to assess left ventricular contractility. Myocardial images in patients with Friedreich's ataxia were found to be precociously abnormal irrespective of the degree of neurological impairment or of the severity of myocardial hypertrophy

  2. There May Be More to Reaching than Meets the Eye: Re-Thinking Optic Ataxia

    Science.gov (United States)

    Jackson, Stephen R.; Newport, Roger; Husain, Masud; Fowlie, Jane E.; O'Donoghue, Michael; Bajaj, Nin

    2009-01-01

    Optic ataxia (OA) is generally thought of as a disorder of visually guided reaching movements that cannot be explained by any simple deficit in visual or motor processing. In this paper we offer a new perspective on optic ataxia; we argue that the popular characterisation of this disorder is misleading and is unrepresentative of the pattern of…

  3. Genetics Home Reference: fragile X-associated tremor/ataxia syndrome

    Science.gov (United States)

    ... Share: Email Facebook Twitter Home Health Conditions FXTAS Fragile X-associated tremor/ataxia syndrome Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description Fragile X-associated tremor/ataxia syndrome ( FXTAS ) is characterized by ...

  4. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review.

    Science.gov (United States)

    Wain, Karen E; Ellingson, Marissa S; McDonald, Jamie; Gammon, Amanda; Roberts, Maegan; Pichurin, Pavel; Winship, Ingrid; Riegert-Johnson, Douglas L; Weitzel, Jeffrey N; Lindor, Noralane M

    2014-08-01

    Heterozygous loss-of-function SMAD4 mutations are associated with juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. Some carriers exhibit symptoms of both conditions, leading to juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome. Three families have been reported with connective tissue abnormalities. To better understand the spectrum and extent of clinical findings in SMAD4 carriers, medical records of 34 patients (20 families) from five clinical practices were reviewed. Twenty-one percent of the patients (7/34) had features suggesting a connective tissue defect: enlarged aortic root (n = 3), aortic and mitral insufficiency (n = 2), aortic dissection (n = 1), retinal detachment (n = 1), brain aneurysms (n = 1), and lax skin and joints (n = 1). Juvenile polyposis-specific findings were almost uniformly present but variable. Ninety-seven percent of the patients had colon polyps that were generally pan-colonic and of variable histology and number. Forty-eight percent of the patients (15/31) had extensive gastric polyposis. Hereditary hemorrhagic telangiectasia features, including epistaxis (19/31, 61%), mucocutaneous telangiectases (15/31, 48%), liver arteriovenous malformation (6/16, 38%), brain arteriovenous malformation (1/26, 4%), pulmonary arteriovenous malformation (9/17, 53%), and intrapulmonary shunting (14/23, 61%), were documented in 76% of the patients. SMAD4 carriers should be managed for juvenile polyposis and hereditary hemorrhagic telangiectasia because symptoms of both conditions are likely yet unpredictable. Connective tissue abnormalities are an emerging component of juvenile polyposis-hereditary hemorrhagic telangiectasia syndrome, and larger studies are needed to understand these manifestations.

  5. Ataxia cerebelosa persistente despues de la administracion toxica de difenilhidantoina

    Directory of Open Access Journals (Sweden)

    Andrés M. Villa

    1994-12-01

    Full Text Available La intoxicacion cronica con difenilhidantoina (DFH es bien conocida como causa de ataxia irreversible en pacientes epilépticos debida a atrofia cerebelosa con perdida de células de Purkinje. No es asi con la intoxicación aguda, puesto que sus signos y síntomas son reversibles. Presentamos un paciente con convulsiones parciales complejas, secundarias a un quiste temporal, que habia sido tratado irregularmente con DFH durante dos años con dosis variables que oscilaban en los 100 mg/dia. Dada la refractariedad de su cuadro convulsivo en una entrevista previa a su ingreso se le indico un aumento brusco de la dosis del fármaco que alcanzo a los 400 mg/dia. Ello ocasiono un sindrome pancerebeloso severo que motivo su internación. Posteriormente a la suspension de la DFH y la exeresis del quiste temporal mejoro su cuadro convulsivo, aunque quedo con ataxia de miembros inferiores y asinergia de tronco, cuadro con el que fue dado de alta. Un año despues, el paciente se encontraba libre de convulsiones, pero su sindrome cerebeloso no se habia modificado. El estudio por imágenes no evidencio atrofia cerebelosa.

  6. Cerebellar ataxia of early onset. Clinical symptoms and MRI findings

    Energy Technology Data Exchange (ETDEWEB)

    Yamashita, Sumimasa; Miyake, Shota; Yamada, Michiko; Iwamoto, Hiroko (Kanagawa Children' s Medical Center, Yokohama (Japan)); Yamada, Kazuhiko

    1989-07-01

    Eight cases of childhood cerebellar ataxia were reported. All these cases showed chronic cerebellar ataxia with early onset, and the other diseases of cerebellum such as infections, neoplasms and storage diseases were excluded by clinical symptoms and laboratory findings including blood counts, blood chemistry, lactate, pyruvate, ceruloplasmine, urinalysis, serum immunoglobulins, amino acid analysis in blood and urine, CSF analysis, leukocyte lysosomal enzymes, MCV, EMG, EEG and brain X-CT. Two pairs of siblings were included in this study. The clinical diagnosis were cerebellar type (5), spinocerebellar type (1), one Marinesco-Sjoegren syndrome and undetermined type (1). The age of onset was 1 to 5 years. The chief complaint was motor developmental delay in 6 cases; among them 5 patients could walk alone at the ages of 2 to 3 years'. Mental retardation was observed in 7 cases and epilepsy in 2. TRH was effective in 5 cases. The MRI study revealed that the area of medial sagittal slice of the cerebellum was reduced significantly in all cases and also that of pons was reduced in 5 cases. Different from typical adult onset spinocerebellar degenerations, most of the present cases have achieved slow developmental milestones and the clinical course was not progressive. Genetic factors are suspected in the pathogenesis of this disease in some cases. (author).

  7. Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia.

    Science.gov (United States)

    Corben, Louise A; Klopper, Felicity; Stagnitti, Monique; Georgiou-Karistianis, Nellie; Bradshaw, John L; Rance, Gary; Delatycki, Martin B

    2017-08-01

    Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with subtle impact on cognition. Inhibitory processes and cognitive flexibility were examined in FRDA by assessing the ability to suppress a predictable verbal response. We administered the Hayling Sentence Completion Test (HSCT), the Trail Making Test, and the Stroop Test to 43 individuals with FRDA and 42 gender- and age-matched control participants. There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion.

  8. Enfermedad cardiovascular en pacientes cubanos afectados por Ataxia de Friedreich.

    Directory of Open Access Journals (Sweden)

    Tania Cruz Mariño

    2010-01-01

    Full Text Available Al describir la ataxia de Friedreich, Nicholaus hizo referencia a la patología cardiaca. Esta enfermedad autosómica recesiva se debe a una mutación dinámica en el gen FRDA, codificándose deficientemente la proteína Frataxina, conduciendo a estrés oxidativo y muerte celular cardiaca. La presente investigación se desarrolló con el objetivo de describir las anomalías cardiovasculares presentes en los pacientes cubanos afectados por ataxia de Friedreich. A los individuos con diagnóstico molecular confirmatorio de la enfermedad se les realizó electrocardiograma y ecocardiograma, así como evaluación clínica mediante escalas validadas internacionalmente: ICARS y SARA. Los trastornos de repolarización ventricular difusos, los trastornos de conducción intraauricular, así como los trastornos de la función diastólica resultaron hallazgos frecuentes. El patrón restrictivo apreciado provee evidencia invivo de que la enfermedad conduce a disfunción diastólica del ventrículo izquierdo. La ocurrencia de un Infarto Agudo del Miocardio silente indica la importancia de identificar formas incipientes de afectación miocárdica.

  9. Dementia in Fragile X-associated Tremor/Ataxia Syndrome

    Directory of Open Access Journals (Sweden)

    Ricardo Nitrini

    Full Text Available Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

  10. Spectrum of centrosome autoantibodies in childhood varicella and post-varicella acute cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Stinton Laura M

    2003-09-01

    Full Text Available Abstract Background Sera from children with post-varicella infections have autoantibodies that react with centrosomes in brain and tissue culture cells. We investigated the sera of children with infections and post-varicella ataxia and related conditions for reactivity to five recombinant centrosome proteins: γγ-enolase, pericentrin, ninein, PCM-1, and Mob1. Methods Sera from 12 patients with acute post-varicella ataxia, 1 with post-Epstein Barr virus (EBV ataxia, 5 with uncomplicated varicella infections, and other conditions were tested for reactivity to cryopreserved cerebellum tissue and recombinant centrosome proteins. The distribution of pericentrin in the cerebellum was studied by indirect immunofluorescence (IIF using rabbit antibodies to the recombinant protein. Antibodies to phospholipids (APL were detected by ELISA. Results Eleven of 12 children with post-varicella ataxia, 4/5 children with uncomplicated varicella infections, 1/1 with post-EBV ataxia, 2/2 with ADEM, 1/2 with neuroblastoma and ataxia, and 2/2 with cerebellitis had antibodies directed against 1 or more recombinant centrosome antigens. Antibodies to pericentrin were seen in 5/12 children with post-varicella ataxia but not in any of the other sera tested. IIF demonstrated that pericentrin is located in axons and centrosomes of cerebellar cells. APL were detected in 75% of the sera from children with post-varicella ataxia and 50% of children with varicella without ataxia and in none of the controls. Conclusion This is the first study to show the antigen specificity of anti-centrosome antibodies in children with varicella. Our data suggest that children with post-varicella ataxia have unique autoantibody reactivity to pericentrin.

  11. Pregnancy and mesenchimal dysplasias (Marfan syndrome, Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia).

    Science.gov (United States)

    Radetskaya, L S; Makatsariya, A D; Bitsadze, V O; Khizroeva, J K

    2018-07-01

    The objective of this article is to attract the attention of clinical physicians to the rare but extremely relevant clinical pathology of mesenchymal dysplasias (Marfan syndrome, Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia) and especially specific characteristics of such diseases during pregnancy. Connective tissue pathology can cover different organs and systems, symptoms of the same disease can vary in different patients thus making diagnostics significantly difficult. Here clinical diagnostic criteria and methods of molecular diagnostics of diseases are described. The pathogenesis of mesenchymal dysplasias is not currently well understood. For the patients with mesenchymal dysplasias pregnancy is fraught with high risk of life-threatening complications. The preferred delivery method for such patients is caesarean section.

  12. The brain in hereditary hemorrhagic telangiectasia with pulmonary AVM: The clinical importance of paradoxical embolism

    International Nuclear Information System (INIS)

    Kim, W.S.; Kinnison, M.L.; Charnas, L.; Rosenbaum, A.E.; White, R.I. Jr.

    1986-01-01

    Despite the literature's emphasis on the presence of intracerebral vascular malformations in hereditary hemorrhagic telangiectasia (HHT), few cases have been documented. The authors prospectively evaluated brain CT scans in 29 consecutive patients with pulmonary arteriovenous malformations (AVMs) and known HHT. Fifty-five percent of the CT scans revealed the signs of embolic phenomena: infarctions (n=11) and intracerebral abscesses (n=5). In only one patient was a small enhancing vascular lesion seen. They conclude that embolic phenomena rather than vascular malformations cause the majority of abnormal CT findings in patients with HHT and pulmonary AVMs. Infarctions and intracerebral abscesses probably result from paradoxical embolization through the AVMs in the lungs. The therapeutic implications seem clear, since 55% of these patients are potentially treatable by balloon occlusion of the pulmonary AVMs

  13. Embolotherapy for pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)

    DEFF Research Database (Denmark)

    Andersen, P E; Kjeldsen, A D; Oxhøj, H

    1998-01-01

    experienced an improved functional level. One patient experienced severe pleurisy and another a rise in temperature following treatment, but otherwise no symptomatic complications were observed. CONCLUSION: Embolotherapy is a definitive treatment for PAVMs: it is very effective with a high success rate......PURPOSE: To evaluate the clinical results of embolization of pulmonary arteriovenous malformations (PAVMs) in patients with hereditary hemorrhagic telangiectasia (HHT), the Rendu-Osler-Weber syndrome. MATERIAL AND METHODS: Twelve patients in the county of Fyn, Denmark, were treated...... with transcatheter embolization of 20 PAVMs using 12 detachable silicone balloons and 26 steel coils. RESULTS: All PAVMs were completely occluded and we observed a significant rise in PaO2 after treatment and a significant decrease in right-to-left shunt estimated by contrast echocardiography. All patients...

  14. Intranasal topical estrogen in the management of epistaxis in hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Minami, Kazuhiko; Haji, Tomoyuki

    2016-01-01

    Application of topical estriol ointment is an effective treatment for hereditary hemorrhagic telangiectasia (HHT) epistaxis. HHT is an autosomal-dominant disease characterized by epistaxis in more than 96% of patients. Management of this major symptom, epistaxis, has not been standardized. This study reports experience with topical application of estriol in patients with HHT. Five patients with a confirmed diagnosis of HHT who first visited the hospital between 2012 and 2013 received 0.1% estriol ointment and were guided to apply the ointment twice daily to the anterior part of both nasal cavities. Severity of epistaxis was valued using epistaxis severity score (ESS) before and 3 months after initiating therapy. Five patients (three males, two females) received treatment. After the initiation of treatment, intensity and frequency of epistaxis became moderate in all patients. ESS decreased significantly from pre- to post-treatment (p = 0.043). No adverse events were recorded during follow-up.

  15. Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.

    Directory of Open Access Journals (Sweden)

    Stefano Lise

    Full Text Available β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5, an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1. In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.

  16. Efficacy of Intravitreal Bevacizumab in Treatment of Proliferative Type 2 Idiopathic Juxtafoveal Telangiectasia

    Directory of Open Access Journals (Sweden)

    Ökkeş Baz

    2017-06-01

    Full Text Available Objectives: To evaluate the effectiveness of intravitreal bevacizumab (IVB in patients with subretinal neovascularization secondary to type 2 juxtafoveal telangiectasia. Materials and Methods: Ten eyes of 10 patients were included in this retrospective study. All cases were treated with IVB (1.25 mg bevacizumab. Visual acuity and slit-lamp anterior and posterior segment examinations were performed at each visit. Central macular thickness (CMT and intraretinal/subretinal fluid were evaluated via spectral domain optical coherence tomography (OCT. Loss of a line in visual acuity chart and presence of fluid on OCT were defined as criteria for repeated treatment. Results: The mean age of patients was 66.0±7.0 years (56-75. The mean follow-up time was 54.7±16.0 month (24-72. The mean BCVA was 0.62±0.35 (0.00-1.00 logMAR at baseline and 0.54±0.35 (0.00-1.00 logMAR at final exam (p=0.03. The mean CMT was 251±25.4 µm at baseline and 239±39.3 µm at final exam (p=0.01. Patients received an average of 1.7±1.0 IVB injections during follow-up. At baseline, all cases had intraretinal/subretinal fluid. There was no fluid at final examination of all cases. Conclusion: IVB treatment may be effective in the treatment of subretinal neovascularization secondary to type 2 juxtafoveal telangiectasia.

  17. Hereditary hemorrhagic telangiectasia and pregnancy: potential adverse events and pregnancy outcomes

    Directory of Open Access Journals (Sweden)

    Bari O

    2017-05-01

    Full Text Available Omar Bari,1 Philip R Cohen2 1School of Medicine, University of California San Diego, La Jolla, CA, USA; 2Department of Dermatology, University of California San Diego, La Jolla, CA, USA Abstract: Hereditary hemorrhagic telangiectasia (HHT is an autosomal dominant condition with a prevalence of ~1 in 5,000 individuals. The pathophysiology of this condition centers on the lack of capillary beds between arterioles and venules, leading to direct contact between these vessels. This results in telangiectases on characteristic locations such as the face, fingers, mouth, and nasal mucosa. Visceral arteriovenous malformations (AVMs are also observed in many patients, and these are most commonly seen in the brain, gastrointestinal tract, and lungs. Liver AVMs are present in many patients with HHT, though these individuals are usually asymptomatic; however, liver AVMs may lead to serious complications, such as high output cardiac failure. Diagnosis of HHT hinges upon fulfilling three out of four criteria: family history of the condition, mucocutaneous telangiectases, spontaneous and recurrent episodes of epistaxis, and visceral AVMs. Management is guided by international consensus guidelines and targets patients’ specific AVMs. Prognosis is good, though severe complications including hemorrhage and paradoxical emboli are possible. Novel therapeutics are being explored in clinical trials; bevacizumab and pazopanib inhibit angiogenesis, while thalidomide bolsters blood vessel maturation. Pregnancy in patients with HHT is considered high risk. While the majority of pregnancies proceed normally, severe complications have been reported in some women with HHT; these include heart failure, intracranial hemorrhage, pulmonary hemorrhage, and stroke. Such complications occur most often in the second and third trimesters when maternal changes such as peripheral vasodilation and increased cardiac output are at their maximum. Awareness of the diagnosis of HHT has

  18. Experience of the Irish National Centre for hereditary haemorrhagic telangiectasia 2003-2008.

    LENUS (Irish Health Repository)

    Ni Bhuachalla, C F

    2012-01-31

    Hereditary haemorrhagic telangiectasia (HHT) is a group of autosomal dominant disorders of vascular structure. The Irish National Centre for HHT at the Mercy University Hospital, Cork, Ireland was founded in 2003. From 2003 to 2008, screening of 164 patients with contrast echocardiography, thoracic computerised tomography (CT) and cerebral magnetic resonance imaging (MRI) has identified 88 patients with definite HHT, 72 (82%) of whom had epistaxis, 70 (80%) had telangiectasia and 81 (92%) had a first-degree relative with HHT. We sought to describe the manifestations of HHT in an Irish population and to determine differences between internationally reported data. The HHT patient database was analysed to describe demographics, clinical manifestations and interventional procedures performed in all referred patients. Contrast echocardiography and\\/or CT were performed in 86 patients with definite HHT, identifying 27 patients (31%) with pulmonary arteriovenous malformations (pAVMs). Nineteen patients with single or multiple pAVMs had 28 embolisation procedures performed, with 1-6 pAVMs embolised per procedure. Cerebral MRI was performed in 78 (89%) patients and 2 (2.3%) had cerebral arteriovenous malformations (cAVMs). HHT prevalence is thought to be 1 in 2500-8000, suggesting that there are many undiagnosed cases in Irish patients. Internationally published data suggest a prevalence of 15-35% for pAVMs and 10-23% for cAVMs in patients with HHT. While the prevalence of pAVMs in our group is consistent with these data, the prevalence of cAVMs is considerably lower, suggesting that Irish patients with HHT may differ genotypically and phenotypically from those in other countries.

