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Sample records for ataxia telangiectasia heterozygous

  1. Ataxia - telangiectasia

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    ... this page: //medlineplus.gov/ency/article/001394.htm Ataxia - telangiectasia To use the sharing features on this page, please enable JavaScript. Ataxia-telangiectasia is a rare childhood disease. It affects ...

  2. Ataxia Telangiectasia

    Science.gov (United States)

    Ataxia-telangiectasia (A-T) is a rare, inherited disease. It affects the nervous system, immune system, and ... young children, usually before age 5. They include Ataxia - trouble coordinating movements Poor balance Slurred speech Tiny, ...

  3. Novel compound heterozygous mutations in a child with Ataxia-Telangiectasia showing unrelated cerebellar disorders.

    Science.gov (United States)

    Piane, Maria; Molinaro, Anna; Soresina, Annarosa; Costa, Silvia; Maffeis, Marianna; Germani, Aldo; Pinelli, Lorenzo; Meschini, Roberta; Plebani, Alessandro; Chessa, Luciana; Micheli, Roberto

    2016-12-15

    We report the case of a 6-year-old female patient with Ataxia Telangiectasia, an extremely rare condition, who developed in addition a left cerebellar astrocytoma and a right cerebellar infarction, considered as two independent events. Children with AT have an increased risk of developing cancer, but only few cases of glioma are reported and, at our knowledge, no other case of unrelated cerebellar glioma and cerebellar infarction in with the same AT patient have been described. The molecular analysis of ATM (Ataxia Telangiectasia Mutated) gene showed that the patient is compound heterozygote for two previously unreported mutations: c.3291delC (p.Phe1097fs) at exon 25 and c.8198A>C (p.Gln2733Pro) at exon 58. The role of the identified ATM gene mutations in the pathogenesis of Ataxia Telangiectasia and the coexisting cerebellar disorders is discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Radiation Dose-effects on Cell Cycle, Apoptosis, and Marker Expression of Ataxia Telangiectasia-Heterozygous Human Breast Epithelial Cells

    Science.gov (United States)

    Cruz, A.; Bors, K.; Jansen, H.; Richmond, R.

    2003-01-01

    Ataxia-telangiectasia (A-T) is a radiation-sensitive genetic condition. AT-heterozygous human mammary epithelial cells (HMEC) were irradiated using a Cs137 source in order to compare cell cycle, apoptosis, and marker expression responses across 3 radiation doses. No differences in cell cycle and apoptosis were found with any of the radiation doses used (30, 60, and 90 rads) compared with the unirradiated control (0 rad). At the same doses, however, differences were found in marker expression, such as keratin 18 (kl8), keratin 14 (k14), insulin-like growth factor I receptor (IGF-IR), and connexin 43 (cx43). This may indicate that radiation sensitivity in the heterozygous state may be initiated through signal transduction responses.

  5. Radiation Dose-effects on Cell Cycle, Apoptosis, and Marker Expression of Ataxia Telangiectasia-Heterozygous Human Breast Epithelial Cells

    Science.gov (United States)

    Cruz, A.; Bors, K.; Jansen, H.; Richmond, R.

    2003-01-01

    Ataxia-telangiectasia (A-T) is a radiation-sensitive genetic condition. AT-heterozygous human mammary epithelial cells (HMEC) were irradiated using a Cs137 source in order to compare cell cycle, apoptosis, and marker expression responses across 3 radiation doses. No differences in cell cycle and apoptosis were found with any of the radiation doses used (30, 60, and 90 rads) compared with the unirradiated control (0 rad). At the same doses, however, differences were found in marker expression, such as keratin 18 (kl8), keratin 14 (k14), insulin-like growth factor I receptor (IGF-IR), and connexin 43 (cx43). This may indicate that radiation sensitivity in the heterozygous state may be initiated through signal transduction responses.

  6. 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).

  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. What Is Ataxia-Telangiectasia?

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    ... About A-T Research Fundraising About Us About Ataxia-telangiectasia About A-T » WHAT IS A- ... develop slurred or distorted speech, and swallowing problems. Ataxia... The onset of this ataxia marks the beginning ...

  9. Genetics Home Reference: ataxia-telangiectasia

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions ataxia-telangiectasia ataxia-telangiectasia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Ataxia-telangiectasia is a rare inherited disorder that affects ...

  10. Cancer Risk-Assessment of Radiation Damage in Ataxia Telangiectasia Heterozygous Human Breast Epithelial Cell Cultures

    Science.gov (United States)

    Applewhite, Lisa C.

    2002-01-01

    This paper describes the study of the markers of cellular changes that are found during the onset of carcinogenesis. Several of the biological factors are markers of stress response, oncoprotein expression, and differentiation factors. Oxidative stress response agents such as heat shock proteins (HSPs) protect cells from oxidative stresses such as ionizing radiation. The onocoprotein HER-2/neu, a specific breast cancer marker, indicates early onset of cancer. Additional structural and morphogenetic markers of differentiation were considered in order to determine initial cellular changes at the initial onset of cancer. As an additional consideration, all-trans retinoic acid (RA), a differentiation agent, was considered because of its known role in regulating normal differentiation and inhibiting tumor proliferation via specific nuclear receptors. This paper discusses study and results of the preliminary analyses of gamma irradiation of AT heterozygous human breast epithelial cells (WH). Comparisons are also made of the effects various RA concentrations post-irradiation.

  11. Ataxia-telangiectasia

    Directory of Open Access Journals (Sweden)

    Nelson Pires Ferreira

    1966-09-01

    Full Text Available São apresentados os casos de dois irmãos com ataxia-telangiectasia, estudados sob os pontos de vista clínico, eletrencefalográfico, liquórico e encefalográfico. O autor resume os achados de diversos autores e chama a atenção para a regressão parcial da síndrome cerebelar em ambos os pacientes, fato ainda não referido na literatura.

  12. 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.

  13. Ataxia-telangiectasia: recommendations for multidisciplinary treatment

    NARCIS (Netherlands)

    Os, N.J.H. van; Haaxma, C.A.; Flier, M. van der; Merkus, P.J.F.M.; Deuren, M. van; Groot, I.J.M. de; Loeffen, J.; Warrenburg, B.P.C. van de; Willemsen, M.A.A.P.

    2017-01-01

    Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's n

  14. Clinical variability in ataxia-telangiectasia.

    Science.gov (United States)

    Lohmann, Ebba; Krüger, Stefanie; Hauser, Ann-Kathrin; Hanagasi, Hasmet; Guven, Gamze; Erginel-Unaltuna, Nihan; Biskup, Saskia; Gasser, Thomas

    2015-07-01

    Ataxia-telangiectasia (A-T) is an autosomal recessive inherited disease characterized by progressive childhood-onset cerebellar ataxia, oculomotor apraxia, choreoathetosis and telangiectasias of the conjunctivae. Further symptoms may be immunodeficiency and frequent infections, and an increased risk of malignancy. As well as this classic manifestation, several other non-classic forms exist, including milder or incomplete A-T phenotypes caused by homozygous or compound heterozygous mutations in the ATM gene. Recently, ATM mutations have been found in 13 Canadian Mennonites with early-onset, isolated, predominantly cervical dystonia, in a French family with generalized dystonia and in an Indian family with dopa-responsive cervical dystonia. In this article, we will describe a Turkish family with three affected sibs. Their phenotypes range from pure cervical dystonia associated with hand tremor to truncal and more generalized dystonic postures. Exome sequencing has revealed the potentially pathogenic compound heterozygous variants p.V2716A and p.G301VfsX19 in the ATM gene. The variants segregated perfectly with the phenotypes within the family. Both mutations detected in ATM have been shown to be pathogenic, and the α-fetoprotein, a marker of ataxia telangiectasia, was found to be increased. This report supports recent literature showing that ATM mutations are not exclusively associated with A-T but may also cause a more, even intra-familial variable phenotype in particular in association with dystonia.

  15. Survival probability in ataxia telangiectasia

    Science.gov (United States)

    Crawford, T O; Skolasky, R L; Fernandez, R; Rosquist, K J; Lederman, H M

    2006-01-01

    Ataxia telangiectasia is a rare, multiorgan neurodegenerative disorder with enhanced vulnerability to cancer and infection. Median survival in two large cohorts of patients with this disease, one prospective and one retrospective, is 25 and 19 years, with a wide range. Life expectancy does not correlate well with severity of neurological impairment. PMID:16790721

  16. Cerebral abnormalities in adults with ataxia-telangiectasia

    National Research Council Canada - National Science Library

    Lin, D D M; Barker, P B; Lederman, H M; Crawford, T O

    2014-01-01

    Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment with cerebellar atrophy, ocular...

  17. [From gene to disease; ataxia telangiectasia

    NARCIS (Netherlands)

    Broeks, A.; Veer, L.J. van 't; Ottenheim, C.; Hiel, J.A.P.; Kleijer, W.J.; Weemaes, C.M.R.

    2003-01-01

    Ataxia telangiectasia (AT) is an autosomal recessive disorder characterised by cerebellar ataxia, telangiectasia, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to cell kill by ionising radiation and abnormally resistant to in

  18. Ataxia-Telangiectasia (A-T)

    Science.gov (United States)

    Ataxia-Telangiectasia (A-T) What is ataxia-telangiectasia (A-T)? A-T is a hereditary progressive neurodegenerative disorder that begins in early childhood. ... nervous system. What are the symptoms of A-T? An affected child usually begins to show signs ...

  19. Molecular pathology of ataxia telangiectasia

    Science.gov (United States)

    Taylor, A M R; Byrd, P J

    2005-01-01

    Ataxia telangiectasia (A-T) is one of a group of autosomal recessive cerebellar ataxias. Presentation is usually by the age of 2 years and ataxia of both upper and lower limbs develops, such that by early teenage most patients require a wheelchair for mobility. Speech and eye movement are also affected. Other important features are t(7;14) translocations, immunodeficiency, a high serum α fetoprotein concentration, growth retardation, telangiectasia—most noticeably on the bulbar conjunctiva—and a very high risk of developing a lymphoid tumour. Patients also show an increased sensitivity to ionising radiation. The classic form of A-T results from the presence of two truncating ATM mutations, leading to total loss of the ATM protein, a protein kinase. Importantly, A-T shows clinical heterogeneity, including milder forms where neurological progression may be slower or of later onset. In these cases there is a correlation between the preservation of neurological function, decreased radiosensitivity, and the degree of retained ATM protein kinase activity. Considerable scope remains for understanding the progress of the disorder in relation to the types of ATM mutation present. PMID:16189143

  20. Ataxia-telangiectasia: recommendations for multidisciplinary treatment.

    Science.gov (United States)

    van Os, Nienke J H; Haaxma, Charlotte A; van der Flier, Michiel; Merkus, Peter J F M; van Deuren, Marcel; de Groot, Imelda J M; Loeffen, Jan; van de Warrenburg, Bart P C; Willemsen, Michèl A A P

    2017-07-01

    Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics. © 2017 Mac Keith Press.

  1. Cognitive phenotype in ataxia-telangiectasia.

    Science.gov (United States)

    Hoche, Franziska; Frankenberg, Emily; Rambow, Jennifer; Theis, Marius; Harding, Jessica Ann; Qirshi, Mayyada; Seidel, Kay; Barbosa-Sicard, Eduardo; Porto, Luciana; Schmahmann, Jeremy D; Kieslich, Matthias

    2014-09-01

    Pediatric cerebrocerebellar neurodegenerative disorders such as ataxia-telangiectasia (AT) have not been examined in detail for neuropsychologic changes. Such studies may contribute to the further understanding of ataxia-telangiectasia and to the role of the cerebrocerebellar system in the development of cognitive function in childhood. Twenty-two patients with the classic phenotype of ataxia-telangiectasia were grouped into early stage cerebellar disease (group AT-I) versus late stage cerebrocerebellar disease (group AT-II) and examined for neurocognitive features. Results were compared with those of healthy control subjects and with standard norms. Patients in AT-I group scored low average compared with standard norms on all tests and were impaired compared with healthy control subjects for verbal intelligence quotient (P ataxia-telangiectasia present early, coinciding with cerebellar pathology and are characteristic of the cerebellar cognitive affective syndrome. Widespread and deeper cognitive deficits manifest in later stages of ataxia-telangiectasia when additional noncerebellar pathology develops. These results are the first indications of distinct cerebellar and extracerebellar and/or subcortical contributions to the range of cognitive domains affected in ataxia-telangiectasia and need to be confirmed in future studies. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Novel ATM mutations with ataxia-telangiectasia.

    Science.gov (United States)

    Liu, Xiao-Li; Wang, Tian; Huang, Xiao-Jun; Zhou, Hai-Yan; Luan, Xing-Hua; Shen, Jun-Yi; Chen, Sheng-Di; Cao, Li

    2016-01-12

    Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia-telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. 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

  4. Myoclonic axial jerks for diagnosing atypical evolution of ataxia telangiectasia.

    Science.gov (United States)

    Nakayama, Tojo; Sato, Yuko; Uematsu, Mitsugu; Takagi, Masatoshi; Hasegawa, Setsuko; Kumada, Satoko; Kikuchi, Atsuo; Hino-Fukuyo, Naomi; Sasahara, Yoji; Haginoya, Kazuhiro; Kure, Shigeo

    2015-03-01

    Ataxia telangiectasia (A-T) is a common inherited cause of early childhood-onset ataxia, distinguished by progressive cerebellum malfunction, capillary vessel extension, and immunodeficiency. The diagnosis of A-T is sometimes difficult to establish in patients with atypical clinical evolution. We experienced a pediatric 12-years-old female patient, who was finally diagnosed with classic A-T, demonstrating progressive dystonic-myoclonic axial jerks with ataxia as a predominant clinical feature. Oculocutaneous telangiectasias and immune status were unremarkable. Her myoclonic jerks were spontaneous or stimulus-sensitive, and partially ameliorated by levodopa treatment, but the ataxia was slowly progressive. A laboratory examination showed moderate atrophy of the vermis and cerebellum on brain magnetic resonance imaging, elevated serum alpha fetoprotein (AFP) levels, and total absence of A-T mutated (ATM) protein activity. We subsequently confirmed compound heterozygous truncating mutations of the ATM gene in this patient. Our findings highlight the importance of recognizing dystonic-myoclonic jerks as one of the extrapyramidal signs of classic A-T. Measurement of AFP levels should be considered in patients with unexplained myoclonic jerk movements with ataxia in whom definitive diagnoses are not identified. Physicians should be aware that there are cases where typical findings of A-T may not be fulfilled. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  5. Neuropathology in classical and variant ataxia-telangiectasia.

    NARCIS (Netherlands)

    Verhagen, M.M.M.; Martin, J.J.; Deuren, M. van; Ceuterick-de Groote, C.; Weemaes, C.M.R.; Kremer, B.; Taylor, M.A.; Willemsen, M.A.A.P.; Lammens, M.M.Y.

    2012-01-01

    Ataxia-telangiectasia (A-T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated alpha-fetoprotein levels. Some patients, classified as variant A-T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms

  6. Eye movements in ataxia-telangiectasia.

    Science.gov (United States)

    Baloh, R W; Yee, R D; Boder, E

    1978-11-01

    The spectrum of eye movement disorders in six patients with ataxia-telangiectasia at different stages of progression was assessed quantitatively by electrooculography. All patients demonstrated abnormalities of voluntary and involuntary saccades. The youngest and least involved patient had significantly increased reaction times of voluntary saccades, but normal accuracy and velocity. The other patients demonstrated increased reaction times and marked hypometria of horizontal and vertical voluntary saccades. Saccade velocity remained normal. Vestibular and optokinetic fast components (involuntary saccades) had normal amplitude and velocity but the eyes deviated tonically in the direction of the slow component. We conclude that patients with ataxia-telangiectasia have a defect in the initiation of voluntary and involuntary saccades in the earliest stages. These findings are distinctly different from those in other familial cerebellar atrophy syndromes.

  7. Uterine tumors in ataxia-telangiectasia.

    Science.gov (United States)

    Gatti, R A; Nieberg, R; Boder, E

    1989-02-01

    Roughly one-third of patients with ataxia-telangiectasia (AT) develop malignant tumors, usually of lymphoid origin. AT patients also exhibit progeric changes. We describe three patients, between the ages of 27 and 32 years, with uterine tumors: one with a frank leiomyosarcoma and chronic T-cell leukemia, one with a multilobulated leiomyoma of uncertain malignant potential, and one with an unremarkable leiomyoma. Thus, the spectrum of tumors in AT patients beyond adolescence includes nonlymphoid malignancies and precocious, benign leiomyomas.

  8. Radio-induced apoptosis is impaired in individuals homozygous and heterozygous for the ataxia-telangiectasia gene(s); Alteration de la reponse apoptotique radio-induite chez des homozygotes et des heterozygotes pour l`ataxie-telangiectasie

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    Duchaud, E.; Ridet, A.; Delic, Y.; Moustacchi, E.; Rosselli, F. [Institut Curie, 75 - Paris (France); Cundari, E. [Consiglio Nazionale delle Ricerche, Rome (Italy)

    1994-11-01

    Ataxia-telangiectasia is a progressive recessive disease featuring neuro degeneration, immunodeficiency, chromosomal instability, radiation hypersensitivity and increased predisposition to cancer. Impaired induction of the tumor suppressor protein p53 after {gamma}-irradiation was recently reported. All together these characteristics may be compatible with an inability to correctly regulate the apoptotic pathway of cell death in this syndrome. We show here that lymphocyte cultures from AT patients are characterized by a 3 times more elevated spontaneous level of apoptotic cells compared to normal ones. In spite of this, 24 h after exposure to {gamma}-irradiation (5 to 10 Gy), AT lymphocytes show a dramatically reduced capacity to undergo apoptosis compared to normal cells. We obtained similar results on EBV-transformed lymphoblasts. Interestingly, lymphoblasts from obligate heterozygous for the AT mutation(s) show the same features as AT lymphoblasts, i.e. an elevated frequency of spontaneous and a reduced level of radio-induced apoptotic figures in comparison to normal cultured cells. In conclusion, we show here, for the first time, that mutation(s) in AT gene(s) results in an impaired ability to correctly regulate the apoptotic pathway of cell death. (author). 26 refs., 4 figs., 2 tabs.

  9. Cerebral abnormalities in adults with ataxia-telangiectasia.

    Science.gov (United States)

    Lin, D D M; Barker, P B; Lederman, H M; Crawford, T O

    2014-01-01

    Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment with cerebellar atrophy, ocular and cutaneous telangiectasia, immunodeficiency, heightened sensitivity to ionizing radiation and susceptibility to developing lymphoreticular malignancy. Supratentorial brain abnormalities have been reported only rarely. In this study, brain MRI was performed in 10 adults with ataxia-telangiectasia having stable neurologic impairment. Intracerebral telangiectasia with multiple punctate hemosiderin deposits were identified in 60% of subjects. These lesions were apparently asymptomatic. They are similar in appearance to radiation-induced telangiectasia and to cryptogenic vascular malformations. Also noted, in the 2 oldest subjects, was extensive white matter T2 hyperintensity, and in 1 of these a space-occupying fluid collection consistent with transudative capillary leak and edema as evidenced by reduced levels of metabolites on MR spectroscopic imaging. Asymptomatic supratentorial vascular abnormalities appear to be common in adults with ataxia-telangiectasia.

  10. Mitochondrial dysfunction in ataxia-telangiectasia.

    Science.gov (United States)

    Valentin-Vega, Yasmine A; Maclean, Kirsteen H; Tait-Mulder, Jacqueline; Milasta, Sandra; Steeves, Meredith; Dorsey, Frank C; Cleveland, John L; Green, Douglas R; Kastan, Michael B

    2012-02-09

    Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated reactive oxygen species, increased aberrant mitochondria, high cellular respiratory capacity, and decreased mitophagy. A fraction of ATM protein is localized in mitochondria, and it is rapidly activated by mitochondrial dysfunction. Unexpectedly, allelic loss of the autophagy regulator Beclin-1 significantly delayed tumor development in ATM-null mice. This effect was not associated with rescue of DNA damage signaling but rather with a significant reversal of the mitochondrial abnormalities. These data support a model in which ATM plays direct roles in modulating mitochondrial homeostasis and suggest that mitochondrial dysfunction and associated increases in mitochondrial reactive oxygen species contribute to the cancer-prone phenotype observed in organisms lacking ATM. Thus, ataxia-telangiectasia should be considered, at least in part, as a mitochondrial disease.

  11. Ataxia-telangiectasia: Immunodeficiency and survival.

    Science.gov (United States)

    van Os, Nienke J H; Jansen, Anne F M; van Deuren, Marcel; Haraldsson, Asgeir; van Driel, Nieke T M; Etzioni, Amos; van der Flier, Michiel; Haaxma, Charlotte A; Morio, Tomohiro; Rawat, Amit; Schoenaker, Michiel H D; Soresina, Annarosa; Taylor, Alexander M R; van de Warrenburg, Bart P C; Weemaes, Corry M R; Roeleveld, Nel; Willemsen, Michèl A A P

    2017-05-01

    Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Complementation analysis of ataxia-telangiectasia

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    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.

  13. Predominance of null mutations in ataxia-telangiectasia

    NARCIS (Netherlands)

    S. Gilad (Shlomit); R. Khosravi (Rami); D. Shkedy (Dganit); G. Uziel; Y. Ziv (Yael); K. Savitsky (Kinneret); G. Rotman (Galit); S. Smith (Sarah); T. Chessa (Antonio); T.J. Jorgensen (Timothy); R. Harnik (Reli); M. Frydman (Moshe); O. Sanal (Ozden); S. Portnoi (Sima); Z. Goldwicz (Zipora); N.G.J. Jaspers (Nicolaas); A. Gatti (Arianna); G.M. Lenoir (Gilbert); M.F. Lavin (Martin); K. Tatsumi (Kouichi); M. Wegner (Michael); Y. Shiloh (Yosef); A. Bar-Shira (Anat)

    1996-01-01

    textabstractAtaxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative

  14. "ATM Gene Mutations Detection in Iranian Ataxia-Telangiectasia Patients "

    OpenAIRE

    Toshio MiyawakiMohammad Hossein Sanati; Behnaz Bayat; Ahmad Aleyasin; Hasti Atashi Shirazi; "Anna Isaian; Abolhassan Farhoudi; Mostafa Moin

    2004-01-01

    Ataxia-Telangiectasia (AT) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, radiation sensitivity and cancer predisposition. The ATM gene on human chromosome 11q22.3 has recently been identified as the gene responsible for ataxia-telangiectasia (AT). The gene mutated in AT, which has been designated as the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. More than 100 mutations are broadly distributed throughout the ATM gene. T...

  15. Neuropathology in classical and variant ataxia-telangiectasia

    NARCIS (Netherlands)

    Verhagen, Mijke M. M.; Martin, Jean-Jacques; van Deuren, Marcel; Groote, Chantal Ceuterick-de; Weemaes, Corry M. R.; Kremer, Berry H. P. H.; Taylor, Malcolm A. R.; Willemsen, Michel A. A. P.; Lammens, Martin

    2012-01-01

    Ataxia-telangiectasia (A-T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated a-fetoprotein levels. Some patients, classified as variant A-T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms, in

  16. Neuropathology in classical and variant ataxia-telangiectasia

    NARCIS (Netherlands)

    Verhagen, Mijke M. M.; Martin, Jean-Jacques; van Deuren, Marcel; Groote, Chantal Ceuterick-de; Weemaes, Corry M. R.; Kremer, Berry H. P. H.; Taylor, Malcolm A. R.; Willemsen, Michel A. A. P.; Lammens, Martin

    2012-01-01

    Ataxia-telangiectasia (A-T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated a-fetoprotein levels. Some patients, classified as variant A-T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms, in

  17. Ataxia telangiectasia: presentation and diagnostic delay.

    Science.gov (United States)

    Devaney, Rebecca; Pasalodos, Sara; Suri, Mohnish; Bush, Andy; Bhatt, Jayesh M

    2017-04-01

    Ataxia telangiectasia (A-T) is a rare progressive, multisystem genetic disease. Families of children with ultra-rare diseases often experience significant diagnostic delays. We reviewed the diagnostic process for A-T in order to identify causes of delay in an attempt to facilitate earlier identification of A-T in the future. A retrospective case note review of 79 children at the National Paediatric A-T clinic seen since May 2009. Data were collected on the nature and age of initial symptoms, the age at first presentation, measurement of alpha feto-protein (AFP) and age of genetic diagnostic confirmation. At presentation, 71 children (90%) had ataxia. The median presentation delay (from first parental concern to presentation) was 8 months (range 0-118 months), and the median diagnostic delay (genetic confirmation of diagnosis) was 12 months (range 1-109 months). There are significant delays in presentation and diagnostic confirmation of A-T. A greater awareness of A-T and early measurement of AFP may help to improve this. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  18. Síndrome de Ataxia-Telangiectasia

    Directory of Open Access Journals (Sweden)

    Amauri Batista da Silva

    1971-06-01

    Full Text Available A ataxia-telangiectasia, doença de Mme. Louis-Bar, é caracterizada pela associação de ataxia cerebelar progressiva, em geral com início na primeira infância, telangiectasas óculo-cutâneas, movimentos coreoatetósicos, tendência a infecções repetidas do sistema respiratório, retardo estaturo-ponderal, demenciação. São mais ou menos freqüentes os tumores do sistema reticuloendotelial. A doença é geralmente familiar, transmitida por genes recessivos, autossômicos, não ligados ao sexo. A alteração bioquímica mais encontrada consiste na diminuição ou ausência completa da fração A das gamaglobulinas, bem como na perturbação das reações de hipersensibilidade retardada. Os AA. relatam o estudo clínico, biológico e pneumencefalográfico de uma criança de 3 anos de idade, apresentando essa enfermidade desde os 18 meses de vida, sem antecedentes familiares.

  19. Bilateral maculopathy in a patient with ataxia telangiectasia.

    Science.gov (United States)

    Gioia, Lauren V; Bonsall, Dean; Moffett, Kathryn; Leys, Monique

    2016-02-01

    We report a case of toxoplasmosis with bilateral maculopathy in a 7-year-old boy diagnosed with ataxia telangiectasia (AT) at age 6. AT manifests as ataxia, apraxia, telangiectasia, and dysarthria. Common ophthalmologic findings in AT include fine conjunctival telangiectasia. Patients also suffer from recurrent sinopulmonary infections; however, serious opportunistic infection is rarely diagnosed. At 8 years of age he developed disseminated Toxoplasma gondii (toxoplasmosis) infection and meningoencephalitis. This ophthalmologic finding and the subsequent toxoplasmosis meningoencephalitis have not been previously reported in AT. Copyright © 2016 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

  20. [Mosaic forms of ataxia-telangiectasia].

    Science.gov (United States)

    Kuranova, M L; Pleskach, N M; Ledashcheva, T A; Mikhel'son, V M; Spivak, I M

    2014-01-01

    Ataxia-telangiectasia (AT) is a severe hereditary autosomal recessive neurodegenerative disease associated with accelerated aging and caused by mutation in both alleles of atm gene. This gene encodes a key protein of cell response to DNA damage--an ATM protein kinase. Normally, upon formation of DNA double strand breaks ATM is autophosphorylated and its active form phospho-ATM (P-ATM) appears. Here we describe a mosaic form of AT in which cells of the same patient with normal atm gene demonstrated the accumulation of P-ATM in response to DNA double-strand breaks-inducing factors whereas in cells bearing a mutant form of atm P-ATM was not detected. The epigenetic markers such as histone deacetylases SIRT1 and SIRT6, and trimethylated forms of histone H3 - H3K9me3 and H3K27me3--were studied in the nuclei of primary fibroblasts derived from patients with different forms of AT and the increase of SIRT6 level was revealed.

  1. Ataxia-telangiectasia. (Clinical and immunological aspects).

    Science.gov (United States)

    Boder, E; Sedgwick, R P

    1970-01-01

    This syndrome was defined by the authors in 1947. Earlier publications of similar disease descriptions were by Syllaba and Henner (1926), Louis-Bar (1941). The authors at present have a stock of 253 cases. The cardinal symptoms of this phakomatosis are: Cerebellar ataxia which begin in infancy and take a slowly progressive course. In the late stages free walking and standing are no longer possible. Progressive atactic speech disorders, cerebellar atrophy in the pneumoencephalogram. Slowly progressing symmetrical skin and mucosal telangiectasia in the face and especially on the conjunctivae at the age of 3 to 6 years. Relapsing sinopulmonary infections with a tendency toward the development of bronchiectases. Apraxia of eye movements. Atrophy of facial skin and premature graying of hair. Recessively hereditary disorder with a high familial manifestation. This syndrome combines the spinocerebellar degeneration, phakomatoses, and infantile dementia processes. Such other conditions as abnormity or absence of thymus, reduction in gamma globulins, amino-aciduria, autosomal-recessive inheritance suggest a genetically determined "error of metabolism".

  2. Unusual and severe disease course in a child with ataxia-telangiectasia.

    NARCIS (Netherlands)

    Meyts, I.; Weemaes, C.M.R.; Wolf-Peeters, C. de; Proesmans, M.; Renard, M.; Uyttebroeck, A.; Boeck, K. de

    2003-01-01

    Ataxia-telangiectasia (AT) is an autosomal recessive syndrome of combined immunodeficiency. Hallmarks of the disease comprise progressive cerebellar ataxia, oculocutaneous telangiectasia, cancer susceptibility and variable humoral and cellular immunodeficiency. We describe a patient with AT presenti

  3. Unusual and severe disease course in a child with ataxia-telangiectasia.

    NARCIS (Netherlands)

    Meyts, I.; Weemaes, C.M.R.; Wolf-Peeters, C. de; Proesmans, M.; Renard, M.; Uyttebroeck, A.; Boeck, K. de

    2003-01-01

    Ataxia-telangiectasia (AT) is an autosomal recessive syndrome of combined immunodeficiency. Hallmarks of the disease comprise progressive cerebellar ataxia, oculocutaneous telangiectasia, cancer susceptibility and variable humoral and cellular immunodeficiency. We describe a patient with AT presenti

  4. Ataxia-telangiectasia presenting with a novel immunodeficiency.

    Science.gov (United States)

    Perreault, Sébastien; Bernard, Geneviève; Lortie, Anne; Le Deist, Françoise; Decaluwe, Hélène

    2012-05-01

    Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene. The patient presented at age 3 years with a perineal cellulitis associated with profound neutropenia and T-cell lymphopenia. Serum immunoglobulin levels and antibody titers were normal. Neurologic evaluation revealed minimal hypotonia and wide-based gait, without other signs of cerebellar dysfunction. The alpha-fetoprotein level was elevated, and molecular genetic testing confirmed the diagnosis of ataxia-telangiectasia, uncovering a novel ATM gene mutation c.3931C>T (p.Gln1311X) in exon 28. This patient presents a unique immunologic pattern with normal immunoglobulin levels, significant lymphopenia, and profound neutropenia. The diagnosis of ataxia-telangiectasia should be considered in children presenting with gait disorder and immunologic defects, regardless of subtype and severity. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Conjunctival Telangiectasia in a Patient with Ataxia Telangiectasia: A Case Report

    Directory of Open Access Journals (Sweden)

    Özge Pınar Akarsu

    2012-01-01

    Full Text Available The purpose of this paper is to report a 7-year-old patient who developed bilateral conjunctival hyperemia while being under treatment of pneumonia in Pediatric Infectious Diseases Clinic at Sisli Etfal Training and Research Hospital. Ophthalmological examination revealed bilateral conjunctival telangiectasias which were thought to be the ophthalmologic sign of ataxia telangiectasia after considering the other clinical findings, laboratory and imaging results, and family history. (Turk J Oph thal mol 2012; 42: 75-7

  6. 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.

  7. Altered corticomotor-cerebellar integrity in young ataxia telangiectasia patients.

    Science.gov (United States)

    Sahama, Ishani; Sinclair, Kate; Fiori, Simona; Pannek, Kerstin; Lavin, Martin; Rose, Stephen

    2014-09-01

    Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia-telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion-weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7-22 years; mean, 12 years) and 11 typically developing age-matched participants (age range, 8-23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel-based morphometry, whereas tract-based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral-postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early-stage white matter motor pathway degeneration within young patients. © 2014 International Parkinson and Movement Disorder Society.

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

    NARCIS (Netherlands)

    Bhatt, J.M.; Bush, A.; Gerven, M.; Nissenkorn, A.; Renke, M.; Yarlett, L.; Taylor, M.; Tonia, T.; Warris, A.; Zielen, S.; Zinna, S.; Merkus, P.J.F.M.

    2015-01-01

    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 immu

  9. Clinical spectrum of ataxia-telangiectasia in adulthood.

    NARCIS (Netherlands)

    Verhagen, M.M.; Abdo, W.; Willemsen, M.A.A.P.; Hogervorst, F.B.L.; Smeets, D.F.C.M.; Hiel, J.A.P.; Brunt, E.R.; Rijn, M.A. van; Majoor Krakauer, D.; Oldenburg, R.A.; Broeks, A.; Last, J.I.; Veer, L.J. van 't; Tijssen, M.A.; Dubois, A.M.; Kremer, H.P.H.; Weemaes, C.M.R.; Taylor, A.M.; Deuren, M. van

    2009-01-01

    OBJECTIVE: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. METHODS: Retrospective analysis of the

  10. Clinical spectrum of ataxia-telangiectasia in adulthood

    NARCIS (Netherlands)

    Verhagen, M. M. M.; Abdo, W. F.; Willemsen, M. A. A. P.; Hogervorst, F. B. L.; Smeets, D. F. C. M.; Hiel, J. A. P.; Brunt, E. R.; van Rijn, M. A.; Krakauer, D. Majoor; Oldenburg, R. A.; Broeks, A.; Last, J. I.; van't Veer, L. J.; Tijssen, M. A. J.; Dubois, A. M. I.; Kremer, H. P. H.; Weemaes, C. M. R.; Taylor, A. M. R.; van Deuren, M.

    2009-01-01

    Objective: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. Methods: Retrospective analysis of the

  11. Clinical spectrum of ataxia-telangiectasia in adulthood.

    NARCIS (Netherlands)

    Verhagen, M.M.; Abdo, W.; Willemsen, M.A.A.P.; Hogervorst, F.B.L.; Smeets, D.F.C.M.; Hiel, J.A.P.; Brunt, E.R.; Rijn, M.A. van; Majoor Krakauer, D.; Oldenburg, R.A.; Broeks, A.; Last, J.I.; Veer, L.J. van 't; Tijssen, M.A.; Dubois, A.M.; Kremer, H.P.H.; Weemaes, C.M.R.; Taylor, A.M.; Deuren, M. van

    2009-01-01

    OBJECTIVE: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. METHODS: Retrospective analysis of the

  12. Clinical spectrum of ataxia-telangiectasia in adulthood

    NARCIS (Netherlands)

    Verhagen, M M M; Abdo, W F; Willemsen, M A A P; Hogervorst, F B L; Smeets, D F C M; Hiel, J A P; Brunt, E R; van Rijn, M A; Majoor Krakauer, D; Oldenburg, R A; Broeks, A; Last, J I; van't Veer, L J; Tijssen, M A J; Dubois, A M I; Kremer, H P H; Weemaes, C M R; Taylor, A M R; van Deuren, M

    2009-01-01

    OBJECTIVE: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. METHODS: Retrospective analysis of the

  13. Clinical spectrum of ataxia-telangiectasia in adulthood

    NARCIS (Netherlands)

    Verhagen, M M M; Abdo, W F; Willemsen, M A A P; Hogervorst, F B L; Smeets, D F C M; Hiel, J A P; Brunt, E R; van Rijn, M A; Majoor Krakauer, D; Oldenburg, R A; Broeks, A; Last, J I; van't Veer, L J; Tijssen, M A J; Dubois, A M I; Kremer, H P H; Weemaes, C M R; Taylor, A M R; van Deuren, M

    2009-01-01

    OBJECTIVE: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype-phenotype relationship for mutations in the ATM gene. METHODS: Retrospective analysis of the

  14. Disorders of Upper Limb Movements in Ataxia-Telangiectasia.

    Directory of Open Access Journals (Sweden)

    Aasef G Shaikh

    Full Text Available Ataxia-telangiectasia is known for cerebellar degeneration, but clinical descriptions of abnormal tone, posture, and movements suggest involvement of the network between cerebellum and basal ganglia. We quantitatively assessed the nature of upper-limb movement disorders in ataxia-telangiectasia. We used a three-axis accelerometer to assess the natural history and severity of abnormal upper-limb movements in 80 ataxia-telangiectasia and 19 healthy subjects. Recordings were made during goal-directed movements of upper limb (kinetic task, while arms were outstretched (postural task, and at rest. Almost all ataxia-telangiectasia subjects (79/80 had abnormal involuntary movements, such as rhythmic oscillations (tremor, slow drifts (dystonia or athetosis, and isolated rapid movements (dystonic jerks or myoclonus. All patients with involuntary movements had both kinetic and postural tremor, while 48 (61% also had resting tremor. The tremor was present in transient episodes lasting several seconds during two-minute recording sessions of all three conditions. Percent time during which episodic tremor was present was greater for postural and kinetic tasks compared to rest. Resting tremor had higher frequency but smaller amplitude than postural and kinetic tremor. Rapid non-rhythmic movements were minimal during rest, but were triggered during sustained arm postures and goal directed arm movements suggesting they are best considered a form of dystonic jerks or action myoclonus. Advancing age did not correlate with the severity of involuntary limb movements. Abnormal upper-limb movements in ataxia-telangiectasia feature classic cerebellar impairment, but also suggest involvement of the network between the cerebellum and basal ganglia.

  15. 14th International Workshop on Ataxia-Telangiectasia ATW2012.

    Science.gov (United States)

    Pandita, Tej K

    2012-10-01

    The fourteenth international Ataxia-Telangiectasia Workshop 2012 (ATW2012) (www.atw2012.com) on ataxia-telangiectasia (AT) and the role of the ataxia telangiectasia mutated (ATM) gene in DNA repair, neurological disease, cancer and related topics was held from February 07 to 11, 2012 in Delhi, India. The international ATW2012 meeting reported the latest advances in ATM research as well as potential therapeutic treatments for A-T. The meeting was attended by a productive mix of scientists, ranging from those prominent in the initial characterization of the underlying genetic defect to young scientists just entering the field. In broad terms, three main themes were discussed at the meeting: first, a wealth of new details emerged on DNA damage signaling/repair mechanisms for which ATM is a critical element; secondly, important functions for ATM in previously unrelated cellular pathways were identified; and thirdly, new physiological effects and potential therapeutic treatments related to A-T were presented. This report summarizes below a sampling of the many interesting results from the meeting. Copyright © 2012. Published by Elsevier B.V. All rights reserved.

  16. Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.

    Science.gov (United States)

    Huang, Yu; Yang, Lu; Wang, Jianchun; Yang, Fan; Xiao, Ying; Xia, Rongjun; Yuan, Xianhou; Yan, Mingshan

    2013-09-01

    Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized mainly by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. This disease is caused by mutations of the ataxia telangiectasia mutated (Atm) gene. More than 500 Atm mutations that are responsible for A-T have been identified so far. However, there have been very few A-T cases reported in China, and only two Chinese A-T patients have undergone Atm gene analysis. In order to systemically investigate A-T in China and map their Atm mutation spectrum, we recruited eight Chinese A-T patients from six unrelated families nationwide. Using direct sequencing of genomic DNA and the multiplex ligation-dependent probe amplification, we identified twelve pathogenic Atm mutations, including one missense, four nonsense, five frameshift, one splicing, and one large genomic deletion. All the Atm mutations we identified were novel, and no homozygous mutation and founder-effect mutation were found. These results suggest that Atm mutations in Chinese populations are diverse and distinct largely from those in other ethnic areas.

  17. Ataxia-telangiectasia: some historic, clinical and pathologic observations.

    Science.gov (United States)

    Boder, E

    1975-01-01

    Although an isolated clinical case report was published in 1926 and another in 1941, ataxia-telangiectasia (A-T) was not established as a distinct entity until 1957, when it was first delineated clinicopathologically. Susceptibility to sinopulmonary infection was identified as the main cause of death and as the third major component of the syndrome; its heredofamilial nature was documented, and it was designated "ataxia-telangiectasia." In a later review of 101 published cases, lymphoreticular malignancy emerged as the second most frequent cause of death. Although the thymus was found to be absent in the first reported autopsy in 1957 and the serum IgA deficiency was first recorded in 1961, A-T was not established as an immunodeficiency disease until 1963. Thymic abnormality and dysgammaglobulinemia explain the 2 main causes of death, sinopulmonary and neoplastic, but the immunodeficiency is probably not the central defect. It does not appear to explain either of the 2 main clinical diagnostic keys, the ataxia and the telangiectasia, or any of the other seemingly unrealted multisystemic facets of this complex disorder. Some of our most provocative long-term clinical observations and recent pathologic findings in our series of 9 autopsies are discussed.

  18. A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia.

    Science.gov (United States)

    Zannolli, Raffaella; Buoni, Sabrina; Betti, Gianni; Salvucci, Sara; Plebani, Alessandro; Soresina, Annarosa; Pietrogrande, Maria C; Martino, Silvana; Leuzzi, Vincenzo; Finocchi, Andrea; Micheli, Roberto; Rossi, Livia Nicoletta; Brusco, Alfredo; Misiani, Filippo; Fois, Alberto; Hayek, Joseph; Kelly, Colleen; Chessa, Luciana

    2012-09-01

    No controlled studies exist regarding the pharmaceutical reduction of ataxia symptoms in ataxia telangiectasia (A-T). In a multicenter, double-blind, randomized, placebo-controlled crossover trial, oral betamethasone (BETA) and placebo were compared in terms of their reduction of ataxia symptoms as assessed with the International Cooperative Ataxia Rating Scale (ICARS). In this study of 13 A-T children, betamethasone reduced the ICARS total score by a median of 13 points in the intent-to-treat population and 16 points in the per-protocol population (ie, median percent decreases of ataxia symptoms of 28% and 31%, respectively). In conclusion, Oral betamethasone could be a promising therapy to relieve ataxia symptoms in A-T patients; however, long-term effectiveness and safety must be established. (Current Controlled Trials, number ISRCTN08774933.) Copyright © 2012 Movement Disorder Society.