  19. Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C.

    Science.gov (United States)

    Koens, L H; Kuiper, A; Coenen, M A; Elting, J W J; de Vries, J J; Engelen, M; Koelman, J H T M; van Spronsen, F J; Spikman, J M; de Koning, T J; Tijssen, M A J

    2016-09-01

    Niemann-Pick type C (NP-C) is a rare autosomal recessive progressive neurodegenerative disorder caused by mutations in the NP-C 1 or 2 gene. Besides visceral symptoms, presentation in adolescent and adult onset variants is often with neurological symptoms. The most frequently reported presenting symptoms of NP-C in adulthood are psychiatric symptoms (38 %), cognitive decline (23 %) and ataxia (20 %). Myoclonus can be present, but its value in early diagnosis and the evolving clinical phenotype in NP-C is unclear. In this paper we present eight Dutch cases of NP-C of whom five with myoclonus. Eight patients with genetically confirmed NP-C were recruited from two Dutch University Medical Centers. A structured interview and neuropsychological tests (for working and verbal memory, attention and emotion recognition) were performed. Movement disorders were assessed using a standardized video protocol. Quality of life was evaluated by questionnaires (Rand-36, SIP-68, HAQ). In four of the five patients with myoclonic jerks simultaneous EEG with EMG was performed. A movement disorder was the initial neurological symptom in six patients: three with myoclonus and three with ataxia. Two others presented with psychosis. Four experienced cognitive deficits early in the course of the disease. Patients showed cognitive deficits in all investigated domains. Five patients showed myoclonic jerks, including negative myoclonus. In all registered patients EEG-EMG coherence analysis and/or back-averaging proved a cortical origin of myoclonus. Patients with more severe movement disorders experienced significantly more physical disabilities. Presenting neurological symptoms of NP-C include movement disorders, psychosis and cognitive deficits. At current neurological examination movement disorders were seen in all patients. The incidence of myoclonus in our cohort was considerably higher (63 %) than in previous publications and it was the presenting symptom in 38 %. A cortical origin

  20. JP-HHT phenotype in Danish patients with SMAD4 mutations

    DEFF Research Database (Denmark)

    Jelsig, A M; Tørring, P M; Kjeldsen, A D

    2016-01-01

    Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14......, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation...

  1. A mitochondrial tRNA(His) gene mutation causing pigmentary retinopathy and neurosensorial deafness.

    Science.gov (United States)

    Crimi, M; Galbiati, S; Perini, M P; Bordoni, A; Malferrari, G; Sciacco, M; Biunno, I; Strazzer, S; Moggio, M; Bresolin, N; Comi, G P

    2003-04-08

    We have identified a heteroplasmic G to A mutation at position 12,183 of the mitochondrial transfer RNA Histidine (tRNA(His)) gene in three related patients. These phenotypes varied according to mutation heteroplasmy: one had severe pigmentary retinopathy, neurosensorial deafness, testicular dysfunction, muscle hypotrophy, and ataxia; the other two had only retinal and inner ear involvement. The mutation is in a highly conserved region of the T(psi)C stem of the tRNA(His) gene and may alter secondary structure formation. This is the first described pathogenic, maternally inherited mutation of the mitochondrial tRNA(His) gene.

  2. Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed Espectro clínico da ataxia cerebelar de início precoce com reflexos mantidos: uma ataxia autossômica recessiva para não ser esquecida

    Directory of Open Access Journals (Sweden)

    José Luiz Pedroso

    2013-06-01

    Full Text Available Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedreich ataxia, and also to perform a clinical spectrum study of this syndrome. In this data, 12 patients from different families met all clinical features for early onset cerebellar ataxia with retained tendon reflexes. Dysarthria and cerebellar atrophy were the most common features in our sample. It is uncertain, however, whether early onset cerebellar ataxia with retained tendon reflexes is a homogeneous disease or a group of phenotypically similar syndromes represented by different genetic entities. Further molecular studies are required to provide definitive answers to the questions that remain regarding early onset cerebellar ataxia with retained tendon reflexes.As ataxias cerebelares autossômicas recessivas são um grupo heterogêneo de doenças neurológicas. Em 1981, foi descrita uma entidade neurológica incluindo ataxia cerebelar progressiva de início precoce, disartria, liberação piramidal e manutenção ou aumento dos reflexos tendíneos nos membros superiores e inferiores. Essa síndrome é conhecida como ataxia cerebelar de início precoce com reflexos mantidos. Neste artigo, o objetivo foi chamar a atenção para o diagnóstico de ataxia cerebelar de início precoce com reflexos mantidos como a segunda causa mais comum de ataxia cerebelar autossômica recessiva, após a ataxia de Friedreich, e também realizar um estudo do espectro cl

  3. Hotspots of missense mutation identify novel neurodevelopmental disorder genes and functional domains

    Science.gov (United States)

    Geisheker, Madeleine R.; Heymann, Gabriel; Wang, Tianyun; Coe, Bradley P.; Turner, Tychele N.; Stessman, Holly A.F.; Hoekzema, Kendra; Kvarnung, Malin; Shaw, Marie; Friend, Kathryn; Liebelt, Jan; Barnett, Christopher; Thompson, Elizabeth M.; Haan, Eric; Guo, Hui; Anderlid, Britt-Marie; Nordgren, Ann; Lindstrand, Anna; Vandeweyer, Geert; Alberti, Antonino; Avola, Emanuela; Vinci, Mirella; Giusto, Stefania; Pramparo, Tiziano; Pierce, Karen; Nalabolu, Srinivasa; Michaelson, Jacob J.; Sedlacek, Zdenek; Santen, Gijs W.E.; Peeters, Hilde; Hakonarson, Hakon; Courchesne, Eric; Romano, Corrado; Kooy, R. Frank; Bernier, Raphael A.; Nordenskjöld, Magnus; Gecz, Jozef; Xia, Kun; Zweifel, Larry S.; Eichler, Evan E.

    2017-01-01

    Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,689 NDD patients identified 21 new patients with identical missense mutations. One recurrent site (p.Ala636Thr) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology. PMID:28628100

  4. A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAAn Repeats Associated with Friedreich’s Ataxia

    Directory of Open Access Journals (Sweden)

    Ryan J. McGinty

    2017-09-01

    Full Text Available Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich’s ataxia. Whereas the length of an expandable repeat is the main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact the likelihood of expansions and disease progression. Detection of these modifiers may lead to understanding and treating repeat expansion diseases. Here, we describe a method for the rapid, genome-wide identification of trans modifiers for repeat expansion in a yeast experimental system. Using this method, we found that missense mutations in the endoribonuclease subunit (Ysh1 of the mRNA cleavage and polyadenylation complex dramatically increase the rate of (GAAn repeat expansions but only when they are actively transcribed. These expansions correlate with slower transcription elongation caused by the ysh1 mutation. These results reveal an interplay between RNA processing and repeat-mediated genome instability, confirming the validity of our approach.

  5. [Spinocerebellar ataxia type 8: the case of a Spanish family].

    Science.gov (United States)

    Mayo-Cabrero, D; Sánchez-Migallón, M; Cantarero, S; García-Ruiz Espiga, P J; Giménez-Pardo, A; Trujillo-Tiebas, M; Ayuso-García, C

    Dominant autosomic ataxias include a group of neurodegenerative diseases characterized by the abnormal expansion of triplets. Male aged 33, with expansion of the SCA 8 gene (100 repetitions), who presented a clinical picture compatible with a pancerebellar syndrome. The patient had been diagnosed 11 years earlier as suffering from previously of histiocytosis X. A clinico genetic study was conducted on the patient and several members of his family (parents and two sisters). Both sisters and the father were found to be carriers of the expansion (110 and 150 repetitions, respectively), and are currently asymptomatic. There is no relation between the number of repetitions and the age of onset of the disease. The normal interval in our population oscillates between 16 37 repetitions, and the pathological interval has not been well determined. There may be a relation between the SCA 8 form and histiocytosis X.

  6. Vitamin B12 deficiency presenting as acute ataxia.

    Science.gov (United States)

    Crawford, John Ross; Say, Daphne

    2013-03-26

    A previously healthy 7-year-old Caucasian boy was hospitalised for evaluation of acute ataxia and failure to thrive, initially suspicious for an intracranial mass. Weight and body mass index were below the third percentile and he demonstrated loss of joint position and vibratory sense on examination. Laboratory studies revealed megaloblastic anaemia while an initial MRI of the brain showed no evidence of mass lesions or other abnormalities. A dietary history revealed the child subscribed to a restrictive vegan diet with little to no intake of animal products or other fortified foods. The child was diagnosed with presumed vitamin B12 deficiency and was treated with intramuscular B12 injections. Neurological symptoms resolved promptly within several days after starting therapy. This case underlines the importance of assessing nutritional status in the evaluation of neurological dysfunction in the pediatric patient.

  7. Deep Brain Stimulation for the Treatment of Tremor and Ataxia Associated with Abetalipoproteinemia

    Directory of Open Access Journals (Sweden)

    Antonios Mammis

    2012-07-01

    Full Text Available Background: Abetalipoproteinemia is a rare disorder of fat absorption, characterized by vitamin deficiency, acanthocytosis, and neurologic symptoms including ataxia and tremor.Case Report: A 41-year-old male with abetalipoproteinemia is presented. He underwent staged bilateral thalamic deep brain stimulation (DBS for the treatment of his tremors. After DBS, the patient achieved significant improvements in his tremors, ataxia, and quality of life.Discussion: Thalamic DBS proved to be both safe and efficacious in the management of ataxia and tremors in a patient with abetalipoproteinemia. This is the first report of DBS in abetalipoproteinemia in the literature. 

  8. Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death

    DEFF Research Database (Denmark)

    Cheng, Wen-Hsing; Wu, Ryan T Y; Wu, Min

    2012-01-01

    to MSeA-induced necrotic death. Co-treatment with the ataxia-telangiectasia mutated (ATM) kinase inhibitor KU55933 desensitized the control shRNA cells, but not WRN shRNA cells, to MSeA treatment. WRN did not affect MSeA-induced ATM phosphorylation on Ser-1981 or H2A.X phosphorylation on Ser-139...

  9. A TAD closer to ATM.

    Science.gov (United States)

    Aymard, Francois; Legube, Gaëlle

    2016-05-01

    Ataxia telangiectasia mutated (ATM) has been known for decades as the main kinase mediating the DNA double-strand break response. Our recent findings suggest that its major role at the sites of breaks likely resides in its ability to modify both the local chromatin landscape and the global chromosome organization in order to promote repair accuracy.

  10. ATM haplotypes and cellular response to DNA damage: association with breast cancer risk and clinical radiosensitivity.

    NARCIS (Netherlands)

    Angele, S.; Romestaing, P.; Moullan, N.; Vuillaume, M.; Chapot, B.; Friesen, M.; Jongmans, W.; Cox, D.G.; Pisani, P.; Gerard, J.P.; Hall, J.

    2003-01-01

    The ATM gene, mutated in the cancer-prone and radiation-sensitive syndrome ataxia-telangiectasia (AT), could predispose to breast cancer (BC) development and adverse radiotherapy responses. Sixteen ATM variants were genotyped in 254 BC cases, 70 of whom were adverse radiotherapy responders (RS-BC),

  11. Treatment of nonneovascular idiopathic macular telangiectasia type 2 with intravitreal ranibizumab: results of a phase II clinical trial.

    Science.gov (United States)

    Toy, Brian C; Koo, Euna; Cukras, Catherine; Meyerle, Catherine B; Chew, Emily Y; Wong, Wai T

    2012-05-01

    To evaluate the safety and preliminary efficacy of intravitreal ranibizumab for nonneovascular idiopathic macular telangiectasia Type 2. Single-center, open-label Phase II clinical trial enrolling five participants with bilateral nonneovascular idiopathic macular telangiectasia Type 2. Intravitreal ranibizumab (0.5 mg) was administered every 4 weeks in the study eye for 12 months with the contralateral eye observed. Outcome measures included changes in best-corrected visual acuity, area of late-phase leakage on fluorescein angiography, and retinal thickness on optical coherence tomography. The study treatment was well tolerated and associated with few adverse events. Change in best-corrected visual acuity at 12 months was not significantly different between treated study eyes (0.0 ± 7.5 letters) and control fellow eyes (+2.2 ± 1.9 letters). However, decreases in the area of late-phase fluorescein angiography leakage (-33 ± 20% for study eyes, +1 ± 8% for fellow eyes) and in optical coherence tomography central subfield retinal thickness (-11.7 ± 7.0% for study eyes and -2.9 ± 3.5% for fellow eyes) were greater in study eyes compared with fellow eyes. Despite significant anatomical responses to treatment, functional improvement in visual acuity was not detected. Intravitreal ranibizumab administered monthly over a time course of 12 months is unlikely to provide a general and significant benefit to patients with nonneovascular idiopathic macular telangiectasia Type 2.

  12. Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination

    DEFF Research Database (Denmark)

    Margolin, David H.; Kousi, Maria; Chan, Yee-Ming

    2013-01-01

    and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4...

  13. Reproducibility of right-to-left shunt quantification using transthoracic contrast echocardiography in hereditary haemorrhagic telangiectasia.

    Science.gov (United States)

    Vorselaars, V M M; Velthuis, S; Huitema, M P; Hosman, A E; Westermann, C J J; Snijder, R J; Mager, J J; Post, M C

    2018-04-01

    Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary arteriovenous malformations (PAVMs) in hereditary haemorrhagic telangiectasia. Shunt quantification is used to find treatable PAVMs. So far, there has been no study investigating the reproducibility of this diagnostic test. Therefore, this study aimed to describe inter-observer and inter-injection variability of TTCE. We conducted a prospective single centre study. We included all consecutive persons screened for presence of PAVMs in association with hereditary haemorrhagic telangiectasia in 2015. The videos of two contrast injections per patient were divided and reviewed by two cardiologists blinded for patient data. Pulmonary right-to-left shunts were graded using a three-grade scale. Inter-observer and inter-injection agreement was calculated with κ statistics for the presence and grade of pulmonary right-to-left shunts. We included 107 persons (accounting for 214 injections) (49.5% male, mean age 45.0 ± 16.6 years). A pulmonary right-to-left shunt was present in 136 (63.6%) and 131 (61.2%) injections for observer 1 and 2, respectively. Inter-injection agreement for the presence of pulmonary right-to-left shunts was 0.96 (95% confidence interval (CI) 0.9-1.0) and 0.98 (95% CI 0.94-1.00) for observer 1 and 2, respectively. Inter-injection agreement for pulmonary right-to-left shunt grade was 0.96 (95% CI 0.93-0.99) and 0.95 (95% CI 0.92-0.98) respectively. There was disagreement in right-to-left shunt grade between the contrast injections in 11 patients (10.3%). Inter-observer variability for presence and grade of the pulmonary right-to-left shunt was 0.95 (95% CI 0.91-0.99) and 0.97 (95% CI 0.95-0.99) respectively. TTCE has an excellent inter-injection and inter-observer agreement for both the presence and grade of pulmonary right-to-left shunts.

  14. Cerebellar Ataxia from Multiple Potential Causes: Hypothyroidism, Hashimoto's Thyroiditis, Thalamic Stimulation, and Essential Tremor

    Directory of Open Access Journals (Sweden)

    Natalya V. Shneyder

    2012-04-01

    Full Text Available Background: Both hypothyroidism and Hashimoto's thyroiditis (HT can rarely be associated with cerebellar ataxia. Severe essential tremor (ET as well as bilateral thalamic deep brain stimulation (DBS may lead to subtle cerebellar signs. Case Report: We report a 74-year-old male with hypothyroidism and a 20-year history of ET who developed cerebellar ataxia after bilateral thalamic DBS. Extensive workup revealed elevated thyroid stimulating hormone and thyroperoxidase antibody titers confirming the diagnosis of HT. Discussion: Our case demonstrates multiple possible causes of cerebellar ataxia in a patient, including hypothyroidism, HT, chronic ET, and bilateral thalamic DBS. Counseling of patients may be appropriate when multiple risk factors for cerebellar ataxia coexist in one individual.

  15. Impact of Mobility Device Use on Quality of Life in Children With Friedreich Ataxia.

    Science.gov (United States)

    Ejaz, Resham; Chen, Shiyi; Isaacs, Charles J; Carnevale, Amanda; Wilson, Judith; George, Kristen; Delatycki, Martin B; Perlman, Susan L; Mathews, Katherine D; Wilmot, George R; Hoyle, J Chad; Subramony, Sub H; Zesiewicz, Theresa; Farmer, Jennifer M; Lynch, David R; Yoon, Grace

    2018-05-01

    To determine how mobility device use impacts quality of life in children with Friedreich ataxia. Data from 111 pediatric patients with genetically confirmed Friedreich ataxia were collected from a prospective natural history study utilizing standardized clinical evaluations, including health-related quality of life using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Module. Mobility device use was associated with worse mean PedsQL total, physical, emotional, social, and academic subscores, after adjusting for gender, age of disease onset, and Friedreich Ataxia Rating Scale score. The magnitude of the difference was greatest for the physical subscore (-19.5 points, 95% CI = -30.00, -8.99, P mobility devices trended toward worse physical subscore (-16.20 points, 95% CI = -32.07, -0.33, P = .05). Mobility device use is associated with significant worsening of all domains of quality of life in children with Friedreich ataxia.

  16. Population genetics and new insight into range of CAG repeats of spinocerebellar ataxia type 3 in the Han Chinese population.

    Directory of Open Access Journals (Sweden)

    Shi-Rui Gan

    Full Text Available Spinocerebellar ataxia type 3 (SCA3, also called Machado-Joseph disease (MJD, is one of the most common SCAs worldwide and caused by a CAG repeat expansion located in ATXN3 gene. Based on the CAG repeat numbers, alleles of ATXN3 can be divided into normal alleles (ANs, intermediate alleles (AIs and expanded alleles (AEs. It was controversial whether the frequency of large normal alleles (large ANs is related to the prevalence of SCA3 or not. And there were huge chaos in the comprehension of the specific numbers of the range of CAG repeats which is fundamental for genetic analysis of SCA3. To illustrate these issues, we made a novel CAG repeat ladder to detect CAG repeats of ATXN3 in 1003 unrelated Chinese normal individuals and studied haplotypes defined by three single nucleotide polymorphisms (SNPs closed to ATXN3. We found that the number of CAG repeats ranged from 13 to 49, among them, 14 was the most common number. Positive skew, the highest frequency of large ANs and 4 AIs which had never been reported before were found. Also, AEs and large ANs shared the same haplotypes defined by the SNPs. Based on these data and other related studies, we presumed that de novo mutations of ATXN3 emerging from large ANs are at least one survival mechanisms of mutational ATXN3 and we can redefine the range of CAG repeats as: ANs≤44, 45 ≤AIs ≤49 and AEs≥50.

  17. Molecular evaluation of a novel missense mutation & an insertional truncating mutation in SUMF1 gene

    Directory of Open Access Journals (Sweden)

    Udhaya H Kotecha

    2014-01-01

    Full Text Available Background & objectives: Multiple suphphatase deficiency (MSD is an autosomal recessive disorder affecting the post translational activation of all enzymes of the sulphatase family. To date, approximately 30 different mutations have been identified in the causative gene, sulfatase modifying factor 1 (SUMF1. We describe here the mutation analysis of a case of MSD. Methods: The proband was a four year old boy with developmental delay followed by neuroregression. He had coarse facies, appendicular hypertonia, truncal ataxia and ichthyosis limited to both lower limbs. Radiographs showed dysostosis multiplex. Clinical suspicion of MSD was confirmed by enzyme analysis of four enzymes of the sulphatase group. Results: The patient was compound heterozygote for a c.451A>G (p.K151E substitution in exon 3 and a single base insertion mutation (c.690_691 InsT in exon 5 in the SUMF1 gene. The bioinformatic analysis of the missense mutation revealed no apparent effect on the overall structure. However, the mutated 151-amino acid residue was found to be adjacent to the substrate binding and the active site residues, thereby affecting the substrate binding and/or catalytic activity, resulting in almost complete loss of enzyme function. Conclusions: The two mutations identified in the present case were novel. This is perhaps the first report of an insertion mutation in SUMF1 causing premature truncation of the protein.

  18. Cerebellar Ataxia from Multiple Potential Causes: Hypothyroidism, Hashimoto's Thyroiditis, Thalamic Stimulation, and Essential Tremor

    OpenAIRE

    Shneyder, Natalya; Lyons, Mark K.; Driver-dunckley, Erika; Evidente, Virgilio Gerald H.

    2012-01-01

    Background: Both hypothyroidism and Hashimoto's thyroiditis (HT) can rarely be associated with cerebellar ataxia. Severe essential tremor (ET) as well as bilateral thalamic deep brain stimulation (DBS) may lead to subtle cerebellar signs. Case Report: We report a 74-year-old male with hypothyroidism and a 20-year history of ET who developed cerebellar ataxia after bilateral thalamic DBS. Extensive workup revealed elevated thyroid stimulating hormone and thyroperoxidase antibody titers c...

  19. The Diagnostic Accuracy of Truncal Ataxia and HINTS as Cardinal Signs for Acute Vestibular Syndrome

    Directory of Open Access Journals (Sweden)

    Sergio Carmona

    2016-08-01

    Full Text Available The head impulse, nystagmus type, test of skew (HINTS protocol set a new paradigm to differentiate peripheral vestibular disease from stroke in patients with acute vestibular syndrome (AVS. The relationship between degree of truncal ataxia and stroke has not been systematically studied in patients with AVS. We studied a group of 114 patients who were admitted to a General Hospital due to AVS, 72 of them with vestibular neuritis (based on positive head impulse, abnormal caloric tests and negative MRI, and the rest with Stroke: 32 in the PICA territory (positive HINTS findings, positive MRI and 10 in the AICA territory (variable findings and grade 3 Ataxia, positive MRI. Truncal ataxia was measured by independent observers as grade 1, mild to moderate imbalance with walking independently; grade 2, severe imbalance with standing, but cannot walk without support; and grade 3, falling at upright posture.When we applied the HINTS protocol to our sample, we obtained 100% sensitivity and 94.4% specificity, similar to previously published findings. Only those patients with stroke presented with grade 3 ataxia. Of those with grade 2 ataxia (n = 38, 11 had cerebellar stroke and 28 had vestibular neuritis, not related to the patient's age. Grade 2-3 ataxia was 92.9% sensitive and 61.1% specific to detect AICA/PICA stroke in patients with AVS, with 100% sensitivity to detect AICA stroke. In turn, two signs (nystagmus of central origin and grade 2-3 Ataxia had 100% sensitivity and 61.1% specificity. Ataxia is less sensitive than HINTS but much easier to evaluate.

  20. Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

    Directory of Open Access Journals (Sweden)

    Sara Anjomani Virmouni

    Full Text Available Friedreich ataxia (FRDA is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats, YG8R (90 and 190 GAA repeats and YG22R (190 GAA repeats.We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R.Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.

  1. A Survey on 100 Children with Acute Ataxia in Mofid Children Hospital Tehran, Iran

    Directory of Open Access Journals (Sweden)

    Parvaneh Karim-Zadeh

    2003-04-01

    Full Text Available Objective: The term “Ataxia” is used to denote disturbances of the body posture and its movement that are normally controlled by the cerebellum. frontal lobes and the posterior columns of the spinal cord. The initial symptom and the most prominent feature of ataxia is abnormal gait which is characterized by lurching and wide base walking. Knowing that, the acute ataxia is among those problems that brings very soon the child to pediatrics neurology department and in view of lack of any survey in this neid in our country, we decided to investigate the etiology of acute ataxia in Islamic Republic of Iran. Materials & Methods: Our patients were recruited from 100 children who were brought to neurology service of Mofid children hospital with the chief complaint of acute ataxia over 2 years period. (sep 2001 to sep 2003. All of those 100 patients were admitted and required investigations were performed. Results: Results of our workup revealed that the most common cause of acute ataxia is acute cerebellar one, which all of them preceded by viral febrile illness. The second frequent cause of acute. Ataxia is due to drug intoxication, which commonly was observed between 2 – 4 years period. Conclusion: The remaining etiologies in descending frequency were as follow, Infectious polyneuropathy, Migraine, Opsoclonus – Myoclonus, Brain tumor, ADEM,MS and Epilepsy.

  2. Ultrastructural and clinical evidence of subretinal debris accumulation in type 2 macular telangiectasia.

    Science.gov (United States)

    Cherepanoff, Svetlana; Killingsworth, Murray C; Zhu, Meidong; Nolan, Timothy; Hunyor, Alex P; Young, Stephanie H; Hageman, Gregory S; Gillies, Mark C

    2012-11-01

    To describe subretinal debris found on ultrastructural examination in an eye with macular telangiectasia (MacTel) type 2 and on optical coherence tomography (OCT) in a subset of patients with MacTel type 2. Blocks from the mid-periphery and temporal perifovea of an eye with clinically documented MacTel type 2 were examined with electron microscopy (EM). Cases came from the Sydney centre of the MacTel project and the practices of the authors. On EM examination, subretinal debris was found in the perifovea with accumulation of degenerate photoreceptor elements in the subretinal space. Despite the substantial subretinal debris, there was minimal retinal pigment epithelial (RPE) reaction. Focal defects were seen in the inner limiting membrane in the perifovea. Of the 65 Sydney MacTel project participants, three (5%) had prominent yellow material at the fovea. OCT revealed smooth mounds between the RPE and the ellipsoid region. The material was hyperautofluorescent. This study suggests that subretinal accumulation of photoreceptor debris may be a feature of MacTel type 2. Ultrastructural and OCT evidence of disease beyond the vasculature, involving photoreceptors and Muller cells, is presented.

  3. Pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Correlations between computed tomography findings and cerebral complications

    Energy Technology Data Exchange (ETDEWEB)

    Etievant, Johan; Si-Mohamed, Salim; Vinurel, Nicolas; Revel, Didier [Hospices Civils de Lyon, Hopital Cardiologique Louis Pradel, Departement d' Imagerie Cardiaque et Thoracique, Diagnostique et Interventionnelle, Bron (France); Universite Claude Bernard Lyon 1, Villeurbanne (France); Dupuis-Girod, Sophie [Hospices Civils de Lyon, Hopital Femme-Mere-Enfant, Service de Genetique, Centre de Reference pour la maladie de Rendu-Osler, Lyon (France); Decullier, Evelyne [Universite Claude Bernard Lyon 1, Villeurbanne (France); Hospices Civils de Lyon, Pole Information Medicale Evaluation Recherche, Lyon (France); Gamondes, Delphine [Hospices Civils de Lyon, Hopital Cardiologique Louis Pradel, Departement d' Imagerie Cardiaque et Thoracique, Diagnostique et Interventionnelle, Bron (France); Khouatra, Chahera [Hospices Civils de Lyon, Hopital Cardiologique Louis Pradel, Service de pneumologie - Centre des Maladies Orphelines Pulmonaires, Lyon (France); Cottin, Vincent [Universite Claude Bernard Lyon 1, Villeurbanne (France); Hospices Civils de Lyon, Hopital Cardiologique Louis Pradel, Service de pneumologie - Centre des Maladies Orphelines Pulmonaires, Lyon (France)

    2018-03-15

    Computed tomography (CT) is the modality of choice to characterise pulmonary arteriovenous malformations (PAVMs) in patients with hereditary haemorrhagic telangiectasia (HHT). Our objective was to determine if CT findings were associated with frequency of brain abscess and ischaemic stroke. This retrospective study included patients with HHT-related PAVMs. CT results, i.e. PAVM presentation (unique, multiple, disseminated or diffuse), the number of PAVMs and the largest feeding artery size, were correlated to prevalence of ischaemic stroke and brain abscess. All CTs were reviewed in consensus by two radiologists. Of 170 patients, 73 patients had unique (42.9 %), 49 multiple (28.8 %), 36 disseminated (21.2 %) and 12 diffuse (7.1 %) PAVMs. Fifteen patients presented with brain abscess; 26 patients presented with ischaemic stroke. The number of PAVMs was significantly correlated with brain abscess (11.5 vs. 6.2, respectively; p=0.025). The mean diameter of the largest feeding artery was significantly correlated with ischaemic stroke frequency (4.9 vs. 3.2 mm, respectively; p=0.0098). The number of PAVMs correlated significantly with risk of brain abscess, and a larger feeding artery significantly with more ischaemic strokes. These findings can lead to a better recognition and management of the PAVMs at risk of cerebral complications. (orig.)

  4. Nasal closure for the treatment of epistaxis secondary to hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Sena Esteves, Sara; Cardoso, Carla; Silva, Ana; Abrunhosa, José; Almeida E Sousa, Cecília

    Hereditary hemorrhagic telangiectasia (HHT), also known by the eponym Osler-Weber-Rendu syndrome, is an autosomal dominant disorder characterised by the presence of multiple arteriovenous malformations (AVMs) affecting multiple organs. Many procedures have been used for epistaxis control in patients with this disorder. The objective of this study was to report the treatment of severe HHT-related epistaxiswith the modified Young's procedure. We describe the treatment of 4 patients with severe blood-transfusion-dependent epistaxis who underwent a modified Young's procedure in a tertiary hospital. The nasal closure was bilateral and complete in all cases. All patients were followed for 12 months or longer. The procedure was well tolerated and complete cessation of bleeding was achieved in all the patients. Young's technique is a safe surgical procedure, well tolerated by patients with severe epistaxis and HHT. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

  5. Prospective randomized trial of sclerotherapy vs standard treatment for epistaxis due to hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Boyer, Holly; Fernandes, Patricia; Le, Chap; Yueh, Bevan

    2015-05-01

    Our previous studies have demonstrated the tolerability and low side-effect profile of office-based sclerotherapy with sodium tetradecyl sulfate (STS) for treating recurrent epistaxis due to hereditary hemorrhagic telangiectasia (HHT). The objective of this study was to use a prospective randomized trial to determine the effectiveness of sclerotherapy with STS vs standard treatment. This prospective randomized trial (conducted from November 1, 2011, through January 31, 2014) involved 17 patients with recurrent epistaxis due to HHT. We defined standard treatment as continuation of any treatment that the patient had previously undergone, such as moisturization, packing, and cautery. We used a crossover design, so study participants were randomized to either sclerotherapy or standard treatment during the first time period, and then to the other during the second period. The primary outcome measure was frequency and severity of epistaxis, as measured by the epistaxis severity score (ESS). The ESS is a 10-point scale, with higher scores corresponding to more bleeding. After controlling for treatment order, bleeding was substantially better controlled after sclerotherapy; the ESS after sclerotherapy was nearly one point lower than after standard treatment (-0.95, 1-sided p = 0.027). Treatment order, baseline ESS, the number of lesions, moisturization practices, and a history of previous blood transfusions did not significantly affect the results. This trial demonstrated that sclerotherapy with STS (vs standard treatment) significantly reduced epistaxis due to HHT. © 2015 ARS-AAOA, LLC.

  6. Thalidomide for Epistaxis in Patients with Hereditary Hemorrhagic Telangiectasia: A Preliminary Study.

    Science.gov (United States)

    Fang, Jia; Chen, Xiaomeng; Zhu, Bijun; Ye, Haibo; Zhang, Weitian; Guan, Jian; Su, Kaiming

    2017-08-01

    To evaluate the effectiveness of thalidomide for epistaxis in hereditary hemorrhagic telangiectasia (HHT), 7 HHT patients with recurrent epistaxis were treated with thalidomide at an initial dose of 50 mg/d, gradually increasing to 100 mg/d if needed. The Epistaxis Severity Score (ESS) was used to evaluate the treatment effects. Patients reported that epistaxis improved 1 to 3 weeks after starting thalidomide. The mean ESS before treatment, at the end of treatment, and 3 months after stopping treatment was 5.03 ± 2.05, 0.90 ± 0.84 ( P = .003), and 1.98 ± 1.33 ( P = .006), respectively. Four patients reported mild to moderate side effects, including drowsiness, dizziness, constipation, nausea, and peripheral neuropathy. Two patients stopped the treatment because of adverse effects. Those results showed that thalidomide may be a treatment choice for recurrent epistaxis in HHT patients, although the side effects should be considered. Further study should focus on guidelines for dosing and course and investigate how to reduce the adverse effects.

  7. Hereditary hemorrhagic telangiectasia in children: endovascular treatment of neurovascular malformations. Results in 31 patients

    International Nuclear Information System (INIS)

    Krings, T.; Chng, S.M.; Ozanne, A.; Alvarez, H.; Lasjaunias, P.L.; Rodesch, G.