  19. Nonalcoholic Steatohepatitis in a Patient with Ataxia-Telangiectasia

    Directory of Open Access Journals (Sweden)

    Trinidad Caballero

    2014-01-01

    Full Text Available Ataxia-telangiectasia (A-T is a rare disease characterized by neurodegenerative alterations, telangiectasia, primary immunodeficiency, extreme sensitivity to radiation, and susceptibility to neoplasms. A-T patients have inactivation of ataxia-telangiectasia-mutated (ATM protein, which controls DNA double-strand break repair and is involved in oxidative stress response, among other functions; dysfunctional control of reactive oxygen species may be responsible for many of the clinical manifestations of this disease. To the best of our knowledge, hepatic lesions of steatohepatitis have not previously been reported in A-T patients. The present study reports the case of a 22-year-old man diagnosed with A-T at the age of 6 years who was referred to our Digestive Disease Unit with a three-year history of hyperlipidemia and liver test alterations. Core liver biopsy showed similar lesions to those observed in nonalcoholic steatohepatitis. Immunohistochemical staining disclosed the absence of ATM protein in hepatocyte nuclei. We suggest that the liver injury may be mainly attributable to the oxidative stress associated with ATM protein deficiency, although other factors may have made a contribution. We propose the inclusion of A-T among the causes of nonalcoholic steatohepatitis, which may respond to antioxidant therapy.

  20. Ataxia-telangiectasia - A historical review and a proposal for a new designation: ATM syndrome.

    Science.gov (United States)

    Teive, Hélio A G; Moro, Adriana; Moscovich, Mariana; Arruda, Walter O; Munhoz, Renato P; Raskin, Salmo; Ashizawa, Tetsuo

    2015-08-15

    The authors review ataxia telangiectasia, emphasizing historical aspects, genetic discoveries, and the clinical presentations of the classical and atypical forms. In fact, ataxia telangiectasia represents a multisystem entity with pleomorphic neurological and systemic manifestations. ATM syndrome is proposed as a more adequate designation for this entity. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Ataxia telangiectasia and Nijmegen breakage syndrome : neurological, immunological and genetic aspects

    NARCIS (Netherlands)

    Hiel, J.A.P.

    2004-01-01

    Ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) are rare autosomal recessive conditions caused by mutations in respectively ATM and NBS1. The encoding proteins ATM and nibrin are involved in the processing of DNA damage and maintenance of genomic stability. Ataxia telangiectasia is d

  2. ATAXIA - TELANGIECTASIA – A HISTORICAL REVIEW AND A PROPOSAL FOR A NEW NAME: ATM SYNDROME

    Science.gov (United States)

    Teive, Hélio A. G.; Moro, Adriana; Moscovich, Mariana; Munhoz, Renato P.; Ashizawa, Tetsuo

    2016-01-01

    The authors review ataxia telangiectasia, emphasizing historical aspects, genetic discoveries and the clinical presentations of the classical and atypical forms. Our conclusion is that the term ataxia telangiectasia is a misnomer because it represents a multisystem entity with pleomorphic neurological and systemic manifestations. ATM syndrome is proposed as a more adequate designation for this entity. PMID:26050521

  3. Ataxia telangiectasia and Nijmegen breakage syndrome : neurological, immunological and genetic aspects

    NARCIS (Netherlands)

    Hiel, J.A.P.

    2004-01-01

    Ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS) are rare autosomal recessive conditions caused by mutations in respectively ATM and NBS1. The encoding proteins ATM and nibrin are involved in the processing of DNA damage and maintenance of genomic stability. Ataxia telangiectasia is d

  4. Mechanisms of Non-canonical Activation of Ataxia Telangiectasia Mutated.

    Science.gov (United States)

    Khoronenkova, S V

    2016-12-01

    ATM is a master regulator of the cellular response to DNA damage. The classical mechanism of ATM activation involves its monomerization in response to DNA double-strand breaks, resulting in ATM-dependent phosphorylation of more than a thousand substrates required for cell cycle progression, DNA repair, and apoptosis. Here, new experimental evidence for non-canonical mechanisms of ATM activation in response to stimuli distinct from DNA double-strand breaks is discussed. It includes cytoskeletal changes, chromatin modifications, RNA-DNA hybrids, and DNA single-strand breaks. Noncanonical ATM activation may be important for the pathology of the multisystemic disease Ataxia Telangiectasia.

  5. Ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis.

    Science.gov (United States)

    Caccavale, Stefano; Bove, Domenico; Bove, Rocco M; LA Montagna, Maddalena

    2017-02-01

    This article explores three neurocutaneous syndromes (NCSs), i.e. genetic disorders producing developmental abnormalities of the skin and an increased risk of neurological complications. In this review, different aspects of ataxia telangiectasia, Menkes kinky hair disease and neurocutaneous melanosis are examined: clinical features, genetic defect, mutation spectrum, pathogenesis, and neurobiological basis; indications for clinical practice are also provided to the readers. The aim of this review is to stress the importance of cooperation among dermatologists, neurologists and psychiatrists, in order to provide patients suffering from these diseases with timely diagnosis and targeted treatments.

  6. Immunodeficiency in ataxia telangiectasia is correlated strongly with the presence of two null mutations in the ataxia telangiectasia mutated gene

    Science.gov (United States)

    Staples, E R; McDermott, E M; Reiman, A; Byrd, P J; Ritchie, S; Taylor, A M R; Davies, E G

    2008-01-01

    Immunodeficiency affects over half of all patients with ataxia telangiectasia (A-T) and when present can contribute significantly to morbidity and mortality. A retrospective review of clinical history, immunological findings, ataxia telangiectasia mutated (ATM) enzyme activity and ATM mutation type was conducted on 80 consecutive patients attending the National Clinic for Ataxia Telangiectasia, Nottingham, UK between 1994 and 2006. The aim was to characterize the immunodeficiency in A-T and determine its relationship to the ATM mutations present. Sixty-one patients had mutations resulting in complete loss of ATM kinase activity (group A) and 19 patients had leaky splice or missense mutations resulting in residual kinase activity (group B). There was a significantly higher proportion of patients with recurrent sinopulmonary infections in group A compared with group B (31 of 61 versus four of 19 P = 0·03) and a greater need for prophylactic antibiotics (30 of 61 versus one of 19 P = 0·001). Comparing group A with group B patients, 25 of 46 had undetectable/low immunoglobulin A (IgA) levels compared with none of 19; T cell lymphopenia was found in 28 of 56 compared with one of 18 and B cell lymphopenia in 35 of 55 compared with four of 18 patients (P = 0·00004, 0·001 and 0·003 respectively). Low IgG2 subclass levels and low levels of antibodies to pneumococcal polysaccharide were more common in group A than group B (16 of 27 versus one of 11 P = 0·01; 34/43 versus six of 17 P = 0·002) patients. Ig replacement therapy was required in 10 (12·5%) of the whole cohort, all in group A. In conclusion, A-T patients with no ATM kinase activity had a markedly more severe immunological phenotype than those expressing low levels of ATM activity. PMID:18505428

  7. p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes.

    Science.gov (United States)

    Prodosmo, Andrea; De Amicis, Andrea; Nisticò, Cecilia; Gabriele, Mario; Di Rocco, Giuliana; Monteonofrio, Laura; Piane, Maria; Cundari, Enrico; Chessa, Luciana; Soddu, Silvia

    2013-03-01

    Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder characterized by radiosensitivity, genomic instability, and predisposition to cancer. A-T is caused by biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene, but heterozygous carriers, though apparently healthy, are believed to be at increased risk for cancer and more sensitive to ionizing radiation than the general population. Despite progress in functional and sequencing-based assays, no straightforward, rapid, and inexpensive test is available for the identification of A-T homozygotes and heterozygotes, which is essential for diagnosis, genetic counseling, and carrier prediction. The oncosuppressor p53 prevents genomic instability and centrosomal amplification. During mitosis, p53 localizes at the centrosome in an ATM-dependent manner. We capitalized on the latter finding and established a simple, fast, minimally invasive, reliable, and inexpensive test to determine mutant ATM zygosity. The percentage of mitotic lymphoblasts or PBMCs bearing p53 centrosomal localization clearly discriminated among healthy donors (>75%), A-T heterozygotes (40%-56%), and A-T homozygotes (<30%). The test is specific for A-T, independent of the type of ATM mutations, and recognized tumor-associated ATM polymorphisms. In a preliminary study, our test confirmed that ATM is a breast cancer susceptibility gene. These data open the possibility of cost-effective, early diagnosis of A-T homozygotes and large-scale screenings for heterozygotes.

  8. Acute lymphoblastic leukemia in early childhood as the presenting sign of ataxia-telangiectasia variant.

    Science.gov (United States)

    Bielorai, Bella; Fisher, Tamar; Waldman, Dalia; Lerenthal, Yaniv; Nissenkorn, Andreea; Tohami, Tali; Marek, Dina; Amariglio, Ninette; Toren, Amos

    2013-09-01

    Ataxia-telangiectasia (A-T), an autosomal recessive disorder is characterized by progressive neurodegeneration, immunodeficiency, sensitivity to ionizing radiation, and predisposition to cancer, especially to lymphoid malignancies. A-T variant is characterized by a milder clinical phenotype and is caused by missense or leaky splice site mutations that produce residual ataxia telangiectasia mutated (ATM) kinase activity. Lymphoid malignancy can precede the diagnosis of A-T, particularly in young children with mild neurological symptoms. We studied a consanguineous family with four A-T variant patients, three of them developed T-ALL at a young age before the diagnosis of A-T was established. ATM mutation analysis detected two new missense mutations both within exon 12: c.1514T>C and c.1547T>C. All four patients are homozygous for the two mutations, while their parents are heterozygous for the mutations. ATM protein level was low in all patients and the response to the radiomimetic agent, neocarzinostatin, was reduced. Leukemic presentation in a young age in three members of consanguineous family led to the identification of a new missense mutation in the ATM gene. The diagnosis of A-T or A-T variant should be considered in children with neurological abnormalities who develop T-ALL at a young age.

  9. Longitudinal analysis of the neurological features of ataxia-telangiectasia.

    Science.gov (United States)

    Jackson, Thomas J; Chow, Gabriel; Suri, Mohnish; Byrd, Philip; Taylor, Malcolm R; Whitehouse, William P

    2016-07-01

    To assess the relationship between genotype and neurological progression in ataxia-telangiectasia (A-T). Clinical and laboratory data were extracted retrospectively from the records of patients attending the UK National Ataxia-Telangiectasia Clinic. Neurological assessments were performed using the A-T Index (Crawford Score) and the A-T Neurological Examination Scale Toolkit (A-T NEST). Variables influencing phenotype were identified by using an information-theoretic approach starting from a maximal model to generate estimates of coefficients for each variable. Per-individual progression was assessed for patients with three or more clinic attendances. The genotype could be determined for 125/135 patients. Crawford and A-T NEST scores were well correlated. For both scoring systems the estimated coefficients were significantly positive for Age x kinase activity but not Age x protein expression. Unlike the per-genotype analysis, the individual progression of neurological scores in the 34 patients that attended on three or more occasions was not smooth and linear (and in some cases improved over time). Residual kinase activity confers a milder phenotype but there is no difference between kinase-dead and protein-null genotypes. The non-linear progression of individual patients' neurological scores may reflect biological complexity, day-to-day variability, limitations of the assessment methods or a combination of all three. © 2016 Mac Keith Press.

  10. Newborn screening for SCID identifies patients with ataxia telangiectasia.

    Science.gov (United States)

    Mallott, Jacob; Kwan, Antonia; Church, Joseph; Gonzalez-Espinosa, Diana; Lorey, Fred; Tang, Ling Fung; Sunderam, Uma; Rana, Sadhna; Srinivasan, Rajgopal; Brenner, Steven E; Puck, Jennifer

    2013-04-01

    Severe combined immunodeficiency (SCID) is characterized by failure of T lymphocyte development and absent or very low T cell receptor excision circles (TRECs), DNA byproducts of T cell maturation. Newborn screening for TRECs to identify SCID is now performed in several states using PCR of DNA from universally collected dried blood spots (DBS). In addition to infants with typical SCID, TREC screening identifies infants with T lymphocytopenia who appear healthy and in whom a SCID diagnosis cannot be confirmed. Deep sequencing was employed to find causes of T lymphocytopenia in such infants. Whole exome sequencing and analysis were performed in infants and their parents. Upon finding deleterious mutations in the ataxia telangiectasia mutated (ATM) gene, we confirmed the diagnosis of ataxia telangiectasia (AT) in two infants and then tested archival newborn DBS of additional AT patients for TREC copy number. Exome sequencing and analysis led to 2 unsuspected gene diagnoses of AT. Of 13 older AT patients for whom newborn DBS had been stored, 7 samples tested positive for SCID under the criteria of California's newborn screening program. AT children with low neonatal TRECs had low CD4 T cell counts subsequently detected (R = 0.64). T lymphocytopenia in newborns can be a feature of AT, as revealed by TREC screening and exome sequencing. Although there is no current cure for the progressive neurological impairment of AT, early detection permits avoidance of infectious complications, while providing information for families regarding reproductive recurrence risks and increased cancer risks in patients and carriers.

  11. Molecular defects in Moroccan patients with ataxia-telangiectasia.

    Science.gov (United States)

    Jeddane, L; Ailal, F; Dubois-d'Enghien, C; Abidi, O; Benhsaien, I; Kili, A; Chaouki, S; Kriouile, Y; El Hafidi, N; Fadil, H; Abilkassem, R; Rada, N; Bousfiha, A A; Barakat, A; Stoppa-Lyonnet, D; Bellaoui, H

    2013-06-01

    Ataxia-telangiectasia (AT) is a rare autosomal recessive disease, affecting neurologic and immune system. Numerous mutations are described in the ATM gene in several populations. However, in Morocco, few data are available concerning this condition. Our main goal is to determine clinical, immunological, and molecular presentation of Moroccan patients with AT. We screened 27 patients, out of 22 unrelated families, for ATM gene mutations. All our patients showed ataxia, ocular telangiectasia, and immunodeficiency, as well as elevated serum alphafetoprotein levels. Mean age at diagnosis was 5.51 years, and consanguinity rate was 81.8 %. Mean age at onset was 2.02 years, and mean time to diagnosis was 3.68 years. We found 14 different mutations in 19 unrelated families, of which 7 were not reported. Our results showed that c.5644C>T mutation was the most common in our series. However, further studies are required to demonstrate a founder effects on ATM gene in Moroccan patients, who showed mutational heterogeneity otherwise. Our data indicate that direct sequencing of coding exons is sufficient for a high detection rate in ATM in Moroccan population.

  12. Novel mutations in ataxia telangiectasia and AOA2 associated with prolonged survival.

    Science.gov (United States)

    Davis, Marie Y; Keene, C Dirk; Swanson, Phillip D; Sheehy, Conor; Bird, Thomas D

    2013-12-15

    Ataxia telangiectasia (AT) and ataxia oculomotor apraxia type 2 (AOA2) are autosomal recessive ataxias caused by mutations in genes involved in maintaining DNA integrity. Lifespan in AT is greatly shortened (20s-30s) due to increased susceptibility to malignancies (leukemia/lymphoma). Lifespan in AOA2 is uncertain. We describe a woman with variant AT with two novel mutations in ATM (IVS14+2T>G and 5825C>T, p.A1942V) who died at age 48 with pancreatic adenocarcinoma. Her mutations are associated with an unusually long life for AT and with a cancer rarely associated with that disease. We also describe two siblings with AOA2, heterozygous for two novel mutations in senataxin (3 bp deletion c.343-345 and 1398T>G, p.I466M) who have survived into their 70s, allowing us to characterize the longitudinal course of AOA2. In contrast to AT, we show that persons with AOA2 can experience a prolonged lifespan with considerable motor disability. Published by Elsevier B.V.

  13. 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.

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

    Science.gov (United States)

    Bhatt, Jayesh M; Bush, Andrew; van Gerven, Marjo; Nissenkorn, Andreea; Renke, Michael; Yarlett, Lian; Taylor, Malcolm; Tonia, Thomy; Warris, Adilia; Zielen, Stefan; Zinna, Shairbanu; Merkus, Peter J F M

    2015-12-01

    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. Copyright ©ERS 2015.

  15. Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: Reflection of inappropriate immune regulation?

    NARCIS (Netherlands)

    L.Y.T. Chiam (L. Y T); M.M.M. Verhagen (Mijke); A. Haraldsson (Ásgeir); N.M. Wulffraat (Nico); G.J.A. Driessen (Gertjan); M.G. Netea (Mihai); C.M.R. Weemaes (Corry); M.M.B. Seyger (Marieke); M. van Deuren (Marcel)

    2011-01-01

    textabstractBackground: Non-infective cutaneous granulomas with unknown pathogenesis occur in various primary immunodeficiencies (PIDs) including ataxia telangiectasia (A-T). Objective: To find a common immunological denominator in these cutaneous granulomas. Methods: The dermatological and immunolo

  16. Ataxia-Telangiectasia Presenting as Cerebral Palsy and Recurrent Wheezing: A Case Report.

    Science.gov (United States)

    Navratil, Marta; Đuranović, Vlasta; Nogalo, Boro; Švigir, Alen; Dumbović Dubravčić, Iva; Turkalj, Mirjana

    2015-09-18

    Ataxia-telangiectasia (A-T) is an autosomal recessive disease that consists of progressive cerebellar ataxia, variable immunodeficiency, sinopulmonary infections, oculocutaneous telangiectasia, radiosensitivity, early aging, and increased incidence of cancer. We report the case of an 8-year-old boy affected by A-T. At 12 months of age, he had a waddling gait, with his upper body leaning forward. Dystonic/dyskinetic cerebral palsy was diagnosed at the age of 3 years. At age 6 he was diagnosed with asthma based on recurrent wheezing episodes. A-T was confirmed at the age 8 years on the basis of clinical signs and laboratory findings (increased alpha fetoprotein--AFP, immunodeficiency, undetectable ataxia-telangiectasia mutated (ATM) protein on immunoblotting, and identification A-T mutation, 5932G>T). The clinical and immunological presentation of ataxia-telangiectasia (A-T) is very heterogeneous and diagnostically challenging, especially at an early age, leading to frequent misdiagnosis.

  17. Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity.

    Science.gov (United States)

    Menotta, Michele; Biagiotti, Sara; Bianchi, Marzia; Chessa, Luciana; Magnani, Mauro

    2012-11-30

    Ataxia telangiectasia (AT) is a rare genetic disease, still incurable, resulting from biallelic mutations in the ataxia telangiectasia-mutated (ATM) gene. Recently, short term treatment with glucocorticoid analogues improved neurological symptoms characteristic of this syndrome. Nevertheless, the molecular mechanism involved in glucocorticoid action in AT patients is not yet known. Here we describe, for the first time in mammalian cells, a short direct repeat-mediated noncanonical splicing event induced by dexamethasone, which leads to the skipping of mutations upstream of nucleotide residue 8450 of ATM coding sequence. The resulting transcript provides an alternative ORF translated in a new ATM variant with the complete kinase domain. This miniATM variant was also highlighted in lymphoblastoid cell lines from AT patients and was shown to be likely active. In conclusion, dexamethasone treatment may partly restore ATM activity in ataxia telangiectasia cells by a new molecular mechanism that overcomes most of the mutations so far described within this gene.

  18. 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.

  19. Ataxia-telangiectasia patients presenting with hyper-IgM syndrome.

    NARCIS (Netherlands)

    Noordzij, J.G.; Wulffraat, N.M.; Haraldsson, A.; Meyts, I.; Veer, L.J. van 't; Hogervorst, F.B.L.; Warris, A.; Weemaes, C.M.R.

    2009-01-01

    Ataxia-telangiectasia (A-T) is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency (decreased serum IgG subclass and/or IgA levels and lymphopenia). However, 10% of A-T patients present with decreased serum IgG and IgA with normal or raised Ig

  20. 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.

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

    OpenAIRE

    Antoccia Antonio; Ferrari Francesca; Angelino Giulia; Scarselli Alessia; Folgori Laura; 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...

  2. Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia.

    NARCIS (Netherlands)

    Hiel, J.A.P.; Engelen, B.G.M. van; Weemaes, C.M.R.; Broeks, A.; Verrips, A.; Laak, H.J. ter; Vingerhoets, H.M.; Heuvel, L.P.W.J. van den; Lammens, M.M.Y.; Gabreëls, F.J.M.; Last, J.I.; Taylor, A.M.R.

    2006-01-01

    The authors report four adult-onset ataxia telangiectasia (AT) patients belonging to two families lacking pronounced cerebellar ataxia but displaying distal spinal muscular atrophy. AT was proven by genetic studies showing ATM mutations and a reduced level of ATM. ATM activity, as measured by phosph

  3. 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

  4. The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia.

    Science.gov (United States)

    Méneret, Aurélie; Ahmar-Beaugendre, Yara; Rieunier, Guillaume; Mahlaoui, Nizar; Gaymard, Bertrand; Apartis, Emmanuelle; Tranchant, Christine; Rivaud-Péchoux, Sophie; Degos, Bertrand; Benyahia, Baya; Suarez, Felipe; Maisonobe, Thierry; Koenig, Michel; Durr, Alexandra; Stern, Marc-Henri; Dubois d'Enghien, Catherine; Fischer, Alain; Vidailhet, Marie; Stoppa-Lyonnet, Dominique; Grabli, David; Anheim, Mathieu

    2014-09-16

    To assess the clinical spectrum of ataxia-telangiectasia (A-T) in adults, with a focus on movement disorders. A total of 14 consecutive adults with A-T were included at 2 tertiary adult movement disorders centers and compared to 53 typical patients with A-T. Clinical evaluation, neurophysiologic and video-oculographic recording, imaging, laboratory investigations, and ATM analysis were performed. In comparison with typical A-T cases, our patients demonstrated later mean age at onset (6.1 vs 2.5 years, p ataxia in 71% and dysarthria and dystonia in 14% each. All patients displayed movement disorders, among which dystonia and subcortical myoclonus were the most common (86%), followed by tremor (43%). Video-oculographic recordings revealed mostly dysmetric saccades and 46% of patients had normal latencies (i.e., no oculomotor apraxia) and velocities. The α-fetoprotein (AFP) level was normal in 7%, chromosomal instability was found in 29% (vs 100% of typical patients, p = 0.0006), and immunoglobulin deficiency was found in 29% (vs 69%, p = 0.057). All patients exhibited 2 ATM mutations, including at least 1 missense mutation in 79% of them (vs 36%, p = 0.0067). There is great variability of phenotype and severity in A-T, including a wide spectrum of movement disorders. Karyotype and repeated AFP level assessments should be performed in adults with unexplained movement disorders as valuable clues towards the diagnosis. In case of a compatible phenotype, A-T should be considered even if age at onset is late and progression is slow. © 2014 American Academy of Neurology.

  5. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia.

    Science.gov (United States)

    Sharma, Nilesh K; Lebedeva, Maria; Thomas, Terace; Kovalenko, Olga A; Stumpf, Jeffrey D; Shadel, Gerald S; Santos, Janine H

    2014-01-01

    Ataxia Telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer. A-T is caused by mutations in the kinase ATM, a master regulator of the DNA double-strand break response. In addition to DNA-damage signaling defects, A-T cells display mitochondrial dysfunction that is thought to contribute to A-T pathogenesis. However, the molecular mechanism leading to mitochondrial dysfunction in A-T remains unclear. Here, we show that lack of ATM leads to reduced mitochondrial DNA (mtDNA) integrity and mitochondrial dysfunction, which are associated to defective mtDNA repair. While protein levels of mtDNA repair proteins are essentially normal, in the absence of ATM levels specifically of DNA ligase III (Lig3), the only DNA ligase working in mitochondria is reduced. The reduction of Lig3 is observed in different A-T patient cells, in brain and pre-B cells derived from ATM knockout mice as well as upon transient or stable knockdown of ATM. Furthermore, pharmacological inhibition of Lig3 in wild type cells phenocopies the mtDNA repair defects observed in A-T patient cells. As targeted deletion of LIG3 in the central nervous system causes debilitating ataxia in mice, reduced Lig3 protein levels and the consequent mtDNA repair defect may contribute to A-T neurodegeneration. A-T is thus the first disease characterized by diminished Lig3. Published by Elsevier B.V.

  6. Ataxia telangiectasia: more variation at clinical and cellular levels.

    Science.gov (United States)

    Taylor, A M R; Lam, Z; Last, J I; Byrd, P J

    2015-03-01

    Ataxia telangiectasia (A-T) is a rare recessively inherited disorder resulting in a progressive neurological decline. It is caused by biallelic mutation of the ATM gene that encodes a 370 kDa serine/threonine protein kinase responsible for phosphorylating many target proteins. ATM is activated by auto(trans)phosphorylation in response to DNA double strand breaks and leads to the activation of cell cycle checkpoints and either DNA repair or apoptosis as part of the cellular response to DNA damage. The allelic heterogeneity in A-T is striking. While the majority of mutations are truncating, leading to instability and loss of the ATM protein from the allele, a significant proportion of patients carry one of a small number of mutations that are either missense or leaky splice site mutations resulting in retention of some ATM with activity. The allelic heterogeneity in ATM, therefore, results in an equally striking clinical heterogeneity. There is also locus heterogeneity because mutation of the MRE11 gene can cause an obvious A-T like disorder both clinically and also at the cellular level and mutation of the RNF168 gene results in a much milder clinical phenotype, neurologically, with the major clinical feature being an immunological defect. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Molecular basis of ataxia telangiectasia and related diseases

    Institute of Scientific and Technical Information of China (English)

    Lindsay G BALL; Wei XIAO

    2005-01-01

    Ataxia telangiectasia (AT) is a rare human disease characterized by extreme cellular sensitivity to radiation and a predisposition to cancer, with a hallmark of onset in early childhood. Several human diseases also share similar symptoms with AT albeit with different degrees of severity and different associated disorders. While all AT patients contain mutations in the AT-mutated gene (ATM), most other ATlike disorders are defective in genes encoding an MRN protein complex consisting of Mre11, Rad50 and Nbs1. Both ATM and MRN function as cellular sensors to DNA double-strand breaks, which lead to the recruitment and phosphorylation of an array of substrate proteins involved in DNA repair, apoptosis and cell-cycle checkpoints, as well as gene regulation, translation initiation and telomere maintenance. ATM is a member of the family of phosphatidylinositol 3-kinase-like protein kinases (PIKK), and the discovery of many ATM substrates provides the underlying mechanisms of heterologous symptoms among AT patients. This review article focuses on recent findings related to the initial recognition of doublestrand breaks by ATM and MRN, as well as a DNA-dependent protein kinase complex consisting of the heterodimer Ku70/Ku80 and its catalytic subunit DNAPKcs, another member of PIKK. This possible interaction suggests that a much greater complex is involved in sensing, transducing and co-ordinating cellular events in response to genome instability.

  8. Chromosome aberrations in ataxia telangiectasia cells exposed to heavy ions

    Science.gov (United States)

    Kawata, T.; Cucinotta, F.; George, K.; Wu, H.; Shigematsu, N.; Furusawa, Y.; Uno, T.; Isobe, K.; Ito, H.

    Understanding of biological effects of heavy ions is important to assess healt h risk in space. One of the most important issues may be to take into account individual susceptibility. Ataxia telangiectasia (A-T) cells are known to exhibit abnormal responses to radiations but the mechanism of hyper radiosensitivity of A-T still remains unknown. We report chromosome aberrations in normal human fibroblasts and AT fibroblasts exposed to low- and high-LET radiations. A chemical-induced premature chromosome condensation (PCC) technique combined with chromosome- painting technique was applied to score chromosome aberrations in G2/M-phase cells. Following gamma irradiation, GM02052 cells were approximately 5 times more sensitive to g-rays than AG1522 cells. GM02052 cells had a much higher frequency of deletions and misrejoining than AG1522 cells. When the frequency of complex type aberrations was compared, GM02052 cells showed more than 10 times higher frequency than AG1522 cells. The results will be compared with those obtained from high-LET irradiations.

  9. Evaluation and Management of Pulmonary Disease in Ataxia-Telangiectasia

    Science.gov (United States)

    McGrath-Morrow, Sharon A.; Gower, W. Adam; Rothblum-Oviatt, Cynthia; Brody, Alan S.; Langston, Claire; Fan, Leland L.; Lefton-Greif, Maureen A.; Crawford, Thomas O.; Troche, Michelle; Sandlund, John T; Auwaerter, Paul G.; Easley, Blaine; Loughlin, Gerald M.; Carroll, John L.; Lederman, Howard M.

    2014-01-01

    Summary Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, resulting in faulty repair of breakages in double-stranded DNA. The clinical phenotype is complex, and is characterized by neurologic abnormalities, immunodeficiencies, susceptibility to malignancies, recurrent sinopulmonary infections, and cutaneous abnormalities. Lung disease is common in patients with A-T and often progresses with age and neurological decline. Diseases of the respiratory system cause significant morbidity and are a frequent cause of death in the A-T population. Lung disease in this population is thought to exhibit features of one or more of the following phenotypes: recurrent sinopulmonary infections with bronchiectasis, interstitial lung disease, and lung disease associated with neurological abnormalities. Here, we review available evidence and present expert opinion on the diagnosis, evaluation, and management of lung disease in A-T, as discussed in a recent multidisciplinary workshop. Although more data are emerging on this unique population, many recommendations are made based on similarities to other more well-studied diseases. Gaps in current knowledge and areas for future research in the field of pulmonary disease in A-T are also outlined. PMID:20583220

  10. Neurodegeneration in ataxia-telangiectasia is caused by horror autotoxicus.

    Science.gov (United States)

    Kuljis, R O; Aguila, M C

    1999-05-01

    Ataxia-telangiectasia (A-T) is a pleiotropic, multi-system disorder with manifestations that include immune deficiency, sensitivity to ionizing radiation and neoplasms. Many of these manifestations are understood in principle since the identification in A-T patients of mutations in a gene encoding a protein kinase that plays a key role in signaling and repair of DNA damage. However, the cause of the neurodegeneration that afflicts patients with A-T for at least a decade before they succumb to overwhelming infections or malignancy remains mysterious. Based on our work in a mouse model of A-T and previous evidence of extra-neural autoimmune disorders in A-T, we postulate that the neurodegenerative process in A-T is not due to a function for A-T mutated (ATM) essential for the postnatal brain, but to an autoimmune process (hence 'horror autotoxicus', Paul Ehrlich's term for autoimmune disorder). This hypothetical mechanism may be analogous to that in the so-called 'paraneoplastic' neurodegenerative syndromes in patients with various malignancies. Thus, alterations in the balance between cellular and humoral immunity in A-T probably result in autoantibodies to cerebral epitopes shared with cells of the immune system. This hypothesis has important implications for the understanding and development of effective palliative and even preventative strategies for A-T, and probably for other so far relentlessly progressive neurodegenerative disorders.

  11. Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives.

    Science.gov (United States)

    Claes, Kathleen; Depuydt, Julie; Taylor, A Malcolm R; Last, James I; Baert, Annelot; Schietecatte, Peter; Vandersickel, Veerle; Poppe, Bruce; De Leeneer, Kim; D'Hooghe, Marc; Vral, Anne

    2013-09-01

    Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient.

  12. Multi-drugs resistant acne rosacea in a child affected by Ataxia-Telangiectasia: successful treatment with Isotretinoin.

    Science.gov (United States)

    Cantarutti, Nicoletta; Claps, Alessia; Angelino, Giulia; Chessa, Luciana; Callea, Francesco; El Hachem, May; Diociaiuti, Andrea; Finocchi, Andrea

    2015-03-28

    Ataxia-Telangiectasia is a rare multisystem autosomal recessive disorder [OMIM 208900], caused by mutations in Ataxia-Telangiectasia Mutated gene. It is characterized by neurological, immunological and cutaneous involvement. Granulomas have been previously reported in Ataxia-Telangiectasia patients, even if acne rosacea has not been described.We report a case of a young Ataxia-Telangiectasia patient with a severe immunological and neurological involvement, who developed granulomatous skin lesions diagnosed by skin biopsy as acne rosacea. Considering the severe clinical picture and the lack of improvement to multiple topic and systemic therapies, treatment with Isotretinoin was started and the skin lesions disappeared after five months. However the therapy was stopped due to drug-hepatotoxicity.Systemic treatment with Isotretinoin should be carefully considered in patient with Ataxia-Telangiectasia for the treatment of multi-drug resistant acne rosacea, however its toxicity may limit long-term use and the risk/benefit ratio of the treatment should be evaluated.

  13. Pulmonary Function in Children and Young Adults With Ataxia Telangiectasia

    Science.gov (United States)

    McGrath-Morrow, Sharon A.; Lederman, Howard M.; Aherrera, Angela D.; Lefton-Greif, Maureen A.; Crawford, Thomas O.; Ryan, Timothy; Wright, Jennifer; Collaco, Joseph M.

    2015-01-01

    Summary Background Pulmonary disease contributes to significant morbidity and mortality in people with ataxia telangiectasia (A-T). To determine the association between age and lung function in children and young adults with A-T and to identify factors associated with decreased lung function, pulmonary function tests were performed in 100 consecutive people with A-T. Methods Children and adults ranging from 6 to 29 years of age and with the diagnosis of A-T were recruited, and underwent pulmonary function tests. Results The mean forced vital capacity % predicted (FVC %) in the population was 56.6 ± 20.0. Males and females between 6 and 10 years of age had similar pulmonary function. Older females were found to have significantly lower FVCs % than both older males (P < 0.02) and younger females (P < 0.001). The use of supplemental gamma globulin was associated with significantly lower FVC %. A modest correlation was found between higher radiation-induced chromosomal breakage and lower FVC % in males. No significant change in FVC % was found in a subset of subjects (n = 25) who underwent pulmonary function testing on two or more occasions over an average of 2 years. Conclusion In children and young adults with A-T, older females and people who required supplemental gamma globulin had significantly lower lung function by cross-sectional analysis. Stable lung function is possible over a 2-year period. Recognition of groups who are at higher risk for lower pulmonary function may help direct care and improve clinical outcomes in people with A-T. PMID:23401357

  14. Growth and nutrition in children with ataxia telangiectasia.

    Science.gov (United States)

    Stewart, Emma; Prayle, Andrew P; Tooke, Alison; Pasalodos, Sara; Suri, Mohnish; Bush, Andy; Bhatt, Jayesh M

    2016-12-01

    Ataxia telangiectasia (A-T) is a rare multisystem disease with high early mortality from lung disease and cancer. Nutritional failure adversely impacts outcomes in many respiratory diseases. Several factors influence nutrition in children with A-T. We hypothesised that children with A-T have progressive growth failure and that early gastrostomy tube feeding (percutaneous endoscopic gastrostomy, PEG) is a favourable management option with good nutritional outcomes. Data were collected prospectively on weight, height and body mass index (BMI) at the national paediatric A-T clinic. Adequacy and safety of oral intake was assessed. Nutritional advice was given at each multidisciplinary review. 101 children (51 girls) had 222 measurements (32 once, 32 twice, 24 thrice) between 2009 and 2016. Median (IQR) age was 9.3 (6.4 to 13.1) years. Mean (SD) weight, height and BMI Z-scores were respectively -1 (1.6), -1.2 (1.2) and -0.4 (1.4). 35/101 children had weight Z-scores below -2 on at least one occasion. Weight, height and BMI Z-scores declined over time. Decline was most obvious after 8 years of age. 14/101 (14%) children had a PEG, with longitudinal data available for 12. In a nested case control study, there was a trend for improvement in weight in those with a PEG (p=0.10). Patients with A-T decline in growth over time. There is an urgent need for new strategies, including an understanding of why growth falters. We suggest early proactive consideration of PEG from age 8 years onwards to prevent progressive growth failure. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Ataxia-telangiectasia and wilms tumor: reduced treatment but early relapse.

    Science.gov (United States)

    Pérez-Villena, Ana; Cormenzana, María; de Prada, Inmaculada; Pérez-Martínez, Antonio; Aleo, Esther

    2013-05-01

    Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, a high incidence of lymphoreticular tumors, and an increased sensitivity to chemoradiotherapy-induced DNA damage. The appropriate cancer therapy remains unknown because of high toxicity rates with full-dose conventional protocols. We present a patient with A-T and nephroblastoma, who received an adapted treatment regimen. To our knowledge this is the second report on nephroblastoma in a patient with A-T but the first with confirmed premortem studies. Although the patient tolerated the chemotherapy regimen well, the patient relapsed and died a year after initial diagnosis.

  16. Identification of ATM mutations in Korean siblings with ataxia-telangiectasia.

    Science.gov (United States)

    Huh, Hee Jae; Cho, Kyoo-Ho; Lee, Ji Eun; Kwon, Min-Jung; Ki, Chang-Seok; Lee, Phil Hyu

    2013-05-01

    Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T.

  17. Targeted Next-Generation Sequencing Revealed Novel Mutations in Chinese Ataxia Telangiectasia Patients: A Precision Medicine Perspective.

    Science.gov (United States)

    Chen, Zhao; Ye, Wei; Long, Zhe; Ding, Dongxue; Peng, Huirong; Hou, Xuan; Qiu, Rong; Xia, Kun; Tang, Beisha; Jiang, Hong

    2015-01-01

    Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia and immunodeficiency due to mutations in the ATM gene. We performed targeted next-generation sequencing (NGS) on three unrelated patients and identified five disease-causing variants in three probands, including two pairs of heterozygous variants (FAT-1:c.4396C>T/p.R1466X, c.1608-2A>G; FAT-2:c.4412_4413insT/p.L1472Ffs*19, c.8824C>T/p.Q2942X) and one pair of homozygous variants (FAT-3: c.8110T>G/p.C2704G, Hom). With regard to precision medicine for rare genetic diseases, targeted NGS currently enables the rapid and cost-effective identification of causative mutations and is an updated molecular diagnostic tool that merits further optimization. This high-throughput data-based strategy would propel the development of precision diagnostic methods and establish a foundation for precision medicine.

  18. Targeted Next-Generation Sequencing Revealed Novel Mutations in Chinese Ataxia Telangiectasia Patients: A Precision Medicine Perspective.

    Directory of Open Access Journals (Sweden)

    Zhao Chen

    Full Text Available Ataxia telangiectasia (AT is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia and immunodeficiency due to mutations in the ATM gene. We performed targeted next-generation sequencing (NGS on three unrelated patients and identified five disease-causing variants in three probands, including two pairs of heterozygous variants (FAT-1:c.4396C>T/p.R1466X, c.1608-2A>G; FAT-2:c.4412_4413insT/p.L1472Ffs*19, c.8824C>T/p.Q2942X and one pair of homozygous variants (FAT-3: c.8110T>G/p.C2704G, Hom. With regard to precision medicine for rare genetic diseases, targeted NGS currently enables the rapid and cost-effective identification of causative mutations and is an updated molecular diagnostic tool that merits further optimization. This high-throughput data-based strategy would propel the development of precision diagnostic methods and establish a foundation for precision medicine.

  19. Assessment of impaired coordination between respiration and deglutition in children and young adults with ataxia telangiectasia.

    Science.gov (United States)

    Lefton-Greif, Maureen A; Perlman, Adrienne L; He, Xuming; Lederman, Howard M; Crawford, Thomas O

    2016-10-01

    This cross-sectional investigation aimed to assess the value of non-invasive measures of temporal respiratory-swallow coupling in individuals with ataxic swallowing. Twenty participants (11 males, 9 females; range 9-21y) with ataxia telangiectasia were presented with water and pudding boluses. Their 193 swallows were compared with 2200 swallows from 82 age-matched healthy controls. The two components of airway protection during swallowing that were analyzed were: direction of peri-deglutitive airflow and duration of deglutitive inhibition of respiratory airflow (DIORA). Safe expiratory patterns of peri-deglutitive airflow occurred significantly less often in participants with ataxia telangiectasia than in age-matched control participants (younger pataxia telangiectasia (p=0.234). With age, mean duration of DIORA decreased in controls (pataxia telangiectasia (p=0.164). Non-invasive quantitative measures of respiratory-swallow coupling capture temporal relationships that plausibly contribute to airway compromise from dysphagia. Changes in respiratory-swallow coupling observed with advancing age in control participants were not seen in participants with ataxia telangiectasia. Measures of perturbations may herald swallowing problems prior to development of pulmonary and nutritional sequelae. © 2016 Mac Keith Press.

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

    Science.gov (United States)

    Sahama, Ishani; Sinclair, Kate; Fiori, Simona; Doecke, James; Pannek, Kerstin; Reid, Lee; Lavin, Martin; Rose, Stephen

    2015-01-01

    Our understanding of the effect of ataxia-telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography. Diffusion MRI were obtained from 12 patients (age range: 7-22 years, mean: 12 years) and 12 typically developing age matched participants (age range 8-23 years, mean: 13 years). White matter fiber tracking and whole tract statistical analyses were used to assess quantitative fractional anisotropy and mean diffusivity differences along the cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal tract length in patients using a linear mixed effects model. White matter tract streamline number and apparent fiber density in patient and control tracts were also assessed. Reduced fractional anisotropy along all analyzed patient tracts were observed (p 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.

  1. Chemo- and radiosensitivity testing in a patient with ataxia telangiectasia and Hodgkin disease

    NARCIS (Netherlands)

    Tamminga, RYJ; Dolsma, WV; Leeuw, JA; Kampinga, HH

    2002-01-01

    Treatment of Hodgkin disease (HD) in ataxia telangiectasia (AT) patients is hampered by hypersensitivity to radiation and chemotherapy. Most patients die, due to toxicity or rarely, to progressive disease. The authors report on a 9-year-old girl with stage IIA HD and AT She was treated with a tailor

  2. Tumor suppressor ataxia telangiectasia mutated functions downstream of TGF-β1 in orchestrating profibrotic responses

    NARCIS (Netherlands)

    Overstreet, Jessica M; Samarakoon, Rohan; Cardona-Grau, Diana; Goldschmeding, Roel|info:eu-repo/dai/nl/102376069; Higgins, Paul J

    2015-01-01

    Effective therapy to prevent organ fibrosis, which is associated with more than half of all mortalities, remains elusive. Involvement of tumor suppressor ataxia telangiectasia mutated (ATM) in the TGF-β1 pathway related to renal fibrosis is largely unknown. ATM activation (pATM(Ser1981)) increased 4

  3. Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia.

    Science.gov (United States)

    Exley, Andrew Robert; Buckenham, Samantha; Hodges, Elizabeth; Hallam, Robert; Byrd, Phil; Last, James; Trinder, Claire; Harris, Susan; Screaton, Nicholas; Williams, Anthony P; Taylor, A Malcolm R; Shneerson, John M

    2011-07-01

    ATM kinase modulates pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age. We address this paradox in a molecularly characterised sequential adult cohort with classical and mild variant ataxia telangiectasia. Immunodeficiency has the characteristics of premature ageing across multiple cellular and molecular immune parameters. This immune ageing occurs without previous CMV infection. Age predicts immunodeficiency in genetically homogeneous ataxia telangiectasia, and in comparison with controls, calendar age is exceeded by immunological age defined by thymic naïve CD4+ T cell levels. Applying ataxia telangiectasia as a model of immune ageing, pneumococcal vaccine responses, characteristically deficient in physiological ageing, are predicted by thymic naïve CD4+ T cell levels. These data suggest inherited defects of DNA repair may provide valuable insight into physiological ageing. Thymic naïve CD4+ T cells may provide a biomarker for vaccine responsiveness in elderly cohorts. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Nano-Mechanical Characterization of Ataxia Telangiectasia Cells Treated with Dexamethasone.

    Science.gov (United States)

    Menotta, Michele; Biagiotti, Sara; Bartolini, Giulia; Marzia, Bianchi; Orazi, Sara; Germani, Aldo; Chessa, Luciana; Magnani, Mauro

    2017-03-01

    Ataxia telangiectasia is a rare genetic disease and no therapy is currently available. Glucocorticoid analogues have been shown to improve the neurological symptoms of treated patients. In the present study ataxia telangiectasia and wild type cells were used as a cellular model and treated with dexamethasone. The cells were subsequently investigated for membrane and whole cell mechanical properties by atomic force microscopy. In addition, cytoskeleton protein dynamics and nuclear shapes were assayed by fluorescence microscopy, while western blots were used to assess actin and tubulin content. At the macro level, dexamethasone directly modified the cell shape, Young's modulus and cytoskeleton protein dynamics. At the nano level, the roughness of the cell surface and the local nano-mechanical proprieties were found to be affected by Dexa. Our results show that ataxia telangiectasia and wild type cells are affected by Dexa, although there are dissimilarities in some macro-level and nano-level features between the tested cell lines. The Young's modulus of the cells appears to depend mainly on nuclear shape, with a slight contribution from the tested cytoskeleton proteins. The current study proposes that dexamethasone influences ataxia telangiectasia cell membranes contents, cell components and cell shape.

  5. The critically ill patient with ataxia-telangiectasia: a case series.

    Science.gov (United States)

    Lockman, Justin L; Iskander, Andrew J; Bembea, Melania; Crawford, Thomas O; Lederman, Howard M; McGrath-Morrow, Sharon; Easley, R Blaine

    2012-03-01

    To describe the presentation, clinical course, and outcomes of critically ill patients with ataxia-telangiectasia. Retrospective case series. Adult and pediatric intensive care units at an urban tertiary academic center. Seven consecutive patients with confirmed diagnosis of ataxia-telangiectasia had nine intensive care admissions between January 1995 and December 2009. None. Mean age at time of admission 15.9 yrs (median, 13.9 yrs; range, 7.3-33.9 yrs). Mean duration of intensive care unit stay was 17 days (median, 9 days; range, 2-39 days). The most common admitting diagnosis was respiratory distress (six of seven patients). There was no difference in ventilator settings or duration of intensive care unit stay between survivors and nonsurvivors (p > .05). Forty-three percent (three of seven patients) survived to intensive care unit discharge with a 3-yr survival that was 14% (one of seven patients). Critically ill patients with ataxia-telangiectasia have complex, multisystem diseases. In this case series, the most common intensive care unit admission diagnosis was respiratory failure. Suspected or confirmed bacterial infections were prevalent. Neuropathologic autopsy findings were similar to those previously reported. Special considerations for the critical care of patients with ataxia-telangiectasia are discussed.

  6. Cognitive and speech-language performance in children with ataxia telangiectasia

    NARCIS (Netherlands)

    Vinck, Anja; Verhagen, Mijke M. M.; van Gerven, Marjo; de Groot, Imelda J. M.; Weemaes, Corry M. R.; Maassen, Ben A. M.; Willemsen, Michel A. A. P.

    2011-01-01

    Objective: To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function. Design: Observational case series. Methods: Cognitive functioning, language, speech and oral-motor functioning were examined in eigh

  7. Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia.

    Science.gov (United States)

    Li, Jiali; Chen, Jianmin; Ricupero, Christopher L; Hart, Ronald P; Schwartz, Melanie S; Kusnecov, Alexander; Herrup, Karl

    2012-05-01

    Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.

  8. Cognitive and speech-language performance in children with ataxia telangiectasia

    NARCIS (Netherlands)

    Vinck, Anja; Verhagen, Mijke M. M.; van Gerven, Marjo; de Groot, Imelda J. M.; Weemaes, Corry M. R.; Maassen, Ben A. M.; Willemsen, Michel A. A. P.

    2011-01-01

    Objective: To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function. Design: Observational case series. Methods: Cognitive functioning, language, speech and oral-motor functioning were examined in eigh

  9. Cognitive and speech-language performance in children with ataxia telangiectasia

    NARCIS (Netherlands)

    Vinck, A.; Verhagen, M.M.; Gerven, M.; Groot, I.J.M. de; Weemaes, C.M.R.; Maassen, B.A.M.; Willemsen, M.A.A.P.

    2011-01-01

    OBJECTIVE: To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function. DESIGN: Observational case series. METHODS: Cognitive functioning, language, speech and oral-motor functioning were examined in eigh

  10. 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.

  11. SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs.

    Science.gov (United States)

    Lee, Peiyee; Martin, Nathan T; Nakamura, Kotoka; Azghadi, Soheila; Amiri, Mandana; Ben-David, Uri; Perlman, Susan; Gatti, Richard A; Hu, Hailiang; Lowry, William E

    2013-01-01

    Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia.

  12. Accurate diagnostics of ataxia-telangiectasia cellular phenotype by employing in vitro lymphocyte radiosensitivity testing

    Directory of Open Access Journals (Sweden)

    Vujić Dragana S.

    2013-01-01

    Full Text Available In this paper we present the data of lymphocyte radiosensitivity testing used for characterization of radiosensitive cellular phenotype and diagnostics of ataxia-telangiectasia disease. We point out the advantage of lymphocyte micronucleus test (CBMN over other cellular tests for assessment of radiosensitivity: the first advantage of CBMN is that primary patient cells are used (less than 1 ml, the second one is that the results of testing are obtained within 3 days and there is no need for establishing a patient-derived cell line, which requires additional time and application of more expensive methods. The third advantage of CBMN method is that it gives information about proliferative ability of cells, which can recognize dysfunctional ataxia-telangiectasia mutated protein. The results are fast and accurate in diagnostics of ataxia-telagiectasia diseases.

  13. Ataxia-telangiectasia: Linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome

    NARCIS (Netherlands)

    Y. Ziv (Yael); M. Frydman (Moshe); E.M. Lange (Ethan); N. Zelnik (N.); G. Rotman (Galit); C. Julier (C.); N.G.J. Jaspers (Nicolaas); E. Dagan (Efrat); D. Abeliovicz (Dvorah); H. Dar (H.); Z. Borochowitz (Z.); M. Lathrop (Mark); A. Gatti (Arianna); Y. Shiloh (Yosef)

    1992-01-01

    textabstractAtaxia-telangiectasia (A-T) is a progressive autosomal recessive disease featuring neurodegeneration, immunodeficiency, chromosomal instability, radiation sensitivity and a highly increased proneness to cancer. A-T is ethnically widespread and genetically heterogeneous, as indicated by t

  14. Ataxia-telangiectasia: Linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome

    NARCIS (Netherlands)

    Y. Ziv (Yael); M. Frydman (Moshe); E.M. Lange (Ethan); N. Zelnik (N.); G. Rotman (Galit); C. Julier (C.); N.G.J. Jaspers (Nicolaas); E. Dagan (Efrat); D. Abeliovicz (Dvorah); H. Dar (H.); Z. Borochowitz (Z.); M. Lathrop (Mark); A. Gatti (Arianna); Y. Shiloh (Yosef)

    1992-01-01

    textabstractAtaxia-telangiectasia (A-T) is a progressive autosomal recessive disease featuring neurodegeneration, immunodeficiency, chromosomal instability, radiation sensitivity and a highly increased proneness to cancer. A-T is ethnically widespread and genetically heterogeneous, as indicated by t

  15. Whole-exome sequence analysis of ataxia telangiectasia-like phenotype.

    Science.gov (United States)

    Hasegawa, Setsuko; Imai, Kohsuke; Yoshida, Kenichi; Okuno, Yusuke; Muramatsu, Hideki; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Kojima, Seiji; Ogawa, Seishi; Morio, Tomohiro; Mizutani, Shuki; Takagi, Masatoshi

    2014-05-15

    A number of diseases exhibit neurodegeneration with/without additional symptoms such as immunodeficiency, increased cancer risk, and microcephalus. Ataxia telangiectasia and Nijmegen breakage syndrome, for example, develop as a result of mutations in genes involved in the DNA damage response. However, such diseases can be difficult to diagnose as they are only rarely encountered by physicians. To overcome this challenge, nine patients with symptoms that resemble those of ataxia telangiectasia, including neurodegeneration, hypogammaglobulinemia, telangiectasia, and/or elevated serum α-fetoprotein, were subjected to whole-exome sequencing (WES) to identify the causative mutations. Molecular diagnosis was achieved in two patients: one displayed CD40 ligand (CD40LG) deficiency, while a second showed a homozygous SIL1 mutation, which has been linked to Marinesco-Sjögren syndrome (MSS). Typical features of CD40LG deficiency and MSS are distinct from the symptoms usually seen in ataxia telangiectasia. These dissociations between phenotype and genotype make it difficult to achieve molecular diagnosis of orphan diseases. Whole-exome sequencing analyses will assist in the molecular diagnosis of such cases and allow the identification of genotypes that would not be expected from the phenotype. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. “A DNA Damage Response (DDR) –independent Role for the Ataxia-Telangiectasia Mutated (ATM) Gene Product"

    OpenAIRE

    Palazzo, Luca

    2010-01-01

    Ataxia-Telangiectasia (A-T) is a recessive hereditary syndrome characterized by cerebellar degeneration, telangiectasia, precocious aging, immunodeficiency, cancer predisposition and insulin-resistant diabetes. A-T is caused by defects in Ataxia-Telagiectasia Mutated (Atm) gene. Atm encodes a ser/thr kinase (ATM) of the PI3 kinase family that plays a crucial role in the DNA damage response (DDR). Although some A-T features are easily explained by defects in DDR, others, like precocious aging,...

  17. Bladder wall telangiectasis causing life-threatening haematuria in ataxia-telangiectasia: a new observation.

    Science.gov (United States)

    Cohen, Jonathan M; Cuckow, Peter; Davies, E Graham

    2008-05-01

    We report two cases of life-threatening haemorrhage from bladder telangiectasia in children with ataxia-telangiectasia (A-T) who had been treated for lymphoma earlier in life. Whilst oculocutaneous telangiectasiae are an almost universal finding in this syndrome, bladder wall telangiectasis has not been reported previously. Both teenagers presented with recurrent severe haematuria due to extensive bladder telangiectasis. Recurrent haemorrhage was controlled with cystoscopic diathermy treatment. As A-T is a DNA repair disorder, it is possible that chemotherapy-mediated damage to the bladder mucosa prompted the development of clinically significant telangiectasis in these patients. We advocate early cystoscopy for A-T patients who develop haematuria to investigate the cause, and cystodiathermy to pre-emptively treat developing lesions prior to haemodynamically significant haemorrhage.

  18. Accurate diagnostics of ataxia-telangiectasia cellular phenotype by employing in vitro lymphocyte radiosensitivity testing

    OpenAIRE

    Vujić Dragana S.; Petrović Sandra Ž.; Leskovac Andreja R.; Joksić Ivana D.; Filipović Jelena G.; Valenta-Šobot Ana P.

    2013-01-01

    In this paper we present the data of lymphocyte radiosensitivity testing used for characterization of radiosensitive cellular phenotype and diagnostics of ataxia-telangiectasia disease. We point out the advantage of lymphocyte micronucleus test (CBMN) over other cellular tests for assessment of radiosensitivity: the first advantage of CBMN is that primary patient cells are used (less than 1 ml), the second one is that the results of testing are obtained within 3 days and there is no nee...

  19. Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2-mediated antioxidant response.

    Science.gov (United States)

    Biagiotti, Sara; Menotta, Michele; Orazi, Sara; Spapperi, Chiara; Brundu, Serena; Fraternale, Alessandra; Bianchi, Marzia; Rossi, Luigia; Chessa, Luciana; Magnani, Mauro

    2016-11-01

    Ataxia telangiectasia (A-T) is a rare incurable neurodegenerative disease caused by biallelic mutations in the gene for ataxia-telangiectasia mutated (ATM). The lack of a functional ATM kinase leads to a pleiotropic phenotype, and oxidative stress is considered to have a crucial role in the complex physiopathology. Recently, steroids have been shown to reduce the neurological symptoms of the disease, although the molecular mechanism of this effect is largely unknown. In the present study, we have demonstrated that dexamethasone treatment of A-T lymphoblastoid cells increases the content of two of the most abundant antioxidants [glutathione (GSH) and NADPH] by up to 30%. Dexamethasone promoted the nuclear accumulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 to drive expression of antioxidant pathways involved in GSH synthesis and NADPH production. The latter effect was via glucose 6-phosphate dehydrogenase activation, as confirmed by increased enzyme activity and enhancement of the pentose phosphate pathway rate. This evidence indicates that glucocorticoids are able to potentiate antioxidant defenses to counteract oxidative stress in ataxia telangiectasia, and also reveals an unexpected role for dexamethasone in redox homeostasis and cellular antioxidant activity. © 2016 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  20. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites

    Science.gov (United States)

    Raymond, D.; Stoessl, A.J.; Hobson, D.; Nakamura, T.; Pullman, S.; Lefton, D.; Okun, M.S.; Uitti, R.; Sachdev, R.; Stanley, K.; San Luciano, M.; Hagenah, J.; Gatti, R.; Ozelius, L.J.; Bressman, S.B.

    2012-01-01

    Objective: To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research. Methods: Movement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations. Result: Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies. Conclusion: Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia. PMID:22345219

  1. 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.

  2. Ataxia-Telangiectasia and RAD3-Related and Ataxia-Telangiectasia-Mutated Proteins in Epithelial Ovarian Carcinoma: Their Expression and Clinical Significance.

    Science.gov (United States)

    Lee, Banghyun; Lee, Hee Jin; Cho, Hye-Yon; Suh, Dong Hoon; Kim, Kidong; No, Jae Hong; Kim, Haeryoung; Kim, Yong-Beom

    2015-07-01

    The expression patterns of the key DNA damage response-related proteins, ataxia-telangiectasia and tfiih/ner complex atp-dependent 5'-3' dna helicase subunit rad3 (RAD3)-related (ATR) and ataxia-telangiectasia-mutated (ATM) proteins in ovarian cancer are not well-known. This study aimed to evaluate the expressions of ATR and ATM proteins, and to investigate their clinical significance in epithelial ovarian carcinoma (EOC). The expressions of nuclear/cytoplasmic Ser428-phosphorylated ATR (p-ATR) and Ser1981-phosphorylated ATM (p-ATM) were evaluated by immunohistochemistry in 100 patients with EOC. The clinical significances of p-ATR and p-ATM protein expression were evaluated in terms of tumor progression and survival. Low expression of cytoplasmic p-ATR was significantly associated with advanced stage, serous histology, large residual mass, and high preoperative serum CA125 level. Univariate survival analysis revealed that low expression of cytoplasmic p-ATR protein was significantly associated with poor disease-free survival and poor overall survival. Our study demonstrates that cytoplasmic ATR protein might serve as a prognostic biomarker for patients with EOC. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  3. 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.

  4. Inmunodeficiencia con ataxia telangiectasia: presentación de 4 casos

    Directory of Open Access Journals (Sweden)

    Ma. Victoria Guntiñas Zamora

    2004-03-01

    Full Text Available Se presentan 4 pacientes con síntomas y signos propios de una inmunodeficiencia con ataxia telangiectasia, tanto desde el punto de vista clínico como de los marcadores serológicos y celulares. En todos los casos la ataxia se evidenció cuando los pacientes comenzaron a caminar, las telangiectasias tuvieron una aparición más tardía y las infecciones fueron manifiestas desde edades muy tempranas. Los defectos inmunológicos fueron heterogéneos, tanto de células B como T. Todos los pacientes se encuentran actualmente bajo tratamiento inmunoestimulante a pesar de lo cual mantienen cuadros infecciosos frecuentes. La enfermedad neurológica progresa. Se recomienda el seguimiento estrecho de los casos por la posible aparición de complicaciones graves como enfermedad pulmonar crónica o neoplasias linforreticulares4 patients with symptoms and signs typical of an immunodeficiency with ataxia telangiectasia from the clinical point of view and from the point of view of the serological and cellular markers are presented. In all the cases, ataxia was confirmed when the patients began to walk. Telangiectasies had a later appearance and the infections manifested at very early ages. The immunological defects of B and T cells were heterogeneous. The patients maintain infectious pictures despite being under immunostimulating treatment. The neurological disease is in progress. It is recommended the close follow-up of the cases due to the possible emergence of severe complications, such as chronic pulmonary disease or lymphoreticular neoplasias.

  5. Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia.

    Science.gov (United States)

    Byrd, P J; Srinivasan, V; Last, J I; Smith, A; Biggs, P; Carney, E F; Exley, A; Abson, C; Stewart, G S; Izatt, L; Taylor, A M

    2012-01-17

    Severe early and late radiation reaction to radiotherapy is extremely rare in breast cancer patients. Such a reaction prompted an investigation into a 44-year-old mother (patient A-T213). A neurological examination was performed and blood lymphocytes and skin fibroblasts were assessed for radiosensitivity chromosomally and by colony-forming assay. The ATM gene was sequenced and ATM mutations modelled by site-directed mutagenesis. The ATM kinase activity was also assessed. Patient A-T213 was normally ambulant with no ataxia and minimal other neurological features. T lymphocytes and skin fibroblasts were unusually radiosensitive, although less sensitive than in classical ataxia telangiectasia (A-T). A lymphoblastoid cell line and skin fibroblasts expressed ATM protein with some retained kinase activity. One missense ATM mutation c.8672G>A (p.Gly2891Asp) and a c.1A>G substitution were identified. In the modelling system, the p.Gly2891Asp mutant protein was expressed and shown to have residual ATM kinase activity. Patient A-T213 has a milder form of A-T with biallelic ATM mutations, which may have contributed to breast cancer development, and certainly caused the severe radiation reaction. Ataxia telangiectasia should be investigated as a potential cause of untoward severe early and late radiation reactions in breast cancer patients.

  6. Clinical course of two Italian siblings with ataxia-telangiectasia-like disorder.

    Science.gov (United States)

    Palmeri, Silvia; Rufa, Alessandra; Pucci, Barbara; Santarnecchi, Emiliano; Malandrini, Alessandro; Stromillo, Maria Laura; Mandalà, Marco; Rosini, Francesca; De Stefano, Nicola; Federico, Antonio

    2013-08-01

    Ataxia-telangiectasia-like disorder (ATLD) due to mutations in the MRE11 gene is a very rare autosomal recessive disease, described so far in only 20 patients. Little is known about the onset of the first symptoms or the clinical course of the disease. The present report contributes to the diagnosis of ATLD and its prognosis at onset. We report 30 years of clinical and ophthalmic observations and the results of quantitative magnetic resonance (MR), MR spectroscopy (proton magnetic resonance spectroscopic imaging) and neuropsychological assessment in the first Italian siblings identified with ATLD. Although the disease had early onset and the clinical picture was initially severe, suggesting ataxia-telangiectasia, neurological impairment, ocular motor apraxia and neuropsychological tests showed very slow deterioration in adult age. The patients developed eye and head motor strategies to compensate ocular motor apraxia. MR measurements and MR spectroscopy disclosed widespread neuronal and axonal involvement. ATLD should be considered in patients with ocular apraxia and ataxia in infancy. The long follow-up provided insights into clinical outcome, with functional neuroimaging studies shedding light on the pathogenetic mechanisms of this rare disease.

  7. Development of global rating instruments for pediatric patients with ataxia telangiectasia.

    Science.gov (United States)

    Nissenkorn, Andreea; Borgohain, Rupam; Micheli, Roberto; Leuzzi, Vincenzo; Hegde, Anaita Udwadia; Mridula, Kandadai Rukmini; Molinaro, Anna; D'Agnano, Daniela; Yareeda, Sireesha; Ben-Zeev, Bruria

    2016-01-01

    Ataxia telangiectasia (AT) is a neurodegenerative disorder with cerebellar and extrapyramidal features. Interventional and epidemiological studies in AT should rely on specific scales which encompass the specific neurological features, as well the early progressive course and the subsequent plateau. The aim of this study was to build a scale of the CGI type (Clinical Global Impression) which is disease specific, as well as to check the feasibility of the ICARS scale for ataxia in this population. We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT. All patients were evaluated for ataxia with ICARS scale. In patients with AT, two CGI scales were scored, unstructured as structured for which separate anchors were provided. Mean ICARS score was 44.7 ± 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p ataxia can be reliably measured in children with AT by using ICARS. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  8. Forward subtractive libraries containing genes transactivated by dexamethasone in ataxia-telangiectasia lymphoblastoid cells.

    Science.gov (United States)

    Biagiotti, Sara; Menotta, Michele; Giacomini, Elisa; Radici, Lucia; Bianchi, Marzia; Bozzao, Cristina; Chessa, Luciana; Magnani, Mauro

    2014-07-01

    Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder caused by biallelic mutations in the Ataxia Telangiectasia-mutated gene. A-T shows a complex phenotype ranging from early-onset progressive neurodegeneration to immunodeficiencies, high incidence of infections, and tumors. Unfortunately, no therapy is up to now available for treating this condition. Recently, the short term treatment of ataxia-telangiectasia patients with glucocorticoids was shown to improve their neurological symptoms and possibly reverse cerebellar atrophy. Thus, corticosteroids represent an attractive approach for the treatment of this neurodegenerative disease. However, the molecular mechanism involved in glucocorticoid action in A-T is yet unknown. The aim of our work is to construct cDNA libraries containing those genes which are transactivated by the glucocorticoid analogue, dexamethasone, in A-T human cells. For this purpose, suppression subtractive hybridization has been performed on ATM-null lymphoblastoid cell transcriptome extracted following drug administration. Annotation of whole genes contained in the libraries has been obtained by coupling subtractive hybridization with microarray analysis. Positive transcripts have been validated by quantitative PCR. Through in silico analyses, identified genes have been classified on the basis of the pathway in which they are involved, being able to address signaling required for dexamethasone action. Most of the induced transcripts are involved in metabolic processes and regulation of cellular processes. Our results can help to unravel the mechanism of glucocorticoid action in the reversion of A-T phenotype. Moreover, the induction of a specific region of the ATM transcript has been identified as putative biomarker predictive of dexamethasone efficacy on ataxic patients.

  9. A Precocious Cerebellar Ataxia and Frequent Fever Episodes in a 16-Month-Old Infant Revealing Ataxia-Telangiectasia Syndrome

    Directory of Open Access Journals (Sweden)

    Luigi Nespoli

    2013-01-01

    Full Text Available Ataxia-telangiectasia (AT is the most frequent progressive cerebellar ataxia in infancy and childhood. Immunodeficiency which includes both cellular and humoral arms has variable severity. Since the clinical presentation is extremely variable, a high clinical suspicion will allow an early diagnosis. Serum alpha-fetoprotein is elevated in 80–85% of patients and therefore could be used as a screening tool. Here, we present a case of a 5-year-old female infant who was admitted to our department at the age of 16 months because of gait disorders and febrile episodes that had begun at 5 months after the cessation of breastfeeding. Serum alfa-fetoprotein level was elevated. Other investigations showed leukocytopenia with lymphopenia, reduced IgG2 and IgA levels, and low titers of specific postimmunization antibodies against tetanus toxoid and Haemophilus B polysaccharide. Peripheral lymphocytes subsets showed reduction of T cells with a marked predominance of T cells with a memory phenotype and a corresponding reduction of naïve T cells; NK cells were very increased (41% with normal activity. The characterization of the ATM gene mutations revealed 2 specific mutations (c.5692C > T/c.7630-2A > C compatible with AT diagnosis. It was concluded that AT syndrome should be considered in children with precocious signs of cerebellar ataxia and recurrent fever episodes.

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

    Science.gov (United States)

    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

    2014-06-27

    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 comparable nucleotide substitution rate in AT-iPS cells. Taken together, these data show that ATM is involved in protection from irradiation-induced cell death.

  11. Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions.

    Science.gov (United States)

    Ambrose, Mark; Gatti, Richard A

    2013-05-16

    In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients-children and adults alike-which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.

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

    Science.gov (United States)

    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

    2014-10-03

    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. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Class switch recombination process in ataxia telangiectasia patients with elevated serum levels of IgM.

    Science.gov (United States)

    Mohammadinejad, Payam; Abolhassani, Hassan; Aghamohammadi, Asghar; Pourhamdi, Shabnam; Ghosh, Sujal; Sadeghi, Bamdad; Nasiri Kalmarzi, Rasoul; Durandy, Anne; Borkhardt, Arndt

    2015-01-01

    Ataxia telangiectasia (AT) is a rare primary immunodeficiency disorder with various clinical manifestations. Increased serum levels of IgM and recurrent infections, mainly sinopulmonary infections, can be the presenting feature in a number of AT patients and may be initially misdiagnosed as hyper-IgM (HIgM) syndrome. This study was designed to investigate class switch recombination (CSR) as a critical mechanism in B lymphocytes' maturation to produce different isotypes of antibody in response to antigen stimulation in AT cases with HIgM presentation. Quantitative IgE production after stimulation by IL-4 and CD40L was considered as an indicator for CSR function. We also compared their results with sex and age matched AT patients without HIgM presentation. We report four AT patients with recurrent infections during infancy and high serum levels of IgM. Laboratory evaluations revealed defective CSR while none of the three AT patients without HIgM presentation had a defect in the CSR process. The characterized defect in AT is a mutation in the ataxia telangiectasia mutated (ATM) gene. This gene may result in CSR defects due to impaired DNA break repair. A special association between AT and HIgM may indicate a new subgroup of AT patients according to their clinical phenotype and CSR condition.

  14. NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease.

    Science.gov (United States)

    Weyemi, Urbain; Redon, Christophe E; Aziz, Towqir; Choudhuri, Rohini; Maeda, Daisuke; Parekh, Palak R; Bonner, Michael Y; Arbiser, Jack L; Bonner, William M

    2015-02-17

    Ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive cerebellar degeneration and a greatly increased incidence of cancer among other symptoms, is caused by a defective or missing ataxia telangiectasia mutated (ATM) gene. The ATM protein has roles in DNA repair and in the regulation of reactive oxygen species (ROS). Here, we provide, to our knowledge, the first evidence that NADPH oxidase 4 (NOX4) is involved in manifesting A-T disease. We showed that NOX4 expression levels are higher in A-T cells, and that ATM inhibition leads to increased NOX4 expression in normal cells. A-T cells exhibit elevated levels of oxidative DNA damage, DNA double-strand breaks and replicative senescence, all of which are partially abrogated by down-regulation of NOX4 with siRNA. Sections of degenerating cerebelli from A-T patients revealed elevated NOX4 levels. ATM-null mice exhibit A-T disease but they die from cancer before the neurological symptoms are manifested. Injecting Atm-null mice with fulvene-5, a specific inhibitor of NOX4 and NADPH oxidase 2 (NOX2), decreased their elevated cancer incidence to that of the controls. We conclude that, in A-T disease in humans and mice, NOX4 may be critical mediator and targeting it will open up new avenues for therapeutic intervention in neurodegeneration.

  15. Analysis of Residual DSBs in Ataxia-Telangiectasia Lymphoblast Cells Initiating Apoptosis

    Directory of Open Access Journals (Sweden)

    Teresa Anglada

    2016-01-01

    Full Text Available In order to examine the relationship between accumulation of residual DNA double-strand breaks (DSBs and cell death, we have used a control and an ATM (Ataxia-Telangiectasia Mutated defective cell line, as Ataxia-Telangiectasia (AT cells tend to accumulate residual DSBs at long times after damage infliction. After irradiation, AT cells showed checkpoint impairment and a fraction of cells displayed an abnormal centrosome number and tetraploid DNA content, and this fraction increased along with apoptosis rates. At all times analyzed, AT cells displayed a significantly higher rate of radiation-induced apoptosis than normal cells. Besides apoptosis, 70–85% of the AT viable cells (TUNEL-negative carried ≥10 γH2AX foci/cell, while only 12–27% of normal cells did. The fraction of AT and normal cells undergoing early and late apoptosis were isolated by flow cytometry and residual DSBs were concretely scored in these populations. Half of the γH2AX-positive AT cells undergoing early apoptosis carried ≥10 γH2AX foci/cell and this fraction increased to 75% in late apoptosis. The results suggest that retention of DNA damage-induced γH2AX foci is an indicative of lethal DNA damage, as cells undergoing apoptosis are those accumulating more DSBs. Scoring of residual γH2AX foci might function as a predictive tool to assess radiation-induced apoptosis.

  16. A patient-derived olfactory stem cell disease model for ataxia-telangiectasia.

    Science.gov (United States)

    Stewart, Romal; Kozlov, Sergei; Matigian, Nicholas; Wali, Gautam; Gatei, Magtouf; Sutharsan, Ratneswary; Bellette, Bernadette; Wraith-Kijas, Amanda; Cochrane, Julie; Coulthard, Mark; Perry, Chris; Sinclair, Kate; Mackay-Sim, Alan; Lavin, Martin F

    2013-06-15

    The autosomal recessive disorder ataxia-telangiectasia (A-T) is characterized by genome instability, cancer predisposition and neurodegeneration. Although the role of ataxia-telangiectasia mutated (ATM) protein, the protein defective in this syndrome, is well described in the response to DNA damage, its role in protecting the nervous system is less clear. We describe the establishment and characterization of patient-specific stem cells that have the potential to address this shortcoming. Olfactory neurosphere (ONS)-derived cells were generated from A-T patients, which expressed stem cell markers and exhibited A-T molecular and cellular characteristics that included hypersensitivity to radiation, defective radiation-induced signaling and cell cycle checkpoint defects. Introduction of full-length ATM cDNA into these cells corrected defects in the A-T cellular phenotype. Gene expression profiling and pathway analysis revealed defects in multiple cell signaling pathways associated with ATM function, with cell cycle, cell death and DNA damage response pathways being the most significantly dysregulated. A-T ONS cells were also capable of differentiating into neural progenitors, but they were defective in neurite formation, number of neurites and length of these neurites. Thus, ONS cells are a patient-derived neural stem cell model that recapitulate the phenotype of A-T, do not require genetic reprogramming, have the capacity to differentiate into neurons and have potential to delineate the neurological defect in these patients.

  17. Ataxia-telangiectasia in the south of Tunisia: A study of 11 cases.

    Science.gov (United States)

    Sfaihi, Lamia; Stoppa Lyonnet, Dominique; Ben Ameur, Salma; Dubois D'enghien, Catherine; Kamoun, Thouraya; Barbouch, Mohamed Ridha; Hachicha, Mongia

    2015-01-01

    Ataxia-telangiectasia (A-T) is a multisystem disorder characterized by progressive neurologic impairment, variable immunodeficiency, impaired organ maturation, X-ray hypersensitivity, oculocutaneous telangiectasia, and a predisposition to malignancy. We performed this study in order to describe clinical, immunological and molecular features of patients with AT followed in the south of Tunisia Methods: we performed a retrospective study (1996-2012) in the south of Tunisia about all cases of A-T in order to describe their clinical, immunological and molecular features. 11 cases of AT were found. The mean age at onset of symptoms was 20 months with extremes varying from 3 months to 4 years. The median time to diagnosis was 3.6 years (range: 0-12 years).The main clinical feature of cerebellar syndrome, ataxia, was present at diagnosis in 8 patients and occurred at mean ages of 2.8 years. Ocular telangiectasia occurred at a mean age of 3.9 years (extremes: 3 months and 7 years). Recurrent sino-pulmonary infections that affected 7 children occurred at the mean age of 4.3 years. The most common humoral immune abnormality was serum IgA deficiency. Lymphopenia was found in 7 cases and lack of CD4 T in 6 cases. Cytogenetic analyses showed chromosomal instability in all children and a translocation (7-14) in two patients. A molecular diagnosis established in 6 patients from 4 families showed 5 different mutations of ATM gene. After an average decline of 5 years and 6 months, 7 patients died of severe pulmonary infection. Among them, 3 were ATM mutated. Morbidity and mortality among patients with A- T are associated with ATM genotype.

  18. 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

    and require more aggressive therapies. OBJECTIVE: The aim of this project was to investigate whether inhibition of Ataxia Telangiectasia and Rad3 related kinase (ATR) may enhance efficacy of phototherapy. METHODS: CTCL cell lines (MyLa2000, SeAx and Mac2a) served as in vitro cell models. ATR and Chk1 were...

  19. T-cell ALL in ataxia telangiectasia cured with only 7 weeks of anti-leukemic therapy

    DEFF Research Database (Denmark)

    Hersby, Ditte S; Sehested, Astrid; Kristensen, Kim

    2015-01-01

    -fetoprotein was 20- to 30-fold elevated, and genetic analysis confirmed the diagnosis of ataxia telangiectasia. Despite receiving only 7 weeks of anti-leukemic therapy, she has stayed in first remission now 8 years after the diagnosis. We speculate that this could be because of increased chemosensitivity of ATM...

  20. Ataxia Telangiectasia

    Science.gov (United States)

    ... Translational Research Research at NINDS Focus on Research Alzheimer's & Related Dementias Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury Stem Cells Traumatic Brain Injury Trans-Agency Activities Interagency Research ...

  1. Ataxia Telangiectasia

    Science.gov (United States)

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  2. Altered mucosal immune response after acute lung injury in a murine model of Ataxia Telangiectasia.

    Science.gov (United States)

    Eickmeier, Olaf; Kim, Su Youn; Herrmann, Eva; Döring, Constanze; Duecker, Ruth; Voss, Sandra; Wehner, Sibylle; Hölscher, Christoph; Pietzner, Julia; Zielen, Stefan; Schubert, Ralf

    2014-05-29

    Ataxia telangiectasia (A-T) is a rare but devastating and progressive disorder characterized by cerebellar dysfunction, lymphoreticular malignancies and recurrent sinopulmonary infections. In A-T, disease of the respiratory system causes significant morbidity and is a frequent cause of death. We used a self-limited murine model of hydrochloric acid-induced acute lung injury (ALI) to determine the inflammatory answer due to mucosal injury in Atm (A-T mutated)- deficient mice (Atm(-/-)). ATM deficiency increased peak lung inflammation as demonstrated by bronchoalveolar lavage fluid (BALF) neutrophils and lymphocytes and increased levels of BALF pro-inflammatory cytokines (e.g. IL-6, TNF). Furthermore, bronchial epithelial damage after ALI was increased in Atm(-/-) mice. ATM deficiency increased airway resistance and tissue compliance before ALI was performed. Together, these findings indicate that ATM plays a key role in inflammatory response after airway mucosal injury.

  3. Management of Individuals With a Mutation in the Ataxia Telangiectasia Mutated Gene.

    Science.gov (United States)

    Mahon, Suzanne M

    2016-01-01

    Advances in genetic testing have led to the identification of multiple genes associated with a hereditary risk for developing breast and other cancers. One such gene is the ataxia telangiectasia mutated (ATM) gene, which is available on many genetic panels offered to individuals with suspected hereditary risk. Genetic testing can often lead to improved understanding and clarification of risk for developing cancer, as well as allow affected individuals to make informed choices about management, including the adoption of primary prevention strategies and more aggressive screening than typically recommended in the general population. This article provides an overview of the role of mutations in the ATM gene in developing malignancies, along with emerging research on treatment implications based on genetic testing results.
.

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

    Energy Technology Data Exchange (ETDEWEB)

    Kapp, L.N.; Painter, R.B. (California Univ., San Francisco, CA (USA). Lab. of Radiobiology)

    1989-11-01

    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{sub 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. Chemo- and radiosensitivity testing in a patient with ataxia telangiectasia and Hodgkin disease.

    Science.gov (United States)

    Tamminga, R Y J; Dolsma, W V; Leeuw, J A; Kampinga, H H

    2002-01-01

    Treatment of Hodgkin disease (HD) in ataxia telangiectasia (AT) patients is hampered by hypersensitivity to radiation and chemotherapy. Most patients die, due to toxicity or, rarely, to progressive disease. The authors report on a 9-year-old girl with stage IIA HD and AT She was treated with a tailored combined modality approach. No unacceptable toxicity was found, but the girl died of a relapse outside the irradiation field. In comparison with fibroblasts of non-AT patients, the fibroblasts of the patient were 3 times as sensitive for radiotherapy but just 1.2 times as sensitive for doxorubicin. A good correlation was shown between in vitro radio- and chemosensitivity testing and the observed clinical toxicity. The authors suggest, therefore, treating AT patients as much as possible according to standard protocols by adjusting the radiotherapy delivery and the chemotherapy regimen to individual doses derived from in vitro radio- and chemosensitivity testing.

  6. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.

    Science.gov (United States)

    Micol, Romain; Ben Slama, Lilia; Suarez, Felipe; Le Mignot, Loïc; Beauté, Julien; Mahlaoui, Nizar; Dubois d'Enghien, Catherine; Laugé, Anthony; Hall, Janet; Couturier, Jérôme; Vallée, Louis; Delobel, Bruno; Rivier, François; Nguyen, Karine; Billette de Villemeur, Thierry; Stephan, Jean-Louis; Bordigoni, Pierre; Bertrand, Yves; Aladjidi, Nathalie; Pedespan, Jean-Michel; Thomas, Caroline; Pellier, Isabelle; Koenig, Michel; Hermine, Olivier; Picard, Capucine; Moshous, Despina; Neven, Bénédicte; Lanternier, Fanny; Blanche, Stéphane; Tardieu, Marc; Debré, Marianne; Fischer, Alain; Stoppa-Lyonnet, Dominique

    2011-08-01

    Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  7. Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.

    Science.gov (United States)

    Campbell, Andrew; Bushman, Jared; Munger, Joshua; Noble, Mark; Pröschel, Christoph; Mayer-Pröschel, Margot

    2016-02-01

    Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia-telangiectasia (A-T), a disease caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. A hallmark of A-T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A-T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A-T astroglia. Metabolic labeling of l-cystine, the major precursor for GSH, revealed that a key component of the defect in A-T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A-T mutant astroglia providing a possible future avenue for targeted therapeutic intervention. © 2015 Wiley Periodicals, Inc.

  8. Immune deficiency in Ataxia-Telangiectasia: a longitudinal study of 44 patients.

    Science.gov (United States)

    Chopra, C; Davies, G; Taylor, M; Anderson, M; Bainbridge, S; Tighe, P; McDermott, E M

    2014-05-01

    Ataxia-Telangiectasia (A-T) is a genetic condition leading to neurological defects and immune deficiency. The nature of the immune deficiency is highly variable, and in some cases causes significant morbidity and mortality due to recurrent sinopulmonary infections. Although the neurological defects in A-T are progressive, the natural history of the immune deficiency in A-T has not been evaluated formally. In this study we analyse the clinical history and immunological data in 44 patients with A-T who attended the National Ataxia-Telangiectasia clinic in Nottingham between 2001 and 2011. Using patient medical records and Nottingham University Hospitals (NUH) National Health Service Trust medical IT systems, data regarding clinical history, use of immunoglobulin replacement therapy, total immunoglobulin levels, specific antibody levels and lymphocyte subset counts were obtained. T cell receptor spectratyping results in some patients were already available and, where possible, repeat blood samples were collected for analysis. This study shows that subtle quantitative changes in certain immunological parameters such as lymphocyte subset counts may occur in patients with A-T over time. However, in general, for the majority of patients the severity of immune deficiency (both clinically and in terms of immunological blood markers) does not seem to deteriorate significantly with time. This finding serves to inform the long-term management of this cohort of patients because, if recurrent respiratory tract infections present later in life, then other contributory factors (e.g. cough/swallowing difficulties, underlying lung disease) should be investigated aggressively. Our findings also offer some form of reassurance for parents of children with A-T, which is otherwise a progressively severely debilitating condition. © 2014 British Society for Immunology.

  9. A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease.

    Science.gov (United States)

    Beraldi, Rosanna; Chan, Chun-Hung; Rogers, Christopher S; Kovács, Attila D; Meyerholz, David K; Trantzas, Constantin; Lambertz, Allyn M; Darbro, Benjamin W; Weber, Krystal L; White, Katherine A M; Rheeden, Richard V; Kruer, Michael C; Dacken, Brian A; Wang, Xiao-Jun; Davis, Bryan T; Rohret, Judy A; Struzynski, Jason T; Rohret, Frank A; Weimer, Jill M; Pearce, David A

    2015-11-15

    Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions.

  10. Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia.

    Science.gov (United States)

    Carranza, Diana; Vega, Ana Karina; Torres-Rusillo, Sara; Montero, Enrique; Martinez, Luis Javier; Santamaría, Manuel; Santos, Juan Luis; Molina, Ignacio J

    2017-03-01

    Ataxia-telangiectasia is a multisystemic disease with severe neurological affectation, immunodeficiency and telangiectasia. The disorder is caused by alterations in the ATM gene, whose size and complexity make molecular diagnosis difficult. We designed a target-enrichment next-generation sequencing strategy to characterize 28 patients from several regions of Spain. This approach allowed us to identify gene variants affecting function in 54 out of the 56 alleles analyzed, although the two unresolved alleles belong to brothers. We found 28 ATM gene mutations, of which 10 have not been reported. A total of 171 gene variants not affecting function were also found, of which 22 are reported to predispose to disease. Interestingly, all Roma (Spanish Gypsies) patients are homozygous for the same mutation and share the H3 ATM haplotype, which is strong evidence of a founder effect in this population. In addition, we generated a panel of 27 primary T cell lines from A-T patients, which revealed significant expression of ATM in two patients and traces of the protein in nine more. None of them retained residual ATM activity, and almost all T cell lines show increased or intermediate radiosensitivity.

  11. Hypergonadotropic hypogonadism and hypersegmented neutrophils in a patient with ataxia-telangiectasia-like disorder: potential diagnostic clues?

    Science.gov (United States)

    Yoshida, Takeshi; Awaya, Tomonari; Shibata, Minoru; Kato, Takeo; Numabe, Hironao; Kobayashi, Junya; Komatsu, Kenshi; Heike, Toshio

    2014-07-01

    Ataxia-telangiectasia-like disorder (ATLD) is a rare autosomal recessive disorder, and has symptoms similar to ataxia-telangiectasia (AT). ATLD is caused by mutations in the MRE11 gene, involved in DNA double-strand break repair (DSBR). In contrast to AT, ATLD patients lack key clinical features, such as telangiectasia or immunodeficiency, and are therefore difficult to be diagnosed. We report a female ATLD patient presenting with hypergonadotropic hypogonadism and hypersegmented neutrophils, previously undescribed features in this disorder, and potential diagnostic clues to differentiate ATLD from other conditions. The patient showed slowly progressive cerebellar ataxia from 2 years of age, and MRI revealed atrophy of the cerebellum, oculomotor apraxia, mild cognitive impairment, writing dystonia, hypergonadotropic hypogonadism with primary amenorrhea, and hypersegmented neutrophils. Western blot assay demonstrated total loss of MRE11 and reduction of ATM-dependent phosphorylation; thus, we diagnosed ATLD. Genetically, a novel missense mutation (c.140C>T) was detected in the MRE11 gene, but no other mutation was found in the patient. Our presenting patient suggests that impaired DSBR may be associated with hypergonadotropic hypogonadism and neutrophil hypersegmentation. In conclusion, when assessing patients with ataxia of unknown cause, ATLD should be considered, and the gonadal state and peripheral blood smear samples evaluated. © 2014 Wiley Periodicals, Inc.