    2005-01-01

    Hereditary hemorrhagic telangiectasia (HHT) is a heterogeneous disease that can present with a variety of clinical manifestations. The neurovascular complications of this disease, especially in children, may be potentially devastating. The purpose of this article was to review the therapeutic results of endovascular treatment of neurovascular malformations in children. A total of 31 patients under the age of 16 were included in this retrospective analysis. All children were treated in a single center. Twenty children presented with 28 arteriovenous (AV) fistulae, including seven children with spinal AV fistulae and 14 children with cerebral AV fistulae (one child had both a spinal and cerebral fistulae). Eleven children had small nidus-type AV malformations. All embolizations were performed employing superselective glue injection. Follow-up ranged between 3 and 168 months (mean 66 months). A total of 115 feeding vessels were embolized in 81 single sessions, resulting in a mean overall occlusion rate of the malformation of 77.4% (ranging from 30 to 100%). Two of 31 patients (6.5%) died as a direct complication of the embolization procedure; two patients (6.5%) had a persistent new neurological deficit; eight patients (26.7%) were clinically unchanged following the procedure; in 13 patients (41.9%) an amelioration of symptoms but no cure could be achieved; and six patients (19.4%) were completely asymptomatic following the endovascular procedure. (orig.)

  8. Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia.

    Science.gov (United States)

    Hosman, A; Westermann, C J J; Snijder, R; Disch, F; Mummery, C L; Mager, J J

    2015-12-01

    Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue. We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide. Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop. Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered.

  9. The effect of bevacizumab (Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Simonds, Jana; Miller, Frank; Mandel, Jess; Davidson, Terence M

    2009-05-01

    Determine the effectiveness of treating epistaxis in hereditary hemorrhagic telangiectasia (HHT) with potassium titanyl phosphate (KTP) laser cautery combined with submucosal injection of 100 mg of bevacizumab. Retrospective pilot study. Bevacizumab was injected throughout the nasal cavity following KTP laser treatment in 10 patients (bevacizumab/KTP group) and compared to nine patients previously treated with KTP laser alone (KTP group). Epistaxis frequency and severity, blood transfusion requirement, intravenous iron supplementation, emergency department visit frequency, and quality of life within 1 month and 1 year pre- and postsurgery were analyzed. Benefit was defined as less than three nosebleeds per week, with less than 10 minutes to stop each nosebleed, and no blood transfusions. The pre- and postsurgery data were analyzed within and between the two groups. The groups were comparable in age and gender. Significant benefit was found in frequency of epistaxis (P epistaxis is superior to KTP laser treatment alone. It significantly decreases frequency and severity of nosebleeds and blood transfusion requirements, and significantly improves work ability and quality of life.

  10. Are patients with severe epistaxis caused by hereditary hemorrhagic telangiectasia satisfied with nostril closure surgery?

    Science.gov (United States)

    Ichimura, Keiichi; Kikuchi, Hisashi; Imayoshi, Shoichiro; Yamauchi, Tomohiko; Ishikawa, Kotaro

    2012-02-01

    Recurrent epistaxis as a manifestation of hereditary hemorrhagic telangiectasia (HHT) is usually difficult to control. Although no treatment is regarded to be completely efficacious, nostril closure is considered a modality of choice for the most severe cases. The cessation of airflow resulting from this procedure can stop bleeding by minimizing risk factors. However, loss of nasal functions is a disadvantage of nostril closure. We conducted a questionnaire survey of patients who underwent nostril closure surgery, regarding the effects and disadvantages of the operation. Seven patients were asked questions on issues including frequency and severity of epistaxis pre- and post-operatively, satisfaction of treatment, and impairment in daily living activities. Most patients reported complete cessation of bleeding. Some still had bleeding, but the frequency and severity were far lower. No transfusions were required in any of the cases. Patients reported some disadvantages, for example, respiratory, olfactory, and phonatory issues. Six out of seven patients were very satisfied with the outcome of surgery. Nostril closure surgery can remarkably reduce frequency and volume of epistaxis. Our survey indicated that satisfactory results were achieved. However, difficulties caused by complete nasal obstruction varied. Thus, individualized coping strategies are required. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  11. A new SETX mutation producing AOA2 in two siblings.

    Science.gov (United States)

    Datta, Neil; Hohler, Anna

    2013-09-01

    In this paper, we document two cases of a new SETX mutation (820:A>G) combined with an established recessive SETX mutation (5927:T>G) causing ataxia with oculomotor apraxia type 2 (AOA2). The patients had a detailed neurological history and examination performed. Radiological imaging was obtained and genetic analysis was obtained. Both siblings demonstrated healthy and normal growth until adolescence. At that time, slowed speech, hypophonia, dysarthria, extraocular muscle dysfunction and some mild choreiform movements began to appear. Family history included some movement disorder difficulties in second degree relatives. The diagnosis of AOA2 was confirmed by genetic testing. We describe a new SETX gene mutation, which when combined with a recognized SETX mutation results in AOA2. The clinical, radiographic and ancillary testing are described.

  12. Early onset and severe clinical course associated with the m.5540G>A mutation in MT-TW

    Directory of Open Access Journals (Sweden)

    Jorge L. Granadillo

    2014-01-01

    Full Text Available We report a patient harboring a de novo m.5540G>A mutation affecting the MT-TW gene coding for the mitochondrial tryptophan-transfer RNA. This patient presented with atonic–myoclonic epilepsy, bilateral sensorineural hearing loss, ataxia, motor regression, ptosis, and pigmentary retinopathy. Our proband had an earlier onset and more severe phenotype than the first reported patient harboring the same mutation. We discuss her clinical presentation and compare it with the only previously published case.

  13. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Canada, but it has since been found in populations worldwide. Related Information What information about a genetic ... are involved in chemical signaling between nerve cells ( neurons ). SYNE1 gene mutations that cause ARCA1 result in ...

  14. Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1 Características clínicas e moleculares de uma família Brasileira com ataxia espinocerebelar tipo 1

    Directory of Open Access Journals (Sweden)

    Iscia Lopes-Cendes

    1996-09-01

    Full Text Available The spinocerebellar ataxias (SCAs are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped: SCA1, SCA2, Machado-Joseph disease (MJD/SCA3, SCA4, SCA5, SCA7 and dentatorubropallidoluysian atrophy (DRPLA. Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.As ataxias espinocerebelares (AECs fazem parte de um grupo de doenças neurodegenerativas que apresentam grande heterogeneidade clínica e genética. Existem até o momento sete genes mapeados responsáveis pelas AECs de transmissão autossômica dominante: SCA1, SCA2, doença de Machado-Joseph (DA/7 ou SCA3, SCA4, SCA5, SCA7 e atrofia dentatorubropalidoluisiana (ADRPL. Uma expansão de um trínucletídeo CAG foi identificada como a mutação responsável na SCA], DMJ e ADRPL. Estudamos uma família brasileira com uma forma autossômica dominante de AEC. Dez indivíduos foram examinados e

  15. Polymorphic human (CTAT)n microsatellite provides a conserved linkage marker for mouse mutants causing cleft palate, vestibular defects, obesity and ataxia

    Energy Technology Data Exchange (ETDEWEB)

    Griffith, A.J.; Burgess, D.L.; Kohrman, D. [Univ. of MIchigan, Ann Arbor, MI (United States)] [and others

    1994-09-01

    The Twirler mutation (Tw) causing cleft palate {plus_minus} cleft lip, vestibular defects and obesity is located within 0.5 cM of an ataxia locus (ax) on mouse chromosome 18. We identified a transgene-induced insertional mutation with vestibular and craniofacial defects that appears to be a new allele of Twirler. Mouse DNA flanking the transgene insertion site was isolated from a cosmid library. An evolutionarily conserved, zoo blot positive cosmid subclone was used to probe a human {lambda} genomic library. From the sequence of a highly homologous human {lambda} clone, we designed STS primers and screened a human P1 library. DNA from two positive P1 clones was hybridized with simple sequence probes, and a (CTAT){sub 12} repeat was detected. Analysis of 62 CEPH parents with primers flanking the repeat identified six alleles containing 9 to 14 copies of the repeat, at frequencies of 0.17, 0.17, 0.17, 0.27, 0.15 and 0.07, respectively. The observed heterozygosity was 49/62 with a calculated PIC value of 0.76. This polymorphic microsatellite marker, designated Umi3, was mapped to the predicted conserved human linkage group by analysis of somatic cell hybrid panels. The anticipated short distance between Umi3 and the disease genes will facilitate detection of linkage in small families. We would like to type appropriate human pedigrees with Umi3 in order to identify patients with inherited disorders homologous to the mouse mutations Twirler and ataxia.

  16. Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency

    DEFF Research Database (Denmark)

    Berryer, Martin H; Hamdan, Fadi F; Klitten, Laura L

    2013-01-01

    De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP-activating protein, cause nonsyndromic intellectual disability (NSID). All disease-causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID...... also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild-type SYNGAP1 in pyramidal cells from cortical...

  17. Molecular genetics of a Chinese family with spinocerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Dan-dan WU

    2015-10-01

    Full Text Available Objective To study the genotype of the members of a Chinese family with spinocerebellar ataxia (SCA. Methods The peripheral blood samples of 6 patients and 40 asymptomatic people belonged to the family were collected. Referring to the clinical manifestations of the proband and second-generation sequencing results, the CAG trinucleotide repeats of the pathogenic gene ATXN2 were amplified by polymerase chain reaction (PCR. The repeated times of the trinucleotide in normally and abnormally amplified alleles were defined by agarose gel electrophoresis and PCR products sequencing. Results Autosomal dominant heredity was the cause of the SCA in this family. Six out of 46 in the fourth-generation were SCA2 patients, 7 were the carriers of pathogenic allele. The repeated times of CAG trinucleotide were within the normal range in one of the two alleles of ATXN2, but they were in abnormal range in the another one. The repeated times of CAG trinucleotide were 40-46 in abnormal alleles of patients. Conclusion Autosomal dominant heredity SCA2 has been diagnosed in this family caused by the dynamic nutation of CAG trinucleotide repeats, and 7 pathogenic allele carriers in this family were confirmed by genetic diagnosis. DOI: 10.11855/j.issn.0577-7402.2015.08.07

  18. Spinocerebellar ataxia type 6 in eastern India: Some new observations

    Directory of Open Access Journals (Sweden)

    Kalyan B Bhattacharyya

    2016-01-01

    Full Text Available Introduction: Spinocerebellar ataxias (SCAs are hereditary, autosomal dominant progressive neurodegenerative disorders showing clinical and genetic heterogeneity. They are usually manifested clinically in the third to fifth decade of life although there is a wide variability in the age of onset. More than 36 different types of SCAs have been reported so far and about half of them are caused by pathological expansion of the trinucleotide, Cytosine Alanine Guanine (CAG repeat. The global prevalence of SCA is 0.3-2 per 100,000 population, SCA3 being the commonest variety worldwide, accounting for 20-50 per cent of all cases, though SCA 2 is generally considered as the commonest one in India. However, SCA6 has not been addressed adequately from India though it is common in the eastern Asian countries like, Japan, Korea and Thailand. Objective: The present study was undertaken to identify the prevalence of SCA6 in the city of Kolkata and the eastern part of India. Materials and Methods: 83 consecutive patients were recruited for the study of possible SCAs and their clinical features and genotype were investigated. Results: 6 of the 83 subjects turned out positive for SCA6, constituting therefore, 13.33% of the patient pool. Discussion: SCA6 is prevalent in the eastern part of India, though not as frequent as the other common varieties. Conclusions: Further community based studies are required in order to understand the magnitude of SCA6 in the eastern part, as well as in other regions of India.

  19. Spinocerebellar ataxia type 6 in eastern India: Some new observations.

    Science.gov (United States)

    Bhattacharyya, Kalyan B; Pulai, Debabrata; Guin, Deb Shankar; Ganguly, Goutam; Joardar, Anindita; Roy, Sarnava; Rai, Saurabh; Biswas, Atanu; Pandit, Alok; Roy, Arijit; Senapati, Asit Kumar

    2016-01-01

    Spinocerebellar ataxias (SCAs) are hereditary, autosomal dominant progressive neurodegenerative disorders showing clinical and genetic heterogeneity. They are usually manifested clinically in the third to fifth decade of life although there is a wide variability in the age of onset. More than 36 different types of SCAs have been reported so far and about half of them are caused by pathological expansion of the trinucleotide, Cytosine Alanine Guanine (CAG) repeat. The global prevalence of SCA is 0.3-2 per 100,000 population, SCA3 being the commonest variety worldwide, accounting for 20-50 per cent of all cases, though SCA 2 is generally considered as the commonest one in India. However, SCA6 has not been addressed adequately from India though it is common in the eastern Asian countries like, Japan, Korea and Thailand. The present study was undertaken to identify the prevalence of SCA6 in the city of Kolkata and the eastern part of India. 83 consecutive patients were recruited for the study of possible SCAs and their clinical features and genotype were investigated. 6 of the 83 subjects turned out positive for SCA6, constituting therefore, 13.33% of the patient pool. SCA6 is prevalent in the eastern part of India, though not as frequent as the other common varieties. Further community based studies are required in order to understand the magnitude of SCA6 in the eastern part, as well as in other regions of India.

  20. Partial Body Weight-Supported Treadmill Training in Spinocerebellar Ataxia.

    Science.gov (United States)

    de Oliveira, Laura Alice Santos; Martins, Camilla Polonini; Horsczaruk, Carlos Henrique Ramos; da Silva, Débora Cristina Lima; Vasconcellos, Luiz Felipe; Lopes, Agnaldo José; Meira Mainenti, Míriam Raquel; Rodrigues, Erika de Carvalho

    2018-01-01

    The motor impairments related to gait and balance have a huge impact on the life of individuals with spinocerebellar ataxia (SCA). Here, the aim was to assess the possibility of retraining gait, improving cardiopulmonary capacity, and challenging balance during gait in SCA using a partial body weight support (BWS) and a treadmill. Also, the effects of this training over functionality and quality of life were investigated. Eight SCA patients were engaged in the first stage of the study that focused on gait training and cardiovascular conditioning. From those, five took part in a second stage of the study centered on dynamic balance training during gait. The first and second stages lasted 8 and 10 weeks, respectively, both comprising sessions of 50 min (2 times per week). The results showed that gait training using partial BWS significantly increased gait performance, treadmill inclination, duration of exercise, and cardiopulmonary capacity in individuals with SCA. After the second stage, balance improvements were also found. Combining gait training and challenging tasks to the postural control system in SCA individuals is viable, well tolerated by patients with SCA, and resulted in changes in capacity for walking and balance.

  1. False-positive head-impulse test in cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Olympia eKremmyda

    2012-11-01

    Full Text Available Abstract:The objective of this study was to compare the findings of the bedside head impulse test (HIT, passive head rotation gain, and caloric irrigation in patients with cerebellar ataxia (CA. In 16 patients with CA and bilaterally pathological bedside HIT, VOR gains were measured during HIT and passive head rotation by scleral search coil technique. Eight of the patients had pathologically reduced caloric responsiveness, while the other eight had normal caloric responses. Those with normal calorics showed a slightly reduced HIT gain (mean±SD: 0.73±0.15. In those with pathological calorics, gains 80ms and 100 ms after the HIT as well as the passive rotation VOR gains were significantly lower. The corrective saccade after head turn occurred earlier in patients with pathological calorics (111±62 ms after onset of the HIT than in those with normal calorics. (191±17 ms, p=0.0064 We indentified two groups of patients with CA: those with an isolated moderate HIT deficit only, probably due to floccular dysfunction, and those with combined HIT, passive rotation and caloric deficit, probably due to a peripheral vestibular deficit. From a clinical point of view, these results show that the bedside HIT alone can be false positive for establishing a diagnosis of a bilateral peripheral vestibular deficit in patients with CA.

  2. Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice

    Directory of Open Access Journals (Sweden)

    Ino Mitsuhiro

    2005-05-01

    Full Text Available Abstract Background ADAM22 is a member of the ADAM gene family, but the fact that it is expressed only in the nervous systems makes it unique. ADAM22's sequence similarity to other ADAMs suggests it to be an integrin binder and thus to have a role in cell-cell or cell-matrix interactions. To elucidate the physiological functions of ADAM22, we employed gene targeting to generate ADAM22 knockout mice. Results ADAM22-deficient mice were produced in a good accordance with the Mendelian ratio and appeared normal at birth. After one week, severe ataxia was observed, and all homozygotes died before weaning, probably due to convulsions. No major histological abnormalities were detected in the cerebral cortex or cerebellum of the homozygous mutants; however, marked hypomyelination of the peripheral nerves was observed. Conclusion The results of our study demonstrate that ADAM22 is closely involved in the correct functioning of the nervous system. Further analysis of ADAM22 will provide clues to understanding the mechanisms of human diseases such as epileptic seizures and peripheral neuropathy.

  3. Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

    DEFF Research Database (Denmark)

    Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten

    2013-01-01

    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective ...... of paternal germ-line repeat sequence instability of the expanded SCA2 locus.European Journal of Human Genetics advance online publication, 10 October 2012; doi:10.1038/ejhg.2012.231....