  12. 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.

  13. Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia.

    Science.gov (United States)

    Worth, Paul F; Srinivasan, Venkataramanan; Smith, Anna; Last, James I; Wootton, Laura L; Biggs, Paul M; Davies, Nicholas P; Carney, Ellen F; Byrd, Philip J; Taylor, A Malcolm R

    2013-04-01

    The major clinical feature of ataxia telangiectasia (A-T) is severe progressive neurodegeneration with onset in infancy. This classical A-T phenotype is caused by biallelic null mutations in the ATM gene, leading to the absence of ATM protein and increased cellular radiosensitivity. We report an unusual case of A-T in a 41-year-old mother, A-T210, who had very mild neurological symptoms despite complete loss of ATM protein. A neurological examination was performed, cellular radiosensitivity was assessed, and the ATM gene was sequenced. Skin fibroblasts and a lymphoblastoid cell line (LCL) were assayed for ATM protein expression and kinase activity. Patient A-T210 showed mild chorea, dystonia, and gait ataxia, walked independently, and drove a car. LCL and skin fibroblasts were radiosensitive and did not express ATM protein. Two ATM-null mutations were identified. The severe neurodegeneration resulting from loss of ATM can be mitigated in some circumstances. Copyright © 2012 Movement Disorders Society.

  14. Growth retardation and growth hormone deficiency in patients with Ataxia telangiectasia.

    Science.gov (United States)

    Voss, Sandra; Pietzner, Julia; Hoche, Franziska; Taylor, Alexander Malcolm R; Last, James I; Schubert, Ralf; Zielen, Stefan

    2014-06-01

    Ataxia telangiectasia (A-T) is a devastating human recessive disorder characterised by progressive cerebellar ataxia, immunodeficiency, genetic instability, and cancer susceptibility. In addition, many patients suffer from growth failure. We analyzed growth and IGF-1/BP3 levels of 24 A-T-patients compared with an age-matched group of healthy controls (n = 36). Ten (41.7%) A-T patients and none of healthy controls had an IGF-1 level below the 3rd percentile for age. The growth hormone (GH) stimulation tests revealed a severe GH deficiency with no increase of >5 ng/ml in six of the ten A-T patients. The IGF-1 generation tests revealed normal increases in IGF-1 values in all patients. Our results show that a disturbance in the GH/IGF-1 axis was present in 58.3% of A-T patients. Low levels of GH were the result of reduced central GH secretion. GH treatment may be a therapeutic option for A-T patients with severe growth failure.

  15. Treatment of acute leukemia in children with ataxia telangiectasia (A-T).

    Science.gov (United States)

    Schoenaker, M H D; Suarez, F; Szczepanski, T; Mahlaoui, N; Loeffen, J L

    2016-12-01

    Early onset ataxia telangiectasia (A-T) is a neurodegenerative DNA-instability disorder, which presents early in childhood. Hallmarks of A-T are progressive ataxia and a dramatic increased risk of developing malignancies (25%), especially of hematological origin. In children these malignancies mainly concern aggressive Non-Hodgkin lymphoma, acute leukemias and Hodgkin lymphoma. Of the acute leukemias, T-cell lymphoblastic leukemia (T-ALL) is by far the most common. Since patients with A-T experience increased toxicity to radio- and chemotherapeutic treatment, the optimal treatment strategy of acute leukemia remains subject of debate. Review of literature of treatment of T-ALL in patients with A-T (n = 18) showed that many patients are not diagnosed with A-T at time of presentation of T-ALL. This implicates that physicians must be aware of symptoms of A-T in young patients presenting with T-ALL. Complete remission rates are high following upfront modified as well as unmodified treatment strategies. Treatment of ALL in children with A-T is feasible and should be performed. Definitive treatment strategy must be determined by shared decision making with patient, caretakers and medical team. Future prospective studies are needed to elucidate optimal treatment strategy. Copyright © 2016. Published by Elsevier Masson SAS.

  16. Deficiency of ataxia telangiectasia mutated kinase modulates cardiac remodeling following myocardial infarction: involvement in fibrosis and apoptosis.

    Directory of Open Access Journals (Sweden)

    Cerrone R Foster

    Full Text Available Ataxia telangiectasia mutated kinase (ATM is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI as a model.Left ventricular (LV structure, function, apoptosis, fibrosis, and protein levels of apoptosis- and fibrosis-related proteins were examined in wild-type (WT and ATM heterozygous knockout (hKO mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS and ejection fraction (EF in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.

  17. 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.

  18. Induced Pluripotent Stem Cells from Ataxia-Telangiectasia Recapitulate the Cellular Phenotype

    Science.gov (United States)

    Nayler, Sam; Gatei, Magtouf; Kozlov, Sergei; Gatti, Richard; Mar, Jessica C.; Wells, Christine A.

    2012-01-01

    Pluripotent stem cells can differentiate into every cell type of the human body. Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) therefore provides an opportunity to gain insight into the molecular and cellular basis of disease. Because the cellular DNA damage response poses a barrier to reprogramming, generation of iPSCs from patients with chromosomal instability syndromes has thus far proven to be difficult. Here we demonstrate that fibroblasts from patients with ataxia-telangiectasia (A-T), a disorder characterized by chromosomal instability, progressive neurodegeneration, high risk of cancer, and immunodeficiency, can be reprogrammed to bona fide iPSCs, albeit at a reduced efficiency. A-T iPSCs display defective radiation-induced signaling, radiosensitivity, and cell cycle checkpoint defects. Bioinformatic analysis of gene expression in the A-T iPSCs identifies abnormalities in DNA damage signaling pathways, as well as changes in mitochondrial and pentose phosphate pathways. A-T iPSCs can be differentiated into functional neurons and thus represent a suitable model system to investigate A-T-associated neurodegeneration. Collectively, our data show that iPSCs can be generated from a chromosomal instability syndrome and that these cells can be used to discover early developmental consequences of ATM deficiency, such as altered mitochondrial function, that may be relevant to A-T pathogenesis and amenable to therapeutic intervention. PMID:23197857

  19. The appropriateness of the mouse model for ataxia-telangiectasia: neurological defects but no neurodegeneration.

    Science.gov (United States)

    Lavin, Martin F

    2013-08-01

    Patients with ataxia-telangiectasia (A-T) are characterised by genome instability, cancer predisposition and a progressive neurodegeneration. A number of model systems have been developed for A-T but none recapitulate all the phenotype. The majority of these models have been generated in mice. While Atm deficient mouse models exhibit much of the phenotype described in patients with A-T, the broad consensus is that they do not display the most debilitating aspect of A-T, i.e. neurodegeneration. Cerebellar atrophy is one of the neuronal characteristics of A-T patients due to defects in neuronal development and progressive loss of Purkinje and granule cells. This is not evident in Atm-deficient mutants but there are multiple reports on neurological abnormalities in these mice. The focus of this review is to evaluate the appropriateness of Atm mutant mouse models for A-T, particularly with reference to neurological abnormalities and how they might relate to neurodegeneration. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia-telangiectasia.

    Science.gov (United States)

    Li, Jiali; Hart, Ronald P; Mallimo, Elyse M; Swerdel, Mavis R; Kusnecov, Alexander W; Herrup, Karl

    2013-12-01

    The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased trimethylation of histone H3 on Lys27 (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) is also important in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3 in ATM deficiency. Chromatin immunoprecipitation and sequencing showed an increase in H3K27me3 'marks' and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle reentry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescued Purkinje cell degeneration and behavioral abnormalities in Atm(-/-) mice, demonstrating that EZH2 hyperactivity is another key factor in A-T neurodegeneration.

  1. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient.

    Directory of Open Access Journals (Sweden)

    Ninette Amariglio

    2009-02-01

    Full Text Available BACKGROUND: Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells. METHODS AND FINDINGS: A boy with ataxia telangiectasia (AT was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors. CONCLUSIONS: This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

  2. 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.

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

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    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).

  4. Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks.

    Science.gov (United States)

    Sordet, Olivier; Redon, Christophe E; Guirouilh-Barbat, Josée; Smith, Susan; Solier, Stéphanie; Douarre, Céline; Conti, Chiara; Nakamura, Asako J; Das, Benu B; Nicolas, Estelle; Kohn, Kurt W; Bonner, William M; Pommier, Yves

    2009-08-01

    Ataxia telangiectasia mutated (ATM), the deficiency of which causes a severe neurodegenerative disease, is a crucial mediator for the DNA damage response (DDR). As neurons have high rates of transcription that require topoisomerase I (TOP1), we investigated whether TOP1 cleavage complexes (TOP1cc)-which are potent transcription-blocking lesions-also produce transcription-dependent DNA double-strand breaks (DSBs) with ATM activation. We show the induction of DSBs and DDR activation in post-mitotic primary neurons and lymphocytes treated with camptothecin, with the induction of nuclear DDR foci containing activated ATM, gamma-H2AX (phosphorylated histone H2AX), activated CHK2 (checkpoint kinase 2), MDC1 (mediator of DNA damage checkpoint 1) and 53BP1 (p53 binding protein 1). The DSB-ATM-DDR pathway was suppressed by inhibiting transcription and gamma-H2AX signals were reduced by RNase H1 transfection, which removes transcription-mediated R-loops. Thus, we propose that Top1cc produce transcription arrests with R-loop formation and generate DSBs that activate ATM in post-mitotic cells.

  5. Control of cell respiration by nitric oxide in Ataxia Telangiectasia lymphoblastoid cells.

    Science.gov (United States)

    Masci, Alessandra; Mastronicola, Daniela; Arese, Marzia; Piane, Maria; De Amicis, Andrea; Blanck, Thomas J J; Chessa, Luciana; Sarti, Paolo

    2008-01-01

    Ataxia Telangiectasia (AT) patients are particularly sensitive to oxidative-nitrosative stress. Nitric oxide (NO) controls mitochondrial respiration via the reversible inhibition of complex IV. The mitochondrial response to NO of AT lymphoblastoid cells was investigated. Cells isolated from three patients and three intrafamilial healthy controls were selected showing within each group a normal diploid karyotype and homogeneous telomere length. Different complex IV NO-inhibition patterns were induced by varying the electron flux through the respiratory chain, using exogenous cell membrane permeable electron donors. Under conditions of high electron flux the mitochondrial NO inhibition of respiration was greater in AT than in control cells (P< or =0.05). This property appears peculiar to AT, and correlates well to the higher concentration of cytochrome c detected in the AT cells. This finding is discussed on the basis of the proposed mechanism of reaction of NO with complex IV. It is suggested that the peculiar response of AT mitochondria to NO stress may be relevant to the mitochondrial metabolism of AT patients.

  6. 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.

  7. Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents.

    Science.gov (United States)

    Ludwig, Luciane Bitelo; Valiati, Victor Hugo; Palazzo, Roberta Passos; Jardim, Laura Bannach; da Rosa, Darlan Pase; Bona, Silvia; Rodrigues, Graziela; Marroni, Norma Possa; Prá, Daniel; Maluf, Sharbel Weidner

    2013-01-01

    Ataxia telangiectasia (AT) is a rare neurodegenerative disorder, inherited in an autosomal recessive manner. Total blood samples were collected from 20 patients with AT, 13 parents of patients, and 17 healthy volunteers. This study aimed at evaluating the frequency of chromosomal breaks in spontaneous cultures, induced by bleomycin and ionizing radiation, and further evaluated the rates of oxidative stress in AT patients and in their parents, compared to a control group. Three cell cultures were performed to each individual: the first culture did not receive induction to chromosomal instability, the second was exposed to bleomycin, and the last culture was exposed to ionizing radiation. To evaluate the rates of oxidative stress, the markers superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid (TBARS) were utilized. Significant differences were observed between the three kinds of culture treatments (spontaneous, bleomycin, and radiation induced) and the breaks and chromosomal aberrations in the different groups. The oxidative stress showed no significant differences between the markers. This study showed that techniques of chromosomal instability after the induction of ionizing radiation and bleomycin are efficient in the identification of syndrome patients, with the ionizing radiation being the most effective.

  8. 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.

  9. A single ataxia telangiectasia gene with a product similar to PI-3 kinase

    Energy Technology Data Exchange (ETDEWEB)

    Savitsky, K.; Bar-Shira, A.; Gilad, S.; Rotman, G.; Ziv, Y.; Vanagaite, L.; Smith, S.; Uziel, T.; Sfez, S.; Ashkenazi, M. [Tel Aviv Univ. (Israel)] [and others

    1995-06-23

    A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3{prime} kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer. 54 refs., 5 figs., 1 tab.

  10. 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.

  11. Quantitative evaluation of brain involvement in ataxia telangiectasia by diffusion weighted MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Firat, Ahmet Kemal [Inonu University Medical Faculty, Turgut Ozal Medical Center, Department of Radiology, Malatya 44280 (Turkey); Karakas, Hakki Muammer [Inonu University Medical Faculty, Turgut Ozal Medical Center, Department of Radiology, Malatya 44280 (Turkey)]. E-mail: hkarakas@inonu.edu.tr; Firat, Yezdan [Inonu University Medical Faculty, Turgut Ozal Medical Center, Department of Otorhinolaryngology, Malatya (Turkey); Yakinci, Cengiz [Inonu University Medical Faculty, Turgut Ozal Medical Center, Department of Pediatrics, Malatya (Turkey)

    2005-11-01

    Objective: To evaluate the value of diffusion weighted imaging (DWI) in diagnosing ataxia telangiectasia (AT) and to investigate the spatial distribution of cerebral microstructural changes caused by the disease. Methods: Six AT patients (9-13 years) and nine healthy control subjects were examined on 1.5 T scanner. In addition to conventional MR images, DWI were performed with a fat suppressed, multishot spin echo EPI sequence using B values of 0, 500 and 1000 s/mm{sup 2}. Mean ADC values were measured from 16 different supra and infratentorial location. The difference between controls and AT patients regarding ADC values, and the accuracy, sensitivity and specificity of them in discrimination were analyzed with t-tests, logistic regression analysis, ANOVA and ROC curves. Results: Conventional images of the controls were normal. In AT patients, the only conventional MR abnormality was cerebellar atrophy. The difference between both groups regarding mean ADC values was not significant for any of the cerebral structures. In contrary to cerebrum, cerebellar mean ADC values of patients and controls were statistically different (p < 0.011-0.0001). Patients and controls were classified with 100% accuracy using ADC values of cerebellar white matter and cortex together (p < 0.016). The cut-off ADC value (0.699 mm{sup 2}/s) for middle cerebellar cortex had produced highest (100%) sensitivity and specificity. There was a difference between superior, middle and inferior cerebellar cortex regarding ADC values (p < 0.026). Superior cerebellar cortex (0.987 {+-} 0.1956 mm{sup 2}/s) had higher ADC values than the middle and inferior cerebellar cortex. Conclusion: DWI provides a supplementary and objective imaging finding in AT. This finding is highly accurate in the radiological discrimination of healthy subjects and AT. Our findings also implicate that AT causes a diffuse atrophy and mostly affects superior part of the cortex.

  12. Safety and caregiver satisfaction with gastrostomy in patients with Ataxia Telangiectasia

    Science.gov (United States)

    2011-01-01

    Background Ataxia Telangiectasia (A-T) is a rare monogenetic neurodegenerative disease with pulmonary, nutritional, and dysphagic complications. Gastrostomy tube (GT) feedings are commonly recommended to manage these co-morbidities. In general, outcomes of GT placement in patients with progressive diseases that develop during childhood are not well characterized. The primary purposes of this study were to determine whether GT placement in patients with A-T would be tolerated and associated with caregiver satisfaction. Methods We completed a retrospective review of 175 patients who visited the A-T Children's Center at Johns Hopkins Hospital from 2001 through 2008, and identified 28 patients with A-T (19 males, 9 females) who underwent GT placement for non-palliative reasons. Information was obtained from medical records, interviews with primary health care providers, and 24 (83%) caregivers of patients with GT's who responded to survey requests. Results Twenty-five (89%) patients tolerated GT placement and were a median of 5.0 (0.4-12.6) years post GT placement at the time of this investigation. Three (11%) patients died within one month of GT placement. In comparison to patients who tolerated GT placement, patients with early mortality were older when GT's were placed (median 24.9 vs. 12.3 years, p = 0.006) and had developed a combination of dysphagia, nutritional, and respiratory problems. Caregivers of patients tolerating GT placement reported significant improvements in mealtime satisfaction and participation in daily activities. Conclusions GT placement can be well tolerated and associated with easier mealtimes in patients with A-T when feeding tubes are placed at young ages. Patients with childhood onset of disorders with predictable progression of the disease process and impaired swallowing may benefit from early versus late placement of feeding tubes. PMID:21569628

  13. Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia.

    Science.gov (United States)

    Kraus, Matan; Lev, Atar; Simon, Amos J; Levran, Inbal; Nissenkorn, Andrea; Levi, Yonit B; Berkun, Yackov; Efrati, Ori; Amariglio, Ninette; Rechavi, Gideon; Somech, Raz

    2014-07-01

    Ataxia telangiectasia (AT) is a rare genetic, multi-system disorder characterized by neurodegeneration, chromosome instability, B and T cell immunodeficiency and a predisposition to cancer. We examined immunologic parameters reflecting cell development and proliferation and their relevancy to the clinical phenotype in affected individuals. AT patients from the AT National Clinic in Israel underwent immunological investigation. Their T and B cell workup included lymphocyte subset counts, immunoglobulin levels, responses to mitogenic stimulations, TCR-Vβ families and BCR immunoglobulin heavy chain spectratyping, TCR rearrangement excision circles (TRECs) and Kappa-deleting recombination excision circles (KRECs). Thirty-seven AT patients (median age 12.7 years, range 4.2-25.1) were evaluated. CD20 B and CD3 T lymphocytes were decreased in 67 % and 64 % of the patients, respectively, while only 33 % of the patients had reduced lymphoproliferative responses. Almost all AT patients displayed extremely low TRECs and KRECs levels, irrespective of their age. Those levels were correlated to one another and to the amounts of CD3+ and CD20+ cells, respectively. Abnormal TCR-Vβ repertoires were found with different degrees of clonality or reduced expression in these AT patients. There was no clear clustering of expansions to specific TCR-Vβ genes. PCR spectratyping analysis of the FR2 IgH BCR gene rearrangements in peripheral blood was abnormal in 50 % of the patients. The immunodeficiency associated with AT is combined, remains low over time and not progressive. It is characterized by low TREC and KREC copies suggestive of abnormal T and B cell neogenesis.

  14. Nucleotide sequence analysis of a candidate gene for ataxia-telangiectasia group D (ATDC)

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    Leonhardt, E.A.; Kapp, L.N.; Young, B.R.; Murnane, J.P. (Univ. of California, San Francisco, CA (United States))

    1994-01-01

    A radioresistant cell clone (1B3) was previously isolated after transfection of an ataxia-telangiectasia (AT) group D cell line with a human cosmid library. A cosmid rescued from the integration site in 1B3 contained human DNA from chromosome position 11q23, the same region shown by both genetic linkage and chromosome transfer to contain the genes for AT complementation groups A/B, C, and D. A gene within the cosmid (ATDC) was found to produce mRNAs of different sizes. A cDNA for one of the most abundant mRNAs (3.0 kb) was isolated from a HeLa cell library. In the present study, the authors sequenced the 3.0-kb cDNA and the surrounding intron DNA in the cosmids. They used polymerase chain reaction, with primers in the introns, to confirm the number of exons and to analyze DNA from AT group D cells for mutations within this gene. Although no mutations were found, they do not rule out the possibility that mutations may be present within the regulatory sequences or coding sequences found in other mRNAs specific for this gene. From the sequence analysis, they found that the ATDC gene product is one of a group of proteins that share multiple zinc finger motifs and an adjacent leucine zipper motif. These proteins have been proposed to form homo- or hetero-dimers involved in nucleic acid binding, consistent with the fact that many of these proteins appear to be transcriptional regulatory factors involved in carcinogenesis and/or differentiation. The likelihood that the ATDC gene product is involved in transcriptional regulation could explain the pleiomorphic characteristics of AT, including abnormal cell cycle regulation. 36 refs., 5 figs., 2 tabs.

  15. Effects of 4-aminopyridine on nystagmus and vestibulo-ocular reflex in ataxia-telangiectasia.

    Science.gov (United States)

    Shaikh, Aasef G; Marti, Sarah; Tarnutzer, Alexander A; Palla, Antonella; Crawford, Thomas O; Zee, David S; Straumann, Dominik

    2013-11-01

    Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disorder with prominent eye movement deficits localizing to the cerebellum. We sought to determine if 4-aminopyridine (4-AP), which putatively enhances the precision of Purkinje neurons, could improve the disorders of eye movements and vestibular function in A-T. The influence of 4-AP on disorders of eye movements and vestibular function was studied in four A-T patients. The effects on the cerebellar control of vestibulo-ocular reflex (VOR) was quantitatively assessed by the decay time constant of per- and post-rotational nystagmus during constant velocity en bloc rotations. The length of the VOR time constant determines the fidelity of the vestibular velocity storage, a neural mechanism that increases the bandwidth of VOR under cerebellar control. The VOR time constant was not increased in A-T patients. The latter is explained by the extent of cerebellar lesion as previously described in A-T and other cerebellar disorders. Nevertheless, 4-AP shortened the VOR time constant during horizontal rotations. Severe disinhibition of velocity storage in subjects with putatively profound cerebellar degeneration manifest periodic alternating nystagmus (PAN). Among two A-T subjects who manifested PAN, 4-AP reduced the peak slow phase velocity of the more severely affected individual and abrogated the PAN in the other. Two A-T subjects manifested horizontal and vertical spontaneous nystagmus (SN) in primary gaze, 4-AP reduced its slow phase velocity. We conclude that in subjects with A-T 4-AP has a prominent effect on the ocular motor and vestibular deficits that are ascribed to the loss of cerebellar Purkinje neurons.

  16. Heterogeneity of chromosomal breakage levels in epithelial tissue of ataxia-telangiectasia homozygotes and heterozygotes.

    Science.gov (United States)

    Rosin, M P; Ochs, H D; Gatti, R A; Boder, E

    1989-09-01

    The objective of this study was to obtain an estimate of the frequency distribution of spontaneous chromosomal breakage occurring in vivo in oral epithelia of 20 ataxia-telangiectasia patients (A-T homozygotes) and 26 parents (A-T obligate heterozygotes). Samples of exfoliated cells were obtained from each individual by swabbing the oral cavity and preparing air-dried slides. The percentage of exfoliated cells with micronuclei (MEC frequency) was used as an in vivo indicator for the amount of chromosomal breakage occurring in the tissue. As a population group, MEC frequencies of the A-T patients differed significantly from controls (mean for A-T patients, 1.51; for controls, 0.29; P less than 0.01). However, the values observed in individual patients ranged from MEC frequencies 10- to 12-fold above control values, to frequencies overlapping the upper values observed in the controls. Similarly, MEC frequencies observed among the A-T heterozygotes differed significantly from controls (mean for A-T heterozygotes, 1.02, mean for controls, 0.29; P less than 0.01). However, only 16 of the 26 individuals sampled had MEC frequencies greater than 0.5%, the 90th percentile for controls (compared with 16 of the 20 A-T patients examined). Of the A-T patients 11 had been previously assigned to complementation groups on the basis of sensitivity to x-irradiation. Seven of the patients belonged to group A and had MEC frequencies ranging from 0.3% to 1.9% with the remaining patients belonging to group C with MEC frequencies of 0.2% to 0.9%. The data presented in this paper suggest that although levels of spontaneous breakage in epithelial tissues of A-T patients and A-T obligate heterozygotes are often significantly elevated, this is not the case in all individuals.

  17. Recessive mutations in the cancer gene Ataxia Telangiectasia Mutated (ATM), at a locus previously associated with metformin response, cause dysglycaemia and insulin resistance.

    Science.gov (United States)

    Connelly, P J; Smith, N; Chadwick, R; Exley, A R; Shneerson, J M; Pearson, E R

    2016-03-01

    To investigate glucose and insulin metabolism in participants with ataxia telangiectasia in the absence of a diagnosis of diabetes. A standard oral glucose tolerance test was performed in participants with ataxia telangiectasia (n = 10) and in a control cohort (n = 10). Serial glucose and insulin measurements were taken to permit cohort comparisons of glucose-insulin homeostasis and indices of insulin secretion and sensitivity. During the oral glucose tolerance test, the 2-h glucose (6.75 vs 4.93 mmol/l; P = 0.029), insulin concentrations (285.6 vs 148.5 pmol/l; P = 0.043), incremental area under the curve for glucose (314 vs 161 mmol/l/min; P = 0.036) and incremental area under the curve for insulin (37,720 vs 18,080 pmol/l/min; P = 0.03) were higher in participants with ataxia telangiectasia than in the controls. There were no significant differences between groups in fasting glucose, insulin concentrations or insulinogenic index measurement (0.94 vs 0.95; P = 0.95). The Matsuda index, reflecting whole-body insulin sensitivity, was lower in participants with ataxia telangiectasia (5.96 vs 11.03; P = 0.019) than in control subjects. Mutations in Ataxia Telangiectasia Mutated (ATM) that cause ataxia telangiectasia are associated with elevated glycaemia and low insulin sensitivity in participants without diabetes. This indicates a role of ATM in glucose and insulin metabolic pathways. © 2016 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

  18. The relationship between nutritional status, vitamin A and zinc levels and oxidative stress in patients with ataxia-telangiectasia.

    Science.gov (United States)

    da Silva, R; dos Santos-Valente, E C; Burim Scomparini, F; Saccardo Sarni, R O; Costa-Carvalho, B T

    2014-01-01

    Ataxia-telangiectasia (A-T) is a rare and degenerative disease that leads to varying degrees of immunodeficiency, oxidative stress, and malnutrition. Vitamin A and zinc are essential for immune function and antioxidant defence. To compare levels of retinol, beta carotene, and zinc in patients with ataxia-telangiectasia and healthy controls. We performed a cross-sectional study with 14 AT patients and 14 healthy controls matched for age and gender. All participants underwent a nutritional and laboratory evaluation comprising concentrations of retinol, beta carotene, serum and erythrocyte zinc, malondialdehyde (MDA), T lymphocyte numbers (CD4(+) and CD8(+)) and immunoglobulin (IgA). The AT patients showed high rates of malnutrition with reduced lean body mass when compared to the control group. However, the concentrations of MDA, retinol, beta carotene, and serum and erythrocyte zinc in AT patients were similar to those of the control group. The retinol levels presented a negative correlation with MDA and positive correlation with IgA serum level. The AT patients assessed showed no change in nutritional status for vitamin A and zinc; however, they presented severe impairment in overall nutritional status observed and correlation between retinol with MDA and IgA. Copyright © 2012 SEICAP. Published by Elsevier Espana. All rights reserved.

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

    Science.gov (United States)

    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, M A A P

    2016-08-01

    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 of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Chromosome Aberrations in Normal and Ataxia-Telangiectasia Cells Exposed to Heavy Ions

    Science.gov (United States)

    Kawata, T.; Ito, H.; Liu, C.; Shigematsu, N.; George, K.; Cucinotta, F. A.

    2007-01-01

    Although cells derived from Ataxia Telangiectasia (AT) patients are known to exhibit abnormal responses to ionizing radiations, its underlying mechanism still remains unclear. Previously, the authors reported that at the same gamma-irradiation dose AT cells show higher frequencies of misrepair and deletions compared to normal human fibroblast cells. In this study, we investigated the effects of heavy ions beams on chromosomal aberrations in normal and AT cells. Normal and AT fibroblast cells arrested at G0/G1 phase were irradiated with 2 Gy of X-rays, 490 MeV/u Silicon (LET 55 keV/m), 500 MeV/u Iron (LET 185 keV/m) and 200 MeV/u Iron (LET 440 keV/m) particles, and then cells were allowed to repair for 24 hours at 37 degrees before subculture. Calyculin-A induced PCC method was employed to collect G2/M chromosomes and whole DNA probes 1 and 3 were used to analyze chromosomal aberrations such as color-junctions, deletions, simple exchanges (incomplete and reciprocal exanges) and complex-type exchanges. The percentages of aberrant cells were higher when normal and AT cells were exposed to heavy ions compared to X-rays, and had a tendency to increase with increasing LET up to 185 keV/m and then decreased at 440 keV/m. When the frequency of color-junctions per cell was compared after X-ray exposure, AT cells had around three times higher frequency of color-junctions (mis-rejoining) than normal cells. However, at 185 keV/m there was no difference in the frequency of color-junctions between two cell lines. It was also found that the frequency of simple exchanges per cell was almost constant in AT cells regardless LET levels, but it was LET dependent for normal cells. Interestingly, the frequency of simple exchanges was higher for AT cells when it was compared at 185 keV/m but AT cells had more complex-type exchanges at the same LET levels. Heavy ions are more efficient in inducing chromosome aberrations in normal and AT cells compared to X-rays, and the aberration types

  1. FVC deterioration, airway obstruction determination, and life span in Ataxia telangiectasia.

    Science.gov (United States)

    Vilozni, Daphna; Lavie, Moran; Sarouk, Ifat; Bar-Aluma, Bat-El; Dagan, Adi; Ashkenazi, Moshe; Ofek, Miryam; Efrati, Ori

    2015-07-01

    Forced vital capacity (FVC) values decrease with progress of the disease in Ataxia telangiectasia (AT). To study the effect of this process on airway obstruction determination and life span in AT. Clinical data and yearly best spirometry maneuvers were collected retrospectively from 37 AT patients (196 spirometry tests) during 5.4 ± 1.8yrs (initial age 4-21 y). Twelve patients were walking (7 of them had recurrent respiratory system infections); 25 subjects were confined to wheelchair, of them 8 patients were towards end-stage lung disease. Spirometry indices included Forced Vital Capacity (FVC), mid-expiratory-flow (FEF25-75), and tidal volume (VT). We calculated FEF25-75/FVC and VT/FVC ratios. FVC declined from 67 ± 8 while walking to 19 ± 6 %predicted values. FEF25-75 values that were elevated (116 ± 23 %predicted) while walking, decreased to 69 ± 27 %predicted at end-stage where 7 patients responded to bronchodilators. VT/FVC ratio was 0.25 ± 0.06 while walking, increased to 0.35 once on wheelchairs, and further increased to 0.57 ± 0.19 at end-stage disease. FEF25-75/FVC ratio was 2.54 ± 0.70 above normal (∼1.0) increasing to 4.16 ± 0.75 at end stage. A sharp elevation was seen in FEF25-75/FVC ratio when FEV1 was still ∼45 %predicted and 2-years prior to death. Having a low baseline-FVC (60% predicted) artificially raises FEF25-75 values, so FEF25-75 of "mild obstruction" values may indicate severe airway obstruction in AT subjects. VT/FVC and FEF25-75/FVC ratios may therefore assist in revealing higher than normal breathing effort. The results further suggest adding VT/FVC and FEF25-75/FVC ratios to pulmonary function assessments in patients with AT. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Liver Disease in Pediatric Patients With Ataxia Telangiectasia: A Novel Report.

    Science.gov (United States)

    Weiss, Batia; Krauthammer, Alexander; Soudack, Michalle; Lahad, Avishay; Sarouk, Ifat; Somech, Raz; Heimer, Gali; Ben-Zeev, Bruria; Nissenkorn, Andreea

    2016-04-01

    Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. Fifty-three patients, 27 (49%) boys, age 14.6 ± 5.2 years (range 5.9-26.1 years), were included. Twenty-three patients (43.4%), age 9.9 ± 5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8 ± 73.8 IU/L, aspartate aminotransferase 70 ± 50 IU/L, alkaline phosphatase 331 ± 134 IU/L, and gamma glutamyl transferase 114.7 ± 8 IU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (P < 0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.

  3. Treatment of EBV-associated nodular sclerosing Hodgkin lymphoma in a patient with ataxia telangiectasia with brentuximab vedotin and reduced COPP plus rituximab.

    Science.gov (United States)

    Meister, Michael T; Voss, Sandra; Schwabe, Dirk

    2015-11-01

    Patients with ataxia telangiectasia (AT) with malignancies face poor prognosis due to increased treatment-related toxicity. Here, we report a 14-year-old male with AT and Hodgkin lymphoma (HL) who received brentuximab vedotin and reduced COPP plus rituximab courses. This treatment resulted in complete remission and showed no severe toxicity. © 2015 Wiley Periodicals, Inc.

  4. An early-onset recessive cerebellar disorder with distal amyotrophy and, in two patients, gross myoclonia: A probable ataxia telangiectasia variant

    NARCIS (Netherlands)

    A.S. de Graaf (A.); G. de Jong (G.); W.J. Kleijer (Wim)

    1995-01-01

    textabstractWe report a family of 4 siblings from a non-consanguineous marriage, presenting with an early onset recessive cerebellar ataxia and progressive distal limb wasting. Ocular or other telangiectasias were absent. There were neither frequent infections nor immunodeficiencies. The two younges

  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 mammals, the ATM (ataxia-telangiectasia-mutated) and ATR (ATM and Rad3-related) protein kinases function as critical regulators of the cellular DNA damage response. The checkpoint functions of ATR and ATM are mediated, in part, by a pair of checkpoint effector kinases termed Chk1 and Chk2...

  6. Ataxia Telangiectasia-Mutated (ATM) kinase activity is regulated by ATP-driven conformational changes in the Mre11/Rad50/Nbs1 (MRN) complex

    NARCIS (Netherlands)

    J.-H. Lee (Ji-Hoon); M.R. Mand (Michael); R.A. Deshpande (Rajashree); E. Kinoshita (Eri); S.-H. Yang (Soo-Hyun); C. Wyman (Claire); T.T. Paull

    2013-01-01

    textabstractThe Ataxia Telangiectasia-Mutated (ATM) protein kinase is recruited to sites of double-strand DNA breaks by the Mre11/Rad50/Nbs1 (MRN) complex, which also facilitates ATM monomerization and activation. MRN exists in at least two distinct conformational states, dependent on ATP binding an

  7. Cell death, chromosome damage and mitotic delay in normal human, ataxia telangiectasia and retinoblastoma fibroblasts after x-irradiation.

    Science.gov (United States)

    Zampetti-Bosseler, F; Scott, D

    1981-05-01

    We recently showed (Scott and Zampetti-Bosseler 1980) that X-ray sensitive mouse lymphoma cells sustain more chromosome damage, mitotic delay and spindle defects than X-ray resistant cells. We proposed that (a) chromosome aberrations contribute much more to lethality than spindle defects, and (b) that DNA lesions are less effectively repaired in the sensitive cells and give rise to more G2 mitotic delay and chromosome aberrations. Our present results on human fibroblasts with reported differential sensitivity to ionizing radiation (i.e. normal donors and patients with ataxia telangiectasia and retinoblastoma) support the first hypothesis since we observed a positive correlation between chromosome aberration frequencies and cell killing and no induced spindle defects. Our second hypothesis is however not substantiated since X-ray sensitive fibroblasts from the ataxia patient suffered less mitotic delay than cells from normal donors. A common lesion for mitotic delay and chromosome aberrations can still be assumed by adopting the hypothesis of Painter and Young (1981) that the defect in ataxia cells is not in repair but in a failure of DNA damage to initiate mitotic delay. In contrast to other reports, we found the retinoblastoma cells to be of normal radiation sensitivity (cell killing and aberration).

  8. An early-onset recessive cerebellar disorder with distal amyotrophy and, in two patients, gross myoclonia: a probable ataxia telangiectasia variant.

    Science.gov (United States)

    de Graaf, A S; de Jong, G; Kleijer, W J

    1995-02-01

    We report a family of 4 siblings from a non-consanguineous marriage, presenting with an early onset recessive cerebellar ataxia and progressive distal limb wasting. Ocular or other telangiectasias were absent. There were neither frequent infections nor immunodeficiencies. The two youngest patients exhibited an incapacitating myoclonus which abated markedly after 20 years. Late onset diabetes was demonstrated in 3 patients. Hypogonadism was not a feature and there was a prolonged survival in the 4 patients. The oldest sibling died of a pancreatic adenocarcinoma. alpha-Fetoprotein was elevated with normal carcinoembryonic antigen values in three patients. Cytogenetic analysis and radioresistant DNA synthesis was compatible with the diagnosis of ataxia-telagiectasia. This family probably represents a rare variant of ataxia-telangiectasia.

  9. 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

  10. [Diagnostics of ataxia-telangiectasia by the express-test found on the method of indirect immunofluorescence].

    Science.gov (United States)

    Kuranova, M L; Ledashcheva, T A; Tulush, E K; Beliaev, D L; Zherebtsov, S V; Pleskach, N M; Prokof'eva, V V; Mikhel'son, V M; Spivak, I M

    2013-01-01

    Ataxia-telangiectasia (AT) is a hereditary severe neurodegenerative disease developing, when mutations take place in both alleles of the atm gene, which encodes the key protein of the cellular response to DNA damage (DDR)--ATM proteinkinase. In response to the occurrence of double-strand DNA breaks, the ATM proteinkinase pass the autophosphorylation, and its active form--the phospho-ATM (P-ATM) appears in cells. In the nuclei of cells having the atm gene, P-ATM is revealed, being absent in cells with mutated forms of this gene, by means of the application of the modified method of indirect immunofluorescence. This peculiarity may be applied in the clinic, in order to confirm the diagnosis of AT.

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

    Science.gov (United States)

    Meschini, Roberta; Morucci, Elisa; Berni, Andrea; Lopez-Martinez, Wilner; Palitti, Fabrizio

    2015-07-01

    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-treatment is favouring the slow component of DSB repair pathway, the one impaired in absence of a functionally ATM protein. Data obtained suggest a fundamental role of chromatin compaction on chromosomal instability in A-T cells. Copyright © 2015 Elsevier B

  12. Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

    Science.gov (United States)

    Deik, A; Johannes, B; Rucker, J C; Sánchez, E; Brodie, S E; Deegan, E; Landy, K; Kajiwara, Y; Scelsa, S; Saunders-Pullman, R; Paisán-Ruiz, C

    2014-12-01

    PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

  13. Do elevated serum IgM levels have to be included in probable diagnosis criteria of patients with ataxia-telangiectasia?

    Science.gov (United States)

    Azarsiz, E; Karaca, N E; Gunaydin, N C; Gulez, N; Ozturk, C; Aksu, G; Genel, F; Kutukculer, N

    2014-01-01

    Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder that is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency. Delay in diagnosis or misdiagnosis is probable due to its wide clinical heterogeneity in infancy. Recurrent sinopulmonary infections are often the only presenting symptom and usually patients have decreased immunoglobulins. A total 10% of patients who present with decreased serum immunoglobulin G and A and with normal or elevated immunoglobulin M levels are often misdiagnosed as hyperimmunoglobulin M syndrome. Definitive diagnosis is made if a patient with progressive cerebellar ataxia has a disease causing mutation on the ATM gene. Ataxia-telangiectasia guideline of the European Society for Immunodeficiencies defines the probable diagnosis criteria. We evaluated twenty ataxia-telangiectasia patients (mean age 13.8±4.1 years) retrospectively who were followed-up for a mean of 38.6±27.0 months. Twelve patients had a family history of consanguinity. A total of 80% patients suffered from various infections. Neoplasms occurred in three of them. Patients showed immunological abnormalities as low IgG (45%), low IgA (65%) and elevated IgM (60%) levels. CD3+CD4+ T lymphocyte frequency was low in 45% patients. The mean AFP concentration at the diagnosis was 191.9±140.1 ng/mL and the raised IgM values did not show any statistically significant relationship with high AFP concentrations. Frequency of the elevated IgM concentrations in (60%) patients raises the concerns about thinking this finding has to be accepted as a probable diagnosis criterium.

  14. Effects of inspiratory muscle training on lung volumes, respiratory muscle strength, and quality of life in patients with ataxia telangiectasia.

    Science.gov (United States)

    Félix, Erika; Gimenes, Ana Cristina; Costa-Carvalho, Beatriz Tavares

    2014-03-01

    Ataxia telangiectasia (AT) is a genetic syndrome caused by a mutation of chromosome 11. The clinical features are cerebellar ataxia, telangiectasia, and progressive loss of muscular coordination, including an inefficient cough secondary to progression of neurological disease. To evaluate the effects of inspiratory muscle training (IMT) on ventilation, lung volume, dyspnoea, respiratory muscle strength, and quality of life in patients with AT. A longitudinal study was conducted with 11 AT patients and nine healthy volunteers. Ventilometry, subjective sensation of dyspnoea, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and quality of life were assessed before and after a 24-week IMT program. The IMT load used was set at 60% of the MIP, and the training was performed for 20 min daily. Patients with AT had lower height and weight and also had lower respiratory muscle strength and lung volume compared with healthy volunteers. Furthermore, patients with AT showed a significant improvement when pre- and post-IMT were compared for ventilatory pattern: Vt (476.5 ± 135 ml vs. 583.3 ± 66 ml, P = 0.015) and f (23.3 ± 6 rpm vs. 20.4 ± 4 rpm, P = 0.018), and VC (1,664 ± 463 ml/kg vs. 2,145 ± 750 ml/kg, P = 0.002). IMT also significantly improved the sensation of dyspnoea (median 0.5; minimum 0; maximum 1.0; P = 0.022) and respiratory muscle strength: MIP (-22.2 ± 2 cmH2O vs. -38 ± 9 cmH2O, P < 0.001) and MEP (29 ± 7 cmH2O vs. 40 ± 8 cmH2O, P = 0.001). The health and vitality domains of the SF-36 also showed significant improvement (P = 0.009 and P = 0.014, respectively) post-IMT. IMT was effective in improving ventilatory pattern, lung volume, respiratory muscle strength, and the health and vitality domains for quality of life in patients with AT. IMT may be an effective adjunct therapy to drug treatment for patients with AT. © 2013 Wiley Periodicals, Inc.

  15. Myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) is caused by heterozygous KCNC1 mutations.

    Science.gov (United States)

    Nascimento, Fábio A; Andrade, Danielle M

    2016-09-01

    Progressive myoclonus epilepsy (PME) is a distinct group of seizure disorders characterized by gradual neurological decline with ataxia, myoclonus and recurring seizures. There are several forms of PME, among which the most recently described is MEAK - myoclonus epilepsy and ataxia due to potassium channel mutation. This particular subtype is caused by a recurrent de novo heterozygous mutation (c.959G>A, p.Arg320His) in the KCNC1 gene, which maps to chromosome 11 and encodes for the Kv3.1 protein (a subunit of the Kv3 subfamily of voltage-gated potassium channels). Loss of Kv3 function disrupts the firing properties of fast-spiking neurons, affects neurotransmitter release and induces cell death. Specifically regarding Kv3.1 malfunctioning, the most affected neurons include inhibitory GABAergic interneurons and cerebellar neurons. Impairment of the former cells is believed to contribute to myoclonus and seizures, whereas dysfunction of the latter to ataxia and tremor. Phenotypically, MEAK patients generally have a normal early development. At the age of 6 to 14 years, they present with myoclonus, which tends to progressively worsen with time. Tonic-clonic seizures may or may not be present, and some patients develop mild cognitive impairment following seizure onset. Typical electroencephalographic features comprise generalized epileptiform discharges and, in some cases, photosensitivity. Brain imaging is either normal or shows cerebellar atrophy. The identification of MEAK has both expanded the phenotypic and genotypic spectra of PME and established an emerging role for de novo mutations in PME.

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

    Science.gov (United States)

    Andrs, Martin; Korabecny, Jan; Nepovimova, Eugenie; Jun, Daniel; Hodny, Zdenek; Kuca, Kamil

    2016-01-01

    The main aim of current cancer research is to find a way to selectively affect the tumor cells, while leaving normal cells intact. Ataxia telangiectasia and Rad3-related kinase (ATR), a member of the phosphatidylinositol-3-related protein kinases (PIKK), represents a candidate target for achieving this goal. ATR kinase is one of the main kinases of the DNA damage response signaling pathway and responds to DNA damage caused by replication stress and various genotoxic agents (i.e. chemotherapy, ionizing radiation, ultraviolet light). ATR activation triggers cell cycle checkpoints, DNA repair and apoptosis, but also resistance of tumor cells to DNA damaging agents, through stress support under replication stress. Thus, the inhibition of ATR leads to increased effectiveness of cancer therapy and in addition enables highly selective targeting of cancer cells through synthetic lethal interactions. Despite this great potential, only a few potent and selective inhibitors of ATR kinase have been developed to date. However, those which have been developed provide great promise, and are under evaluation in many current preclinical and clinical trials. The purpose of this review is to summarize the potential of ATR inhibitors and the medicinal chemistry efforts which resulted in their identification.

  17. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours

    Science.gov (United States)

    Reiman, A; Srinivasan, V; Barone, G; Last, J I; Wootton, L L; Davies, E G; Verhagen, M M; Willemsen, M A; Weemaes, C M; Byrd, P J; Izatt, L; Easton, D F; Thompson, D J; Taylor, A M

    2011-01-01

    Background: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T. Methods: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity. Results: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype. Conclusion: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age. PMID:21792198

  18. Betamethasone therapy in ataxia telangiectasia: unraveling the rationale of this serendipitous observation on the basis of the pathogenesis.

    Science.gov (United States)

    Giardino, G; Fusco, A; Romano, R; Gallo, V; Maio, F; Esposito, T; Palamaro, L; Parenti, G; Salerno, M C; Vajro, P; Pignata, C

    2013-05-01

    Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive neurological dysfunction. To date, only supportive care aimed to halt the progressive neurodegeneration is available for the treatment. Recently, an improvement of neurological signs during short-term treatment with betamethasone has been reported. To date, the molecular and biochemical mechanisms by which the steroid produces such effects have not yet been elucidated. Therefore, a review of the literature was carried out to define the potential molecular and functional targets of the steroid effects in A-T. Glucocorticoids (GCs) are capable of diffusing into the CNS by crossing the blood-brain barrier (BBB) where they exert effects on the suppression of inflammation or as antioxidant. GCs have been shown to protect post-mitotic neurons from apoptosis. Eventually, GCs may also modulate synaptic plasticity. A better understanding of the mechanisms of action of GCs in the brain is needed, because in A-T during the initial phase of cell loss the neurological impairment may be rescued by interfering in the biochemical pathways. This would open a new window of intervention in this so far incurable disease. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

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

    Energy Technology Data Exchange (ETDEWEB)

    Jaspers, N.G.J. (Erasmus Universiteit, Rotterdam (Netherlands). Dept. of Cell Biology and Genetics; Nederlandse Centrale Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek, Rijswijk. Medical Biological Lab.); Bootsma, D. (Erasmus Universiteit, Rotterdam (Netherlands). Dept. of Cell Biology and Genetics)

    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 ..gamma..-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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Kleijer, W.J.; Kraan, M. van der; Los, F.J. [Erasmus Univ., Rotterdam (Netherlands). Dept. of Clinical Genetics; Jaspers, N.G.J. [Erasmus Univ., Rotterdam (Netherlands). Lab. of Cell Biology and Genetics

    1994-12-01

    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).

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    Science.gov (United States)

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

    2011-04-08

    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.

  3. A radiation hybrid map of human chromosome 11q22-q23 containing the ataxia-telangiectasia disease locus

    Energy Technology Data Exchange (ETDEWEB)

    Richard, C.W. III; Cox, D.R.; Kapp, L.; Murnane, J. (Univ. of California, San Francisco, CA (United States)); Cornelis, F.; Julier, C.; Lathrop, M.; James, M.R. (Centre d' Etude du Polymorphisme Humain, Paris (France))

    1993-07-01

    The authors describe a high-resolution radiation hybrid map of human chromosome 11q22-q23 containing the ataxia-telangiectasia (AT) disease gene loci. The order and intermarker distances of 32 chromosome 11q22-q23 markers were determined by a multipoint maximum likelihood method analysis of the cosegregation of markers in 100 radiation hybrids. The radiation hybrid map of polymorphic loci was consistent with genetic linkage maps of common markers. Several genes, including [alpha]B-crystallin, adrenal ferrodoxin, CBL2, collagenase, dopamine receptor type 2, neural cell adhesion molecule, progesterone receptor, and stromelysins 1 and 2, were placed in relation to previously ordered, genetically mapped polymorphic loci. Five new markers ([alpha]B-crystallin, adrenal ferrodoxin, CJ52.114, CJ52.3, and D11S535) were ordered within the current published flanking markers for the AT group A and group C disease loci. A candidate AT group D gene (ATDC) identified by Kapp et al. was mapped telomeric to THY1, outside the flanking markers identified by multipoint linkage analysis for the major AT locus. 29 refs., 1 fig., 2 tabs.

  4. Detection of aneuploidy in sperm of an ataxia telangiectasia patient using three-chromosome fluorescence in situ hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Lowe, X.R.; Baulch, J.E. [Lawrence Livermore National Lab., CA (United States); Arnheim, N. [USC, Los Angeles, CA (United States)] [and others

    1994-09-01

    Ataxia telangiectasia (A-T) is an inherited, recessive, cancer-prone disorder. Fluorescence in situ hybridization (FISH) with DNA probes specific for three chromosomes was applied to sperm of an A-T patient to determine if there may be an increased germinal risk for aneuploidy. Air-dried sperm smears were treated with proteinase K and were decondensed with DTT and LIS. The slides were then hybridized with fluorescently labeled repetitive DNA probes specific for chromosomes X, Y and 8, and a total of 11,825 sperm cells were scored. The ratio of sperm bearing X-8 and Y-8 was 1:1, as predicted. The frequencies of hyperhaploidy were 3.9, 1.0, 17.6 and 7.8 per 10,000 cells for categories X-X-8, Y-Y-8, X-Y-8 and 8-8-(X or Y), respectively, In addition, the frequency of diploidy (X-Y-8-8) was 18.6 and auto-diploidies (X-X-8-8 and Y-Y-8-8) were 1.0 and 2.0, respectively. These frequencies were not significantly different when compared with levels in healthy men (p > 0.1). Our finding suggests that chromosome X, Y and 8 aneuploidies are not elevated in the sperm of A-T patients, but studies with additional patients and chromosomes are needed.

  5. Defective signaling through the B cell antigen receptor in Epstein-Barr virus-transformed ataxia-telangiectasia cells.

    Science.gov (United States)

    Khanna, K K; Yan, J; Watters, D; Hobson, K; Beamish, H; Spring, K; Shiloh, Y; Gatti, R A; Lavin, M F

    1997-04-04

    A characteristic series of immunological abnormalities are observed in the human genetic disorder ataxia-telangiectasia (A-T). The recent cloning of a gene mutated in this syndrome provides additional evidence for a defect in intracellular signaling in A-T. We have investigated the possibility that signaling through the B cell antigen receptor is one manifestation of the A-T defect. In response to cross-linking of the B cell receptor, several A-T cell lines were defective in their mitogenic response; in addition Ca2+ mobilization from internal stores was either absent or considerably reduced in these cell lines in response to cross-linking. The defect in signaling was not due to difference in expression of surface immunoglobulin. The defective response in A-T cells was also evident in several arms of the intracellular cascade activated by B cell cross-linking. Tyrosine phosphorylation of phospholipase Cgamma1, a key step in activation of the enzyme, was reduced or negligible in some A-T cell lines. This defect in signaling was also seen at the level of Lyn tyrosine kinase activation and its association with and activation of phosphatidylinositol 3-kinase. Our results provide evidence for a role for the ATM gene product in intracellular signaling which may account at least in part for the abnormalities in B cell function in A-T.

  6. Ataxia-Telangiectasia Mutated and the Mre11-Rad50-NBS1 Complex:Promising Targets for Radiosensitization

    Directory of Open Access Journals (Sweden)

    Kuroda,Shinji

    2012-04-01

    Full Text Available Radiotherapy plays a central part in cancer treatment, and use of radiosensitizing agents can greatly enhance this modality. Although studies have shown that several chemotherapeutic agents have the potential to increase the radiosensitivity of tumor cells, investigators have also studied a number of molecularly targeted agents as radiosensitizers in clinical trials based on reasonably promising preclinical data. Recent intense research into the DNA damage-signaling pathway revealed that ataxia-telangiectasia mutated (ATM and the Mre11-Rad50-NBS1 (MRN complex play central roles in DNA repair and cell cycle checkpoints and that these molecules are promising targets for radiosensitization. Researchers recently developed three ATM inhibitors (KU-55933, CGK733, and CP466722 and an MRN complex inhibitor (mirin and showed that they have great potential as radiosensitizers of tumors in preclinical studies. Additionally, we showed that a telomerase-dependent oncolytic adenovirus that we developed (OBP-301 [telomelysin] produces profound radiosensitizing effects by inhibiting the MRN complex via the adenoviral E1B55kDa protein. A recent Phase I trial in the United States determined that telomelysin was safe and well tolerated in humans, and this agent is about to be tested in combination with radiotherapy in a clinical trial based on intriguing preclinical data demonstrating that telomelysin and ionizing radiation can potentiate each other. In this review, we highlight the great potential of ATM and MRN complex inhibitors, including telomelysin, as radiosensitizing agents.

  7. Ataxia-telangiectasia (A-T): An emerging dimension of premature ageing.

    Science.gov (United States)

    Shiloh, Yosef; Lederman, Howard M

    2017-01-01

    A-T is a prototype genome instability syndrome and a multifaceted disease. A-T leads to neurodegeneration - primarily cerebellar atrophy, immunodeficiency, oculocutaneous telangiectasia (dilated blood vessels), vestigial thymus and gonads, endocrine abnormalities, cancer predisposition and varying sensitivity to DNA damaging agents, particularly those that induce DNA double-strand breaks. With the recent increase in life expectancy of A-T patients, the premature ageing component of this disease is gaining greater awareness. The complex A-T phenotype reflects the ever growing number of functions assigned to the protein encoded by the responsible gene - the homeostatic protein kinase, ATM. The quest to thoroughly understand the complex A-T phenotype may reveal yet elusive ATM functions. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Ataxia.

    Science.gov (United States)

    Akbar, Umar; Ashizawa, Tetsuo

    2015-02-01

    Ataxia is a disorder of balance and coordination resulted from dysfunctions involving cerebellum and its afferent and efferent connections. While a variety of disorders can cause secondary ataxias, the list of genetic causes of ataxias is growing longer. Genetic abnormalities may involve mitochondrial dysfunction, oxidative stress, abnormal mechanisms of DNA repair, possible protein misfolding, and abnormalities in cytoskeletal proteins. Few ataxias are fully treatable while hope for efficacious gene therapy and pharmacotherapy is emerging. A discussion of the ataxias is presented here with brief mention of acquired ataxias, and a greater focus on inherited ataxias. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Identification of defective illegitimate recombinational repair of oxidatively-induced DNA double-strand breaks in ataxia-telangiectasia cells

    Science.gov (United States)

    Dar, M. E.; Winters, T. A.; Jorgensen, T. J.

    1997-01-01

    Ataxia-telangiectasia (A-T) is an autosomal-recessive lethal human disease. Homozygotes suffer from a number of neurological disorders, as well as very high cancer incidence. Heterozygotes may also have a higher than normal risk of cancer, particularly for the breast. The gene responsible for the disease (ATM) has been cloned, but its role in mechanisms of the disease remain unknown. Cellular A-T phenotypes, such as radiosensitivity and genomic instability, suggest that a deficiency in the repair of DNA double-strand breaks (DSBs) may be the primary defect; however, overall levels of DSB rejoining appear normal. We used the shuttle vector, pZ189, containing an oxidatively-induced DSB, to compare the integrity of DSB rejoining in one normal and two A-T fibroblast cells lines. Mutation frequencies were two-fold higher in A-T cells, and the mutational spectrum was different. The majority of the mutations found in all three cell lines were deletions (44-63%). The DNA sequence analysis indicated that 17 of the 17 plasmids with deletion mutations in normal cells occurred between short direct-repeat sequences (removing one of the repeats plus the intervening sequences), implicating illegitimate recombination in DSB rejoining. The combined data from both A-T cell lines showed that 21 of 24 deletions did not involve direct-repeats sequences, implicating a defect in the illegitimate recombination pathway. These findings suggest that the A-T gene product may either directly participate in illegitimate recombination or modulate the pathway. Regardless, this defect is likely to be important to a mechanistic understanding of this lethal disease.

  10. The innate immune response transcription factor relish is necessary for neurodegeneration in a Drosophila model of ataxia-telangiectasia.

    Science.gov (United States)

    Petersen, Andrew J; Katzenberger, Rebeccah J; Wassarman, David A

    2013-05-01

    Neurodegeneration is a hallmark of the human disease ataxia-telangiectasia (A-T) that is caused by mutation of the A-T mutated (ATM) gene. We have analyzed Drosophila melanogaster ATM mutants to determine the molecular mechanisms underlying neurodegeneration in A-T. Previously, we found that ATM mutants upregulate the expression of innate immune response (IIR) genes and undergo neurodegeneration in the central nervous system. Here, we present evidence that activation of the IIR is a cause of neurodegeneration in ATM mutants. Three lines of evidence indicate that ATM mutations cause neurodegeneration by activating the Nuclear Factor-κB (NF-κB) transcription factor Relish, a key regulator of the Immune deficiency (Imd) IIR signaling pathway. First, the level of upregulation of IIR genes, including Relish target genes, was directly correlated with the level of neurodegeneration in ATM mutants. Second, Relish mutations inhibited upregulation of IIR genes and neurodegeneration in ATM mutants. Third, overexpression of constitutively active Relish in glial cells activated the IIR and caused neurodegeneration. In contrast, we found that Imd and Dif mutations did not affect neurodegeneration in ATM mutants. Imd encodes an activator of Relish in the response to gram-negative bacteria, and Dif encodes an immune responsive NF-κB transcription factor in the Toll signaling pathway. These data indicate that the signal that causes neurodegeneration in ATM mutants activates a specific NF-κB protein and does so through an unknown activator. In summary, these findings suggest that neurodegeneration in human A-T is caused by activation of a specific NF-κB protein in glial cells.

  11. 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.

  12. 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.

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

    Science.gov (United States)

    Maciejczyk, Mateusz; Mikoluc, Bozena; Pietrucha, Barbara; Heropolitanska-Pliszka, Edyta; Pac, Malgorzata; Motkowski, Radosław; Car, Halina

    2017-04-01

    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. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  15. Medical Management of Pediatric Malignant Bowel Obstruction in a Patient with Burkitt's Lymphoma and Ataxia Telangiectasia Using Continuous Ambulatory Drug Delivery System.

    Science.gov (United States)

    Ghoshal, Arunangshu; Salins, Naveen; Damani, Anuja; Deodhar, Jayita; Muckaden, M A

    2016-01-01

    Malignant bowel obstruction (MBO) is commonly seen in patients with advanced abdominal cancers. The incidence of pediatric MBO in a patient with Burkitt's lymphoma and ataxia telangiectasia is rare, with no published case reports till now. Conservative management of inoperable MBO results in relief of symptoms and improves quality of life. An 11-year-old boy with Burkitt's lymphoma and ataxia telangiectasia was referred to pediatric palliative care with MBO. The objective of this report is to demonstrate conservative management of pediatric MBO using continuous ambulatory drug delivery system. The patient was initiated on continuous ambulatory drug delivery (CADD) system for symptom relief. MBO was reversed with conservative management and the child was discharged on self-collapsible portable elastomeric continuous infusion pump under the supervision of a local family physician. The child remained comfortable at home for 4 weeks until his death. His parents were satisfied with the child's symptom control, quality of life, and were able to care for the child at home. In a resource-limited setting, managing patients at home using elastomeric continuous infusion pumps instead of expensive automated CADD is a practical pharmacoeconomic approach.

  16. DNA-dependent protein kinase regulates DNA end resection in concert with Mre11-Rad50-Nbs1 (MRN) and ataxia telangiectasia-mutated (ATM).

    Science.gov (United States)

    Zhou, Yi; Paull, Tanya T

    2013-12-27

    The resection of DNA double strand breaks initiates homologous recombination (HR) and is critical for genomic stability. Using direct measurement of resection in human cells and reconstituted assays of resection with purified proteins in vitro, we show that DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a classic nonhomologous end joining factor, antagonizes double strand break resection by blocking the recruitment of resection enzymes such as exonuclease 1 (Exo1). Autophosphorylation of DNA-PKcs promotes DNA-PKcs dissociation and consequently Exo1 binding. Ataxia telangiectasia-mutated kinase activity can compensate for DNA-PKcs autophosphorylation and promote resection under conditions where DNA-PKcs catalytic activity is inhibited. The Mre11-Rad50-Nbs1 (MRN) complex further stimulates resection in the presence of Ku and DNA-PKcs by recruiting Exo1 and enhancing DNA-PKcs autophosphorylation, and it also inhibits DNA ligase IV/XRCC4-mediated end rejoining. This work suggests that, in addition to its key role in nonhomologous end joining, DNA-PKcs also acts in concert with MRN and ataxia telangiectasia-mutated to regulate resection and thus DNA repair pathway choice.

  17. Concordance of ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients.

    Science.gov (United States)

    Kim, Hee Sung; Kim, Min A; Hodgson, Darren; Harbron, Christopher; Wellings, Robert; O'Connor, Mark J; Womack, Christopher; Yin, Xiaolu; Bang, Yung-Jue; Im, Seok-Ah; Lee, Byung Lan; Kim, Woo Ho

    2013-01-01

    ATM (ataxia telangiectasia mutated) is one of several DNA repair proteins that are suggested to sensitize tumor cells to the poly(ADP-ribose) polymerase inhibitor olaparib when deficient. The aim of this study was to assess the spatiotemporal concordance of ATM immunohistochemistry (IHC) in gastric cancer in order to determine if measurements made at the level of various sample types and times could be inferred as having the potential to be relevant to treatment decisions made at the patient level. Two independent cohorts composed of 591 gastric cancer patients divided into a gastrectomy cohort (n = 450) and a metastasis cohort (n = 141) were used in this study. A total of 2,705 ATM IHC samples were examined, including 450 whole tissue, 3 sets of 450 tissue microarray (TMA), 301 biopsy, 222 metastatic tumor and 2 additional whole tissue samples of 50 cases from the gastrectomy cohort, and 141 pairs of primary and metastatic tumors from the metastasis cohort. The prevalence of ATM negativity was 13.1% in biopsies, 13.9, 15.1, and 16.0% in TMAs and 15.9% in whole tissue samples of the gastrectomy cohort, and 21.4% in primary tumor and 21.5% in metastatic tumor samples of the metastasis cohort. coefficients were 0.341 for biopsy, 0.572 as the average of 3 TMAs and 0.415 for the largely synchronous metastatic tumors of the gastrectomy cohort, and 0.153 for the largely asynchronous metastatic tumors of the metastasis cohort. Using whole tissue sections from tumor resections or primary tumor, respectively, as the reference standards, specificity and sensitivity were 91.6 and 41.0% for biopsy, 93.9 and 61.9% as the average of 3 TMAs, and 86.6 and 58.8% for metastatic tumors of the gastrectomy cohort and 81.7 and 33.3% for metastatic tumors of the metastasis cohort, respectively. Although we have demonstrated that the IHC assay for ATM was robust and reproducible in gastric tumor samples, we have also found that measurements were subject to significant discordance across

  18. Ataxia-telangiectasia group D complementing gene (ATDC promotes lung cancer cell proliferation by activating NF-κB pathway.

    Directory of Open Access Journals (Sweden)

    Zhong-Ping Tang

    Full Text Available Previous studies suggested Ataxia-telangiectasia group D complementing gene (ATDC as an oncogene in many types of cancer. However, its expression and biological functions in non-small cell lung cancer (NSCLC remain unclear. Herein, we investigated its expression pattern in 109 cases of human NSCLC samples by immunohistochemistry and found that ATDC was overexpressed in 62 of 109 NSCLC samples (56.88%. ATDC overexpression correlated with histological type (p<0.0001, tumor status (p = 0.0227 and histological differentiation (p = 0.0002. Next, we overexpressed ATDC in normal human bronchial epithelial cell line HBE and depleted its expression in NSCLC cell lines A549 and H1299. MTT and colony formation assay showed that ATDC overexpression promoted cell proliferation while its depletion inhibited cell growth. Furthermore, cell cycle analysis showed that ATDC overexpression decreased the percentage of cells in G1 phase and increased the percentage of cells in S phase, while ATDC siRNA treatment increased the G1 phase percentage and decreased the S phase percentage. Further study revealed that ATDC overexpression could up-regulate cyclin D1 and c-Myc expression in HBE cells while its depletion down-regulated cyclin D1 and c-Myc expression in A549 and H1299 cells. In addition, ATDC overexpression was also associated with an increased proliferation index, cyclin D1 and c-Myc expression in human NSCLC samples. Further experiments demonstrated that ATDC up-regulated cyclin D1 and c-Myc expression independent of wnt/β-catenin or p53 signaling pathway. Interestingly, ATDC overexpression increased NF-κB reporter luciferase activity and p-IκB protein level. Correspondingly, NF-κB inhibitor blocked the effect of ATDC on up-regulation of cyclin D1 and c-Myc. In conclusion, we demonstrated that ATDC could promote lung cancer proliferation through NF-κB induced up-regulation of cyclin D1 and c-Myc.

  19. The gene for the ataxia-telagiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21

    National Research Council Canada - National Science Library

    Saar, K; Stumm, M; Wegner, R.D. [Humboldt Univ. (Germany)

    1997-01-01

    ...), also known as ataxia-telangiectasia variants, are two clinically indistinguishable autosomal recessive familial cancer syndromes that share with ataxia-telangiectasia similar cellular, immunological...

  20. Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature b-cell malignancies

    Science.gov (United States)

    Sandlund, J. T.; Hudson, M. M.; Kennedy, W.; Onciu, M.; Kastan, M. B.

    2014-01-01

    Children with ataxia-telangiectasia (A-T) and cancer have a poorer prognosis due in part to increased treatment-related toxicity. We piloted a curative intent approach in five children with A-T who presented with advanced stage (III, n=2; IV, n=3) B-NHL (diffuse large B-cell lymphoma, n=4; Burkitt leukemia, n=1) using a modified LMB-based protocol. Two achieved sustained CCR (one, CCR at 6 years; one, pulmonary death after 3 years in CCR). Two died from toxicity during induction and 1 failed induction with progressive disease. Novel therapeutic approaches which overcome drug resistance and are less toxic are needed for children with A-T and B-NHL. PMID:23900766

  1. Nitric oxide induces ataxia telangiectasia mutated (ATM) protein-dependent γH2AX protein formation in pancreatic β cells.

    Science.gov (United States)

    Oleson, Bryndon J; Broniowska, Katarzyna A; Schreiber, Katherine H; Tarakanova, Vera L; Corbett, John A

    2014-04-18

    In this study, the effects of cytokines on the activation of the DNA double strand break repair factors histone H2AX (H2AX) and ataxia telangiectasia mutated (ATM) were examined in pancreatic β cells. We show that cytokines stimulate H2AX phosphorylation (γH2AX formation) in rat islets and insulinoma cells in a nitric oxide- and ATM-dependent manner. In contrast to the well documented role of ATM in DNA repair, ATM does not appear to participate in the repair of nitric oxide-induced DNA damage. Instead, nitric oxide-induced γH2AX formation correlates temporally with the onset of irreversible DNA damage and the induction of apoptosis. Furthermore, inhibition of ATM attenuates cytokine-induced caspase activation. These findings show that the formation of DNA double strand breaks correlates with ATM activation, irreversible DNA damage, and ATM-dependent induction of apoptosis in cytokine-treated β cells.

  2. Caffeine Suppresses Apoptosis of Bladder Cancer RT4 Cells in Response to Ionizing Radiation by Inhibiting Ataxia Telangiectasia Mutated-Chk2-p53 Axis

    Directory of Open Access Journals (Sweden)

    Zhe-Wei Zhang

    2015-01-01

    Full Text Available Background: Caffeine suppresses ataxia telangiectasia and Rad3 related and ataxia telangiectasia mutated (ATM activities; ATM is the major kinase for DNA damage detection. This study aimed to investigate the effects of caffeine on DNA damage responses in cells from the bladder cancer cell line RT4 those were exposed to ionizing radiation (IR. Methods: Immunofluorescent staining was performed to investigate changes in the proteins involved in DNA damage responses with or without caffeine. A mouse xenograft model was used to study the effects of caffeine on the DNA damage responses. Western blotting was used to investigate the effects of caffeine pretreatment on the ATM-Chk2-p53-Puma axis, while real-time polymerase chain reaction (RT-PCR assessed changes in messenger RNA levels of p53 and downstream targets responding to IR. Finally, terminal deoxynucleotidyl transferase-dUTP nick end labeling assay. Western blotting and colony formation assay were used to measure the effects of caffeine on radiation-related apoptosis. All of the data were analyzed with a two-tailed Student′s t-test. Results: Immunofluorescent staining showed that caffeine pretreatment profoundly suppressed the formation of γH2AXand p53-binding protein 1 foci in RT4 cells in response to irradiation. Cellular and animal experiments suggested that this suppression was mediated by suppression of the ATM-Chk2-p53-Puma DNA damage-signaling axis. RT-PCR indicated caffeine also attenuated transactivation of p53 and p53-inducible genes. The colony formation assay revealed that caffeine displayed radioprotective effects on RT4 cells in response to low-dose radiation compared to the radiosensitization effects on T24 cells. Conclusion: Caffeine may inhibit IR-related apoptosis of bladder cancer RT4 cells by suppressing activation of the ATM-Chk2-p53-Puma axis.

  3. Caffeine Suppresses Apoptosis of Bladder Cancer RT4 Cells in Response to Ionizing Radiation by Inhibiting Ataxia Telangiectasia Mutated-Chk2-p53 Axis

    Institute of Scientific and Technical Information of China (English)

    Zhe-Wei Zhang; Jing Xiao; Wei Luo; Bo-Han Wang; Ji-Min Chen

    2015-01-01

    Background:Caffeine suppresses ataxia telangiectasia and Rad3 related and ataxia telangiectasia mutated (ATM) activities;ATM is the major kinase for DNA damage detection.This study aimed to investigate the effects of caffeine on DNA damage responses in cells from the bladder cancer cell line RT4 those were exposed to ionizing radiation (IR).Methods:Immunofluorescent staining was performed to investigate changes in the proteins involved in DNA damage responses with or without caffeine.A mouse xenograft model was used to study the effects of caffeine on the DNA damage responses.Western blotting was used to investigate the effects of caffeine pretreatment on the ATM-Chk2-p53-Puma axis,while real-time polymerase chain reaction (RT-PCR) assessed changes in messenger RNA levels of p53 and downstream targets responding to IR.Finally,terminal deoxynucleotidyl transferase-dUTP nick end labeling assay.Western blotting and colony formation assay were used to measure the effects of caffeine on radiation-related apoptosis.All of the data were analyzed with a two-tailed Student's t-test.Results:Immunofluorescent staining showed that caffeine pretreatment profoundly suppressed the formation ofγH2AXand p53-binding protein 1 foci in RT4 cells in response to irradiation.Cellular and animal experiments suggested that this suppression was mediated by suppression of the ATM-Chk2-p53-Puma DNA damage-signaling axis.RT-PCR indicated caffeine also attenuated transactivation of p53 and p53-inducible genes.The colony formation assay revealed that caffeine displayed radioprotective effects on RT4 cells in response to low-dose radiation compared to the radiosensitization effects on T24 cells.Conclusion:Caffeine may inhibit IR-related apoptosis of bladder cancer RT4 cells by suppressing activation of the ATM-Chk2-p53-Puma axis.

  4. Epstein-barr virus-associated extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT Lymphoma) arising in the parotid gland of a child with ataxia telangiectasia.

    Science.gov (United States)

    Bennett, Jennifer A; Bayerl, Michael G

    2015-03-01

    Hematologic malignancies, in particular T-cell lymphomas/leukemias, are prevalent in patients with ataxia telangiectasia (AT), with most reported cases being clinically aggressive and high grade. Epstein-Barr virus (EBV) is often associated with lymphoid proliferations/neoplasms arising in immunodeficient patients. Reports of low-grade B-cell neoplasms in the ataxia telangiectasia population are extremely rare. Here, we describe a case of EBV-associated extranodal marginal zone lymphoma (mucosa-associated lymphoid tissue lymphoma) of the parotid gland in a 16-year-old boy with AT. In addition, we review the literature of hematologic malignancies in the AT population as well as the occurrence of EBV in mucosa-associated lymphoid tissue lymphoma.

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

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    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.

  6. Inhibition of Transforming Growth Factor-Beta1 SignalingAttenuates Ataxia Telangiectasia Mutated Activity in Response toGenotoxic Stress

    Energy Technology Data Exchange (ETDEWEB)

    Kirshner, Julia; Jobling, Michael F.; Pajares, Maria Jose; Ravani, Shraddha A.; Glick, Adam; Lavin, Martin F.; Koslov, Sergei; Shiloh, Yosef; Barcellos-Hoff, Mary Helen

    2006-01-01

    Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor {beta} (TGF{beta})-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF{beta} inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf{beta}I null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF{beta} type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced H2AX radiation-induced foci; and increased radiosensitivity compared with TGF{beta} competent cells. We determined that loss of TGF{beta} signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF{beta} restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf{beta}I, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF{beta} may be used to advantage in cancer therapy.

  7. 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.

  8. The response of normal and ataxia-telangiectasia cells to bleomycin: relationships between chromosome damage, cell cycle delay and cell killing.

    Science.gov (United States)

    Zampetti-Bosseler, F; Scott, D

    1985-08-01

    In agreement with our earlier observation (Scott and Zampetti-Bosseler, 1982) on X-irradiated normal and ataxia-telangiectasia (A-T) fibroblasts, we now report that after bleomycin or neocarzinostatin treatment also, A-T cells exhibit less G2 delay than normal cells. We confirm that A-T cells sustain more chromosome damage and lethality than normal cells after bleomycin. These observations support the hypothesis (Painter and Young, 1980) that A-T cells are defective in the recognition of certain lesions which normally lead to delays in progression through the cell cycle, during which they are repaired, and which, if unrepaired, lead to cell-lethal chromosome damage. However, we find that after bleomycin, as opposed to X-rays, the contribution of this type of lesion to cell death is minimal. The predominant lesions leading to cell death after bleomycin are not manifested at chromosome aberrations and do not lead to G2 delay or DNA-synthesis inhibition. A-T cells are defective in the recognition and/or repair of both types of lesion.

  9. Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase Inhibition Is Synthetically Lethal in XRCC1 Deficient Ovarian Cancer Cells

    Science.gov (United States)

    Sultana, Rebeka; Abdel-Fatah, Tarek; Perry, Christina; Moseley, Paul; Albarakti, Nada; Mohan, Vivek; Seedhouse, Claire; Chan, Stephen; Madhusudan, Srinivasan

    2013-01-01

    Introduction Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response. Methods In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO) and human ovarian cancer cells using ATR inhibitors (NU6027). In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed. Results ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells. Conclusions Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells. PMID:23451157

  10. Ataxia telangiectasia mutated and Rad3 related (ATR protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.

    Directory of Open Access Journals (Sweden)

    Rebeka Sultana

    Full Text Available INTRODUCTION: Ataxia telangiectasia mutated and Rad3 Related (ATR protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response. METHODS: In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO and human ovarian cancer cells using ATR inhibitors (NU6027. In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed. RESULTS: ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells. CONCLUSIONS: Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells.

  11. Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy.

    Science.gov (United States)

    Pena, S D J; Coimbra, R L M

    2015-02-01

    We have recently performed exome analysis in a 7 year boy who presented in infancy with an encephalopathy characterized by ataxia and myoclonic epilepsy. Parents were not consanguineous and there was no family history of the disease. Exome analysis did not show any pathogenic variants in genes known to be associated with seizures and/or ataxia in children, including all known human channelopathies. However, we have identified a mutation in KCNA2 that we believe to be responsible for the disease in our patient. This gene, which encodes a member of the potassium channel, voltage-gated, shaker-related subfamily, has not been previously described as a cause of disease in humans, but mutations of the orthologous gene in mice (Kcna2) are known to cause both ataxia and convulsions. The mutation is c.890C>A, leading to the amino acid substitution p.Arg297Gln, which involves the second of the critical arginines in the S4 voltage sensor. This mutation is characterized as pathogenic by five different prediction programs. RFLP analysis and Sanger sequencing confirmed the presence of the mutation in the patient, but not in his parents, characterizing it as de novo. We believe that this discovery characterizes a new channelopathy. © 2014 John Wiley | Clinical Exome Genome Reports.

  12. [Jaridonin, a new diterpenoid from Isodon rubescens, induces cell cycle arrest in gastric cancer cells through activating ataxia telangiectasia mutated kinase].

    Science.gov (United States)

    Ma, Y C; Su, N; Zhao, N M; Li, Q Y; Zhang, M; Zhao, H W; Liu, H M; Qin, Y H

    2016-04-01

    To study the effects of Jaridonin, a novel diterpenoid from isodon rubescens, on the cell cycle of human gastric cancer cells and its molecular mechanism of action. Flow cytometry was used to analyze the cell cycle distribution and expression of ataxia telangiectasia mutated kinase (ATM) after Jaridonin treatment. Western blot was performed to detect the expression of cell cycle-related proteins. The results of flow cytometry showed that the percentages of MGC-803 cells in G(2)/M phase at 6 hours after 0, 10, 20 μmol/L Jaridonin-treatment were (10.8±2.2)%, (18.2±2.5)%, (27.3±3.2)%, respectively; those at 12 hours after Jaridonin-treatment were (12.0±1.5)%, (24.1±2.0)% and (39.7±5.2)%, respectively, indicating a G2/M phase arrest of MGC-803 cells was resulted in a time- and dose-dependent manner. The expressions of ATM, Chk1, Chk2, phosphorylated Cdc2 and CDK2 were up-regulated in the MGC-803 cells after Jaridonin treatment, while the levels of Cdc2 and CDK2 were decreased. KU-55933, an inhibitor of ATM, reversed the expression of relevant proteins and G(2)/M phase arrest induced by Jaridonin. Jaridonin can significantly induce G(2)/M arrest in gastric cancer MGC-803 cells. Its mechanism may be related to the activation of ATM and Chk1/2, and inactivation of Cdc2 and CDK2 phosphorylation.

  13. Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated-p53 activation.

    Science.gov (United States)

    Kaur, Manjinder; Agarwal, Rajesh; Agarwal, Chapla

    2006-05-01

    Prostate cancer is the second leading cancer diagnosed in elderly males in the Western world. Epidemiologic studies suggest that dietary modifications could be an effective approach in reducing various cancers, including prostate cancer, and accordingly cancer-preventive efficacy of dietary nutrients has gained increased attention in recent years. We have recently shown that grape seed extract (GSE) inhibits growth and induces apoptotic death of advanced human prostate cancer DU145 cells in culture and xenograft. Because prostate cancer is initially an androgen-dependent malignancy, here we used LNCaP human prostate cancer cells as a model to assess GSE efficacy and associated mechanisms. GSE treatment of cells led to their detachment within 12 hours, as occurs in anoikis, and caused a significant decrease in live cells mostly due to their apoptotic death. GSE-induced anoikis and apoptosis were accompanied by a strong decrease in focal adhesion kinase levels, but an increase in caspase-3, caspase-9, and poly(ADP-ribose) polymerase cleavage; however, GSE caused both caspase-dependent and caspase-independent apoptosis as evidenced by cytochrome c and apoptosis-inducing factor release into cytosol. Additional studies revealed that GSE causes DNA damage-induced activation of ataxia telangiectasia mutated kinase and Chk2, as well as p53 Ser(15) phosphorylation and its translocation to mitochondria, suggesting this to be an additional mechanism for apoptosis induction. GSE-induced apoptosis, cell growth inhibition, and cell death were attenuated by pretreatment with N-acetylcysteine and involved reactive oxygen species generation. Together, these results show GSE effects in LNCaP cells and suggest additional in vivo efficacy studies in prostate cancer animal models.

  14. G{sub 2}/M-phase arrest and release in ataxia telangiectasia and normal cells after exposure to ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Hong, J.H.; Gatti, R.A.; Huo, Y.K.; Chiang, C.S.; McBride, W.H. [Univ. of California School of Medicine, Los Angeles, CA (United States)

    1994-10-01

    Cells from patients with ataxia telangiectasia (AT) are abnormal in their response to irradiation as judged by clonogenic survival and accumulation in G{sub 2} phase. The relationship of the results of these two assays, however, is still a matter of controversy. Flow cytometry was used to measure the distribution of cells in the phases of the cell cycle after 2 Gy irradiation in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) and SV40-transformed fibroblasts. AT cells showed increased and prolonged accumulation in G{sub 2}/M phase regardless of the cell type (lymphoblastoid or fibroblast) or complementation group (A, C or D). To test the hypothesis that prolonged accumulation of AT cells in G{sub 2} phase after irradiation was not simply a reflection of their radiosensitivity, we gave iso-survival radiation doses to SV40-transformed fibroblasts of two AT and one control cell lines. The two AT cell lines exited from the G{sub 2}/M-phase block more slowly than control cells after each dose tested. This implies that prolonged accumulation in G{sub 2}/M phase in AT cells is not directly related to radiosensitivity as measured by clonogenic survival, but that factors involved in the exit from G{sub 2} phase after irradiation may be abnormally regulated. We found that G{sub 2}-phase arrest of AT cells did not necessarily result in a fatal consequence in the first cell cycle after irradiation. Furthermore, G{sub 2}-phase arrest did not lead to detectable DNA fragmentation characteristic of apoptosis as judged by gel electrophoresis. 37 refs., 6 figs.

  15. Functional significance for a heterogenous ribonucleoprotein A18 signature RNA motif in the 3'-untranslated region of ataxia telangiectasia mutated and Rad3-related (ATR) transcript.

    Science.gov (United States)

    Yang, Ruiqing; Zhan, Ming; Nalabothula, Narasimha Rao; Yang, Qingyuan; Indig, Fred E; Carrier, France

    2010-03-19

    The predominantly nuclear heterogenous ribonucleoprotein A18 (hnRNP A18) translocates to the cytosol in response to cellular stress and increases translation by specifically binding to the 3'-untranslated region (UTR) of several mRNA transcripts and the eukaryotic initiation factor 4G. Here, we identified a 51-nucleotide motif that is present 11.49 times more often in the 3'-UTR of hnRNP A18 mRNA targets than in the UniGene data base. This motif was identified by computational analysis of primary sequences and secondary structures of hnRNP A18 mRNA targets against the unaligned sequences. Band shift analyses indicate that the motif is sufficient to confer binding to hnRNP A18. A search of the entire UniGene data base indicates that the hnRNP A18 motif is also present in the 3'-UTR of the ataxia telangiectasia mutated and Rad3-related (ATR) mRNA. Validation of the predicted hnRNP A18 motif is provided by amplification of endogenous ATR transcript on polysomal fractions immunoprecipitated with hnRNP A18. Moreover, overexpression of hnRNP A18 results in increased ATR protein levels and increased phosphorylation of Chk1, a preferred ATR substrate, in response to UV radiation. In addition, our data indicate that inhibition of casein kinase II or GSK3beta significantly reduced hnRNP A18 cytosolic translocation in response to UV radiation. To our knowledge, this constitutes the first demonstration of a post-transcriptional regulatory mechanism for ATR activity. hnRNP A18 could thus become a new target to trigger ATR activity as back-up stress response mechanisms to functionally compensate for absent or defective responders.

  16. 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

  17. Ataxia-Telangiectasia Children's Project

    Science.gov (United States)

    ... CURE TEAM Walt Disney World® Marathon Weekend Star Wars™ Half Marathon - The Dark Side ... America New Insights Into Inflammation, Swallowing, and Aging in A-T Testing Drugs to Protect A-T Brain Cells from DNA ...

  18. 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

  19. 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...

  20. Ataxia-telangiectasia: an overview.

    Science.gov (United States)

    Boder, E

    1985-01-01

    The more subtle clinical findings that facilitate early diagnosis and the most provocative long-term clinical observations in our series of patients are emphasized. The most striking pathological findings in our own series of 11 complete autopsies are reviewed in relation to new findings from 57 autopsy reports in the recent literature. Clinical and pathological findings in our oldest patient, who died at age 32, are systematically compared with those of her sister, who died 20 years earlier at age 10 1/2 and who was the subject of the first autopsy in AT, thus providing a rare comparison of the early and late stages of the disease. The clinical and pathological findings, including the gliovascular malformations in the CNS described recently in autopsies on older patients, reveal that AT is characterized throughout its course by multisystemic progeric changes. It is proposed, therefore, that AT can serve as a model for the study of premature aging. Clinical diagnosis, laboratory markers, and special diagnostic procedures, along with general management, immunotherapy, and rehabilitative measures, are reviewed in Part II.

  1. More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes

    Science.gov (United States)

    Pearson, Toni S.