  4. Optic ataxia and the function of the dorsal stream: contributions to perception and action.

    Science.gov (United States)

    Pisella, Laure; Sergio, Lauren; Blangero, Annabelle; Torchin, Héloïse; Vighetto, Alain; Rossetti, Yves

    2009-12-01

    Optic ataxia (OA) is one of the symptoms pertaining to Bálint's Syndrome. It has been described clinically for nearly 80 years before it became a cornerstone of the most popular dual stream theory of the visual brain. Over the last 10 years a regain of interest for this neurological condition lead to a number of precise analyses of the deficits found in optic ataxia, giving rise to a renewed outline of its very definition and hence of the function(s) of the occipito-parietal (dorsal) stream. In absence of concomitant clinical symptoms, we review evidence that misreaching errors in central vision result from the "hand effect": an erroneous dynamic spatial processing of proprioceptive information from the hand. When visual feedback of the hand is provided (closed-loop condition), pure optic ataxia is restricted to peripheral vision. This central versus peripheral vision distinction is repeatedly used to argue that action and perception are not unique and dissociated systems. New assessments of optic ataxia patients are provided, confirming on one hand that their visuomotor deficit is specific to peripheral vision (i.e. when the gaze and the hand goals are dissociated), on the other hand that they disclose perceptual deficits in peripheral vision. These results are coherent with the recent demonstration that optic ataxia patients exhibit a general contralesional deficit for dynamic visuo-spatial processing, affecting both hand and eye movements [Gaveau, V., Pélisson, D., Blangero, A., Urquizar, C., Prablanc, C.,Vighetto, A., et al. (2008). A common parietal module for saccade and reach: Eye-hand coordination and saccadic control in optic ataxia. Neuropsychologia, 46, 475-486]. Such module(s) within the dorsal stream could be used for both action and perception in the periphery. It is concluded that optic ataxia cannot be considered as a unitary and specific visuo-manual deficit, and that the modular organisation of the dorsal stream allows for numerous dorsal

  5. Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases.

    Science.gov (United States)

    Mallaret, Martial; Renaud, Mathilde; Redin, Claire; Drouot, Nathalie; Muller, Jean; Severac, Francois; Mandel, Jean Louis; Hamza, Wahiba; Benhassine, Traki; Ali-Pacha, Lamia; Tazir, Meriem; Durr, Alexandra; Monin, Marie-Lorraine; Mignot, Cyril; Charles, Perrine; Van Maldergem, Lionel; Chamard, Ludivine; Thauvin-Robinet, Christel; Laugel, Vincent; Burglen, Lydie; Calvas, Patrick; Fleury, Marie-Céline; Tranchant, Christine; Anheim, Mathieu; Koenig, Michel

    2016-07-01

    Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.

  6. Hepatic artery embolization for treatment of patients with hereditary hemorrhagic telangiectasia and symptomatic hepatic vascular malformations

    Energy Technology Data Exchange (ETDEWEB)

    Chavan, Ajay [Hannover Medical School, Department of Diagnostic Radiology, Hannover (Germany); Klinikum Oldenburg, Department of Radiology and Nuclear Medicine, Oldenburg (Germany); Caselitz, Martin; Wagner, Siegfried; Manns, Michael [Hannover Medical School, Department of Gastroenterology and Hepatology, Hannover (Germany); Gratz, Karl-Friedrich [Hannover Medical School, Department of Nuclear Medicine, Hannover (Germany); Lotz, Joachim; Kirchhoff, Timm; Galanski, Michael [Hannover Medical School, Department of Diagnostic Radiology, Hannover (Germany); Piso, Plinio [Hannover Medical School, Department of Abdominal and Transplantation Surgery, Hannover (Germany)

    2004-11-01

    At present there is no established therapy for treating patients with hereditary hemorrhagic telangiectasia (HHT) and symptomatic hepatic involvement. We present the results of a prospective study with 15 consecutive patients who were treated with staged hepatic artery embolization (HAE). Branches of the hepatic artery were selectively catheterized and embolized in stages using polyvinyl alcohol particles (PVA) and platinum microcoils or steel macrocoils. Prophylactic antibiotics, analgesics and anti-emetics were administered after every embolization. Clinical symptomatology and cardiac output were assessed before and after therapy as well as at the end of follow-up (median 28 months; range 10-136 months). Five patients had abdominal pain and four patients had symptoms of portal hypertension. The cardiac output was raised in all patients, with cardiac failure being present in 11 patients. After treatment, pain resolved in all five patients, and portal hypertension improved in two of the four patients. The mean cardiac output decreased significantly (P<0.001) from 12.57{+-}3.27 l/min pre-treatment to 8.36{+-}2.60 l/min at the end of follow-up. Symptoms arising from cardiac failure resolved or improved markedly in all but one patient. Cholangitis and/or cholecystitis occurred in three patients of whom two required a cholecystectomy. One patient with pre-existent hepatic cirrhosis died as a complication of the procedure. Staged HAE yields long-term relief of clinical symptoms in patients with HHT and hepatic involvement. Patients with pre-existing hepatic cirrhosis may be poor candidates for HAE. (orig.)

  7. Sinonasal quality of life outcomes following laser treatment of epistaxis related to hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Kuan, Edward C; Peng, Kevin A; Thompson, Christopher F; Suh, Jeffrey D; Wang, Marilene B

    2017-04-01

    Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder which manifests as recurrent, episodic, and potentially debilitating epistaxis. In this study, we aim to (1) characterize baseline sinonasal symptoms for HHT patients and to (2) analyze changes in sinonasal symptoms before and after laser surgical treatment for HHT. We performed a retrospective chart review of sinonasal outcome test-22 (SNOT-22) scores before and after one or more laser surgical treatments for HHT-related epistaxis between January 1, 2010 and December 1, 2015 at a tertiary academic medical center with an HHT Foundation-approved Center of Excellence. Preoperative and all subsequent postoperative SNOT-22 scores (short-term, epistaxis. Mean preoperative, short-term postoperative, and long-term postoperative SNOT-22 scores were 34.6 ± 5.4, 33.9 ± 5.5, and 18.8 ± 4.6, respectively. When analyzing subcategory scores, there was a significant improvement in the rhinologic domain from short-term to long-term postoperatively (13.5 vs. 7.3; p = 0.004), in the non-rhinologic otolaryngic domain from short-term to long-term postoperatively (2.8 vs. 1.7; p = 0.014), and in the psychological domain from preoperative and short-term postoperative to long-term postoperatively (12.2 and 10.0 vs. 6.0; p = 0.015 and 0.01, respectively). Following laser surgery for HHT-related epistaxis, patients' rhinologic symptoms worsened on the short run postoperatively but improved over time. The main benefit of laser treatment appears to be long-term improvement in psychological factors. This study once again underscores the important role of the otolaryngologist in managing sinonasal manifestations of HHT.

  8. The minimal important difference of the epistaxis severity score in hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Yin, Linda X; Reh, Douglas D; Hoag, Jeffrey B; Mitchell, Sally E; Mathai, Stephen C; Robinson, Gina M; Merlo, Christian A

    2016-05-01

    Hereditary hemorrhagic telangiectasia (HHT) is a disease of abnormal angiogenesis, causing epistaxis in over 96% of patients. The Epistaxis Severity Score (ESS) was developed as a standardized measurement of nasal symptoms among HHT patients. The minimal important difference (MID) of a disease index estimates the smallest change that a patient and clinician would identify as important. This study aims to establish the MID of the ESS in a diverse population of HHT patients. Retrospective cross-sectional study in patients with a diagnosis of HHT using Curacao criteria or genetic testing. The ESS questionnaire and Medical Outcomes Study 36-Item Short Form (SF-36) were administered to participants recruited through the HHT Foundation Web site. Demographics and relevant medical histories were collected from all participants. An anchor-based method using a change of 5 in the Physical Component Summary (PCS) of the SF-36 and a distributional method were used to estimate the MID. A total of 604 subjects were recruited between April and August 2008. All participants reported epistaxis. An increasing ESS in the study cohort showed a significant negative correlation to the PCS (r = -0.43, P < 0.001). The MID was determined to be 0.41 via the anchor-based approach and 1.01 via the distribution-based approach, giving a mean MID of 0.71. Using both the anchor-based and distribution-based approaches, the estimated MID for the ESS in HHT is 0.71. Further implications include key metrics to help guide treatment responses in clinical care and essential information to calculate power and sample size for future clinical trials. 4. Laryngoscope, 126:1029-1032, 2016. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

  9. Quality of life in patients with hereditary hemorrhagic telangiectasia in Norway: a population based study.

    Science.gov (United States)

    Geirdal, Amy Østertun; Dheyauldeen, Sinan; Bachmann-Harildstad, Gregor; Heimdal, Ketil

    2012-06-01

    Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant disease characterized by the presence of recurrent epistaxis and small characteristic malformations of the peripheral blood vessels near the surface of the skin or mucosal linings. Arteriovenous malformations (AVM) of the lung, liver, and CNS are also known clinical findings. The purpose of this study was to examine quality of life (QoL) in patients with HHT in Norway. Sixty-six affected patients (39 women and 27 men) were included. QoL on overall-, health-related (HR-QoL), and disease-specific levels were measured with Cantril's Ladder (CL), Short Form 36 (SF-36), and a Symptom-specific QoL question in HHT patients (SFB-HHT-Q), respectively. Comparisons were made between patients and an age and gender adjusted normative sample from the Norwegian population (N = 990). Overall, the results reflected that several HHT disease-related variables were associated with reduced QoL on all three levels; overall QoL (CL), HR-QoL (SF36) as well as disease-specific QoL (SFB-HHT-Q), while demographic variables impacted HR-QoL in HHT patients. Compared to the normative sample, all subscales of SF36, but bodily pain, were significantly poorer in the HHT patients. HHT disease variables had the strongest association with QoL compared to demographic variables. The results substantiate that disease severity is associated with poorer QoL in this patients. Pain contributed independently to all levels of QoL. Copyright © 2012 Wiley Periodicals, Inc.

  10. Lifestyle and dietary influences on nosebleed severity in hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Silva, B Maneesha; Hosman, Anna E; Devlin, Hannah L; Shovlin, Claire L

    2013-05-01

    To identify factors influencing the severity of epistaxis in hereditary hemorrhagic telangiectasia (HHT). Participants with and without HHT were recruited from a specialist service and online following advertisement by the HHT Foundation International. Both groups were asked to complete a nonbiased questionnaire. The reported effects of specific treatments or lifestyle factors on epistaxis were assigned positive values if beneficial, negative values if detrimental, or zero if "no difference" and were summed to enable statistical analysis. Epistaxis affected 649 of 666 (97%) participants with HHT and was significantly more frequent than in control participants. Specialist invasive treatments were reported as beneficial, laser therapy more frequently than cauterization. Medical treatments commonly used for HHT epistaxis (female hormones, antiestrogens, tranexamic acid, aminocaproic acid, nasal creams, and bevacizumab) also had significantly positive (beneficial) scores. Lifestyle and dietary factors were generally detrimental, but room humidification, nasal lubrication, and saline treatments were all reported as beneficial (95% confidence intervals greater than zero). Multiple food items were volunteered as being detrimental to epistaxis. The most frequently reported items were alcohol (n = 45; 6.8% of participants) and spices (n = 26, 3.9% of participants). Remaining foods reported to exacerbate epistaxis were also found to be high in salicylates (including red wine, spices, chocolate, coffee, and certain fruits), natural antiplatelet activity (garlic, ginger, ginseng, ginkgo biloba, and vitamin E15), or omega-3 acids (oily fish, salmon). This study supports existing treatments and suggests lifestyle and dietary maneuvers that may also improve nosebleeds in HHT. 2c. Copyright © 2013 The American Laryngological, Rhinological, and Otological Society, Inc.

  11. Epidemiology of Cerebellar Ataxia on the Etiological Basis: A Cross Sectional Study

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    Simindokht Hosseini Seyede

    2009-12-01

    Full Text Available Cerebellar ataxias are a heterogenous group of disorders, clinically and etiologically, that result in considerable health burden. Finding out about the various etiologies, and their relative prevalences in the population suffering from cerebellar ataxia helps the clinician to perform a better management, in treatment process. This is a cross sectional study designed to estimate the relative prevalence of each etiologic factor. One-hundred and thirty-five patients ,in the range of 6 to 73 years from march 1993 to march1999, were classified in different groups on the basis of etiological findings. Relative prevalence of each of the etiological factors , common accompanying disorders besides ataxia in the patients,CT and MRI changes,and CSF alterations are studied and recorded. A widely spread age group, and the extended number of the cases under study, are the advantages of the current study over the previously reported case series. Among the etiologic groups, multiple sclerosis, cerebrovascular accidents and hereditary cerebellar ataxia, were the most common etiologic factors associated with cerebellar ataxia respectively.

  12. Clinical characteristics of patients with cerebellar ataxia associated with anti-GAD antibodies

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    Tiago Silva Aguiar

    Full Text Available ABSTRACT The enzyme glutamic acid decarboxylase (GAD, present in GABAergic neurons and in pancreatic beta cells, catalyzes the conversion of gamma-aminobutyric acid (GABA. The cerebellum is highly susceptible to immune-mediated mechanisms, with the potentially treatable autoimmune cerebellar ataxia associated with the GAD antibody (CA-GAD-ab being a rare, albeit increasingly detected condition. Few cases of CA-GAD-ab have been described. Methods This retrospective and descriptive study evaluated the clinical characteristics and outcomes of patients with CA-GAD-ab. Result Three patients with cerebellar ataxia, high GAD-ab titers and autoimmune endocrine disease were identified. Patients 1 and 2 had classic stiff person syndrome and insidious-onset cerebellar ataxia, while Patient 3 had pure cerebellar ataxia with subacute onset. Patients received intravenous immunoglobulin therapy with no response in Patients 1 and 3 and partial recovery in Patient 2. Conclusion CA-GAD-ab is rare and its clinical presentation may hamper diagnosis. Clinicians should be able to recognize this potentially treatable autoimmune cerebellar ataxia.

  13. Modifications of resting state networks in spinocerebellar ataxia type 2.

    Science.gov (United States)

    Cocozza, Sirio; Saccà, Francesco; Cervo, Amedeo; Marsili, Angela; Russo, Cinzia Valeria; Giorgio, Sara Maria Delle Acque; De Michele, Giuseppe; Filla, Alessandro; Brunetti, Arturo; Quarantelli, Mario

    2015-09-01

    We aimed to investigate the integrity of the Resting State Networks in spinocerebellar ataxia type 2 (SCA2) and the correlations between the modification of these networks and clinical variables. Resting-state functional magnetic resonance imaging (RS-fMRI) data from 19 SCA2 patients and 29 healthy controls were analyzed using an independent component analysis and dual regression, controlling at voxel level for the effect of atrophy by co-varying for gray matter volume. Correlations between the resting state networks alterations and disease duration, age at onset, number of triplets, and clinical score were assessed by Spearman's coefficient, for each cluster which was significantly different in SCA2 patients compared with healthy controls. In SCA2 patients, disruption of the cerebellar components of all major resting state networks was present, with supratentorial involvement only for the default mode network. When controlling at voxel level for gray matter volume, the reduction in functional connectivity in supratentorial regions of the default mode network, and in cerebellar regions within the default mode, executive and right fronto-parietal networks, was still significant. No correlations with clinical variables were found for any of the investigated resting state networks. The SCA2 patients show significant alterations of the resting state networks, only partly explained by the atrophy. The default mode network is the only resting state network that shows also supratentorial changes, which appear unrelated to the cortical gray matter volume. Further studies are needed to assess the clinical significance of these changes. © 2015 International Parkinson and Movement Disorder Society.

  14. Characteristics of Handwriting of People With Cerebellar Ataxia: Three-Dimensional Movement Analysis of the Pen Tip, Finger, and Wrist.

    Science.gov (United States)

    Fujisawa, Yuhki; Okajima, Yasutomo

    2015-11-01

    There are several functional tests for evaluating manual performance; however, quantitative manual tests for ataxia, especially those for evaluating handwriting, are limited. This study aimed to investigate the characteristics of cerebellar ataxia by analyzing handwriting, with a special emphasis on correlation between the movement of the pen tip and the movement of the finger or wrist. This was an observational study. Eleven people who were right-handed and had cerebellar ataxia and 17 people to serve as controls were recruited. The Scale for the Assessment and Rating of Ataxia was used to grade the severity of ataxia. Handwriting movements of both hands were analyzed. The time required for writing a character, the variability of individual handwriting, and the correlation between the movement of the pen tip and the movement of the finger or wrist were evaluated for participants with ataxia and control participants. The writing time was longer and the velocity profile and shape of the track of movement of the pen tip were more variable in participants with ataxia than in control participants. For participants with ataxia, the direction of movement of the pen tip deviated more from that of the finger or wrist, and the shape of the track of movement of the pen tip differed more from that of the finger or wrist. The severity of upper extremity ataxia measured with the Scale for the Assessment and Rating of Ataxia was mostly correlated with the variability parameters. Furthermore, it was correlated with the directional deviation of the trajectory of movement of the pen tip from that of the finger and with increased dissimilarity of the shapes of the tracks. The results may have been influenced by the scale and parameters used to measure movement. Ataxic handwriting with increased movement noise is characterized by irregular pen tip movements unconstrained by the finger or wrist. The severity of ataxia is correlated with these unconstrained movements. © 2015 American

  15. Telangiectasia hemorrágica hereditária: ácido tranexâmico no tratamento de úlcera plantar Hereditary hemorrhagic telangiectasia: tranexamic acid for plantar ulcer

    Directory of Open Access Journals (Sweden)

    Gabriella Corrêa de Albuquerque

    2005-12-01

    Full Text Available Relato de um caso de úlcera plantar por fístula arteriovenosa em paciente portador de telangiectasia hemorrágica hereditária ou doença de Rendu-Osler-Weber tratado com ácido tranexâmico. Este fármaco é utilizado para tratamento de epistaxe, referindo-se o principal achado deste artigo ao uso eficaz desse medicamento na terapia de úlceras plantares hemorrágicas. São descritos os aspectos fisiopatológicos e clínicos da doença e as propriedades antifibrinolíticas do ácido tranexâmico. Este foi bem tolerado e apresentou evidências de eficácia na utilização para controle do sangramento e cicatrização da úlcera.Case report of one patient with Hereditary Hemorrhagic Telangiectasia, also known as Rendu-Osler-Weber syndrome, treated with Tranexamic Acid for arteriovenous plantar ulcer. This drug has proved effective in controlling epistaxis, but the main point of this report is to expose the success use of this medication in the therapy of skin bleeding ulcer. The pathophysiologic and clinical features of the disease are reviewed and also the pharmacological aspects of the antifibrinolytic drugs. This drug was well tolerated by the patient and show evidence of good activity in the bleeding and healed the ulcer.