    2016-01-01

    Background The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized. Methods A PubMed literature search was performed in October 2015 utilizing pairwise combinations of disease-related terms (autosomal recessive ataxia, ataxia–telangiectasia, ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), Friedreich ataxia, ataxia with vitamin E deficiency), and symptom-related terms (movement disorder, dystonia, chorea, choreoathetosis, myoclonus). Results Involuntary movements occur in the majority of patients with ataxia–telangiectasia and AOA1, and less frequently in patients with AOA2, Friedreich ataxia, and ataxia with vitamin E deficiency. Clinical presentations with an isolated hyperkinetic movement disorder in the absence of ataxia include dystonia or dystonia with myoclonus with predominant upper limb and cervical involvement (ataxia–telangiectasia, ataxia with vitamin E deficiency), and generalized chorea (ataxia with oculomotor apraxia type 1, ataxia-telangiectasia). Discussion An awareness of atypical presentations facilitates early and accurate diagnosis in these challenging cases. Recognition of involuntary movements is important not only for diagnosis, but also because of the potential for effective targeted symptomatic treatment. PMID:27536460

  2. Milestones in ataxia

    Science.gov (United States)

    Klockgether, Thomas; Paulson, Henry

    2010-01-01

    The past 25 years have seen enormous progress in the deciphering of the genetic and molecular basis of ataxias resulting in an improved understanding of their pathogenesis. The most significant milestones during this period were the cloning of the genes associated with the common spinocerebellar ataxias (SCAs), ataxia telangiectasia (AT) and Friedreich ataxia (FRDA). To date, the causative mutations of more than 30 SCAs and 20 recessive ataxias have been identified. In addition, there are numerous acquired ataxias with defined molecular causes so that the entire number of distinct ataxia disorders exceeds 50 and possibly approaches 100. Despite this enormous heterogeneity, a few recurrent pathopyhsiological themes stand out. These include protein aggregation, failure of protein homoestasis, perturbations in ion channel function, defects in DNA repair and mitochondrial dysfunction. The clinical phenotypes of the most common ataxia disorders have been firmly established, and their natural history is being studied in ongoing large observational trials. Effective therapies for ataxias are still lacking. However, novel drug targets are under investigation, and it is expected that there will be an increasing number of therapeutic trials in ataxia. PMID:21626557

  3. [Chronic ataxia in childhood].

    Science.gov (United States)

    Erazo Torricelli, Ricardo

    2013-01-01

    Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling.

  4. A novel mouse model for ataxia-telangiectasia with a N-terminal mutation displays a behavioral defect and a low incidence of lymphoma but no increased oxidative burden.

    Science.gov (United States)

    Campbell, Andrew; Krupp, Brittany; Bushman, Jared; Noble, Mark; Pröschel, Christoph; Mayer-Pröschel, Margot

    2015-11-15

    Ataxia-telangiectasia (A-T) is a rare multi-system disorder caused by mutations in the ATM gene. Significant heterogeneity exists in the underlying genetic mutations and clinical phenotypes. A number of mouse models have been generated that harbor mutations in the distal region of the gene, and a recent study suggests the presence of residual ATM protein in the brain of one such model. These mice recapitulate many of the characteristics of A-T seen in humans, with the notable exception of neurodegeneration. In order to study how an N-terminal mutation affects the disease phenotype, we generated an inducible Atm mutant mouse model (Atm(tm1Mmpl/tm1Mmpl), referred to as A-T [M]) predicted to express only the first 62 amino acids of Atm. Cells derived from A-T [M] mutant mice exhibited reduced cellular proliferation and an altered DNA damage response, but surprisingly, showed no evidence of an oxidative imbalance. Examination of the A-T [M] animals revealed an altered immunophenotype consistent with A-T. In contrast to mice harboring C-terminal Atm mutations that disproportionately develop thymic lymphomas, A-T [M] mice developed lymphoma at a similar rate as human A-T patients. Morphological analyses of A-T [M] cerebella revealed no substantial cellular defects, similar to other models of A-T, although mice display behavioral defects consistent with cerebellar dysfunction. Overall, these results suggest that loss of Atm is not necessarily associated with an oxidized phenotype as has been previously proposed and that loss of ATM protein is not sufficient to induce cerebellar degeneration in mice. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Aberrant CD8+ T-Cell Responses and Memory Differentiation upon Viral Infection of an Ataxia-Telangiectasia Mouse Model Driven by Hyper-Activated Akt and mTORC1 Signaling

    Science.gov (United States)

    D'Souza, Anthony D.; Parish, Ian A.; McKay, Sharen E.; Kaech, Susan M.; Shadel, Gerald S.

    2011-01-01

    Immune system-related pathology is common in ataxia-telangiectasia (A-T) patients and mice that lack the protein kinase, A-T mutated (ATM). However, it has not been studied how ATM influences immune responses to a viral infection. Using the lymphocytic choriomeningitis virus (LCMV) infection model, we show that ATM−/− mice, despite having fewer naïve CD8+ T cells, effectively clear the virus. However, aberrant CD8+ T-cell responses are observed, including defective expansion and contraction, effector-to-memory differentiation, and a switch in viral-epitope immunodominance. T-cell receptor-activated, but not naïve, ATM−/− splenic CD8+ T cells have increased ribosomal protein S6 and Akt phosphorylation and do not proliferate well in response to IL-15, a cytokine important for memory T-cell development. Accordingly, pharmacological Akt or mammalian target of rapamycin complex 1 (mTORC1) inhibition during T-cell receptor activation alone rescues the IL-15 proliferation defect. Finally, rapamycin treatment during LCMV infection in vivo increases the number of memory T cells in ATM−/− mice. Altogether, these results show that CD8+ T cells lacking ATM have hyperactive Akt and mTORC1 signaling in response to T-cell receptor activation, which results in aberrant cytokine responses and memory T-cell development. We speculate that similar signaling defects contribute to the immune system pathology of A-T, and that inhibition of Akt and/or mTORC1 may be of therapeutic value. PMID:21641396

  6. Allele and genotype frequency of a genetic variant in ataxia telangiectasia mutated gene affecting glycemic response to metformin in South Indian population

    Directory of Open Access Journals (Sweden)

    Saranya Vilvanathan

    2014-01-01

    Full Text Available Allele and genotype frequency of a genetic variant in ATM gene affecting glycemic response to metformin in South Indian population . Context: The novel polymorphism in ATM gene (rs11212617, which is implicated to have association with metformin response, exhibits inter-ethnic variability in the allele and genotype frequency distribution . Aims and Design: The objective of the present study is to establish the allele and genotype frequency of rs11212617 single nucleotide polymorphism in ATM gene, in South Indian population and to find if this variant has any role in the etiology of type 2 diabetes mellitus . Materials and Methods: The study was performed in 2 cohorts of populations, 112 healthy volunteers and 118 type 2 diabetes mellitus patients. Genomic deoxyribonucleic acid (DNA was extracted from peripheral blood leucocytes by phenol-chloroform method and genotyping was performed by real-time polymerase chain reaction using TaqMan assay. Results: In South Indian population, the frequency of major A allele was 0.65 and the minor C allele was 0.35. AA and CC are the homozygous genotypes with frequency of 0.39 and 0.09 respectively. The frequency of heterozygous genotype AC (0.52 was found to be higher than the homozygotes. There was no significant difference in the frequency distribution in the diabetic population, which implies that this variant does not have any causative role in the disease etiology. The frequency distributions were found to be significantly different from the distributions in other ethnic populations such as Caucasians, Chinese, Japanese and Africans. But there was no significant difference when compared with the Gujarati Indians of Houston. Conclusion: The frequency distribution of this novel variant in South Indian population forms a framework for further gene disease association studies to establish the association of this variant with metformin response. Our study could not find any association of this variant with

  7. Methods for detection of ataxia telangiectasia mutations

    Energy Technology Data Exchange (ETDEWEB)

    Gatti, Richard A.

    2005-10-04

    The present invention is directed to a method of screening large, complex, polyexonic eukaryotic genes such as the ATM gene for mutations and polymorphisms by an improved version of single strand conformation polymorphism (SSCP) electrophoresis that allows electrophoresis of two or three amplified segments in a single lane. The present invention also is directed to new mutations and polymorphisms in the ATM gene that are useful in performing more accurate screening of human DNA samples for mutations and in distinguishing mutations from polymorphisms, thereby improving the efficiency of automated screening methods.

  8. The effect of ataxia-telangiectasia mutated kinase-dependent hyperphosphorylation of checkpoint kinase-2 on oligodeoxynucleotide 7909 containing CpG motifs-enhanced sensitivity to X-rays in human lung adenocarcinoma A549 cells

    Directory of Open Access Journals (Sweden)

    Liu XQ

    2015-06-01

    Full Text Available Xiaoqun Liu,1,* Xiangdong Liu,2,* Tiankui Qiao,1 Wei Chen,1 Sujuan Yuan1 1Department of Oncology, 2Department of Ophthalmology, Affiliated Jinshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Objective: The aim of the study reported here was to further investigate the potential effect of ataxia-telangiectasia mutated (ATM kinase-dependent hyperphosphorylation of checkpoint kinase-2 (Chk2 on radiosensitivity enhanced by oligodeoxynucleotide 7909 containing CpG motifs (CpG ODN7909 in human lung adenocarcinoma A549 cells. Methods: In vitro A549 cells were randomly separated into control, CpG, X-ray, CpG+X-ray, ATM kinase-small interfering RNA (siRNA+CpG+X-ray (ATM-siRNA, and Chk2-siRNA+CpG+X-ray (Chk2-siRNA groups. siRNAs were adopted to silence the ATM and Chk2 genes. Expression and phosphorylation of ATM kinase and Chk2 were detected by Western blot assay. Cell colonies were observed under inverted phase-contrast microscopy. Cellular survival curves were fitted using a multi-target single-hitting model. Cell cycle and apoptosis were analyzed by flow cytometry. Results: Expression of ATM kinase and Chk2 was similar among the control, CpG, X-ray, and CpG+X-ray groups. Phosphorylated ATM kinase and Chk2 were significantly increased in the CpG+X-ray group compared with in the X-ray group (t=6.00, P<0.01 and t=3.13, P<0.05, respectively, though these were hardly detected in the control and CpG groups. However, expression of ATM kinase and Chk2 was clearly downregulated in the ATM-siRNA and Chk2-siRNA groups, respectively. Similarly, their phosphorylation levels were also significantly decreased in the ATM-siRNA group (t=14.35, P<0.01 and t=8.46, P<0.01, respectively and a significant decrease in phosphorylated Chk2 was observed in the Chk2-siRNA group (t=7.28, P<0.01 when compared with the CpG+X-ray group. Further, the number of A549 cells at Gap 2/mitotic phase and the apoptosis

  9. Irradiated HMEC from A-T Heterozygous Breast Tissue

    Science.gov (United States)

    Richmond, Robert; Bors, Karen; Cruz, Angela; Pettengil, Olive; Curreri, Peter A. (Technical Monitor)

    2002-01-01

    Women who are heterozygous for ataxia-telangiectasia (A-T) carry a single defective ATM gene in chromosome 11 q22-23, and have been statistically determined with high significance within a defined database to be approximately 5-fold more susceptible for developing breast cancer than their noma1 counterpart. Breast cancer susceptibility of these A-T heterozygotes has been hypothesized to include consequence of response to damage caused by low levels of ionizing radiation. Prophylactic mastectomy specimens were donated by a 41 year-old obligate A-T heterozygote who was located prior to her elective surgery through an existing pedigree. Harvest of that breast tissue provided an isolate of long-term growth human mammary epithelial cells (HMEC), designated WH612/3. An isolate of presumed normal long-term growth HMEC, designated 48R, was obtained from Dr. Martha Stampfer (Lawrence Berkeley Laboratory, University of California), and the A-T heterozygous HMEC were transformed with E6 and E7 oncogenes of human papilloma virus Type-16 in the laboratory of Dr. Ray White (Hunt- Cancer Institute, University of Utah) for use in this study. The objective of this study is to study the expression of end points that may bear on cancer outcome following irradiation of HMEC. Specific end points are cell survival, cell cycle, p53 expression, and apoptosis. Survival curves, immunostaining, and flow cytometery are used to examine these end points. Radiation-induced cell killing shows less shoulder development in the survival curve for WH61U3 compared to 48R HMEC, suggesting less repair of damage in the former HMEC. Additional information is included in the original extended abstract.

  10. Variation in Telangiectasia Predisposing Genes Is Associated With Overall Radiation Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Tanteles, George A. [Department of Genetics, University of Leicester, Leicester (United Kingdom); Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Murray, Robert J.S. [Department of Genetics, University of Leicester, Leicester (United Kingdom); Mills, Jamie [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Barwell, Julian [Department of Genetics, University of Leicester, Leicester (United Kingdom); Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Chakraborti, Prabir [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Chan, Steve [Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham (United Kingdom); Cheung, Kwok-Leung [Division of Breast Surgery, University of Nottingham, Nottingham (United Kingdom); Ennis, Dawn [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Khurshid, Nazish [Department of Genetics, University of Leicester, Leicester (United Kingdom); Lambert, Kelly [Department of Breast Surgery, University Hospitals of Leicester, Glenfield Hospital, Leicester (United Kingdom); Machhar, Rohan; Meisuria, Mitul [Department of Genetics, University of Leicester, Leicester (United Kingdom); Osman, Ahmed; Peat, Irene [Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester (United Kingdom); Sahota, Harjinder [Department of Genetics, University of Leicester, Leicester (United Kingdom); Woodings, Pamela [Department of Clinical Oncology, Derby Hospitals NHS Foundation Trust, Derby (United Kingdom); Talbot, Christopher J., E-mail: cjt14@le.ac.uk [Department of Genetics, University of Leicester, Leicester (United Kingdom); and others

    2012-11-15

    Purpose: In patients receiving radiotherapy for breast cancer where the heart is within the radiation field, cutaneous telangiectasiae could be a marker of potential radiation-induced heart disease. We hypothesized that single nucleotide polymorphisms (SNPs) in genes known to cause heritable telangiectasia-associated disorders could predispose to such late, normal tissue vascular damage. Methods and Materials: The relationship between cutaneous telangiectasia as a late normal tissue radiation injury phenotype in 633 breast cancer patients treated with radiotherapy was examined. Patients were clinically assessed for the presence of cutaneous telangiectasia and genotyped at nine SNPs in three candidate genes. Candidate SNPs were within the endoglin (ENG) and activin A receptor, type II-like 1 (ACVRL1) genes, mutations in which cause hereditary hemorrhagic telangiectasia and the ataxia-telangiectasia mutated (ATM) gene associated with ataxia-telangiectasia. Results: A total of 121 (19.1%) patients exhibited a degree of cutaneous telangiectasiae on clinical examination. Regression was used to examine the associations between the presence of telangiectasiae in patients who underwent breast-conserving surgery, controlling for the effects of boost and known brassiere size (n=388), and individual geno- or haplotypes. Inheritance of ACVRL1 SNPs marginally contributed to the risk of cutaneous telangiectasiae. Haplotypic analysis revealed a stronger association between inheritance of a ATM haplotype and the presence of cutaneous telangiectasiae, fibrosis and overall toxicity. No significant association was observed between telangiectasiae and the coinheritance of the candidate ENG SNPs. Conclusions: Genetic variation in the ATM gene influences reaction to radiotherapy through both vascular damage and increased fibrosis. The predisposing variation in the ATM gene will need to be better defined to optimize it as a predictive marker for assessing radiotherapy late effects.

  11. Cerebellar ataxias.

    Science.gov (United States)

    Manto, Mario; Marmolino, Daniele

    2009-08-01

    The term 'cerebellar ataxias' encompasses the various cerebellar disorders encountered during daily practice. Patients exhibit a cerebellar syndrome and can also present with pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. The clinical diagnosis of subtypes of ataxias is complicated by the salient overlap of the phenotypes between genetic subtypes. The identification of the causative mutations of many hereditary ataxias and the development of relevant animal models bring hope for effective therapies in neurodegenerative ataxias. We describe the current classification of cerebellar ataxias and underline the recent discoveries in molecular pathogenesis. Cerebellar disorders can be divided into sporadic forms and inherited diseases. Inherited ataxias include autosomal recessive cerebellar ataxias, autosomal dominant cerebellar ataxias/spinocerebellar ataxia) and episodic ataxias, and X-linked ataxias. From a motor control point of view, the leading theories of ataxia are based on neural representations or 'internal models' to emulate fundamental natural processes such as body motion. Recent molecular advances have direct implications for research and daily practice. We provide a framework for the diagnosis of ataxias. For the first time, the therapeutic agents under investigation are targeted to deleterious pathways.

  12. Friedreich's Ataxia

    Science.gov (United States)

    Friedreich's ataxia is an inherited disease that damages your nervous system. The damage affects your spinal cord and the ... of 5 and 15. The main symptom is ataxia, which means trouble coordinating movements. Specific symptoms include ...

  13. Diagnosis of Ataxia

    Science.gov (United States)

    ... Donate to the National Ataxia Foundation Diagnosis of Ataxia Being diagnosed with Ataxia can be overwhelming. Below ... help you to understand ataxia better. What is Ataxia? The word "ataxia", comes from the Greek word, " ...

  14. 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

  15. Evidence that the Nijmegen breakage syndrome protein, an early sensor of double-strand DNA breaks (DSB), is involved in HIV-1 post-integration repair by recruiting the ataxia telangiectasia-mutated kinase in a process similar to, but distinct from, cellular DSB repair.

    Science.gov (United States)

    Smith, Johanna A; Wang, Feng-Xiang; Zhang, Hui; Wu, Kou-Juey; Williams, Kevin Jon; Daniel, René

    2008-01-22

    Retroviral transduction involves integrase-dependent linkage of viral and host DNA that leaves an intermediate that requires post-integration repair (PIR). We and others proposed that PIR hijacks the host cell double-strand DNA break (DSB) repair pathways. Nevertheless, the geometry of retroviral DNA integration differs considerably from that of DSB repair and so the precise role of host-cell mechanisms in PIR remains unclear. In the current study, we found that the Nijmegen breakage syndrome 1 protein (NBS1), an early sensor of DSBs, associates with HIV-1 DNA, recruits the ataxia telangiectasia-mutated (ATM) kinase, promotes stable retroviral transduction, mediates efficient integration of viral DNA and blocks integrase-dependent apoptosis that can arise from unrepaired viral-host DNA linkages. Moreover, we demonstrate that the ATM kinase, recruited by NBS1, is itself required for efficient retroviral transduction. Surprisingly, recruitment of the ATR kinase, which in the context of DSB requires both NBS1 and ATM, proceeds independently of these two proteins. A model is proposed emphasizing similarities and differences between PIR and DSB repair. Differences between the pathways may eventually allow strategies to block PIR while still allowing DSB repair.

  16. Progressive cerebellar atrophy: hereditary ataxias and disorders with spinocerebellar degeneration.

    Science.gov (United States)

    Wolf, Nicole I; Koenig, Michel

    2013-01-01

    The hereditary ataxias with onset in childhood are a group of heterogeneous disorders, usually with autosomal recessive inheritance. In many of them, magnetic resonance imaging (MRI) shows cerebellar atrophy. The most prominent exception to this is Friedreich's ataxia, where MRI shows normal cerebellar volume, but sometimes spinal cord atrophy. In several of the hereditary ataxias, the causative gene plays an important role in DNA repair: ataxia telangiectasia and ataxia telangiectasia-like disorder, and ataxia with oculomotor apraxia type I and II. Mitochondrial metabolism is impaired in another group of inherited ataxias including the emergent group of defects in coenzyme Q10 synthesis. Few of these disorders are amenable to effective treatment, the most important of these being vitamin E-responsive ataxia. The autosomal dominant spinocerebellar ataxias are rare in childhood. Some of them, especially SCA7 and SCA2, may begin in childhood or even infancy, family history being positive in these cases. Additional clinical clues such as presence or absence of neuropathy or oculomotor apraxia still help in making a definitive diagnosis albeit there are still many unsolved cases. In pontocerebellar hypoplasia, a neurodegenerative disease with prenatal onset, the genetic basis of the different subtypes has recently been elucidated and involves genes with different functions.

  17. Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

    Energy Technology Data Exchange (ETDEWEB)

    Kurimasa, Akihiro; Burma, Sandeep; Henrie, Melinda; Ouyang, Honghai; Osaki, Mitsuhiko; Ito, Hisao; Nagasawa, Hatsumi; Little, John B.; Oshimura, Mitsuo; Li, Gloria C.; Chen, David J.

    2002-04-15

    Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.

  18. Causes of Ataxia

    Science.gov (United States)

    ... Donate to the National Ataxia Foundation Causes of Ataxia The hereditary ataxias are genetic, which means they ... the disease is inherited as a recessive gene. Ataxia Gene Identified in 1993 The first ataxia gene ...

  19. Treating telangiectasias: my method.

    Science.gov (United States)

    Ferrara, F; Ferrara, G

    2013-04-01

    The authors propose a new classification of telangiectasias: conditions involving demonstrated reflux are classified as type A telangiectasias; clustered, spider telangiectasias not related to reflux and with vein diameters of >0.2 mm are classified as type B, while isolated telangiectatic veins of ≤0.2 mm diameter are classed as type C. This histological and pathophysiological approach is the basis for the Authors' Multi-Therapy Treatment Protocol (MTT). The treatment regimen provides for initial treatment of type A telangiectasias with just conventional reflux sclerotherapy, followed three weeks later by treatment of type B telangiectasias with 0.25-0.5% polidocanol foam, associated with both external compression and tumescent vasoconstriction (START technique). This is then followed after a further three months by dermal stimulation with mesoglycan (LIDS technique) to reinforce the district underlying the type C telangiectasias. The MTT Protocol was used on 63 patients (125 limbs). A 12-month follow-up showed the treatment regimen to provide better aesthetic and functional results than classical sclerotherapy, with few adverse effects and greater patient satisfaction.

  20. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts

    Science.gov (United States)

    Worgul, Basil V.; Smilenov, Lubomir; Brenner, David J.; Junk, Anna; Zhou, Wei; Hall, Eric J.

    2002-01-01

    It is important to know whether the human population includes genetically predisposed radiosensitive subsets. In vitro studies have shown that cells from individuals homozygous for ataxia telangiectasia (A-T) are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene (ATM(+/-)) may be slightly more radiosensitive in vitro, it remained to be determined whether the greater susceptibility of ATM(+/-) cells translates into an increased sensitivity for late effects in vivo, though there is a suggestion that radiotherapy patients that are heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. We chose cataractogenesis in the lens as a means to assay for the effects of ATM deficiency in a late-responding tissue. One eye of wild-type, Atm heterozygous and homozygous knockout mice was exposed to 0.5-, 1.0-, 2.0-, or 4.0-Gy x rays. The animals were followed weekly for cataract development by conventional slit-lamp biomicroscopy. Cataract development in the animals of all three groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Most important in the present context is that cataracts appeared earlier in the heterozygous versus wild-type animals. The data suggest that ATM heterozygotes in the human population may also be radiosensitive. This may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage.

  1. Comparison of kinetics of X-ray-induced cell killing in normal, ataxia telagiectasia and hereditary retinoblastoma fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Nagasawa, H.; Little, J.B. (Harvard School of Public Health, Boston, MA (USA). Lab. of Radiobiology)

    1983-05-01

    Survival, cumulative labeling indices and chromosomal aberrations were studied in normal, ataxia telangiectasia (AT) and hereditary retinoblastoma fibroblasts after X-irradiation during density-inhibition of growth and immediate release by subculture to low density. Th

  2. Friedreich ataxia

    Science.gov (United States)

    ... for Friedreich ataxia includes: Counseling Speech therapy Physical therapy Walking aids or wheelchairs Orthopedic devices (braces) may be needed for scoliosis and foot problems. Treating heart disease and diabetes help people ...

  3. Acute cerebellar ataxia

    Science.gov (United States)

    Cerebellar ataxia; Ataxia - acute cerebellar; Cerebellitis; Post-varicella acute cerebellar ataxia; PVACA ... Acute cerebellar ataxia in children, particularly younger than age 3, may occur several weeks after an illness caused by a virus. ...

  4. What is Ataxia

    Science.gov (United States)

    ... Events | Sign Up for Newsletter What is Ataxia? Ataxia a·tax·i·a, /əˈtaksēə, āˈtaksēə/ noun The ... 553-0020 763-553-0167 (Fax) What is Ataxia? What is Ataxia? Ataxia is a rare neurological ...

  5. Trial in Adult Subjects With Spinocerebellar Ataxia

    Science.gov (United States)

    2017-08-22

    Spinocerebellar Ataxias; Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia Type 2; Spinocerebellar Ataxia Type 3; Spinocerebellar Ataxia Type 6; Spinocerebellar Ataxia Type 7; Spinocerebellar Ataxia Type 8; Spinocerebellar Ataxia Type 10

  6. Friedreich's Ataxia Research Alliance

    Science.gov (United States)

    ... Tools Raising Awareness Advocacy Memorials What is Friedreich's Ataxia? About FARA Mission & Organization Financials Leadership & Staff Scientific ... Tools Raising Awareness Advocacy Memorials What is Friedreich's Ataxia? FARA News / Blogs Ride Ataxia 2017 AAI Grant ...

  7. National Ataxia Foundation

    Science.gov (United States)

    ... Facebook Page - Twitter - YouTube Giving a talk on Ataxia? - Ataxia Presentation Thank You To Our Partners Get ... new NAF App today The new NAF Store - Ataxia Awareness Merchandise & More... Shop NAF Today! Donate Now! ...

  8. Gene for ataxia-telangiectasia complementation group D (ATDC)

    Energy Technology Data Exchange (ETDEWEB)

    Murnane, John P. (San Francisco, CA); Painter, Robert B. (Burlingame, CA); Kapp, Leon N. (San Rafael, CA); Yu, Loh-Chung (Redwood City, CA)

    1995-03-07

    Disclosed herein is a new gene, an AT gene for complementation group D, the ATDC gene and fragments thereof. Nucleic acid probes for said gene are provided as well as proteins encoded by said gene, cDNA therefrom, preferably a 3 kilobase (kb) cDNA, and recombinant nucleic acid molecules for expression of said proteins. Further disclosed are methods to detect mutations in said gene, preferably methods employing the polymerase chain reaction (PCR). Also disclosed are methods to detect AT genes from other AT complementation groups.

  9. Gene for ataxia-telangiectasia complementation group D (ATDC)

    Energy Technology Data Exchange (ETDEWEB)

    Murnane, J.P.; Painter, R.B.; Kapp, L.N.; Yu, L.C.

    1995-03-07

    Disclosed herein is a new gene, an AT gene for complementation group D, the ATDC gene and fragments thereof. Nucleic acid probes for the gene are provided as well as proteins encoded by the gene, cDNA therefrom, preferably a 3 kilobase (kb) cDNA, and recombinant nucleic acid molecules for expression of the proteins. Further disclosed are methods to detect mutations in the gene, preferably methods employing the polymerase chain reaction (PCR). Also disclosed are methods to detect AT genes from other AT complementation groups. 30 figs.

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

    African Journals Online (AJOL)

    TNHJOURNALPH

    also had human immunoglobulin therapy and was ... and mortality in children. Delay in diagnosis and pulmonary complications contribute to a .... Eye movement disorder was seen in ... speech dysarthria was seen in almost all the patients.

  11. Neuroimaging Findings and Repeat Neuroimaging Value in Pediatric Chronic Ataxia.

    Science.gov (United States)

    Salman, Michael S; Chodirker, Bernard N; Bunge, Martin

    2016-11-01

    Chronic ataxia, greater than two months in duration, is encountered relatively commonly in clinical pediatric neurology practise and presents with diagnostic challenges. It is caused by multiple and diverse disorders. Our aims were to describe the neuroimaging features and the value of repeat neuroimaging in pediatric chronic ataxia to ascertain their contribution to the diagnosis and management. A retrospective charts and neuroimaging reports review was undertaken in 177 children with chronic ataxia. Neuroimaging in 130 of 177 patients was also reviewed. Nineteen patients had head computed tomography only, 103 brain magnetic resonance imaging only, and 55 had both. Abnormalities in the cerebellum or other brain regions were associated with ataxia. Neuroimaging was helpful in 73 patients with 30 disorders: It was diagnostic in 9 disorders, narrowed down the diagnostic possibilities in 14 disorders, and revealed important but non-diagnostic abnormalities, e.g. cerebellar atrophy in 7 disorders. Having a normal magnetic resonance imaging scan was mostly seen in genetic diseases or in the early course of ataxia telangiectasia. Repeat neuroimaging, performed in 108 patients, was generally helpful in monitoring disease evolution and in making a diagnosis. Neuroimaging was not directly helpful in 36 patients with 10 disorders or by definition the 55 patients with unknown disease etiology. Normal or abnormal neuroimaging findings and repeat neuroimaging are very valuable in the diagnosis and management of disorders associated with pediatric chronic ataxia.

  12. The patient with ataxia.

    Science.gov (United States)

    Maggs, F G

    2014-01-01

    In this article we look at the causes of ataxia, and how the patient presenting with ataxia should be managed. One of the difficulties in managing the patient with ataxia is that acute ataxia has many causes, but usually these can be teased out by means of a careful history and examination. Investigations can then be targeted at confirming or disproving the differential diagnosis. Some patients with ataxia need to be managed in hospital, but many can be investigated, and receive therapy, as an outpatient.

  13. 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.

  14. Ethnicity and geographic distribution of pediatric chronic ataxia in Manitoba.

    Science.gov (United States)

    Salman, Michael S; Masood, Shaheen; Azad, Meghan; Chodirker, Bernard N

    2014-01-01

    Genetic and environmental factors are important determinants of disease distribution. Several disorders associated with ataxia are known to occur more commonly in certain ethnic groups; for example, the disequilibrium syndrome in the Hutterites. The aim of this study was to determine the ethnic and geographic distribution of pediatric patients with chronic ataxia in Manitoba, Canada. We identified 184 patients less than 17 years-of-age with chronic ataxia during 1991-2008 from multiple sources. Their diagnosis, ethnicity and place of residence were determined following a chart review. Most patients resided in Manitoba (N=177) and the majority in Winnipeg, the provincial capital. Thirty five Aboriginal, 29 Mennonite and 11 Hutterite patients resided in Manitoba. The latter two groups were significantly overrepresented in our cohort. Ataxia telangiectasia, mitochondrial disorders, and non-progressive ataxia of unknown etiology associated with pyramidal tracts signs and developmental delay were significantly more common in Mennonite patients. Four of five patients with neuronal migration disorders associated with chronic ataxia were Aboriginal. Few isolated disorders with chronic ataxia occurred in the 11 Hutterite patients including a Joubert syndrome related disorder. Three disorders associated with chronic ataxia were more prevalent than expected in Mennonites in Manitoba. Few rare disorders were more prevalent in the Hutterite and Aboriginal population. Further research is needed to determine the risk factors underlying these variations in prevalence within different ethnic groups. The unique risk factor profiles of each ethnic group need to be considered in health promotion endeavors. Ethnie et distribution géographique de l'ataxie chronique chez des patients d'âge pédiatrique au Manitoba.

  15. 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.

  16. Inherited ataxia with slow saccades

    Directory of Open Access Journals (Sweden)

    R T Chakor

    2012-01-01

    Full Text Available Ataxia is a symptom of cerebellar dysfunction. Slowly progressive ataxia, dysarthria in an adult with a positive family history suggests an inherited cerebellar ataxia. We present an adult with gradually progressive ataxia and slow saccades. There was history of similar illness in his son. Genetic testing for spinocerebellar ataxia 2 was positive. We discuss the various inherited ataxias, causes of acute, progressive ataxia syndromes, episodic ataxias and ataxia associated with other neurological signs like peripheral neuropathy, pyramidal features, movement disorders and cognitive decline.

  17. Cerebellar and afferent ataxias.

    Science.gov (United States)

    Pandolfo, Massimo; Manto, Mario

    2013-10-01

    Ataxia is the predominant manifestation of many acquired and inherited neurologic disorders affecting the cerebellum, its connections, and the afferent proprioceptive pathways. This article reviews the phenomenology and etiologies of cerebellar and afferent ataxias and provides indications for a rational approach to diagnosis and management. The pathophysiology of ataxia is being progressively understood and linked to the functional organization of the cerebellum. The impact of cerebellar diseases on different neurologic functions has been better defined and shown not to be limited to loss of motor coordination. The role of autoimmunity is increasingly recognized as a cause of sporadic cases of ataxia. Large collaborative studies of long duration are providing crucial information on the clinical spectrum and natural history of both sporadic ataxias (such as the cerebellar form of multiple system atrophy) and inherited ataxias. New dominant and recessive ataxia genes have been identified. On the therapeutic front, progress mostly concerns the development of treatments for Friedreich ataxia. Ataxia is the clinical manifestation of a wide range of disorders. In addition to accurate clinical assessment, MRI plays a major role in the diagnostic workup, allowing us to distinguish degenerative conditions from those due to other types of structural damage to the cerebellar or proprioceptive systems. Diagnostic algorithms based on clinical features, imaging, and neurophysiologic and biochemical parameters can be used to guide genetic testing for hereditary ataxias, the diagnosis of which is likely to be greatly improved by the introduction of new-generation DNA-sequencing approaches. Some rare forms of ataxia can be treated, so their diagnosis should not be missed. Proven symptomatic treatments for ataxia are still lacking, but intensive physical therapy appears to be helpful.

  18. GENETICS OF SPINOCEREBELLAR ATAXIAS

    OpenAIRE

    Hirano, Makito; Ueno, Satoshi

    2004-01-01

    Over the last decade, more than 25 genes responsible for spinocerebellar ataxias (SCAs) have been isolated. This review classifies hereditary SCAs into two groups: autosomal dominant and recessive ataxias, and sunmiarizes the genetic features of these diseases with some clinical characteristics. The unraveling of the molecular cause of a growing number of ataxia has revealed that these diseases are the consequences of a large variety of different mechanisms, even involving novel, unsuspected ...

  19. Genetics Home Reference: episodic ataxia

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions episodic ataxia episodic ataxia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Episodic ataxia is a group of related conditions that affect ...

  20. Spinocerebellar Ataxia Type 10 (SCA10)

    Science.gov (United States)

    NATIONAL ATAXIA FOUNDATION FREQUENTLY ASKED QUESTIONS ABOUT ... Spinocerebellar Ataxia Type 10 (SCA10) What is spinocerebellar ataxia type 10? Spinocerebellar ataxia type 10 (SCA10) is one specific type of ataxia among a group ...

  1. Spinocerebellar Ataxia Type 5 (SCA5)

    Science.gov (United States)

    NATIONAL ATAXIA FOUNDATION FREQUENTLY ASKED QUESTIONS ABOUT ... Spinocerebellar Ataxia Type 5 (SCA5) What is spinocerebellar ataxia type 5? Spinocerebellar ataxia type 5 is one specific type of ataxia among a group of ...

  2. Congenital polycythemia with homozygous and heterozygous mutations of von Hippel-Lindau gene: five new Caucasian patients.

    Science.gov (United States)

    Bento, Maria Celeste; Chang, Ko Tung; Guan, Yongli; Liu, Enli; Caldas, Gabriela; Gatti, Richard A; Prchal, Josef T

    2005-01-01

    We report on five Caucasian patients with congenital polycythemia and mutations of the von Hipple-Lindau (VHL) gene: a compound heterozygote for the novel exon 1 (VHL 235C->T) and previously reported VHL 562C->G mutations; three homozygotes for Chuvash VHL 598C->T mutation; and a heterozygote for VHL 523->G mutation who also has ataxia-telangiectasia; a rare autosomal disease of childhood onset.

  3. Acetazolamide-responsive ataxia.

    Science.gov (United States)

    Kotagal, Vikas

    2012-11-01

    Acetazolamide-responsive ataxia represents a unique collection of genetically distinct episodic ataxia (EA) disorders associated with paroxysmal cerebellar symptoms many of which are responsive to medical treatment with acetazolamide, a carbonic anhydrase inhibitor. Among all of the subtypes of episodic ataxia, types 2 (EA2), 3 (EA3), and 5 (EA5) are thought be the most medication responsive. Some patients with episodic ataxia type 1 (EA1) will also describe improvement with acetazolamide. Each of these individual genetic syndromes is characterized by its own unique mechanism and clinical presentation. In this review, the author provides an overview of the pathophysiology of acetazolamide-responsive ataxia, its natural history, and its clinical management. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  4. 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.

  5. Diet for Ataxia

    Science.gov (United States)

    ... citrus fruits and their juices - as well as bananas or foods with banans as ingredients. Foods with ... his contributions in the production of this fact sheet. WHAT IS GLUTEN ATAXIA? Patients with celiac disease ...

  6. Splenic Involvement in Hereditary Hemorrhagic Telangiectasia

    Directory of Open Access Journals (Sweden)

    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.

  7. Telangiectasia in aluminium workers: a follow up.

    OpenAIRE

    Thériault, G.; Gingras, S.; Provencher, S

    1984-01-01

    A five step investigation was carried out to gain a better understanding of the morbidity that accompanied the development of telangiectasia on aluminium workers and to find its cause. Fifty workers with multiple telangiectasia when matched with normal controls showed the same amount of illness except that evidence of ischaemia on the ECG was found in nine cases and one control. The cases did not show an excess of abnormal biochemical tests. The basic histopathological lesion affected the sur...

  8. Rehabilitative Trial With Cerebello-Spinal tDCS in Neurodegenerative Ataxia

    Science.gov (United States)

    2017-09-05

    Ataxia, Cerebellar; Cerebellar Ataxia; Spinocerebellar Ataxias; Ataxia, Spinocerebellar; Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia Type 2; Spinocerebellar Ataxia 3; Spinocerebellar Degenerations; Friedreich Ataxia; Ataxia With Oculomotor Apraxia; Multiple System Atrophy

  9. Spinocerebellar ataxia type 6.

    Science.gov (United States)

    Solodkin, Ana; Gomez, Christopher M

    2012-01-01

    The autosomal dominant spinocerebellar ataxias (SCA) are a genetically heterogeneous group of neurodegenerative disorders characterized by progressive motor incoordination, in some cases with ataxia alone and in others in association with additional progressive neurological deficits. Spinocerebellar ataxia type 6 (SCA6) is the prototype of a pure cerebellar ataxia, associated with a severe form of progressive ataxia and cerebellar dysfunction. SCA6, originally classified as such by Zhuchenko et al. (1997), is caused by a CAG repeat expansion in the CACNA1A gene which encodes the α1A subunit of the P/Q-type voltage-gated calcium channel. SCA6 is one of ten polyglutamine-encoding CAG nucleotide repeat expansion disorders comprising other neurodegenerative disorders such as Huntington's disease. The present review describes clinical, genetic, and pathological manifestations associated with this illness. Currently, there is no treatment for this neurodegenerative disease. Successful therapeutic strategies must target a valid pathological mechanism; thus, understanding the underlying mechanisms of disease is crucial to finding a proper treatment. Hence, this chapter will discuss as well the molecular mechanisms possibly associated with SCA6 pathology and their implication for the development of future treatment.

  10. Brain pathology of spinocerebellar ataxias

    NARCIS (Netherlands)

    Seidel, Kay; Siswanto, Sonny; Brunt, Ewout R. P.; den Dunnen, Wilfred; Korf, Horst-Werner; Rueb, Udo

    2012-01-01

    The autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of neurodegenerative diseases with progressive ataxia and cerebellar degeneration. The current classification of this disease group is based on the underlying genetic defects and their typical disease courses. Accordin

  11. Brain pathology of spinocerebellar ataxias

    NARCIS (Netherlands)

    Seidel, Kay; Siswanto, Sonny; Brunt, Ewout R. P.; den Dunnen, Wilfred; Korf, Horst-Werner; Rueb, Udo

    2012-01-01

    The autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of neurodegenerative diseases with progressive ataxia and cerebellar degeneration. The current classification of this disease group is based on the underlying genetic defects and their typical disease courses. Accordin

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Adjuvant irradiation in breast cancer patients with A.T.M. gene heterozygous mutations: Special focus on clinical efficacy/toxicity; Toxicite et efficacite de la radiotherapie adjuvante chez les patientes traitees pour un cancer du sein et porteuses d'une mutation heterozygote du gene de l'ataxie-telangiectasie

    Energy Technology Data Exchange (ETDEWEB)

    Chargari, C.; Kirova, Y.M.; Even, C.; Monnier, L.; Dendale, R.; Campana, F.; Fourquet, A. [institut Curie, Dept. de Radiotherapie, 75 - Paris (France); Chargari, C. [Hopital d' Instruction des Armees du Val-de-Grace, Service d' Oncologie Radiotherapie, 75 - Paris (France)

    2009-06-15

    Dysfunction of the ataxia telangiectasia mutated (A.T.M.) gene has been related to defective cell cycle control and genomic instability due to the impaired repair of DNA double strand breaks. Although increased radiosensitivity in A.T.M. heterozygous patients has been suggested in preclinical data, clinical implication of A.T.M. variant remains debated. Despite frequent in vitro hypersensitivity in patients with severe radiation-induced delayed toxicity, heterozygoty for A.T.M. gene does not represent the major cause of unexpected complications after radiation therapy. This might be partially due to potential coexistence of alterations in additional genes that would play a role in development of late radiation-induced adverse response. Although several data suggest that some A.T.M. polymorphisms would increase grade 3 subcutaneous fibrosis at lower doses compared with patients who did not possess these genetic alterations, the relationship between the presence of A.T.M. mutations or sequence variants and radiation-induced toxicity remains controversial in part because of their biological and functional significance. Considering the lack of prospective data, patients with A.T.M. mutation should be considered as candidates for both dose volume and dose reduction clinical trials. (authors)

  14. Childhood Cerebellar Ataxia

    Science.gov (United States)

    Fogel, Brent L.

    2012-01-01

    Childhood presentations of ataxia, an impairment of balance and coordination caused by damage to or dysfunction of the cerebellum, can often be challenging to diagnose. Presentations tend to be clinically heterogeneous but key considerations may vary based on the child's age at onset, the course of illness, and subtle differences in phenotype. Systematic investigation is recommended for efficient diagnosis. In this review, we outline common etiologies and describe a comprehensive approach to the evaluation of both acquired and genetic cerebellar ataxia in children. PMID:22764177

  15. Epilepsy and Spinocerebellar Ataxia

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-07-01

    Full Text Available A large consanguinous family from Saudi Arabia with 4 affected children presenting with an autosomal recessive ataxia, generalized tonic-clonic epilepsy and mental retardation is reported from the Institut de Genetique, Universite Louis Pasteur, Illkirch, France; Division of Pediatric Neurology, King Saud University, Riyadh, Saudi Arabia; and other centers.

  16. Primary Episodic Ataxias

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2007-10-01

    Full Text Available The clinical and genetic diagnosis, genotype-phenotype correlations, pathophysiology and treatment of primary episodic ataxia syndromes are reviewed by researchers from Departments of Neurology, UCLA School of Medicine, Los Angeles, CA; National Hospital for Neurology, Queen Square, London, UK; Johns Hopkins University School of Medicine, Baltimore, MD; and University of Rochester School of Medicine, NY, USA.