  16. The history of spinocerebellar ataxia type 10 in Brazil: travels of a gene A história da ataxia espinocerebelar tipo 10 no Brasil: as viagens de um gene

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    Hélio A.G. Teive

    2007-12-01

    Full Text Available The authors report the history of spinocerebellar ataxia 10 (SCA10, since its first report in a large Portuguese-ancestry Family with autosomal dominant pure cerebellar ataxia, till the final identification of further families without Mexican ancestry. These families present a quite different phenotype from those SCA10 families described in Mexico.Os autores apresentam a história da descoberta da ataxia espinocerebelar tipo 10 (AEC10 no Brasil, desde o primeiro relato em uma família com ancestrais portugueses com ataxia cerebelar pura, autossômica dominante, até a identificação de famílias sem ancestrais mexicanos. Essas famílias apresentam um fenótipo de AEC10, com ataxia cerebelar "pura", distinta daquele descrito nas famílias no México.

  17. Nuclear Magnetic Resonance skull in Cuban families first diagnosed with Friedreich's ataxia

    International Nuclear Information System (INIS)

    Cruz Marinno, Tania; Alvarez Cuesta, Jose Alberto; Aguilera Rodriguez, Raul; Velazquez Perez, Luis

    2011-01-01

    Friedreich's ataxia is characterized by age of onset before 25 years, progressive ataxia, dysarthria, absent deep tendon reflexes and impaired vibration sense. This research was conducted in order to describe the imaging features of central nervous system structures in the early Cuban families diagnosed with the disease. A team of 0.23 Tesla-PANORAMA-Phylips Medical Systems, with a standard head coil, axial slices were obtained using 5mm thick FLAIR sequences, T1 and T2, and sagittal T1 and T2 in three individuals with confirmatory molecular diagnosis of Friedreich's ataxia and six healthy controls matched by age and sex. The morphological structures most affected are the cervical spinal cord, cerebellum and pons, which provides in vivo evidence that the disease leads to atrophy of these structures

  18. Impact of Dual Task on Parkinson's Disease, Stroke and Ataxia Patients' Gait: A Comparative Analysis

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    Michelly Arjona Maciel

    2014-01-01

    Full Text Available Introduction: Performing dual task for neurological patients is complex and it can be influenced by the localization of the neurological lesion. Objective: Comparing the impact of dual task on gait in patients with Parkinson's disease, stroke and ataxia. Method: Subjects with Parkinson's disease (PD in initial phase, stroke and ataxia, with independent gait, were evaluated while doing simple gait, with cognitive, motor and cognitive-motor gait demand, assessing average speed and number of steps. Results: Ataxia and stroke patients, compared with PD, showed an increase in the number of steps and decrease the average speed on the march with cognitive demand. Subjects with PD performed better on tasks when compared to others. Conclusion: In this study the impact of dual task was lower in Parkinson's disease patients.

  19. Contribution of Somatic and Dendritic SK Channels in the Firing Rate of Deep Cerebellar Nuclei: Implication in Cerebellar Ataxia

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    Samira Abbasi

    2016-01-01

    Discussion: Therefore, inhibition of SK channel in DCN can cause cerebellar ataxia, and SK channel openers can have a therapeutic effect on cerebellar ataxia. In addition, the location of SK channels could be important in therapeutic goals. Dendritic SK channels can be a more effective target compared to somatic SK channels

  20. White matter damage is related to ataxia severity in SCA3.

    Science.gov (United States)

    Kang, J-S; Klein, J C; Baudrexel, S; Deichmann, R; Nolte, D; Hilker, R

    2014-02-01

    Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.

  1. Structural and Functional Magnetic Resonance Imaging of the Cerebellum: Considerations for Assessing Cerebellar Ataxias.

    Science.gov (United States)

    Deistung, Andreas; Stefanescu, Maria R; Ernst, Thomas M; Schlamann, Marc; Ladd, Mark E; Reichenbach, Jürgen R; Timmann, Dagmar

    2016-02-01

    Magnetic resonance imaging (MRI) of the brain is of high interest for diagnosing and understanding degenerative ataxias. Here, we present state-of-the-art MRI methods to characterize structural alterations of the cerebellum and introduce initial experiments to show abnormalities in the cerebellar nuclei. Clinically, T1-weighted MR images are used to assess atrophy of the cerebellar cortex, the brainstem, and the spinal cord, whereas T2-weighted and PD-weighted images are typically employed to depict potential white matter lesions that may be associated with certain types of ataxias. More recently, attention has also focused on the characterization of the cerebellar nuclei, which are discernible on spatially highly resolved iron-sensitive MR images due to their relatively high iron content, including T2 (*)-weighted images, susceptibility-weighted images (SWI), effective transverse relaxation rate (R2 (*)) maps, and quantitative susceptibility maps (QSM). Among these iron-sensitive techniques, QSM reveals the best contrast between cerebellar nuclei and their surroundings. In particular, the gyrification of the dentate nuclei is prominently depicted, even at the clinically widely available field strength of 3 T. The linear relationship between magnetic susceptibility and local iron content allows for determination of iron deposition in cerebellar nuclei non-invasively. The increased signal-to-noise ratio of ultrahigh-field MRI (B0 ≥ 7 T) and advances in spatial normalization methods enable functional MRI (fMRI) at the level of the cerebellar cortex and cerebellar nuclei. Data from initial fMRI studies are presented in three common forms of hereditary ataxias (Friedreich's ataxia, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6). Characteristic changes in the fMRI signal are discussed in the light of histopathological data and current knowledge of the underlying physiology of the fMRI signal in the cerebellum.

  2. The effects of epistaxis on health-related quality of life in patients with hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Merlo, Christian A; Yin, Linda X; Hoag, Jeffrey B; Mitchell, Sally E; Reh, Douglas D

    2014-11-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease mainly characterized by epistaxis in more than 96% of patients. Recently, a validated questionnaire known as the HHT Epistaxis Severity Score (ESS) was developed. However, little is known about the relationship between epistaxis and quality of life. We hypothesize that epistaxis severity is a major factor predicting health-related quality of life (HR-QoL) in HHT patients. This is a cross-sectional study. The ESS questionnaire and Medical Outcomes Study 36-item short form (SF-36) were administered to subjects through an Internet survey. All participants had a definitive diagnosis of HHT through Curaçao criteria or genetic testing. Demographic information, genetics, and extensive histories were also collected. Descriptive analyses were performed with calculations of means and standard deviations (SDs) for continuous variables and proportions for categorical variables. Linear regressions were then performed to assess the association between HR-QoL and ESS. A total of 604 subjects participated between April and August 2008. All patients reported epistaxis, 285 (47.2%) had telangiectasias, and 545 (90.2%) had a family history of HHT; 167 (27.6%) patients had mild epistaxis (ESS epistaxis (≥4 ESS epistaxis (ESS ≥7). Patients with severe epistaxis had lower scores for both the Physical Component Summary (PCS) and the Mental Component Summary (MCS) of HR-QoL when compared to those with mild epistaxis (p epistaxis. © 2014 ARS-AAOA, LLC.

  3. Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia.

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    Eun-Jung Choi

    Full Text Available Endoglin (ENG is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1. HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng(2fl/2fl mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl mice: R26CreER (all cell types after tamoxifen treatment, SM22α-Cre (smooth muscle and endothelial cell and LysM-Cre (lysozyme M-positive macrophage. An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF was injected into the brain to induce focal angiogenesis. We found that SM22α-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.

  4. SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome.

    Science.gov (United States)

    Krieger, Michael; Roos, Andreas; Stendel, Claudia; Claeys, Kristl G; Sonmez, Fatma Mujgan; Baudis, Michael; Bauer, Peter; Bornemann, Antje; de Goede, Christian; Dufke, Andreas; Finkel, Richard S; Goebel, Hans H; Häussler, Martin; Kingston, Helen; Kirschner, Janbernd; Medne, Livija; Muschke, Petra; Rivier, François; Rudnik-Schöneborn, Sabine; Spengler, Sabrina; Inzana, Francesca; Stanzial, Franco; Benedicenti, Francesco; Synofzik, Matthis; Lia Taratuto, Ana; Pirra, Laura; Tay, Stacey Kiat-Hong; Topaloglu, Haluk; Uyanik, Gökhan; Wand, Dorothea; Williams, Denise; Zerres, Klaus; Weis, Joachim; Senderek, Jan

    2013-12-01

    Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be

  5. Pediatric Opsoclonus-Myoclonus-Ataxia Syndrome Associated With Anti-N-methyl-D-aspartate Receptor Encephalitis.

    Science.gov (United States)

    Player, Brittany; Harmelink, Matthew; Bordini, Brett; Weisgerber, Michael; Girolami, Michael; Croix, Michael

    2015-11-01

    The full clinical spectrum of anti-N-methyl-D-aspartate receptor encephalitis is unknown in the pediatric population. We describe a previously healthy 4-year-old girl presenting with opsoclonus-myoclonus together with ataxia who had NR1-specific, anti-N-methyl-D-aspartate receptor antibodies in the cerebral spinal fluid. The presence of NR1-specific, anti-N-methyl-D-aspartate receptor antibodies in the setting of opsoclonus-myoclonus and ataxia syndrome may represent an expansion of the clinical presentations of anti-N-methyl-D-aspartate receptor encephalitis. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Increased cerebellar PET glucose metabolism corresponds to ataxia in Wernicke-Korsakoff syndrome.

    Science.gov (United States)

    Fellgiebel, Andreas; Siessmeier, Thomas; Winterer, Georg; Lüddens, Hartmut; Mann, Klaus; Schmidt, Lutz G; Bartenstein, Peter

    2004-01-01

    To investigate a possible relationship between cerebellar glucose metabolism and recovery from ataxia in the first months of acute Wernicke-Korsakoff syndrome. Two cases of alcoholic Wernicke-Korsakoff syndrome were followed up with the clinical status and cerebral glucose metabolism over a 4- and 9-month period. Initially both patients showed severe ataxia and elevated cerebellar glucose metabolism that decreased corresponding to the restitution of stance and gait. Increased cerebellar glucose metabolism at the onset of the illness may reflect the reorganization process of disturbed motor skills and may indicate cerebellar plasticity.

  7. The dynamic regulation of cortical excitability is altered in episodic ataxia type 2

    DEFF Research Database (Denmark)

    Helmich, Rick C; Siebner, Hartwig R; Giffin, Nicola

    2010-01-01

    -pulse transcranial magnetic stimulation at an interstimulus interval of 2 and 10 ms to assess intracortical inhibition and facilitation, respectively. The time course of burst-induced excitability changes differed between groups. Healthy controls showed a short-lived increase in excitability that was only present 50...... different from either controls or patients with episodic ataxia type 2. Together, these findings indicate that patients with episodic ataxia type 2 have an excessive increase in motor cortex excitability following a strong facilitatory input. We argue that this deficient control of cortical excitability may...

  8. Cerebellar Ataxia and Coenzyme Q Deficiency Through Loss of Unorthodox Kinase Activity

    OpenAIRE

    Stefely, Jonathan A.; Licitra, Floriana; Laredj, Leila; Reidenbach, Andrew G.; Kemmerer, Zachary A.; Grangeray, Anais; Jaeg-Ehret, Tiphaine; Minogue, Catherine E.; Ulbrich, Arne; Hutchins, Paul D.; Wilkerson, Emily M.; Ruan, Zheng; Aydin, Deniz; Hebert, Alexander S.; Guo, Xiao

    2016-01-01

    The UbiB protein kinase-like (PKL) family is widespread—comprising one-quarter of microbial PKLs and five human homologs—yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical ana...

  9. Targeting the CACNA1A IRES as a Treatment for Spinocerebellar Ataxia Type 6.

    Science.gov (United States)

    Pastor, Parviz Daniel Hejazi; Du, Xiaofei; Fazal, Sarah; Davies, Andre N; Gomez, Christopher M

    2018-02-01

    We have discovered that the P/Q-type voltage-gated Ca 2+ channel (VGCC) gene, CACNA1A, encodes both the α1A (Cav2.1) subunit and a newly recognized transcription factor, α1ACT, by means of a novel internal ribosomal entry site (IRES) within the α1A C-terminal coding region. α1ACT, when mutated with an expansion of the polyglutamine tract in the C-terminus, gives rise to spinocerebellar ataxia type 6 (SCA6). Because silencing of the entire CACNA1A gene would result in the loss of the essential Cav2.1 channel, the IRES controlling α1ACT expression is an excellent target for selective silencing of α1ACT as a therapeutic intervention for SCA6. We performed a high-throughput screen of FDA-approved small molecules using a dual luciferase reporter system and identified ten hits able to selectively inhibit the IRES. We identified four main candidates that showed selective suppression of α1ACT relative to α1A in HEK cells expressing a native CACNA1A vector. We previously pursued another avenue of molecular intervention through miRNA silencing. We studied three human miRNAs (miRNA-711, -3191-5p, -4786) that would potentially bind to sequences within the CACNA1A IRES region, based on an miRNA prediction program. Only miRNA-3191-5p was found to selectively inhibit the translation of α1ACT in cells. We developed a hyperacute model of SCA6 in mice by injecting a pathogenic form of the IRES-mediated α1ACT (AAV9-α1ACTQ33). Finally, we tested the effectiveness of the miRNA therapy by co-expressing either control miRNA or miRNA-3191-5p and found that miRNA-3191-5p decreased the levels of α1ACTQ33 and prevented the hyperacute disease in mice. These studies provide the proof of principle that a therapy directed at selectively preventing α1ACT expression could be used to treat SCA6.

  10. Cerebellar transcranial direct current stimulation in patients with ataxia: A double-blind, randomized, sham-controlled study.

    Science.gov (United States)

    Benussi, Alberto; Koch, Giacomo; Cotelli, Maria; Padovani, Alessandro; Borroni, Barbara

    2015-10-01

    Numerous studies have highlighted the possibility of modulating the excitability of cerebellar circuits using transcranial direct current stimulation. The present study investigated whether a single session of cerebellar anodal transcranial direct current stimulation could improve symptoms in patients with ataxia. Nineteen patients with ataxia underwent a clinical and functional evaluation pre- and post-double-blind, randomized, sham, or anodal transcranial direct current stimulation. There was a significant interaction between treatment and time on the Scale for the Assessment and Rating of Ataxia, on the International Cooperative Ataxia Rating Scale, on the 9-Hole Peg Test, and on the 8-Meter Walking Time (P transcranial direct current stimulation can transiently improve symptoms in patients with ataxia and might represent a promising tool for future rehabilitative approaches. © 2015 International Parkinson and Movement Disorder Society.

  11. Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) in a sibling pair with a homozygous p.A467T POLG mutation.

    LENUS (Irish Health Repository)

    McHugh, John C

    2012-02-01

    Two siblings who developed fifth-decade-onset, concurrent progressive sensory ataxia, dysarthria, and ophthalmoparesis were found to be homozygous for the p.A467T mutation of the polymerase gamma (POLG) gene. The clinical course in both subjects was progression to severe disability. The enlarging spectrum of sensory ataxic neuropathies associated with mitochondrial DNA (mtDNA) instability and POLG mutations should be recognized and considered in the differential diagnosis of this unusual presentation.

  12. Cardiopatía dilatada en ataxia de Friedreich: el punto sin retorno Dilated cardiomyopathy in Friedreich's ataxia: point of no return

    Directory of Open Access Journals (Sweden)

    Luis E Silva

    2012-04-01

    Full Text Available Las cardiopatías infiltrativas se caracterizan por el depósito de sustancias en el miocardio que causan un impacto negativo en la arquitectura de la pared ventricular. La ataxia espino-cerebelosa de Friedreich es una enfermedad degenerativa, heredada, con carácter autosómico recesivo. Clínicamente se caracteriza por ataxia de extremidades y tronco, hiporreflexia, neuropatía periférica, retinopatía y cardiopatía, entre otros. La afectación cardíaca es muy frecuente y se detectan alteraciones en estudios pos-mortem en 95% a 100% de los pacientes. La tasa de mortalidad es elevada y se considera una enfermedad incurable, a pesar de la existencia actual de múltiples medicamentos en estudio basados en los fundamentos fisiopatológicos de esta afección.Infiltrative heart diseases are characterized by deposit of substances in the myocardium that cause a negative impact on the architecture of the ventricular wall. Friedreich's spino-cerebellar ataxia is a degenerative disease, inherited in an autosomal recessive pattern. Clinically it is characterized by limb and trunk ataxia, hyporeflexia, peripheral neuropathy, retinopathy and heart disease among others. Cardiac involvement is common and on post-mortem studies cardiac abnormalities are found in 95% to 100% of patients. The mortality rate is high and it is considered an incurable disease, despite the current existence of multiple medications being studied, based on the pathophysiological basis of this condition.

  13. A combined nucleic acid and protein analysis in Friedreich ataxia: implications for diagnosis, pathogenesis and clinical trial design.

    Directory of Open Access Journals (Sweden)

    Francesco Saccà

    Full Text Available BACKGROUND: Friedreich's ataxia (FRDA is the most common hereditary ataxia among caucasians. The molecular defect in FRDA is the trinucleotide GAA expansion in the first intron of the FXN gene, which encodes frataxin. No studies have yet reported frataxin protein and mRNA levels in a large cohort of FRDA patients, carriers and controls. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled 24 patients with classic FRDA phenotype (cFA, 6 late onset FRDA (LOFA, all homozygous for GAA expansion, 5 pFA cases who harbored the GAA expansion in compound heterozygosis with FXN point mutations (namely, p.I154F, c.482+3delA, p.R165P, 33 healthy expansion carriers, and 29 healthy controls. DNA was genotyped for GAA expansion, mRNA/FXN was quantified in real-time, and frataxin protein was measured using lateral-flow immunoassay in peripheral blood mononuclear cells (PBMCs. Mean residual levels of frataxin, compared to controls, were 35.8%, 65.6%, 33%, and 68.7% in cFA, LOFA, pFA and healthy carriers, respectively. Comparison of both cFA and pFA with controls resulted in 100% sensitivity and specificity, but there was overlap between LOFA, carriers and controls. Frataxin levels correlated inversely with GAA1 and GAA2 expansions, and directly with age at onset. Messenger RNA expression was reduced to 19.4% in cFA, 50.4% in LOFA, 52.7% in pFA, 53.0% in carriers, as compared to controls (p<0.0001. mRNA levels proved to be diagnostic when comparing cFA with controls resulting in 100% sensitivity and specificity. In cFA and LOFA patients mRNA levels correlated directly with protein levels and age at onset, and inversely with GAA1 and GAA2. CONCLUSION/SIGNIFICANCE: We report the first explorative study on combined frataxin and mRNA levels in PBMCs from a cohort of FRDA patients, carriers and healthy individuals. Lateral-flow immunoassay differentiated cFA and pFA patients from controls, whereas determination of mRNA in q-PCR was sensitive and specific only in cFA.

  14. Response of sensitive human ataxia and resistant T-1 cell lines to accelerated heavy ions

    International Nuclear Information System (INIS)

    Tobias, C.A.; Blakely, E.A.; Chang, P.Y.; Lommel, L.; Roots, R.

    1983-07-01

    The radiation dose responses of fibroblast from a patient with Ataxia telangiectasis (AT-2SF) and an established line of human T-1 cells were studied. Nearly monoenergetic accelerated neon and argon ions were used at the Berkeley Bevalac with various residual range values. The LET of the particles varied from 30 keV/μm to over 1000 keV/μm. All Ataxia survival curves were exponential functions of the dose. Their radiosensitivity reached peak values at 100 to 200 keV/μm. Human T-1 cells have effective sublethal damage repair as has been evidenced by split dose experiments, and they are much more resistant to low LET than to high LET radiation. The repair-misrepair model has been used to interpret these results. We have obtained mathematical expressions that describe the cross sections and inactivation coefficients for both human cell lines as a function of the LET and the type of particle used. The results suggest either that high-LET particles induce a greater number of radiolesions per track or that heavy-ions at high LET induce lesions that kill cells more effectively and that are different from those produced at low LET. We assume that the lesions induced in T-1 and Ataxia cells are qualitatively similar and that each cell line attempts to repair these lesions. The result in most irradiated Ataxia cells, however, is either lethal misrepair or incomplete repair leading to cell death. 63 references, 10 figures, 1 table

  15. Cerebellar Ataxia with Bilateral Vestibulopathy: Description of a Syndrome and Its Characteristic Clinical Sign

    Science.gov (United States)

    Migliaccio, Americo A.; Halmagyi, G. Michael; McGarvie, Leigh A.; Cremer, Phillip D.

    2004-01-01

    We report four patients with the syndrome of cerebellar ataxia with bilateral vestibulopathy (CABV) and, using search coil oculography, we validate its characteristic clinical sign, namely impairment of the visually enhanced vestibulo-ocular reflex (VVOR) or doll's head reflex. In our four patients, CABV began in the sixth decade of life; they are…

  16. Spinocerebellar Ataxia Type 6 Protein Aggregates Cause Deficits in Motor Learning and Cerebellar Plasticity

    NARCIS (Netherlands)

    Mark, Melanie D; Krause, Martin; Boele, Henk-Jan; Kruse, Wolfgang; Pollok, Stefan; Kuner, Thomas; Dalkara, Deniz; Koekkoek, Sebastiaan; De Zeeuw, Chris I; Herlitze, Stefan

    2015-01-01

    Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca(2+) channels (Cav2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that

  17. Induced pluripotent stem cell - derived neurons for the study of spinocerebellar ataxia type 3

    DEFF Research Database (Denmark)

    Hansen, Susanne Kofoed; Stummann, Tina C.; Madsen, Helena Borland

    2016-01-01

    The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) is caused by a CAG-repeat expansion in the ATXN3 gene. In this study, induced pluripotent stem cell (iPSC) lines were established from two SCA3 patients. Dermal fibroblasts were reprogrammed using an integration-free method...

  18. Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6.

    NARCIS (Netherlands)

    Globas, C.; Montcel, S.T. du; Baliko, L.; Boesch, S.; Depondt, C.; DiDonato, S.; Durr, A.; Filla, A.; Klockgether, T.; Mariotti, C.; Melegh, B.; Rakowicz, M.; Ribai, P.; Rola, R.; Schmitz-Hubsch, T.; Szymanski, S.; Timmann, D.; Warrenburg, B.P.C. van de; Bauer, P.; Schols, L.

    2008-01-01

    Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We

  19. GAD Antibody-Associated Late-Onset Cerebellar Ataxia in Two Female Siblings

    Directory of Open Access Journals (Sweden)

    Joseph Kuchling

    2014-11-01

    Full Text Available Background: Anti-glutamic acid decarboxylase antibody (GAD-ab-associated cerebellar ataxia is a rare neurological disorder characterized by cerebellar symptoms concomitant with high GAD-ab levels in serum and cerebrospinal fluid (CSF. Case Report: We report on 2 female siblings (aged 74 and 76 years presenting with gradual progression of rotational vertigo, gait ataxia and vertical diplopia, continuously progressing for 6 months and 6 years, respectively. Autoimmune laboratory examinations showed remarkably increased serum and CSF GAD-ab levels. Their medical histories revealed late-onset type 1 diabetes mellitus (T1DM and other concomitant autoimmune disorders (Grave's disease, Hashimoto's thyroiditis. Cerebral MRI and laboratory examinations were unremarkable. The diagnosis of GAD-ab-associated cerebellar ataxia with particular brainstem involvement was established in both women. After the exclusion of an underlying malignancy, immunosuppressive therapy has been initiated in both patients, which resulted in stabilization in one and in clinical improvement in the other patient. Discussion: The unique association of autoantibody-mediated cerebellar ataxia and late-onset T1DM in 2 siblings with similar clinical and paraclinical phenotypes strengthens the concept that hereditary factors might play a relevant role also in autoimmune diseases so far considered to be sporadic. Moreover, the occurrence of continuous vertical diplopia broadens the clinical spectrum of GAD-ab-associated neurological syndromes.

  20. Magnetic resonance imaging findings in patients presenting with (sub)acute cerebellar ataxia

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, Tanja [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Neuroradiology, Hamburg (Germany); The Johns Hopkins Hospital School of Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Neuroradiology, Baltimore, MD (United States); Thomalla, Goetz [University Medical Center Hamburg-Eppendorf, Department of Neurology, Hamburg (Germany); Goebell, Einar [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Neuroradiology, Hamburg (Germany); Piotrowski, Anna [The Johns Hopkins University School of Medicine, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (United States); Yousem, David Mark [The Johns Hopkins Hospital School of Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Neuroradiology, Baltimore, MD (United States)

    2015-02-17

    Acute or subacute cerebellar inflammation is mainly caused by postinfectious, toxic, neoplastic, vascular, or idiopathic processes and can result in cerebellar ataxia. Previous magnetic resonance (MR) studies in single patients who developed acute or subacute ataxia showed varying imaging features. Eighteen patients presenting with acute and subacute onset of ataxia were included in this study. Cases of chronic-progressive/hereditary and noncerebellar causes (ischemia, multiple sclerosis lesions, metastasis, bleedings) were excluded. MR imaging findings were then matched with the clinical history of the patient. An underlying etiology for ataxic symptoms were found in 14/18 patients (postinfectious/infectious, paraneoplastic, autoimmune, drug-induced). In two of five patients without MR imaging findings and three of eight patients with minimal imaging features (cerebellar atrophy, slight signal alterations, and small areas of restricted diffusion), adverse clinical outcomes were documented. Of the five patients with prominent MR findings (cerebellar swelling, contrast enhancement, or broad signal abnormalities), two were lost to follow-up and two showed long-term sequelae. No correlation was found between the presence of initial MRI findings in subacute or acute ataxia patients and their long-term clinical outcome. MR imaging was more flagrantly positive in cases due to encephalitis. (orig.)

  1. Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3)

    NARCIS (Netherlands)

    Seidel, K.; Meister, M.; Dugbartey, G. J.; Zijlstra, M. P.; Vinet, J.; Brunt, E. R. P.; van Leeuwen, F. W.; Rueb, U.; Kampinga, H. H.; den Dunnen, W. F. A.

    2012-01-01

    K. Seidel, M. Meister, G. J. Dugbartey, M. P. Zijlstra, J. Vinet, E. R. P. Brunt, F. W. van Leeuwen, U. Rub, H. H. Kampinga and W. F. A. den Dunnen (2012) Neuropathology and Applied Neurobiology38, 548558 Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type

  2. Evidence of oxidative stress and mitochondrial dysfunction in spinocerebellar ataxia type 2 (SCA2) patient fibroblasts

    DEFF Research Database (Denmark)

    Cornelius, Nanna; Wardman, Jonathan H; Hargreaves, Iain P

    2017-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-2 gene. We show increased oxidative stress, abnormalities in the antioxidant system, changes in complexes involved in oxidative phosphorylation and changes in mitochondrial mor...

  3. Spinocerebellar ataxia type 3 (Machado-Joseph disease) : severe destruction of the lateral reticular nucleus

    NARCIS (Netherlands)

    Rub, U; de Vos, RAI; Schultz, C; Brunt, ER; Paulson, H; Braak, H

    The lateral reticular nucleus (LRT) of the medulla oblongata is a precerebellar nucleus involved in proprioception and somatomotor automatisms. We investigated this nucleus in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3, Machado-Joseph

  4. Magnetic resonance imaging findings in patients presenting with (sub)acute cerebellar ataxia.

    Science.gov (United States)

    Schneider, Tanja; Thomalla, Götz; Goebell, Einar; Piotrowski, Anna; Yousem, David Mark

    2015-06-01

    Acute or subacute cerebellar inflammation is mainly caused by postinfectious, toxic, neoplastic, vascular, or idiopathic processes and can result in cerebellar ataxia. Previous magnetic resonance (MR) studies in single patients who developed acute or subacute ataxia showed varying imaging features. Eighteen patients presenting with acute and subacute onset of ataxia were included in this study. Cases of chronic-progressive/hereditary and noncerebellar causes (ischemia, multiple sclerosis lesions, metastasis, bleedings) were excluded. MR imaging findings were then matched with the clinical history of the patient. An underlying etiology for ataxic symptoms were found in 14/18 patients (postinfectious/infectious, paraneoplastic, autoimmune, drug-induced). In two of five patients without MR imaging findings and three of eight patients with minimal imaging features (cerebellar atrophy, slight signal alterations, and small areas of restricted diffusion), adverse clinical outcomes were documented. Of the five patients with prominent MR findings (cerebellar swelling, contrast enhancement, or broad signal abnormalities), two were lost to follow-up and two showed long-term sequelae. No correlation was found between the presence of initial MRI findings in subacute or acute ataxia patients and their long-term clinical outcome. MR imaging was more flagrantly positive in cases due to encephalitis.

  5. Mucocutaneous leishmaniasis in an 11-year-old girl with ataxia ...

    African Journals Online (AJOL)

    LETTER TO THE EDITOR. Mucocutaneous leishmaniasis in an 11-year-old girl with ataxia telangectasia Бcase report. Leishmaniasis is a protozoal disease caused by flagellates of the genus Leishmania and transmit- ted by sand fly. The reservoir hosts are humans, dogs, and rodents. It has three different morphological.

  6. Speech changes after coordinative training in patients with cerebellar ataxia: a pilot study

    Czech Academy of Sciences Publication Activity Database

    Tykalová, T.; Pospíšilová, M.; Čmejla, R.; Jeřábek, J.; Mareš, Pavel; Rusz, J.

    2016-01-01

    Roč. 37, č. 2 (2016), s. 293-296 ISSN 1590-1874 Institutional support: RVO:67985823 Keywords : spinocerebellar ataxia * rehabilitation * physiotherapy * ataxic dysarthria * postural alignment * acoustic analysis Subject RIV: FH - Neurology Impact factor: 1.749, year: 2016

  7. [Progressive ataxia and cognitive deficits caused by premutation in the fragile-X-mental retardation gene

    NARCIS (Netherlands)

    Roks, G.; Sistermans, E.A.; Vries, L.B.A. de; Nijssen, P.C.

    2005-01-01

    A 75-year-old man had progressive difficulty with walking, intention tremor, ataxia, and mild cognitive deficits. MRI scan ofthe brain showed symmetrical hyperintensities in the middle cerebellar peduncles. DNA analysis ofthe fragile-X gene revealed an expansion of 150-200 repetitions in the

  8. Boucher Neuhäuser Syndrome - A rare cause of inherited hypogonadotropic hypogonadism. A case of two adult siblings with two novel mutations in PNPLA6.

    Science.gov (United States)

    Langdahl, Jakob H; Frederiksen, Anja L; Nguyen, Nina; Brusgaard, Klaus; Juhl, Claus B

    2017-02-01

    Boucher Neuhäuser Syndrome (BNS) is a rare clinical syndrome with autosomal recessive inheritance defined by early-onset ataxia, hypogonadism and chorioretinal dystrophy. We present two siblings diagnosed with BNS in late adult life identified with compound heterozygous state of two novel PNPLA6 mutations. Five healthy siblings were non- or heterozygous carriers of the mutations. The cases, which presented with ataxia in childhood and hypogonadotropic hypogonadism (HH), were diagnosed at age 17 and 25, respectively, when examined for delayed puberty. The youngest case, a 55-year old male, was referred to our department in 2006 for evaluation of secondary causes of osteoporosis, which he developed despite adequate testosterone replacement therapy. The unusual medical history with childhood ataxia and hypogonadotropic hypogonadism lead to further examinations and eventually the diagnosis of BNS. The older sister of the proband also displayed the triad of ataxia, HH and chorioretinal dystrophy accompanied by cerebellar atrophy and in 2014, we found the mutations in PNPLA6. BNS is a rare cause of HH and secondary osteoporosis, but should be considered in patients presenting with one or more of the key features. Genetic screening is becoming increasingly available and inexpensive and accordingly this may be considered earlier and by broader indication in unusual phenotypic presentations. The increasing knowledge of causes for inherited diseases should extend the use of genetic screening, as the correct diagnosis will benefit the patients. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Supporting a Youth with Cerebellar Ataxia into Adolescence.