  17. [Hereditary episodic ataxia].

    Science.gov (United States)

    Riant, F; Vahedi, K; Tournier-Lasserve, E

    2011-05-01

    Episodic ataxia (EA) designates a group of autosomal dominant channelopathies that manifest as paroxysmal attacks of imbalance and incoordination. EA conditions are clinically and genetically heterogeneous. Seven types of EA have been reported so far but the majority of clinical cases result from two recognized entities. Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia and dysarthria, and interictal myokymia. Onset occurs during the first two decades of life. Associated epilepsy has been reported in some EA1 patients. EA1 is caused by mutations of the KCNA1 gene coding for the voltage-gated potassium channel Kv1.1. Mutation is mostly missense mutations. Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. Episodic ataxia type 2 (EA2) is characterized by episodes lasting longer than in EA1, that manifest by ataxia, dysarthria, vertigo, and also, in most of the cases, an interictal nystagmus. Other clinical features as developmental delay or epilepsy can be present in some patients. Brain MRI shows frequently a vermian atrophy. Onset occurs typically in childhood or early adolescence, but can sometimes be in adulthood. EA2 is caused by mutations in CACNA1A, a gene coding for the neuronal voltage-gated calcium channel Cav1.1. For two-thirds of the cases, mutations lead to a stop codon. This type is most often responsive to acetazolamide that reduces the frequency and severity of attacks, but does not appear to prevent the progression of interictal symptoms. This article summarizes current knowledge on episodic ataxia type 1 and 2 and describes briefly the other types of EA. Molecular analysis of KCNA1 or CACNA1A provides a confirmation of the diagnosis of EA1 and EA2. Other types remain rare phenotypic variants. Among them, only two genes have been identified: CACNB4 in EA5 and SLC1A3 in EA6 and mutations have been found in a very few cases. No mutation

  18. A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia.

    Science.gov (United States)

    Choquet, Karine; La Piana, Roberta; Brais, Bernard

    2015-07-01

    Episodic ataxias (EAs) are a heterogeneous group of neurological disorders characterized by recurrent attacks of ataxia. Mutations in KCNA1 and CACNA1A account for the majority of EA cases worldwide. We recruited a two-generation family affected with EA of unknown subtype and performed whole-exome sequencing on two affected members. This revealed a novel heterozygous mutation c.211_212insA (p.I71NfsX27) leading to a premature stop codon in FGF14. Mutations in FGF14 are known to cause spinocerebellar ataxia type 27 (SCA27). Sanger sequencing confirmed segregation within the family. Our findings expand the phenotypic spectrum of SCA27 by underlining the possible episodic nature of this ataxia.

  19. 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.

  20. Spinocerebellar Ataxia Type 2

    OpenAIRE

    Velázquez-Pérez, Luis; Rodríguez-Labrada, Roberto; Freund, Hans-Joachim; Auburger, Georg

    2012-01-01

    1. Introduction: The autosomal dominant cerebellar ataxias (ADCA) are a clinically, pathologically and genetically heterogeneous group of neurodegenerative disorders caused by degeneration of cerebellum and its afferent and efferent connections. The degenerative process may additionally involves the ponto- medullar systems, pyramidal tracts, basal ganglia, cerebral cortex, peripheral nerves (ADCA I) and the retina (ADCA II), or can be limited to the cerebellum (ADCA III) (Harding et al., 1993...

  1. Cerebral oedema in episodic ataxia.

    Science.gov (United States)

    Crevits, L; Cambron, M; Anseeuw, S

    2009-03-01

    We report a patient with episodic ataxia (presumably of type 2) who developed cerebral oedema secondary to a common infection (presumably viral). Cerebral oedema may be a part of the clinical spectrum of familial episodic ataxia and argues for an overlap with hemiplegic migraine. It is suggested to consider a diagnosis of episodic ataxia or familial hemiplegic migraine in catastrophic reactions to apparent trivial trauma or infection.

  2. Familial episodic ataxia type II.

    Science.gov (United States)

    Mugundhan, K; Thiruvarutchelvan, K; Sivakumar, S

    2011-10-01

    The familial episodic ataxia type II is a rare, dominantly inherited disease characterized by episodes of ataxia of early onset, often with completely normal cerebellar function between attacks. We report a family with affected members who had features of episodic ataxia type II and cerebellar atrophy on MRI imaging. All the affected members were successfully treated with acetazolamide, a carbonic anhydrase inhibitor. They are asymptomatic at 2 year follow-up.

  3. Genetics Home Reference: ataxia-pancytopenia syndrome

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions ataxia-pancytopenia syndrome ataxia-pancytopenia syndrome Printable PDF Open All Close All ... Javascript to view the expand/collapse boxes. Description Ataxia-pancytopenia syndrome is a rare condition that affects ...

  4. Genetics Home Reference: ataxia neuropathy spectrum

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions ataxia neuropathy spectrum ataxia neuropathy spectrum Enable Javascript to view the expand/ ... boxes. Download PDF Open All Close All Description Ataxia neuropathy spectrum is part of a group of ...

  5. 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.

  6. Spinocerebellar ataxia 13 and 25.

    Science.gov (United States)

    Stevanin, Giovanni; Dürr, Alexandra

    2012-01-01

    Spinocerebellar ataxia (SCA) types 13 and 25 are two genetic entities among the autosomal dominant cerebellar ataxias, initially mapped in two French families to chromosomes 19q and 2p, respectively. The SCA13 locus was confirmed by the identification of a second kindred of Filipino ancestry. SCA13 patients have cerebellar ataxia of adult onset, or of early onset when associated with mental impairment. SCA25 patients present with cerebellar ataxia with sensory neuropathy and frequent gastrointestinal features. While the gene responsible for SCA25 is still unknown, missense mutations affecting the potassium channel KCNC3 function have been identified.

  7. Neuro-Ophthalmological Findings in Children and Adolescents with Chronic Ataxia

    Science.gov (United States)

    Salman, Michael S.; Chodirker, Bernard N.

    2015-01-01

    Abstract Chronic ataxia is a challenging problem in paediatric neurology. It is caused by a multitude of disorders that at least initially have similar or non-specific phenotype. Some of these disorders have associated neuro-ophthalmological signs (N-OS). The aims of this study are to describe the N-OS and their frequencies in general and by disease aetiology in paediatric patients with chronic ataxia. The authors identified 184 patients under age 17 years with chronic ataxia (>2 months duration or recurrent) during 1991–2008 from multiple sources. Diagnoses and N-OS were ascertained following charts review. Mean age (SD) was 15 (7.7) years. Median duration of follow-up was 6.4 years. There were 214 N-OS in 115 patients (median = 2, range = 1–5 N-OS/patient). Strabismus was present in 29.3% of patients, nystagmus 27.7%, impaired smooth pursuit 23.4%, hypometric saccades 10.3%, decreased visual acuity 9.2%, abnormal optic discs 8.7%, abnormal pupillary examination 2.7%, hypermetric saccades 2.2%, impaired ductions 1.6%, and abnormal visual fields in 1.1% of patients. N-OS were reported most commonly among patients with the following disorders (commonest N-OS): hypoxic-ischaemic encephalopathy following birth (strabismus), episodic ataxia (nystagmus), neuronal ceroid lipofuscinosis (abnormal optic discs), neuronal migration disorder (strabismus), ischaemic stroke (nystagmus), Joubert syndrome–related disorders (strabismus), leukodystrophy (nystagmus), Friedreich ataxia (hypometric saccades, impaired smooth pursuit, nystagmus), mitochondrial disease (strabismus, nystagmus), ataxia telangiectasia (impaired smooth pursuit), and Angelman syndrome (strabismus). N-OS occur commonly in children with chronic ataxia. Although non-specific, they vary with disease aetiology, potentially aiding in the assessment of these patients. PMID:27928345

  8. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

    Science.gov (United States)

    Mitoma, Hiroshi; Adhikari, Keya; Aeschlimann, Daniel; Chattopadhyay, Partha; Hadjivassiliou, Marios; Hampe, Christiane S; Honnorat, Jérôme; Joubert, Bastien; Kakei, Shinji; Lee, Jongho; Manto, Mario; Matsunaga, Akiko; Mizusawa, Hidehiro; Nanri, Kazunori; Shanmugarajah, Priya; Yoneda, Makoto; Yuki, Nobuhiro

    2016-04-01

    In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.

  9. Genetics of the dominant ataxias

    NARCIS (Netherlands)

    Verbeek, Dineke S.; van de Warrenburg, Bart P. C.

    2011-01-01

    The relevant clinical, genetic, and cell biologic aspects of the dominantly inherited spinocerebellar ataxias (SCAs) are reviewed in this article. SCAs are diseases of the entire nervous system; in addition to cerebellar ataxia, the central (but not obligate) disease feature, many noncerebellar comp

  10. Falls in degenerative cerebellar ataxias

    NARCIS (Netherlands)

    van de Warrenburg, Bart P C; Steijns, Janneke A G; Munneke, Marten; Kremer, Berry P H; Bloem, Bastiaan R

    2005-01-01

    We retrospectively and prospectively assessed the frequency and characteristics of falls in patients with degenerative cerebellar ataxias. The results show that falls occur very frequently in patients with degenerative cerebellar ataxias and that these falls are serious and often lead to injuries or

  11. Telangiectasia in aluminium workers: a follow up.

    Science.gov (United States)

    Thériault, G; Gingras, S; Provencher, S

    1984-08-01

    A five step investigation was carried out to gain a better understanding of the morbidity that accompanied the development of telangiectasia on aluminium workers and to find its cause. Fifty workers with multiple telangiectasia when matched with normal controls showed the same amount of illness except that evidence of ischaemia on the ECG was found in nine cases and one control. The cases did not show an excess of abnormal biochemical tests. The basic histopathological lesion affected the surrounding tissue rather than the vessels themselves. Working in the current environment and wearing masks seems to protect young workers from developing the lesions. The Soderberg and not the prebake process was associated with the lesions; the causative agent is probably a gas that contains both hydrocarbons and fluoride components emitted from the electrolytic reactors.

  12. Prevalence of ataxia in children

    Science.gov (United States)

    Stoyanov, Cristina T.; Marasigan, Rhul; Jenkins, Mary E.; Konczak, Jürgen; Morton, Susanne M.; Bastian, Amy J.

    2014-01-01

    Objective: To estimate the prevalence of childhood ataxia resulting from both genetic and acquired causes. Methods: A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Five databases were searched for articles reporting a frequency measure (e.g., prevalence, incidence) of ataxia in children. Included articles were first grouped according to the World Health Organization (WHO) regions and subsequently classified according to etiology (genetic, acquired, or mixed). Each article was assessed for its risk of bias on the domains of sampling, measurement, and analysis. Incidence values were converted to prevalence estimates whenever possible. European prevalence estimates for different etiologies of ataxia were summed to gauge the overall prevalence of childhood ataxia. Results: One hundred fifteen articles were included in the review. More than 50% of the data originated from the Europe WHO region. Data from this region also showed the least susceptibility to bias. Little data were available for Africa and Southeast Asia. The prevalence of acquired ataxias was found to vary more greatly across regions than the genetic ataxias. Ataxic cerebral palsy was found to be a significant contributor to the overall prevalence of childhood ataxia across WHO regions. The prevalence of childhood ataxias in Europe was estimated to be ∼26/100,000 children and likely reflects a minimum prevalence worldwide. Conclusions: The findings show that ataxia is a common childhood motor disorder with a higher prevalence than previously assumed. More research concerning the epidemiology, assessment, and treatment of childhood ataxia is warranted. PMID:24285620

  13. Friedreich Ataxia: Molecular Mechanisms, Redox Considerations, and Therapeutic Opportunities

    Science.gov (United States)

    Lefevre, Sophie; Sliwa, Dominika; Seguin, Alexandra; Camadro, Jean-Michel; Lesuisse, Emmanuel

    2010-01-01

    Abstract Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repeat expansion, in the first intron of the FXN gene. Fewer than 5% of the patients are heterozygous and carry point mutations in the other allele. The molecular consequences of the GAA triplet expansion is transcription silencing and reduced expression of the encoded mitochondrial protein, frataxin. The precise cellular role of frataxin is not known; however, it is clear now that several mitochondrial functions are not performed correctly in patient cells. The affected functions include respiration, iron–sulfur cluster assembly, iron homeostasis, and maintenance of the redox status. This review highlights the molecular mechanisms that underlie the disease phenotypes and the different hypothesis about the function of frataxin. In addition, we present an overview of the most recent therapeutic approaches for this severe disease that actually has no efficient treatment. Antioxid. Redox Signal. 13, 0000–0000. PMID:20156111

  14. Chinese patients with Huntington's disease initially presenting with spinocerebellar ataxia.

    Science.gov (United States)

    Dong, Y; Sun, Y-M; Liu, Z-J; Ni, W; Shi, S-S; Wu, Z-Y

    2013-04-01

    Recent studies have described Huntington's disease (HD) patients with atypical onset of ataxia. Symptoms in these patients can overlap with those of spinocerebellar ataxia (SCA). We retrospectively examined clinical data for 82 HD probands and found 7 had initially been clinically diagnosed as SCA cases. Clinical features in these patients were further investigated and the number of CAG repeats in the huntingtin (HTT) gene was determined by direct sequencing. Genetic screenings for SCAs in the 7 patients were all negative. By contrast, HTT was heterozygous in each patient. The distribution of CAG number in the 7 patients was statistically the same as that in the other 75 patients. Each of 7 HD patients had presented with atypical onset of ataxia. The mean time from onset to HTT genetic testing was 5.6 ± 5.52 years. Three of the patients developed chorea, but the others did not. Our observations confirm the clinical heterogeneity of HD in Han Chinese. Based on these findings, testing for HTT expansions should be considered for clinically diagnosed SCA patients who test negatively in genetic screening of SCA genes.

  15. MME mutation in dominant spinocerebellar ataxia with neuropathy (SCA43).

    Science.gov (United States)

    Depondt, Chantal; Donatello, Simona; Rai, Myriam; Wang, François Charles; Manto, Mario; Simonis, Nicolas; Pandolfo, Massimo

    2016-10-01

    To identify the causative gene mutation in a 5-generation Belgian family with dominantly inherited spinocerebellar ataxia and polyneuropathy, in which known genetic etiologies had been excluded. We collected DNA samples of 28 family members, including 7 living affected individuals, whose clinical records were reviewed by a neurologist experienced in ataxia. We combined linkage data of 21 family members with whole exome sequencing in 2 affected individuals to identify shared heterozygous variants mapping to potentially linked regions. Variants were screened for rarity and for predicted damaging effect. A candidate mutation was confirmed by Sanger sequencing and tested for cosegregation with the disease. Affected individuals presented with late-onset sensorimotor axonal polyneuropathy; all but one also had cerebellar ataxia. We identified a variant in the MME gene, p.C143Y, that was absent from control databases, cosegregated with the phenotype, and was predicted to have a strong damaging effect on the encoded protein by all algorithms we used. MME encodes neprilysin (NEP), a zinc-dependent metalloprotease expressed in most tissues, including the central and peripheral nervous systems. The mutated cysteine 143 forms a disulfide bridge, which is 100% conserved in NEP and in similar enzymes. The recent identification of recessive MME mutations in 10 unrelated individuals from Japan with axonal polyneuropathy further supports the causality of the mutation, despite the dominant mode of inheritance and the presence of cerebellar involvement in our study family. Functional studies are needed to identify the mechanisms underlying these differences.

  16. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures.

    Science.gov (United States)

    Jen, J C; Wan, J; Palos, T P; Howard, B D; Baloh, R W

    2005-08-23

    Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause episodic ataxia, hemiplegic migraine, and seizures. Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter. We examined our patient population with episodic ataxia and hemiplegic migraine but with no mutation in either CACNA1A or ATP1A2. We looked for mutations in SLC1A3, which encodes the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft. A patient with episodic ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls. Expression studies of the mutant EAAT1 showed decreased expression of the protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant EAAT1 decreased the activity of wild-type EAAT1 but not of two other transporters EAAT2 or EAAT3, suggesting that mutant EAAT1 specifically multimerizes with wild-type EAAT1 to exert its dominant negative effect. Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and episodic ataxia.

  17. Parkinsonism in spinocerebellar ataxia.

    Science.gov (United States)

    Park, Hyeyoung; Kim, Han-Joon; Jeon, Beom S

    2015-01-01

    Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease (PD) like phenotype and atypical parkinsonism have been described especially in SCA2, SCA3, and SCA17 with geographic differences in prevalence. SCA2 is the most frequently reported subtype of SCA related to parkinsonism worldwide. Parkinsonism in SCA2 has unique genetic characteristics, such as low number of expansions and interrupted structures, which may explain the sporadic cases with low penetrance. Parkinsonism in SCA17 is more remarkable in Asian populations especially in Korea. In addition, an unclear cutoff of the pathologic range is the key issue in SCA17 related parkinsonism. SCA3 is more common in western cohorts. SCA6 and SCA8 have also been reported with a PD-like phenotype. Herein, we reviewed the epidemiologic, clinical, genetic, and pathologic features of parkinsonism in SCAs.

  18. Cerebral abscesses among Danish patients with hereditary haemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, A D; Tørring, P M; Nissen, H;

    2013-01-01

    Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs), which due to paradoxical embolization may cause cerebral abscess.......Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs), which due to paradoxical embolization may cause cerebral abscess....

  19. Audiological findings in children with ataxia-telangiectasia (A-T) syndrome.

    Science.gov (United States)

    Afifi, Pretty O; Elsanadiky, Hanaa Hussein

    2017-01-01

    To assess peripheral and central hearing in children with A-T. 3 children diagnosed with A-T according to the diagnostic criteria for A-T of the European Society for Immunodeficiencies. Involuntary movements were seen in the form of chorea-athetosis together with tremors. They were examined to assess both peripheral and central hearing was assessed (hearing thresholds). Sound-field testing, tympanometry, acoustic reflexes, Otoacoustic Emissions (OAEs) and Auditory Brainstem Responses (ABR) were done for all of them. Basic Audiological evaluation is of a limited value as the children are not co-operative. Sound field testing could not be done. Bilateral normal middle ear functions as reflected by Tympanometry and Acoustic Reflexes. Advanced Audiological evaluation including OAEs and ABR are more valuable in assessing hearing in children with A-T. Bilateral pass response at all test frequencies in DPOAEs. Abnormal ABR findings were obtained in the form of a delay in wave V latency more than 2 SD with subsequent increased in I-V interpeak latency with no significant interaural latency difference. Consistent with bilateral normal peripheral hearing sensitivity with central hearing affection. The rarity of the disease, make it difficult to be applied on many cases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. High-LET Radiation Induced Chromosome Aberrations in Normal and Ataxia Telangiectasia Fibroblast Cells

    Science.gov (United States)

    Kawata, Tetsuya; George, Ms Kerry; Cucinotta, Francis A.; Shigematsu, Naoyuki; Ito, Hisao; Furusawa, Yoshiya; Uno, Takashi

    We investigated the effects of heavy ions beams on chromosomal aberrations in normal and AT cells. Normal and AT fibroblast cells arrested at G0/G1 phase were irradiated with 2 Gy of X-rays, 490 MeV/u Silicon (LET 55 keV/micron), 500 MeV/u Iron (LET 185 keV/micron) and 200 MeV/u Iron (LET 440 keV/micron) particles, and then cells were allowed to repair for 24 hours at 37 degrees before subculture. Calyculin-A induced PCC method was employed to collect G2/M chromosomes and whole DNA probes 1 and 3 were used to analyze chromosomal aberrations such as color-junctions, deletions, simple exchanges (incomplete and reciprocal exchanges) and complex-type exchanges. The percentages of aberrant cells were higher when normal and AT cells were exposed to heavy ions compared to X-rays, and had a tendency to increase with increasing LET up to 185 keV/micron and then decreased at 440 keV/micron. When the frequency of color-junctions per cell was compared after X-ray exposure, AT cells had around three times higher frequency of color-junctions (mis-rejoining) than normal cells. However, at 185 keV/micron there was no difference in the frequency of color-junctions between two cell lines. It was also found that the frequency of simple exchanges per cell was almost constant in AT cells regardless LET levels, but it was LET dependent for normal cells. Interestingly, the frequency of simple exchanges was higher for normal fibroblast cells when it was compared at 185 keV/micron, but AT cells had more complex-type exchanges at the same LET levels. Heavy ions are more efficient in inducing chromosome aberrations in normal and AT cells compared to X-rays, and the aberration types between normal and AT fibroblast appeared different probably due to difference in the ATM gene function.

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

    Science.gov (United States)

    Smida, Michal; Fece de la Cruz, Ferran; Kerzendorfer, Claudia; Uras, Iris Z; Mair, Barbara; Mazouzi, Abdelghani; Suchankova, Tereza; Konopka, Tomasz; Katz, Amanda M; Paz, Keren; Nagy-Bojarszky, Katalin; Muellner, Markus K; Bago-Horvath, Zsuzsanna; Haura, Eric B; Loizou, Joanna I; Nijman, Sebastian M B

    2016-12-06

    Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.

  2. 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

    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...

  3. Genetics Home Reference: Friedreich ataxia

    Science.gov (United States)

    ... Hypertrophic Cardiomyopathy National Institute of Neurological Disorders and Stroke: Friedreich's Ataxia Fact Sheet General Information from MedlinePlus (5 links) Diagnostic Tests Drug Therapy Genetic Counseling Palliative Care Surgery and Rehabilitation Related Information ...

  4. Cardiac transplantation in Friedreich ataxia.

    Science.gov (United States)

    Yoon, Grace; Soman, Teesta; Wilson, Judith; George, Kristen; Mital, Seema; Dipchand, Anne I; McCabe, Jane; Logan, William; Kantor, Paul

    2012-09-01

    In this article, we describe a 14-year-old boy with a confirmed diagnosis of Friedreich ataxia who underwent cardiac transplantation for left ventricular failure secondary to dilated cardiomyopathy with restrictive physiology. His neurological status prior to transplantation reflected early signs of neurological disease, with evidence of dysarthria, weakness, mild gait impairment, and limb ataxia. We review the ethical issues considered during the process leading to the decision to offer cardiac transplantation.

  5. Cardiac Transplantation in Friedreich Ataxia

    OpenAIRE

    Yoon, Grace; Soman, Teesta; Wilson, Judith; George, Kristen; Mital, Seema; Dipchand, Anne I; McCabe, Jane; Logan, William; Kantor, Paul

    2012-01-01

    In this paper, we describe a 14-year-old boy with a confirmed diagnosis of Friedreich ataxia who underwent cardiac transplantation for left ventricular failure secondary to dilated cardiomyopathy with restrictive physiology. His neurological status prior to transplantation reflected early signs of neurologic disease, with evidence of dysarthria, weakness, mild gait impairment, and limb ataxia. We review the ethical issues considered during the process leading to the decision to offer cardiac ...

  6. Episodic ataxias 1 and 2.

    Science.gov (United States)

    Baloh, Robert W

    2012-01-01

    The episodic ataxias are autosomal dominant disorders usually beginning in the first two decades of life. Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia, typically lasting seconds, and interictal myokymia, while episodic ataxia type 2 (EA2) is manifested by longer episodes of ataxia (hours) with interictal nystagmus. The EA1 gene (KCNA1) codes for the six transmembrane segments (S1 to S6) of the Kv1.1 potassium channel subunit and the EA2 gene (CACNA1A) encodes for the Ca(v)2.1 subunit of the P/Q calcium channel complex. EA1 mutations are always missense while most EA2 mutations disrupt the reading frame. Studies of the biophysical properties of the mutant Kv1.1 and Ca(v)2.1 channels in Xenopus oocytes and mammalian cell lines demonstrate clear physiologic consequences of the genetic mutations although no consistent pattern for genotype-phenotype correlation has emerged. Genetic testing for EA1 and EA2 is available, but since no single mutation is prominent for either KCNA1 or CACNA1A, all of the coding regions of the genes need to be screened for mutations. Acetazolamide can be dramatic in controlling episodes of ataxia with EA2 but is typically less beneficial with EA1. 2012 Elsevier B.V. All rights reserved.

  7. Characterization of the dominant inheritance mechanism of Episodic Ataxia type 2.

    Science.gov (United States)

    Dorgans, Kevin; Salvi, Julie; Bertaso, Federica; Bernard, Ludivine; Lory, Philippe; Doussau, Frederic; Mezghrani, Alexandre

    2017-10-01

    Episodic Ataxia type 2 (EA2) is an autosomal dominant neuronal disorder linked to mutations in the Cav2.1 subunit of P/Q-type calcium channels. In vitro studies have established that EA2 mutations induce loss of channel activity and that EA2 mutants can exert a dominant negative effect, suppressing normal Cav2.1 activity through protein misfolding and trafficking defects. To date, the role of this mechanism in the disease pathogenesis is unknown because no animal model exists. To address this issue, we have generated a mouse bearing the R1497X nonsense mutation in Cav2.1 (Cav2.1(R1497X)). Phenotypic analysis of heterozygous Cav2.1(R1497X) mice revealed ataxia associated with muscle weakness and generalized absence epilepsy. Electrophysiological studies of the cerebellar circuits in heterozygous Cav2.1(R1497X) mice highlighted severe dysregulations in synaptic transmission of the two major excitatory inputs as well as alteration of the spontaneous activity of Purkinje cells. Moreover, these neuronal dysfunctions were associated with a strong suppression of Cav2.1 channel expression in the cerebellum of heterozygous Cav2.1(R1497X) mice. Finally, the presence of Cav2.1 in cerebellar lipid raft microdomains was strongly impaired in heterozygous Cav2.1(R1497X) mice. Altogether, these results reveal a pathogenic mechanism for EA2 based on a dominant negative activity of mutant channels. Copyright © 2017. Published by Elsevier Inc.

  8. 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.

  9. Brain pathology of spinocerebellar ataxias.

    Science.gov (United States)

    Seidel, Kay; Siswanto, Sonny; Brunt, Ewout R P; den Dunnen, Wilfred; Korf, Horst-Werner; Rüb, Udo

    2012-07-01

    The autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of neurodegenerative diseases with progressive ataxia and cerebellar degeneration. The current classification of this disease group is based on the underlying genetic defects and their typical disease courses. According to this categorization, ADCAs are divided into the spinocerebellar ataxias (SCAs) with a progressive disease course, and the episodic ataxias (EA) with episodic occurrences of ataxia. The prominent disease symptoms of the currently known and genetically defined 31 SCA types result from damage to the cerebellum and interconnected brain grays and are often accompanied by more specific extra-cerebellar symptoms. In the present review, we report the genetic and clinical background of the known SCAs and present the state of neuropathological investigations of brain tissue from SCA patients in the final disease stages. Recent findings show that the brain is commonly seriously affected in the polyglutamine SCAs (i.e. SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) and that the patterns of brain damage in these diseases overlap considerably in patients suffering from advanced disease stages. In the more rarely occurring non-polyglutamine SCAs, post-mortem neuropathological data currently are scanty and investigations have been primarily performed in vivo by means of MRI brain imaging. Only a minority of SCAs exhibit symptoms and degenerative patterns allowing for a clear and unambiguous diagnosis of the disease, e.g. retinal degeneration in SCA7, tau aggregation in SCA11, dentate calcification in SCA20, protein depositions in the Purkinje cell layer in SCA31, azoospermia in SCA32, and neurocutaneous phenotype in SCA34. The disease proteins of polyglutamine ataxias and some non-polyglutamine ataxias aggregate as cytoplasmic or intranuclear inclusions and serve as morphological markers. Although inclusions may impair axonal transport, bind transcription factors, and block protein

  10. Acetazolamide-responsive exercise-induced episodic ataxia associated with a novel homozygous DARS2 mutation.

    Science.gov (United States)

    Synofzik, Matthis; Schicks, Julia; Lindig, Tobias; Biskup, Saskia; Schmidt, Thorsten; Hansel, Jochen; Lehmann-Horn, Frank; Schöls, Ludger

    2011-10-01

    Leukoencephalopathy with brain stem and spinal cord involvement and brain lactate elevation (LBSL) was recently shown to be caused by mutations in the DARS2 gene, encoding a mitochondrial aspartyl-tRNA synthetase. So far, affected individuals were invariably compound heterozygous for two mutations in DARS2, and drug treatments have remained elusive. Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions. The patient presented with exercise-induced paroxysmal gait ataxia and areflexia as an atypical phenotype associated with a novel homozygous DARS2 mutation. These features showed an excellent dose-dependent, sustained treatment response to a carbonic anhydrase inhibitor. Pathogenic mutations in episodic ataxia genes were excluded, thus making it highly unlikely that this phenotype was because of episodic ataxia as a second disorder besides LBSL. This case demonstrates that DARS2 mutation homozygosity is not lethal, as suggested earlier, but compatible with a rather benign disease course. More importantly, it extends the phenotypic spectrum of LBSL and reveals that at least some DARS2-associated phenotypic features might be readily treatable. However, future observations of paroxsymal ataxia and, possibly, areflexia in other DARS2-mutated patients are warranted to further corroborate our finding that DARS2 mutations can lead to a paroxsymal ataxia phenotype.

  11. Genetics Home Reference: spinocerebellar ataxia type 3

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions SCA3 spinocerebellar ataxia type 3 Printable PDF Open All Close All ... to view the expand/collapse boxes. Description Spinocerebellar ataxia type 3 ( SCA3 ) is a condition characterized by ...

  12. Genetics Home Reference: spinocerebellar ataxia type 2

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions SCA2 spinocerebellar ataxia type 2 Printable PDF Open All Close All ... to view the expand/collapse boxes. Description Spinocerebellar ataxia type 2 ( SCA2 ) is a condition characterized by ...

  13. 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...

  14. Genetics Home Reference: spinocerebellar ataxia type 1

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions SCA1 spinocerebellar ataxia type 1 Printable PDF Open All Close All ... to view the expand/collapse boxes. Description Spinocerebellar ataxia type 1 ( SCA1 ) is a condition characterized by ...

  15. Ataxias and Cerebellar or Spinocerebellar Degeneration

    Science.gov (United States)

    ... Disorders Definition Treatment Prognosis Clinical Trials Organizations Publications Definition Ataxia often occurs when parts of the nervous system that control movement are damaged. People with ataxia experience a failure of muscle control in their arms ...

  16. Pulmonary hypertension in hereditary haemorrhagic telangiectasia

    Institute of Scientific and Technical Information of China (English)

    Veronique; MM; Vorselaars; Sebastiaan; Velthuis; Repke; J; Snijder; Jan; Albert; Vos; Johannes; J; Mager; Martijn; C; Post

    2015-01-01

    Hereditary haemorrhagic telangiectasia(HHT) is an autosomal dominant inherited disorder characterised by vascular malformations in predominantly the brain,liverand lungs.Pulmonary hypertension(PH) is increasingly recognised as a severe complication of HHT.PH may be categorised into two distinct types in patients with HHT.Post-capillary PH most often results from a high pulmonary blood flow that accompanies the high cardiac output state associated with liver arteriovenous malformations.Less frequently,the HHT-related gene mutations in ENG or ACVRL1 appear to predispose patients with HHT to develop pre-capillary pulmonary arterial hypertension.Differentiation between both forms of PH by right heart catheterisation is essential,since both entities are associated with severe morbidity and mortality with different treatment options.Therefore all HHT patients should be referred to an HHT centre.

  17. Novel Point Mutations in Frataxin Gene in Iranian Patients with Friedreich’s Ataxia

    Directory of Open Access Journals (Sweden)

    Mohammad Mehdi HEIDARI*

    2014-01-01

    Full Text Available How to Cite This Article: Heidari MM , Khatami M, Pourakrami J. Novel Point Mutations in Frataxin Gene in Iranian Patients withFriedreich’s Ataxia. Iran J Child Neurol. 2014 Winter; 8(1:32-36. ObjectiveFriedreich’s ataxia is the most common form of hereditary ataxia with autosomal recessive pattern. More than 96% of patients are homozygous for GAA repeat extension on both alleles in the first intron of FXN gene and the remainingpatients have been shown to be heterozygous for a GAA extension in one allele and point mutation in other allele.Materials & MethodsIn this study, exons of 1, 2, 3, and 5 of frataxin gene were searched by single strand conformation polymorphism polymerase chain reaction (PCR-SSCP in 5 patients with GAA extension in one allele. For detection of exact mutation,samples with band shifts were sent for DNA sequencing.Results Three novel point mutations were found in patients heterozygous for the GAA repeat expansion, p.S81A, p.Y123D, and p.S192C. ConclusionOur results showed that these point mutations in one allele with GAA extension in another allele are associated with FRDA signs. Thus, these results emphasize the importance of performing molecular genetic analysis for point mutations inFRDA patients. References:Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: an overview. J Med Genet 2000;37(1:1-8.Harding AE, Zilkha KJ. ‘Pseudo-dominant’ inheritance in Friedreich’s ataxia. J Med Genet 1981;18(4:285-7.Schulz JB, Boesch S, Burk K, Durr A, Giunti P, Mariotti C, et al. Diagnosis and treatment of Friedreich ataxia: a European perspective. Nat Rev Neurol 2009;5(4:222-34.Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 1997;6(11:1771-80.Sharma R, De Biase I, Gomez M, Delatycki MB, Ashizawa T, Bidichandani SI. Friedreich ataxia in carriers of unstable borderline

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

    National Research Council Canada - National Science Library

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

    2017-01-01

    ... hemorrhagic telangiectasia (HHT), a rare disease in which epistaxis is a cardinal symptom. Purpose To assess the quality of life in a population of Spanish patients with HHT and compare it with the general population...

  19. Clinical challenges in the ataxias

    Institute of Scientific and Technical Information of China (English)

    S.H. Subramony

    2011-01-01

    Ataxias are rare diseases and the etiologic heterogeneity make individual entities even rarer. There are still substantial numbers of patients who are still poorly understood. Available assessment techniques still point to large numbers of patients needed for clinical trials and the need for cooperative efforts, better assessment tools and novel trial designs. Better understanding of neural circuitry abnormalities may lead to more effective symptomatic therapy. Opportunities exist for targeting at risk individuals for effective therapies but how this can be done is not clear. Preventive strategies may become feasible in many ataxias.

  20. [The genetics of spinocerebellar ataxias].

    Science.gov (United States)

    Jacobi, H; Minnerop, M; Klockgether, T

    2013-02-01

    Spinocerebellar ataxias are genetically heterogeneous autosomal dominant ataxia disorders. To date more than 30 different subtypes are known. In Germany particularly SCA1, SCA2, SCA3 and SCA6 are prevalent, as well as the less frequent subtypes SCA5, SCA14, SCA15, SCA17 and SCA28. Genetic causes range from coding repeat expansions (polyglutamine diseases), to non-coding expansions as well as conventional mutations. In some subtypes the genetic background is currently unknown. Age of onset, typical clinical findings and geographic distribution may help to reach a correct diagnosis; however a definitive diagnosis requires molecular genetic testing.

  1. Novel Point Mutations in Frataxin Gene in Iranian Patients with Friedreich’s Ataxia

    Directory of Open Access Journals (Sweden)

    Mohammad Mehdi HEIDARI*

    2013-12-01

    Full Text Available Abstract How to Cite This Article: Heidari MM , Khatami M, Pourakrami J. Novel Point Mutations in Frataxin Gene in Iranian Patients with Friedreich’s Ataxia. Iran J Child Neurol. 2014 Winter; 8(1:32-36. Objective Friedreich’s ataxia is the most common form of hereditary ataxia with autosomal recessive pattern. More than 96% of patients are homozygous for GAA repeat extension on both alleles in the first intron of FXN gene and the remaining patients have been shown to be heterozygous for a GAA extension in one allele and point mutation in other allele. Materials & Methods In this study, exons of 1, 2, 3, and 5 of frataxin gene were searched by single strand conformation polymorphism polymerase chain reaction (PCR-SSCP in 5 patients with GAA extension in one allele. For detection of exact mutation, samples with band shifts were sent for DNA sequencing. Results Three novel point mutations were found in patients heterozygous for the GAA repeat expansion, p.S81A, p.Y123D, and p.S192C. Conclusion Our results showed that these point mutations in one allele with GAA extension in another allele are associated with FRDA signs. Thus, these results emphasize the importance of performing molecular genetic analysis for point mutations in FRDA patients.

  2. Hereditary Cerebellar Ataxias: A Korean Perspective

    Directory of Open Access Journals (Sweden)

    Ji Sun Kim

    2015-05-01

    Full Text Available Hereditary ataxia is a heterogeneous disorder characterized by progressive ataxia combined with/without peripheral neuropathy, extrapyramidal symptoms, pyramidal symptoms, seizure, and multiple systematic involvements. More than 35 autosomal dominant cerebellar ataxias have been designated as spinocerebellar ataxia, and there are 55 recessive ataxias that have not been named systematically. Conducting genetic sequencing to confirm a diagnosis is difficult due to the large amount of subtypes with phenotypic overlap. The prevalence of hereditary ataxia can vary among countries, and estimations of prevalence and subtype frequencies are necessary for planning a diagnostic strategy in a specific population. This review covers the various hereditary ataxias reported in the Korean population with a focus on the prevalence and subtype frequencies as the clinical characteristics of the various subtypes.

  3. 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

  4. 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.

    2014-01-01

    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

  5. Movement disorders in spinocerebellar ataxias

    NARCIS (Netherlands)

    Gaalen, J. van; Giunti, P.; Warrenburg, B.P.C. van de

    2011-01-01

    Autosomal dominant spinocerebellar ataxias (SCAs) can present with a large variety of noncerebellar symptoms, including movement disorders. In fact, movement disorders are frequent in many of the various SCA subtypes, and they can be the presenting, dominant, or even isolated disease feature. When c

  6. Reliability and discriminant validity of ataxia rating scales in early onset ataxia.

    Science.gov (United States)

    Brandsma, Rick; Lawerman, Tjitske F; Kuiper, Marieke J; Lunsing, Roelineke J; Burger, Huibert; Sival, Deborah A

    2017-04-01

    To determine whether ataxia rating scales are reliable disease biomarkers for early onset ataxia (EOA). In 40 patients clinically identified with EOA (28 males, 12 females; mean age 15y 3mo [range 5-34y]), we determined interobserver and intraobserver agreement (interclass correlation coefficient [ICC]) and discriminant validity of ataxia rating scales (International Cooperative Ataxia Rating Scale [ICARS], Scale for Assessment and Rating of Ataxia [SARA], and Brief Ataxia Rating Scale [BARS]). Three paediatric neurologists independently scored ICARS, SARA and BARS performances recorded on video, and also phenotyped the primary and secondary movement disorder features. When ataxia was the primary movement disorder feature, we assigned patients to the subgroup 'EOA with core ataxia' (n=26). When ataxia concurred with other prevailing movement disorders (such as dystonia, myoclonus, and chorea), we assigned patients to the subgroup 'EOA with comorbid ataxia' (n=12). ICC values were similar in both EOA subgroups of 'core' and 'comorbid' ataxia (0.92-0.99; ICARS, SARA, and BARS). Independent of the phenotype, the severity of the prevailing movement disorder predicted the ataxia rating scale scores (β=0.83-0.88; pataxia rating scales is high. However, the discriminative validity for 'ataxia' is low. For adequate interpretation of ataxia rating scale scores, application in uniform movement disorder phenotypes is essential. © 2016 Mac Keith Press.

  7. Late onset hereditary episodic ataxia.

    Science.gov (United States)

    Damak, M; Riant, F; Boukobza, M; Tournier-Lasserve, E; Bousser, M-G; Vahedi, K

    2009-05-01

    Episodic ataxias (EA) are hereditary paroxysmal neurological diseases with considerable clinical and genetic heterogeneity. So far seven loci have been reported and four different genes have been identified. Analysis of additional sporadic or familial cases is needed to better delineate the clinical and genetic spectrum of EA. A two generation French family with late onset episodic ataxia was examined. All consenting family members had a brain MRI with volumetric analysis of the cerebellum. Haplotype analysis was performed for the EA2 locus (19p13), the EA5 locus (2q22), the EA6 locus (5p13) and the EA7 locus (19q13). Mutation screening was performed for all exons of CACNA1A (EA2), EAAT1 (EA6) and the coding sequence of KCNA1 (EA1). Four family members had episodic ataxia with onset between 48 and 56 years of age but with heterogeneity in the severity and duration of symptoms. The two most severely affected had daily attacks of EA with a slowly progressive and disabling permanent cerebellar ataxia and a poor response to acetazolamide. Brain MRI showed in three affected members a decrease in the ratio of cerebellar volume:total intracranial volume, indicating cerebellar atrophy. No deleterious mutation was found in CACNA1A, SCA6, EAAT1 or KCNA1. In addition, the EA5 locus was excluded. A new phenotype of episodic ataxia has been described, characterised clinically by a late onset and progressive permanent cerebellar signs, and genetically by exclusion of the genes so far identified in EA.

  8. Orthology Guided Assembly in highly heterozygous crops

    DEFF Research Database (Denmark)

    Ruttink, Tom; Sterck, Lieven; Rohde, Antje

    2013-01-01

    Despite current advances in next-generation sequencing data analysis procedures, de novo assembly of a reference sequence required for SNP discovery and expression analysis is still a major challenge in genetically uncharacterized, highly heterozygous species. High levels of polymorphism inherent...

  9. Novel missense variant of CACNA1A gene in a Slovak family with episodic ataxia type 2.

    Science.gov (United States)

    Petrovicova, Andrea; Brozman, Miroslav; Kurca, Egon; Gobo, Tibor; Dluha, Jana; Kalmarova, Klaudia; Nosal, Vladimir; Hikkelova, Martina; Krajciova, Adriana; Burjanivova, Tatiana; Sivak, Stefan

    2017-03-01

    Episodic ataxias (EAs) are rare dominantly inherited neurological disorders characterized by recurrent episodes of ataxia lasting minutes to hours. The most common subtype is EA type 2 (EA2) caused by pathogenic variants of calcium voltage-gated channel subunit alpha1 A gene (CACNA1A) on chromosome 19p13. We examined a Slovak three-generation family. Genomic DNA of the family members was extracted from peripheral blood and amplified by polymerase chain reaction. CACNA1A variants were screened by Sanger sequencing. We identified four family members with recurrent episodes of ataxia. Complex differential diagnosis was performed. Genetic analysis with direct sequencing revealed a novel heterozygous variant of CACNA1A - c.5264A>G (p.Glu1755Gly) located in the pore loop of domain IV of calcium channel alpha-1A subunit. We identified a novel missense variant of a voltage-dependent P/Q-type calcium channel alpha-1A subunit in a Slovak three-generation family with recurrent episodes of ataxia. The heterozygous missense variant resulted in changing a highly conserved glutamic acid within the pore loop of domain IV.