    Science.gov (United States)

    Meneses, Veronica; Gonzalez-Castillo, Zurisadai; Edgar, Veronica B; Augustyn, Marilyn

    2017-04-01

    Zoe, a 13-year-old white girl, presents as a new patient to your pediatric clinic with complaints of frequent emesis, anxiety, and learning problems, and previous diagnosis of cerebellar ataxia. Parents accompany Zoe and state, "it is really hard for her to go out, she gets sick and falls easily." She was born full term by vaginal delivery without complications. Given globally delayed milestones, she received early intervention services. Feeding problems began at infancy, including gastroesophageal reflux and aspiration pneumonia.At age 2, Zoe saw a neurologist and brain MRI revealed cerebellar atrophy. She recently saw a geneticist and genetic studies are pending. Parents report receiving "little" information regarding prognosis; through their own research, they read about individuals having similar symptoms in adulthood, with a degenerative pattern. They worry that Zoe is "still very young and we do not know what her future will be like."Despite ongoing speech and feeding challenges, the parents report difficulty finding a speech and language therapist in their area. Zoe does see an otolaryngologist for frequent otitis media and hearing loss and an ophthalmologist for vision problems. Still, she continues to fall further behind in school. Furthermore, she is intensely afraid of falling at school and has few friends, resulting in the family being at a loss regarding "what to do about school."She lives with both parents and 2 healthy older sisters. Her mother has Crohn's disease and has been unable to work. Her maternal aunt is close to Zoe and has hypothyroidism. Her father works as an insurance agent and resources have been "tight." Zoe's mother describes "making" Zoe go out to the movies, "otherwise she just stays home." Zoe usually needs assistance to walk in public, to keep from stumbling. Parents share that simply being in a public place or meeting a new physician may trigger emesis. Zoe does enjoy interacting with neighborhood children and says she wants to

  10. A magic bullet to specifically eliminate mutated mitochondrial genomes from patients' cells

    Science.gov (United States)

    Moraes, Carlos T

    2014-01-01

    When mitochondrial diseases result from mutations found in the mitochondrial DNA, engineered mitochondrial-targeted nucleases such as mitochondrial-targeted zinc finger nucleases are shown to specifically eliminate the mutated molecules, leaving the wild-type mitochondrial DNA intact to replicate and restore normal copy number. In this issue, Gammage and colleagues successfully apply this improved technology on patients' cells with two types of genetic alterations responsible for neuropathy ataxia and retinitis pigmentosa (NARP) syndrome and Kearns Sayre syndrome and progressive external ophthalmoplegia (PEO). PMID:24623377

  11. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy

    DEFF Research Database (Denmark)

    Syrbe, Steffen; Hedrich, Ulrike B S; Riesch, Erik

    2015-01-01

    disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype....... They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing...

  12. Amplatzer Vascular Plugs Versus Coils for Embolization of Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Tau, Noam, E-mail: taunoam@gmail.com; Atar, Eliyahu [Rabin Medical Center – Beilinson and HaSharon Campuses, Department of Diagnostic Imaging (Israel); Mei-Zahav, Meir [Schneider Children’s Medical Center of Israel, Department of Pulmonology and National HHT Center (Israel); Bachar, Gil N. [Rabin Medical Center – Beilinson and HaSharon Campuses, Department of Diagnostic Imaging (Israel); Dagan, Tamir; Birk, Einat; Bruckheimer, Elchanan [Schneider Children’s Medical Center of Israel, Institute of Pediatric Cardiology (Israel)

    2016-08-15

    PurposeCoil embolization of pulmonary arteriovenous malformations (PAVMs) has a high re-canalization/re-perfusion rate. Embolization with Amplatzer plugs has been previously described, but the long-term efficacy is not established. This study reports the experience of a referral medical center with the use of coils and Amplatzer plugs for treating PAVMs in patients with hereditary hemorrhagic telangiectasia.MethodsThe study was approved by the Institutional Review Board with waiver of informed consent. The cohort included all patients who underwent PAVM embolization in 2004–2014 for whom follow-up imaging scans were available. The medical files were retrospectively reviewed for background data, embolization method (coils, Amplatzer plugs, both), and complications. Re-canalization of treated PAVMs was assessed from intrapulmonary angiograms (following percutaneous procedures) or computed tomography angiograms. Fisher’s exact test and Pearson Chi-squared test or t test were used for statistical analysis, with significance at p < 0.05.Results16 patients met the study criteria. Imaging scans were available for 63 of the total 110 PAVMs treated in 41 procedures. Coils were used for embolization in 37 PAVMs, Amplatzer plugs in 21, and both in five. Median follow-up time was 7.7 years (range 1.4–18.9). Re-canalization was detected in seven vessels, all treated with coils; there were no cases of re-canalization in plug-occluded vessels (p = 0.0413).ConclusionThe use of Amplatzer plugs for the embolization of PAVMs in patients with hemorrhagic telangiectasia is associated with a significantly lower rate of re-canalization of feeding vessels than coils. Long-term prospective studies are required to confirm these findings.

  13. Amplatzer Vascular Plugs Versus Coils for Embolization of Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia

    International Nuclear Information System (INIS)

    Tau, Noam; Atar, Eliyahu; Mei-Zahav, Meir; Bachar, Gil N.; Dagan, Tamir; Birk, Einat; Bruckheimer, Elchanan

    2016-01-01

    PurposeCoil embolization of pulmonary arteriovenous malformations (PAVMs) has a high re-canalization/re-perfusion rate. Embolization with Amplatzer plugs has been previously described, but the long-term efficacy is not established. This study reports the experience of a referral medical center with the use of coils and Amplatzer plugs for treating PAVMs in patients with hereditary hemorrhagic telangiectasia.MethodsThe study was approved by the Institutional Review Board with waiver of informed consent. The cohort included all patients who underwent PAVM embolization in 2004–2014 for whom follow-up imaging scans were available. The medical files were retrospectively reviewed for background data, embolization method (coils, Amplatzer plugs, both), and complications. Re-canalization of treated PAVMs was assessed from intrapulmonary angiograms (following percutaneous procedures) or computed tomography angiograms. Fisher’s exact test and Pearson Chi-squared test or t test were used for statistical analysis, with significance at p < 0.05.Results16 patients met the study criteria. Imaging scans were available for 63 of the total 110 PAVMs treated in 41 procedures. Coils were used for embolization in 37 PAVMs, Amplatzer plugs in 21, and both in five. Median follow-up time was 7.7 years (range 1.4–18.9). Re-canalization was detected in seven vessels, all treated with coils; there were no cases of re-canalization in plug-occluded vessels (p = 0.0413).ConclusionThe use of Amplatzer plugs for the embolization of PAVMs in patients with hemorrhagic telangiectasia is associated with a significantly lower rate of re-canalization of feeding vessels than coils. Long-term prospective studies are required to confirm these findings.

  14. Probiotics and infective endocarditis in patients with hereditary hemorrhagic telangiectasia: a clinical case and a review of the literature.

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    Boumis, Evangelo; Capone, Alessandro; Galati, Vincenzo; Venditti, Carolina; Petrosillo, Nicola

    2018-02-01

    In the last decades, probiotics have been widely used as food supplements because of their putative beneficial health effects. They are generally considered safe but rare reports of serious infections caused by bacteria included in the definition of probiotics raise concerns on their potential pathogenic role in patients with particular predisposing factors. Patients with hereditary hemorrhagic telangiectasia (HHT) are exposed to infections because of telangiectasias and arteriovenous malformations (AVMs). We describe what is, to our knowledge, the first case of infective endocarditis (IE) caused by Lactobacillus rhamnosus in a patient with HHT. A systematic review of the relevant medical literature is presented. A patient with HHT and an aortic bioprosthesis was admitted because of prolonged fever not responding to antibiotics. The patient had a history of repeated serious infections with hospitalizations and prolonged use of antibiotics, and used to assume large amounts of different commercial products containing probiotics. Weeks before the onset of symptoms the patient had been treated with nasal packings and with surgical closure of a nasal bleeding site because of recurrent epistaxis. A diagnosis of IE of the aortic bioprosthesis was made. All blood coltures were positive for L. rhamnosus. The patients responded to a cycle of 6 weeks of amoxicillin/clavulanate plus gentamicin. A systematic review of IE linked to consumption of probiotics, and of infective endocarditis in patients with HHT was conducted. 10 cases of IE linked to probiotics consumption and 6 cases of IE in patients with HHT were found. Consumption of probiotics can pose a risk of serious infections in patients with particular predisposing factors. Patients with HHT can be considered at risk because of their predisposition to infections. Prophylaxis with antibiotics before nasal packings in patients with HHT can be considered.

  15. Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE.

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    Yuan, Junhui; Higuchi, Yujiro; Nagado, Tatsui; Nozuma, Satoshi; Nakamura, Tomonori; Matsuura, Eiji; Hashiguchi, Akihiro; Sakiyama, Yusuke; Yoshimura, Akiko; Takashima, Hiroshi

    2013-03-01

    DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next-generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot. © 2013 Peripheral Nerve Society.

  16. DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population.

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    Lenato, Gennaro M; Lastella, Patrizia; Di Giacomo, Marilena C; Resta, Nicoletta; Suppressa, Patrizia; Pasculli, Giovanna; Sabbà, Carlo; Guanti, Ginevra

    2006-02-01

    Hereditary haemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by localized angiodysplasia due to mutations in endoglin, ALK-1 gene, and a still unidentified locus. The lack of highly recurrent mutations, locus heterogeneity, and the presence of mutations in almost all coding exons of the two genes makes the screening for mutations time-consuming and costly. In the present study, we developed a DHPLC-based protocol for mutation detection in ALK1 and ENG genes through retrospective analysis of known sequence variants, 20 causative mutations and 11 polymorphisms, and a prospective analysis on 47 probands with unknown mutation. Overall DHPLC analysis identified the causative mutation in 61 out 66 DNA samples (92.4%). We found 31 different mutations in the ALK1 gene, of which 15 are novel, and 20, of which 12 are novel, in the ENG gene, thus providing for the first time the mutational spectrum in a cohort of Italian HHT patients. In addition, we characterized the splicing pattern of ALK1 gene in lymphoblastoid cells, both in normal controls and in two individuals carrying a mutation in the non-invariant -3 position of the acceptor splice site upstream exon 6 (c.626-3C>G). Functional essay demonstrated the existence, also in normal individuals, of a small proportion of ALK1 alternative splicing, due to exon 5 skipping, and the presence of further aberrant splicing isoforms in the individuals carrying the c.626-3C>G mutation. 2006 Wiley-Liss, Inc.

  17. Genetic inactivation of mGlu5 receptor improves motor coordination in the Grm1crv4 mouse model of SCAR13 ataxia.

    Science.gov (United States)

    Bossi, Simone; Musante, Ilaria; Bonfiglio, Tommaso; Bonifacino, Tiziana; Emionite, Laura; Cerminara, Maria; Cervetto, Chiara; Marcoli, Manuela; Bonanno, Giambattista; Ravazzolo, Roberto; Pittaluga, Anna; Puliti, Aldamaria

    2018-01-01

    Deleterious mutations in the glutamate receptor metabotropic 1 gene (GRM1) cause a recessive form of cerebellar ataxia, SCAR13. GRM1 and GRM5 code for the metabotropic glutamate type 1 (mGlu1) and type 5 (mGlu5) receptors, respectively. Their different expression profiles suggest they could have distinct functional roles. In a previous study, homozygous mice lacking mGlu1 receptors (Grm1 crv4/crv4 ) and exhibiting ataxia presented cerebellar overexpression of mGlu5 receptors, that was proposed to contribute to the mouse phenotype. To test this hypothesis, we here crossed Grm1 crv4 and Grm5 ko mice to generate double mutants (Grm1 crv4/crv4 Grm5 ko/ko ) lacking both mGlu1 and mGlu5 receptors. Double mutants and control mice were analyzed for spontaneous behavior and for motor activity by rotarod and footprint analyses. In the same mice, the release of glutamate from cerebellar nerve endings (synaptosomes) elicited by 12mM KCl or by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was also evaluated. Motor coordination resulted improved in double mutants when compared to Grm1 crv4/crv4 mice. Furthermore, in in vitro studies, glutamate release elicited by both KCl depolarization and activation of AMPA autoreceptors resulted reduced in Grm1 crv4/crv4 mice compared to wild type mice, while it presented normal levels in double mutants. Moreover, we found that Grm1 crv4/crv4 mice showed reduced expression of GluA2/3 AMPA receptor subunits in cerebellar synaptosomes, while it resulted restored to wild type level in double mutants. To conclude, blocking of mGlu5 receptor reduced the dysregulation of glutamate transmission and improved motor coordination in the Grm1 crv4 mouse model of SCAR13, thus suggesting the possible usefulness of pharmacological therapies based on modulation of mGlu5 receptor activity for the treatment of this type of ataxia. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome.

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    Castro, Hoanna; Kul, Emre; Buijsen, Ronald A M; Severijnen, Lies-Anne W F M; Willemsen, Rob; Hukema, Renate K; Stork, Oliver; Santos, Mónica

    2017-06-01

    A CGG-repeat expansion in the premutation range in the Fragile X mental retardation 1 gene (FMR1) has been identified as the genetic cause of Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that manifests with action tremor, gait ataxia and cognitive impairments. In this study, we used a bigenic mouse model, in which expression of a 90CGG premutation tract is activated in neural cells upon doxycycline administration-P90CGG mouse model. We, here, demonstrate the behavioural manifestation of clinically relevant features of FXTAS patients and premutation carrier individuals in this inducible mouse model. P90CGG mice display heightened anxiety, deficits in motor coordination and impaired gait and represent the first FXTAS model that exhibits an ataxia phenotype as observed in patients. The behavioural phenotype is accompanied by the formation of ubiquitin/FMRpolyglycine-positive intranuclear inclusions, as another hallmark of FXTAS, in the cerebellum, hippocampus and amygdala. Strikingly, upon cessation of transgene induction the anxiety phenotype of mice recovers along with a reduction of intranuclear inclusions in dentate gyrus and amygdala. In contrast, motor function deteriorates further and no reduction in intranuclear inclusions can be observed in the cerebellum. Our data thus demonstrate that expression of a 90CGG premutation expansion outside of the FMR1 context is sufficient to evoke an FXTAS-like behavioural phenotype. Brain region-specific neuropathology and (partial) behavioural reversibility make the inducible P90CGG a valuable mouse model for testing pathogenic mechanisms and therapeutic intervention methods. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. In Vivo Modelling of ATP1A3 G316S-Induced Ataxia in C. elegans Using CRISPR/Cas9-Mediated Homologous Recombination Reveals Dominant Loss of Function Defects.

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    Altar Sorkaç

    Full Text Available The NIH Undiagnosed Diseases Program admitted a male patient with unclassifiable late-onset ataxia-like symptoms. Exome sequencing revealed a heterozygous de novo mutation converting glycine 316 to serine in ATP1A3, which might cause disease. ATP1A3 encodes the Na+/K+ ATPase pump α3-subunit. Using CRISPR/Cas9-mediated homologous recombination for genome editing, we modelled this putative disease-causing allele in Caenorhabditis elegans, recreating the patient amino acid change in eat-6, the orthologue of ATP1A3. The impact of the mutation on eat-6 function at the neuromuscular junction was examined using two behavioural assays: rate of pharyngeal pumping and sensitivity to aldicarb, a drug that causes paralysis over time via the inhibition of acetylcholinesterase. The patient allele decreased pumping rates and caused hypersensitivity to aldicarb. Animals heterozygous for the allele exhibited similar defects, whereas loss of function mutations in eat-6 were recessive. These results indicate that the mutation is dominant and impairs the neuromuscular function. Thus, we conclude that the de novo G316S mutation in ATP1A3 likely causes or contributes to patient symptoms. More broadly, we conclude that, for conserved genes, it is possible to rapidly and easily model human diseases in C. elegans using CRIPSR/Cas9 genome editing.

  20. Far-infrared radiation protects viability in a cell model of Spinocerebellar Ataxia by preventing polyQ protein accumulation and improving mitochondrial function.

    Science.gov (United States)

    Chang, Jui-Chih; Wu, Shey-Lin; Hoel, Fredrik; Cheng, Yu-Shan; Liu, Ko-Hung; Hsieh, Mingli; Hoel, August; Tronstad, Karl Johan; Yan, Kuo-Chia; Hsieh, Ching-Liang; Lin, Wei-Yong; Kuo, Shou-Jen; Su, Shih-Li; Liu, Chin-San

    2016-07-29

    Far infrared radiation (FIR) is currently investigated as a potential therapeutic strategy in various diseases though the mechanism is unknown. Presently, we tested if FIR mediates beneficial effects in a cell model of the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3). SCA3 is caused by a mutation leading to an abnormal polyglutamine expansion (PolyQ) in ataxin-3 protein. The consequent aggregation of mutant ataxin-3 results in disruption of vital cell functions. In this study, neuroblastoma cells (SK-N-SH) was transduced to express either non-pathogenic ataxin-3-26Q or pathogenic ataxin-3-78Q proteins. The cells expressing ataxin-3-78Q demonstrated decreased viability, and increased sensitivity to metabolic stress in the presence rotenone, an inhibitor of mitochondrial respiration. FIR exposure was found to protect against these effects. Moreover, FIR improved mitochondrial respiratory function, which was significantly compromised in ataxin-3-78Q and ataxin-3-26Q expressing cells. This was accompanied by decreased levels of mitochondrial fragmentation in FIR treated cells, as observed by fluorescence microscopy and protein expression analysis. Finally, the expression profile LC3-II, Beclin-1 and p62 suggested that FIR prevent the autophagy inhibiting effects observed in ataxin-3-78Q expressing cells. In summary, our results suggest that FIR have rescuing effects in cells expressing mutated pathogenic ataxin-3, through recovery of mitochondrial function and autophagy.