  10. [Acute benign ataxia in childhood].

    Science.gov (United States)

    Grippo, J; Arroyo, H A; Rocco, R D; Iraola, J

    1979-01-01

    The patogenesis and etiology of acute ataxia in childhood is not well known. It may occur without previous symptoms or may be the expression of specific infectious diseases. Forty patients hospitalized at the Hospital de Niños de Buenos Aires en 1972-1978, were studied. The neurological manifestations showed an acute onset, being ataxia the main sign, associate to tremor, nystagmus, dysartria, oculo-motor paresia, muscular weakness, and hyporeflexia. Most of the patients (82%) became cured within the first four weeks. It is advisable to establish a follow-up with periodic controls, mainly in those patients in whom an association with previous infectious diseases did not exist to be able to detect an association with degenerative or desmyelinizing diseases.

  11. Cognitive dysfunction in spinocerebellar ataxias

    Directory of Open Access Journals (Sweden)

    Helio Afonso Ghizoni Teive

    Full Text Available Abstract Spinocerebellar ataxias (SCAs comprise a heterogeneous group of complex neurodegenerative diseases, characterized by the presence of progressive cerebellar ataxia, associated or otherwise with ophthalmoplegia, pyramidal signs, extrapyramidal features, pigmentary retinopathy, peripheral neuropathy, cognitive dysfunction and dementia. Objective: To verify the presence of cognitive dysfunction among the main types of SCA described in the literature. Methods: the review was conducted using the search system of the PUBMED and OMIM databases. Results: Cognitive dysfunction occurs in a considerable proportion of SCA, particularly in SCA 3, which is the most frequent form of SCA worldwide. Dementia has been described in several other types of SCA such as SCA 2, SCA 17 and DRPLA. Mental retardation is a specific clinical feature of SCA 13. Conclusions: The role of the cerebellum in cognitive functions has been observed in different types of SCAs which can manifest varying degrees of cognitive dysfunction, dementia and mental retardation.

  12. Autosomal recessive cerebellar ataxias : the current state of affairs

    NARCIS (Netherlands)

    Vermeer, S.; van de Warrenburg, B. P. C.; Willemsen, M. A. A. P.; Cluitmans, M.; Scheffer, H.; Kremer, B. P.; Knoers, N. V. A. M.

    2011-01-01

    Among the hereditary ataxias, autosomal recessive cerebellar ataxias (ARCAs) encompass a diverse group of rare neurodegenerative disorders in which a cerebellar syndrome is the key clinical feature. The clinical overlap between the different cerebellar ataxias, the occasional atypical phenotypes, an

  13. 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 ...

  14. Genetics Home Reference: ataxia with vitamin E deficiency

    Science.gov (United States)

    ... Home Health Conditions ataxia with vitamin E deficiency ataxia with vitamin E deficiency Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description Ataxia with vitamin E deficiency is a disorder that ...

  15. 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.

  16. 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.

  17. Results of an electronic mail survey on hormones and telangiectasias.

    Science.gov (United States)

    Ricci, Stefano

    2005-02-01

    The relationship between the development of telangiectasias and hormonal intake has not been well studied and is empirically managed by phlebologists. To understand the behavior of the international phlebologic community regarding the treatment of leg telangiectasia in patients taking oral contraceptives or receiving postmenopausal hormone replacement therapy. Simple questions concerning the causal effects of hormones, their influence on treatment, and general behavior were asked by an electronic mail questionnaire sent to 131 phlebologists in my personal database. The 61 answers received show the existence of two opposite "parties" concerning the influence of hormones on telangiectasia: cause and treatment. Opposite opinions without any scientific basis underline the ignorance surrounding a subject that concerns 50% of our patients.

  18. Leukemogenesis in heterozygous PU.1 knockout mice.

    Science.gov (United States)

    Genik, Paula C; Vyazunova, Irina; Steffen, Leta S; Bacher, Jeffery W; Bielefeldt-Ohmann, Helle; McKercher, Scott; Ullrich, Robert L; Fallgren, Christina M; Weil, Michael M; Ray, F Andrew

    2014-09-01

    Most murine radiation-induced acute myeloid leukemias involve biallelic inactivation of the PU.1 gene, with one allele being lost through a radiation-induced chromosomal deletion and the other allele affected by a recurrent point mutation in codon 235 that is likely to be spontaneous. The short latencies of acute myeloid leukemias occurring in nonirradiated mice engineered with PU.1 conditional knockout or knockdown alleles suggest that once both copies of PU.1 have been lost any other steps involved in leukemogenesis occur rapidly. Yet, spontaneous acute myeloid leukemias have not been reported in mice heterozygous for a PU.1 knockout allele, an observation that conflicts with the understanding that the PU.1 codon 235 mutation is spontaneous. Here we describe experiments that show that the lack of spontaneous leukemia in PU.1 heterozygous knockout mice is not due to insufficient monitoring times or mouse numbers or the genetic background of the knockout mice. The results reveal that spontaneous leukemias that develop in mice of the mixed 129S2/SvPas and C57BL/6 background of knockout mice arise by a pathway that does not involve biallelic PU.1 mutation. In addition, the latency of radiation-induced leukemia in PU.1 heterozygous mice on a genetic background susceptible to radiation-induced leukemia indicates that the codon 235 mutation is not a rate-limiting step in radiation leukemogenesis driven by PU.1 loss.

  19. Fundus albipunctatus associated with compound heterozygous mutations in RPE65

    DEFF Research Database (Denmark)

    Schatz, Patrik; Preising, Markus; Lorenz, Birgit

    2011-01-01

    To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations.......To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations....

  20. Spinocerebellar ataxias: genotype-phenotype correlations in 104 Brazilian families

    Directory of Open Access Journals (Sweden)

    Hélio A. G. Teive

    2012-01-01

    Full Text Available OBJECTIVE: Spinocerebellar ataxias are neurodegenerative disorders involving the cerebellum and its connections. There are more than 30 distinct subtypes, 16 of which are associated with an identified gene. The aim of the current study was to evaluate a large group of patients from 104 Brazilian families with spinocerebellar ataxias. METHODS: We studied 150 patients from 104 families with spinocerebellar ataxias who had received molecular genetic testing for spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, 10, 12, 17, and dentatorubral-pallidoluysian atrophy. A statistical analysis of the results was performed using basic descriptive statistics and the correlation coefficient (r, Student's t-test, chi-square test, and Yates' correction. The statistical significance level was established for p-values <0.05. RESULTS: The results show that the most common subtype was spinocerebellar ataxia 3, which was followed by spinocerebellar ataxia 10. Moreover, the comparison between patients with spinocerebellar ataxia 3, spinocerebellar ataxia 10, and other types of spinocerebellar ataxia revealed distinct clinical features for each type. In patients with spinocerebellar ataxia 3, the phenotype was highly pleomorphic, although the most common signs of disease included cerebellar ataxia (CA, ophthalmoplegia, diplopia, eyelid retraction, facial fasciculation, pyramidal signs, and peripheral neuropathy. In patients with spinocerebellar ataxia 10, the phenotype was also rather distinct and consisted of pure cerebellar ataxia and abnormal saccadic eye movement as well as ocular dysmetria. Patients with spinocerebellar ataxias 2 and 7 presented highly suggestive features of cerebellar ataxia, including slow saccadic ocular movements and areflexia in spinocerebellar ataxia 2 and visual loss in spinocerebellar ataxia 7. CONCLUSIONS: Spinocerebellar ataxia 3 was the most common subtype examined, followed by spinocerebellar ataxia 10. Patients with spinocerebellar

  1. Spinocerebellar ataxia in the Italian Spinone dog is associated with an intronic GAA repeat expansion in ITPR1.

    Science.gov (United States)

    Forman, Oliver P; De Risio, Luisa; Matiasek, Kaspar; Platt, Simon; Mellersh, Cathryn

    2015-02-01

    Spinocerebellar ataxia in the Italian Spinone dog breed is characterised by a progressive gait abnormality that manifests from approximately 4 months of age. The disorder shows an autosomal recessive mode of inheritance, and affected individuals are usually euthanized by one year of age on welfare grounds due to an inability to ambulate. Using a homozygosity mapping technique with six cases and six controls, we mapped the disease locus to chromosome 20 of the canine genome. Linkage analysis across an extended pedigree confirmed the association, with microsatellite C20.374 achieving a maximal LOD score of 4.41. All five genes within the disease-associated interval were exon resequenced, although no exonic candidate mutations were identified. A targeted resequencing approach was therefore adopted to sequence the entire disease-associated interval. Analysis of the sequencing data revealed a GAA repeat expansion in intron 35 of ITPR1, which was homozygous in all cases and heterozygous in obligate carriers. Partial impairment of cerebellar ITPR1 expression in affected dogs was demonstrated by immunohistochemistry. Given the association of ITPR1 mutations with spinocerebellar ataxia (SCA) type 15 (also designated SCA16) in humans and that an intronic GAA repeat expansion has been shown to cause Friedreich ataxia, the repeat expansion is an excellent candidate for the cause of spinocerebellar ataxia in the Italian Spinone. This finding represents the first naturally occurring pathogenic intronic GAA repeat expansion in a non-human species and a novel mechanism for ITPR1 associated spinocerebellar ataxia.

  2. A three-year-old boy with glucose transporter type 1 deficiency syndrome presenting with episodic ataxia.

    Science.gov (United States)

    Ohshiro-Sasaki, Akiko; Shimbo, Hiroko; Takano, Kyoko; Wada, Takahito; Osaka, Hitoshi

    2014-01-01

    Glucose transporter type 1 deficiency syndrome is a metabolic encephalopathy that results from impaired glucose transport into the brain as the result of a mutation of the SLC2A1 gene. It has been recognized recently that these patients can present with a much broader clinical spectrum than previously thought. We describe a 3-year-old boy presenting with episodic ataxia. Our patient exhibited periodic abnormal eye movements, including opsoclonus, since he was 4 months of age. At 2 years of age, he experienced acute cerebellar ataxia after a vaccination. Since then, he has had periodic attacks of ataxic gait, repeated vomiting, and abnormal eye movement. He was diagnosed as having episodic ataxia type 2 because the administration of acetazolamide seemed effective. By 3 years and 10 months of age, he exhibited mild mental retardation and mild trunk ataxia. The attacks were more likely to occur when he was hungry. Molecular analysis revealed that the SLC2A1 gene had a de novo mutation of heterozygous seven nucleotide insertion within exon 7, resulting in a frameshift. He has recently begun a modified Atkins diet; the frequency of attacks has been reduced, and his psychomotor and language skills have begun to develop. Glucose transporter type 1 deficiency syndrome should be considered in the differential diagnosis in children with episodic ataxia, even if acetazolamide is effective. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Hereditary benign telangiectasia without family history in China

    Institute of Scientific and Technical Information of China (English)

    CAI Lin; SUN Qing-miao; ZANG Dong-jie; ZHANG Jian-zhong

    2011-01-01

    A case of hereditary benign telangiectasia without family history was reported. A 39-year-old woman presented with small and tiny telangiectases on the face, neck, upper trunk and forearms at birth. The numbers and sizes of the lesions increased gradually and she had no hemorrhagic diathesis and systemic diseases. No similar patients were found in her family. Upon physical examination, telangiectases were found on the face, neck, upper trunk and forearms; and a telangiectatic erythema was found on the right forearm 25 mm ×40 mm in size. Histopathology examination showed a normal epidermis and dilation of the capillaries at upper dermis. Hereditary benign telangiectasia without family history was diagnosed.

  4. [Pathogenic Genes of A Hereditary Hemorrhagic Telangiectasia Pedigree].

    Science.gov (United States)

    Cheng, Xiao-Hui; Tu, Chuan-Qing; Sun, Shun-Chang; Li, Jan-Yun; Zhang, Xu-Yan; Wang, Dian-Wen; Huang, Can

    2015-08-01

    To identify the mutation of ENG and ALK1 genes in a hereditary hemorrhagic telangiectasia pedigree. 14 exons of ENG gene and 9 exons of ALK1 gene in 11 menbers of this pedigree 4 generation were amplified by reverse transcription-polymerase chain reaction (RT-PCR), the PCR products were screened by direct sequencing. A nonsense mutation c.447G > A was found in exon 4 of ENG gen of the pedigreee, resulting in change of Trp 149 into Stop, while no gene mutation was found in ALK1 gene. The hereditary hemorrhagic telangiectasia in this pedigree is caused by the nonsense mutation c.447G > A in ENG gene.

  5. The scale for the assessment and rating of ataxia correlates with dysarthria assessment in Friedreich's ataxia.

    Science.gov (United States)

    Eigentler, Andreas; Rhomberg, Johanna; Nachbauer, Wolfgang; Ritzer, Irmgard; Poewe, Werner; Boesch, Sylvia

    2012-03-01

    Dysarthria is an acquired neurogenic sensorimotor speech symptom and an integral part within the clinical spectrum of ataxia syndromes. Ataxia measurements and disability scores generally focus on the assessment of motor functions. Since comprehensive investigations of dysarthria in ataxias are sparse, we assessed dysarthria in ataxia patients using the Frenchay Dysarthria Assessment. The Frenchay Dysarthria Assessment is a ten-item validated test in which eight items focus on the observation of oral structures and speech functions. Fifteen Friedreich's ataxia patients and 15 healthy control individuals were analyzed using clinical and logopedic methodology. All patients underwent neurological assessment applying the Scale for the Assessment and Rating of Ataxia. In Friedreich's ataxia patients, the Frenchay sub-item voice showed to be most affected compared to healthy individuals followed by items such as reflexes, palate, tongue, and intelligibility. Scoring of lips, jaw, and respiration appeared to be mildly affected. Ataxia severity in Friedreich's ataxia patients revealed a significant correlation with the Frenchay dysarthria sum score. The introduction of a binary Adapted Dysarthria Score additionally allowed allocation to distinct dysarthria pattern in ataxias. The Frenchay Dysarthria Assessment proved to be a valid dysarthria measure in Friedreich's ataxia. Its availability in several languages provides a major advantage regarding the applicability in international clinical studies. Shortcomings of the Frenchay test are the multiplicity of items tested and its alphabetic coding. Numerical scoring and condensation of assessments in a modified version may, however, provide an excellent clinical tool for the measurement and scoring of dysarthria in ataxic speech disorders.

  6. The clinical characteristics of spinocerebellar ataxia 36: a study of 2121 Japanese ataxia patients.

    Science.gov (United States)

    Sugihara, Katsunobu; Maruyama, Hirofumi; Morino, Hiroyuki; Miyamoto, Ryosuke; Ueno, Hiroki; Matsumoto, Masayasu; Kaji, Ryuji; Kitaguchi, Hiroshi; Yukitake, Motohiro; Higashi, Yasuto; Nishinaka, Kazuto; Oda, Masaya; Izumi, Yuishin; Kawakami, Hideshi

    2012-08-01

    Spinocerebellar ataxia 36 is caused by the expansion of the intronic GGCCTG hexanucleotide repeat in NOP56. The original article describing this condition demonstrated that patients with spinocerebellar ataxia 36 present with tongue atrophy, a finding that had not been seen in previous types of spinocerebellar ataxias. A total of 2121 patients with clinically diagnosed spinocerebellar ataxia participated in the study. We screened our patient samples for spinocerebellar ataxia 36 using the repeat-primed polymerase chain reaction method and also determined the clinical features of spinocerebellar ataxia 36. Of the ataxia cases examined, 12 were identified as spinocerebellar ataxia 36. Of these, 7 cases (6 families) were autosomal dominant, 4 cases (three families) had a positive family history but were not autosomal dominant, and 1 case was sporadic. The average age of onset was 51.7 years, and disease progression was slow. The main symptoms and signs of disease included ataxia, dysarthria, and hyperreflexia. Approximately half the affected patients demonstrated nystagmus, bulging eyes, and a positive pathological reflex, although dysphagia, tongue atrophy, and hearing loss were rare. Moreover, the observed atrophy of the cerebellum and brain stem was not severe. The patients identified in this study were concentrated in western Japan. The frequency of spinocerebellar ataxia 36 was approximately 1.2% in the autosomal dominant group, and the age of onset for this condition was later in comparison with other spinocerebellar ataxia subtypes.

  7. The prevalence of familial hemiplegic migraine with cerebellar ataxia and spinocerebellar ataxia type 6 in Portugal.

    Science.gov (United States)

    Barros, José; Ruano, Luis; Domingos, Joana; Tuna, Assunção; Damásio, Joana; Alonso, Isabel; Silveira, Isabel; Sequeiros, Jorge; Coutinho, Paula

    2014-05-01

    CACNA1A gene disorders present a variable familial phenotype of ataxia, migraine with aura, and/or hemiplegic migraine. Prevalence data for these conditions are scarce. The aim of this study is to report a minimal prevalence estimate for familial hemiplegic migraine with cerebellar ataxia and spinocerebellar ataxia type 6 in Portugal. This is a multisource population-based prevalence study. Patients and families with spinocerebellar ataxia type 6 and familial hemiplegic migraine and cerebellar ataxia identified through the Portuguese survey of hereditary ataxias and spastic paraplegias were re-evaluated. Prevalent patients were confirmed to be alive and affected at the 1st of January 2013. One family with spinocerebellar ataxia type 6 and 2 families with other CACNA1A gene mutations were identified. From these families, 23 patients were alive and living in Portugal in the prevalence day, for an estimated national prevalence per 100,000 inhabitants of 0.21 for familial hemiplegic migraine with cerebellar ataxia and of 0.01 for spinocerebellar ataxia type 6. The prevalence of familial hemiplegic migraine with cerebellar ataxia and spinocerebellar ataxia type 6 are both probably low in Portugal. © 2013 American Headache Society.

  8. [Friedrich's ataxia: clinical difficulties and genetic possibilities

    NARCIS (Netherlands)

    Warrenburg, B.P.C. van de; Knoers, N.V.A.M.; Kremer, H.P.H.

    2002-01-01

    Atypical Friedreich's ataxia was diagnosed by DNA-analysis in 4 patients, 2 men aged 70 and 67 and 2 women aged 32 and 37, who had features that included an onset of ataxia after the age of 25, retained tendon reflexes or hyperreflexia, absence of Babinski's sign, and/or a slowly progressive course.

  9. Spinocerebellar ataxia type 23 : a genetic update

    NARCIS (Netherlands)

    Verbeek, Dineke S.

    2009-01-01

    The spinocerebellar ataxia type 23 locus was identified in 2004 based on linkage analysis in a large, two-generation Dutch family. The age of onset ranged 43-56 years and the phenotype was characterized by a slowly progressive, isolated ataxia. Neuropathological examination revealed neuronal loss in

  10. Genes and genetic testing in hereditary ataxias.

    Science.gov (United States)

    Sandford, Erin; Burmeister, Margit

    2014-07-22

    Ataxia is a neurological cerebellar disorder characterized by loss of coordination during muscle movements affecting walking, vision, and speech. Genetic ataxias are very heterogeneous, with causative variants reported in over 50 genes, which can be inherited in classical dominant, recessive, X-linked, or mitochondrial fashion. A common mechanism of dominant ataxias is repeat expansions, where increasing lengths of repeated DNA sequences result in non-functional proteins that accumulate in the body causing disease. Greater understanding of all ataxia genes has helped identify several different pathways, such as DNA repair, ubiquitination, and ion transport, which can be used to help further identify new genes and potential treatments. Testing for the most common mutations in these genes is now clinically routine to help with prognosis and treatment decisions, but next generation sequencing will revolutionize how genetic testing will be done. Despite the large number of known ataxia causing genes, however, many individuals with ataxia are unable to obtain a genetic diagnosis, suggesting that more genes need to be discovered. Utilization of next generation sequencing technologies, expression studies, and increased knowledge of ataxia pathways will aid in the identification of new ataxia genes.

  11. Antigliadin antibody in sporadic adult ataxia

    Directory of Open Access Journals (Sweden)

    Mahdi Aloosh

    2012-09-01

    Full Text Available Background: The most common neurologic manifestationof gluten sensitivity is ataxia, which accounts for up to 40%of idiopathic sporadic ataxia. Timing of diagnosis of glutenataxia is vital as it is one of the very few treatable causes ofsporadic ataxia and causes irreversible loss of Purkinje cells.Antigliadin antibody (AGA of the IgG type is the bestmarker for neurological manifestations of gluten sensitivity.This study was conducted to measure the prevalence ofgluten ataxia in a group of Iranian patients with idiopathicataxia.Methods: For 30 patients with idiopathic cerebellar ataxia, aquestionnaire about clinical and demographic data wascompleted. Serum AGA (IgA and IgG and antiendomysialantibody (AEA were assessed. Gluten ataxic patientsunderwent duodenal biopsy. Magnetic resonanceimaging was done for all patients to see if cerebellaratrophy is present.Results: Only 2 patients had a positive IgG AGA (6.7%who both had a positive AEA while none of themshowed changes of celiac disease in their duodenalbiopsies. Only presence of gastrointestinal symptomsand pursuit eye movement disorders were higher inpatients with gluten ataxia.Conclusion: Prevalence of gluten ataxia in Iranianpatients with idiopathic ataxia seems to be lower thanmost of other regions. This could be explained by smallsample size, differences in genetics and nutritionalhabits and also effect of serologic tests in clinical versusresearch setting. Further researches with larger samplesize are recommended.

  12. 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.

  13. An update on Spino-cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    Banashree Mondal

    2013-01-01

    Full Text Available The dominantly inherited ataxias, also known as Spino-cerebellar ataxias (SCAs, are rapidly expanding entities. New mutations are being identified at remarkable regularity. Recent awareness of molecular abnormalities in SCAs has addressed some of the long sought questions, but gaps in knowledge still exist. Three major categories of SCAs, according to molecular mechanisms, have evolved over recent few years: Polyglutamate expansion ataxia, non-coding zone repeat ataxia, and ataxia due to conventional mutation. Using the fulcrum of these mechanisms, the article provides an update of SCAs. Shared and specific clinical features, genetic abnormalities, and possible links between molecular abnormalities and cerebellar degeneration have been discussed. Emphasis has been placed on the mechanisms of polyglutamate toxicity.

  14. 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....

  15. Friedreich's ataxia 1979: an overview.

    Science.gov (United States)

    Barbeau, A

    1979-05-01

    This overview summarizes the investigations carried out during the second part of Phase Two of the Quebec Cooperative Study of Friedreich's Ataxia. These investigations outline in more details the fundamental role played by an abnormality in the fatty acid composition (deficient linoleic acid, 18:2) of the cholesterol esters of high density lipoproteins (HDL) in the phenotypic expression of the disease. They postulate a defective incorporation of linoleic acid to surface phosphatidylcholine of chylomicrons and consequent relative and absolute decreases in lipoprotein protein components because of overpacking with defective cholesteryl esters. Secondarily to these changes, the postulated lack of activation of the lipoamide dehydrogenase (LAD) of the pyruvate dehydrogenase (PDH) complex could result in slow pyruvate oxidation, glucose intolerance, deficient synthesis of acetylcholine, and depletion of glutamic and aspartic acid pools. In parallel, abnormal phosphatidyl-choline molecules could be incorporated to membranes, resulting in specific defects in some functions of these membranes, including transport of calcium and/or taurine and myelinization. The framework of an understanding of Friedreich's ataxia is now available, but much fundamental and clinical work remains to be done to fill in and prove each one of these postulated steps.

  16. Late-onset episodic ataxia associated with SLC1A3 mutation.

    Science.gov (United States)

    Choi, Kwang-Dong; Jen, Joanna C; Choi, Seo Young; Shin, Jin-Hong; Kim, Hyang-Sook; Kim, Hyo-Jung; Kim, Ji-Soo; Choi, Jae-Hwan

    2017-03-01

    Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.

  17. Reviewing the genetic causes of spastic-ataxias

    NARCIS (Netherlands)

    de Bot, Susanne T.; Willemsen, Michel A. A. P.; Vermeer, Sascha; Kremer, Hubertus P. H.; van de Warrenburg, Bart P. C.

    2012-01-01

    Although the combined presence of ataxia and pyramidal features has a long differential, the presence of a true spastic-ataxia as the predominant clinical syndrome has a rather limited differential diagnosis. Autosomal recessive ataxia of Charlevoix-Saguenay, late-onset Friedreich ataxia, and heredi

  18. Telangiectasia nevoide unilateral adquirida em homem hígido Acquired unilateral nevoid telangiectasia in a healthy men

    Directory of Open Access Journals (Sweden)

    Juliana Merheb Jordão

    2010-12-01

    Full Text Available A Telangiectasia Nevoide Unilateral é uma dermatose vascular rara, caracterizada por áreas de telangiectasia superficial, em uma distribuição linear unilateral, descrita, em 1899, por Zeisler e Blaschko. Diversas teorias foram desenvolvidas para explicar sua etiopatogenia, sendo a provável (e a mais fundamentada a relação com elevação dos níveis de estrogênio. Há duas formas: a congênita e a adquirida. Esta, geralmente, se relaciona a hepatopatias, em pacientes do sexo masculino. Em homens hígidos, a ocorrência da forma adquirida é rara, com poucos relatos na literatura, sendo sua causa desconhecida. Este trabalho tem como objetivo relatar um caso de telangiectasia nevoide unilateral adquirida em homem jovem, sem comorbidades, alterações clínicas e/ou laboratoriais sugestivas de hiperestrogenismo.Unilateral nevoid telangiectasia is a rare vascular dermatosis, characterized by areas of superficial telangiectases distributed in a linear unilateral pattern. It was described in 1899 by Zeisler and Blascko. Several theories where developed in order to explain its etiopathogenesis. The most widely accepted is the one which establishes its probable association with an increase in the estrogen levels. There are two types: congenital and acquired. The latter is associated with hepatopathies in male patients. The acquired form is rarely observed in healthy men, with a few cases reported in the medical literature, and its etiology is unknown. This study reports the case of a healthy young man with acquired unilateral nevoid telangiectasia, without any comorbidities, clinical and /or laboratory findings indicative of hyperestrogenism.

  19. 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.

  20. Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4.

    Science.gov (United States)

    Bras, Jose; Alonso, Isabel; Barbot, Clara; Costa, Maria Manuela; Darwent, Lee; Orme, Tatiana; Sequeiros, Jorge; Hardy, John; Coutinho, Paula; Guerreiro, Rita

    2015-03-05

    Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3'-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms.

  1. Neurodegeneration in Friedreich’s Ataxia: From Defective Frataxin to Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Cláudio M. Gomes

    2013-01-01

    Full Text Available Friedreich’s ataxia is the most common inherited autosomal recessive ataxia and is characterized by progressive degeneration of the peripheral and central nervous systems and cardiomyopathy. This disease is caused by the silencing of the FXN gene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. This small protein with an α/β sandwich fold undergoes complex processing and imports into the mitochondria, generating isoforms with distinct N-terminal lengths which may underlie different functionalities, also in respect to oligomerization. Missense mutations in the FXN coding region, which compromise protein folding, stability, and function, are found in 4% of FRDA heterozygous patients and are useful to understand how loss of functional frataxin impacts on FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic phenotypes, including deregulation of iron homeostasis and increased oxidative stress. Increasing amount of data suggest that oxidative stress contributes to neurodegeneration in Friedreich’s ataxia.

  2. Paroxysmal ataxia and dysarthria in multiple sclerosis.

    Science.gov (United States)

    Iorio, R; Capone, F; Plantone, D; Batocchi, A P

    2014-01-01

    Paroxysmal ataxia and dysarthria are part of the spectrum of transient neurological disturbances that can be frequently encountered in multiple sclerosis (MS). Prompt recognition of these symptoms is important because they can be the only manifestation of a MS relapse and symptomatic therapy is often beneficial. We report a patient who developed paroxysmal ataxia and dysarthria, documented by video imaging, while he was recovering from a MS relapse. Treatment with carbamazepine resulted in the complete reversal of the paroxysmal ataxia and dysarthria. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. [Peripheral neuropathies associated with hereditary cerebellar ataxias].

    Science.gov (United States)

    Anheim, M; Tranchant, C

    2011-01-01

    Inherited cerebellar ataxias constitute a complicated and heterogeneous group of neurodegenerative disorders affecting the cerebellum and/or spinocerebellar tract, spinal cord and peripheral nerves. A peripheral neuropathy is frequently seen in inherited cerebellar ataxias although it rarely reveals the disease. Moreover, the peripheral neuropathy is helpful for the diagnostic procedure and contributes to the functional prognosis of the disease. Thus, electroneuromyography is essential in the algorithm for the diagnosis of inherited cerebellar ataxias, as well as brain MRI (looking especially for cerebellar atrophy) and the assessment of several biomarkers (alpha-foetoprotein, vitamin E, albumin, LDL cholesterol, lactic acid, phytanic acid).

  4. More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes

    OpenAIRE

    Pearson, Toni S.

    2016-01-01

    Background The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized. Methods A PubMed literature search was performed in October 2015 util...

  5. More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes

    OpenAIRE

    2016-01-01

    Background The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized. Methods A PubMed literature search was performed in October 2015 util...

  6. Differences in saccade dynamics between spinocerebellar ataxia 2 and late-onset cerebellar ataxias.

    Science.gov (United States)

    Federighi, Pamela; Cevenini, Gabriele; Dotti, Maria T; Rosini, Francesca; Pretegiani, Elena; Federico, Antonio; Rufa, Alessandra

    2011-03-01

    The cerebellum is implicated in maintaining the saccadic subsystem efficient for vision by minimizing movement inaccuracy and by learning from endpoint errors. This ability is often disrupted in degenerative cerebellar diseases, as demonstrated by saccade kinetic abnormalities. The study of saccades in these patients may therefore provide insights into the neural substrate underlying saccadic motor control. We investigated the different extent of saccade dynamic abnormalities in spinocerebellar ataxia type 2 and late-onset cerebellar ataxias, genetically undefined and with prevalent cerebellar atrophy. Reflexive and voluntary saccades of different amplitude (10°-18°) were studied in seven patients with spinocerebellar ataxia 2, eight patients with late-onset cerebellar ataxia and 25 healthy controls. Quantitative analysis of saccade parameters and measures of saccade accuracy were performed. Detailed neurological, neurophysiological and magnetic resonance imaging assessment was obtained for each patient. Genetic and laboratory screening for spinocerebellar ataxias and other forms of late-onset cerebellar ataxias were also performed. A lower peak saccade velocity and longer duration was observed in patients with spinocerebellar ataxia 2 with respect to those with late-onset cerebellar ataxia and controls. Unlike subjects with spinocerebellar ataxia 2, patients with late-onset cerebellar ataxia showed main sequence relationships to similar saccades made by normal subjects. Saccades were significantly more inaccurate, namely hypometric, in late-onset cerebellar ataxia than in spinocerebellar ataxia 2 and inaccuracy increased with saccade amplitude. The percentage of hypometric primary saccades and of larger secondary corrective saccades were consistently higher in late-onset cerebellar ataxia than in spinocerebellar ataxia 2 and controls. No other significant differences were found between groups. Two different mechanisms were adopted to redirect the fovea as fast

  7. 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.

  8. The gene for the ataxia-telagiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21

    Energy Technology Data Exchange (ETDEWEB)

    Saar, K.; Stumm, M.; Wegner, R.D. [Humboldt Univ. (Germany)] [and others

    1997-03-01

    Nijmegen breakage syndrome (NBS; Seemanova II syndrome) and Berlin breakage syndrome (BBS), also known as ataxia-telangiectasia variants, are two clinically indistinguishable autosomal recessive familial cancer syndromes that share with ataxia-telangiectasia similar cellular, immunological, and chromosomal but not clinical findings. Classification in NBS and BBS was based on complementation of their hypersensitivity to ionizing radiation in cell-fusion experiments. Recent investigations have questioned the former classification into two different disease entities, suggesting that NBS/BBS is caused by mutations in a single radiosensitivity gene. We now have performed a whole-genome screen in 14 NBS/BBS families and have localized the gene for NBS/BBS to a 1-cM interval on chromosome 8q21, between markers D8S271 and D8S270, with a peak LOD score of 6.86 at D8S1811. This marker also shows strong allelic association to both Slavic NBS and German BBS patients, suggesting the existence of one major mutation of Slavic origin. Since the same allele is seen in both former complementation groups, genetic homogeneity of NBS/BBS can be considered as proved. 21 refs., 2 figs., 2 tabs.

  9. Genetics Home Reference: ataxia with oculomotor apraxia

    Science.gov (United States)

    ... high amounts of a protein called alpha-fetoprotein (AFP) in their blood. (An increase in the level ... tissue. The effect of abnormally high levels of AFP or CPK in people with ataxia with oculomotor ...

  10. [Pathophysiology of Ataxia in Fisher Syndrome].

    Science.gov (United States)

    Kuwabara, Satoshi

    2016-12-01

    Fisher syndrome is regarded as a peculiar inflammatory neuropathy associated with ophthalmoplegia, ataxia, and areflexia. The disorder is associated with preceding infection, cerebrospinal fluid albumino-cytological dissociation, and spontaneous recovery, and regarded as a variant of Guillain-Barré syndrome. The discovery of anti-GQ1b IgG antibodies led to dramatic advances in understanding the pathophysiology of Fisher syndrome. The lesions in Fisher syndrome are determined by expression of ganglioside GQ1b in the human nervous system. This review article focuses on the pathophysiology of ataxia in Fisher syndrome. Current evidence suggests that antibody attack on Group Ia neurons in the dorsal root ganglia is mainly responsible for the sensory ataxia. Involvement of the muscle spindles might also contribute to the development of ataxia.

  11. Febrile Episodic Ataxia with Novel Mutation

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2004-01-01

    Full Text Available An episodic ataxia type 2 (EA2 kindred with ataxic spells induced by fever or high environmental temperature and a novel CACNA1A mutation were identified and reported from the Universities of Mississippi and Minnesota.

  12. Cerebellar Involvement in Ataxia and Generalized Epilepsy

    NARCIS (Netherlands)

    L. Kros (Lieke)

    2015-01-01

    markdownabstract__Abstract__ The work described in this thesis was performed in order to elucidate the role of different cerebellar modules in ataxia and generalized epilepsy using various techniques including in vivo electrophysiology, optogenetics, pharmacological interventions, immunohistology a

  13. [A case of 77-year-old male with spinocerebellar ataxia type 31 with left dominant dystonia].

    Science.gov (United States)

    Saito, Rie; Kikuno, Shota; Maeda, Meiko; Uesaka, Yoshikazu; Ida, Masahiro

    2014-01-01

    We report on the case of a 77-year-old male with genetically proven spinocerebellar ataxia type 31 (SCA31) who had dystonia. He was referred to our hospital for evaluation following a 6-year history of slowly progressive unsteadiness of his left leg during walking and dysarthria at the age of 62 years old. On the basis of his symptoms, we diagnosed him as spinocerebellar degeneration (SCD), and prescribed taltirelin hydrate. However, his symptoms continued to worsen. He required a cane for walking at the age of 63 years, and a wheelchair at the age of 66 years. He was admitted to our hospital following acute cerebral infarction at the age of 77 years. On examination at admission, right hemiparesis and cerebellar ataxia were detected. And left hallux moved involuntarily toward the top surface of the foot at rest, that is dystonia. The dystonia was not associated with cerebral infarction, because it had been several years with dystonia that he got cerebral infarction. Genetic analysis revealed that this patient harbored a heterozygous SCA31 mutation. Previously there have been no reports of SCA31 associated with dystonia. Our case report support clinical heterogeneity of SCA31, and highlight the importance of considering this type in patients with dystonia and ataxia. Patients with the combination of dystonia and ataxia and a family history of a neurodegenerative disorder should be tested for SCA31.

  14. 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.

  15. UNILATERAL RETINAL VASCULAR MALFORMATION IN HEREDITARY HEMORRHAGIC TELANGIECTASIA

    Directory of Open Access Journals (Sweden)

    Ananth Bhandary

    2014-07-01

    Full Text Available Hereditary hemorrhagic telangeiectasia (HHT is an autosomal dominant genetic disorder that leads to vascular malformations. It was first recognized in the 19th century as a familial disorder with abnormal vascular structures causing bleeding from the nose and gastrointestinal tract. HHT is characterized by telangiectatic lesions of the nose, lips, lungs, brain, and spinal cord. The reported incidence in Europe and Japan is between 1:5000 and 1:8000; but is widely variable in other regions. It is seen more frequently in whites. Ocular involvement has been reported in patients with HHT. Although conjunctival telangiectasia is the most common manifestation, rarely intraocular vascular lesions such as retinal telangiectasia and arteriovenous malformations in the retina, are seen. We describe a patient with HHT who had an abnormal unilateral retinal vascular abnormality along with tortuous conjunctival vasculature in the other eye, which has not been reported till date

  16. Writer's cramp in spinocerebellar ataxia Type 1

    Science.gov (United States)

    Khwaja, Geeta Anjum; Srivastava, Abhilekh; Ghuge, Vijay Vishwanath; Chaudhry, Neera

    2016-01-01

    Dystonia can be encountered in a small subset of patients with spinocerebellar ataxia (SCA), but task specific dystonia is extremely rare. We report a case of a 48-year-old male with confirmed SCA Type 1 (SCA1) with mild progressive cerebellar ataxia and a prominent and disabling Writer's cramp. This case highlights the ever-expanding phenotypic heterogeneity of the SCA's in general and SCA1 in particular. PMID:27695243

  17. Genetic and molecular aspects of spinocerebellar ataxias

    OpenAIRE

    Honti, Viktor; Vécsei, László

    2005-01-01

    The group of spinocerebellar ataxias (SCAs) includes more than 20 subgroups based only on genetic research. The “ataxia genes” are autosomal; the “disease-alleles” are dominant, and many of them, but not all, encode a protein with an abnormally long polyglutamine domain. In DNA, this domain can be detected as an elongated CAG repeat region, which is the basis of genetic diagnostics. The polyglutamine tails often tend to aggregate and form inclusions. In some cases, protein–protein interaction...

  18. Cerebellar ataxia and functional genomics : Identifying the routes to cerebellar neurodegeneration

    NARCIS (Netherlands)

    Smeets, C J L M; Verbeek, D S

    2014-01-01

    Cerebellar ataxias are progressive neurodegenerative disorders characterized by atrophy of the cerebellum leading to motor dysfunction, balance problems, and limb and gait ataxia. These include among others, the dominantly inherited spinocerebellar ataxias, recessive cerebellar ataxias such as

  19. Cerebellar ataxia and functional genomics : Identifying the routes to cerebellar neurodegeneration

    NARCIS (Netherlands)

    Smeets, C J L M; Verbeek, D S

    2014-01-01

    Cerebellar ataxias are progressive neurodegenerative disorders characterized by atrophy of the cerebellum leading to motor dysfunction, balance problems, and limb and gait ataxia. These include among others, the dominantly inherited spinocerebellar ataxias, recessive cerebellar ataxias such as Fried

  20. Contribution of Oxidative stress to Endothelial Dysfunction in Hereditary Hemorrhagic Telangiectasia

    Directory of Open Access Journals (Sweden)

    Mirjana eJerkic

    2015-02-01

    Full Text Available Oxidative stress causes endothelial dysfunction and is implicated in the pathogenesis of cardiovascular diseases. Our studies suggested that reactive oxygen species (ROS play a crucial role in Hereditary Hemorrhagic Telangiectasia (HHT disease, a vascular dysplasia affecting 1 in 5,000-8,000 people. Mutations in endoglin (ENG and activin receptor-like kinase (ACVRL1 genes are responsible for HHT1 and HHT2 and are associated with arteriovenous malformations. Endoglin and ACVRL1 interact with endothelial NO synthase (eNOS and regulate its activation. Mice heterozygous for these genes (Eng+/− and Acvrl1+/- show reduced endoglin or ACVRL1 protein levels in endothelial cells causing eNOS uncoupling, generation of reactive oxygen species (ROS rather than nitric oxide (NO•, leading to impaired NO• mediated vasodilation. ROS production is increased in several organs of Eng+/− and Acvrl1+/− mice, including lungs, liver, and colon, affected in HHT. The major source of increased oxidative stress in these tissues is eNOS-derived ROS and not mitochondrial or NADPH oxidase-dependent ROS. Eng+/− and Acvrl1+/− mice also develop with age signs of pulmonary arterial hypertension (PH attributable to eNOS-derived ROS, which was preventable by antioxidant treatment. To date, only one pilot study has been carried out in HHT patients, and it showed beneficial effects of antioxidant therapy on epistaxis. We suggest that more clinical studies are warranted to investigate whether antioxidants would prevent, delay or attenuate manifestations of disease in individuals with HHT, based on our experimental data in mouse models.

  1. Reliability and discriminant validity of ataxia rating scales in early onset ataxia

    NARCIS (Netherlands)

    Brandsma, Rick; Lawerman, Tjitske F.; Kuiper, Marieke J; Lunsing, Roelineke J; Burger, Huibert; Sival, Deborah A

    AIM: To determine whether ataxia rating scales are reliable disease biomarkers for early onset ataxia (EOA). METHOD: In 40 patients clinically identified with EOA (28 males, 12 females; mean age 15y 3mo [range 5-34y]), we determined interobserver and intraobserver agreement (interclass correlation

  2. Reliability and discriminant validity of ataxia rating scales in early onset ataxia

    NARCIS (Netherlands)

    Brandsma, Rick; Lawerman, Tjitske F.; Kuiper, Marieke J.; Lunsing, Roelineke J.; Burger, Huibert; Sival, Deborah A.

    AIM To determine whether ataxia rating scales are reliable disease biomarkers for early onset ataxia (EOA). METHOD In 40 patients clinically identified with EOA (28 males, 12 females; mean age 15y 3mo [range 5-34y]), we determined interobserver and intraobserver agreement (interclass correlation

  3. Reliability and discriminant validity of ataxia rating scales in early onset ataxia

    NARCIS (Netherlands)

    Brandsma, R.; Lawerman, T. F.; Kuiper, M. J.; Geffen, van Joke; Lunsing, I. J.; Burger, H.; de Koning, T. J.; de Vries, J. J.; de Koning-Tijssen, M. A. J.; Sival, D. A.

    Objective: To determine observer-agreement and discriminantvalidity of ataxia rating scales.Background: In children and young adults, Early Onset Ataxia(EOA) is frequently concurrent with other Movement Disorders,resulting in moderate inter-observer agreement among MovementDisorder professionals. To

  4. Reliability and discriminant validity of ataxia rating scales in early onset ataxia

    NARCIS (Netherlands)

    Brandsma, R.; Lawerman, T. F.; Kuiper, M. J.; Geffen, van Joke; Lunsing, I. J.; Burger, H.; de Koning, T. J.; de Vries, J. J.; de Koning-Tijssen, M. A. J.; Sival, D. A.

    2015-01-01

    Objective: To determine observer-agreement and discriminantvalidity of ataxia rating scales.Background: In children and young adults, Early Onset Ataxia(EOA) is frequently concurrent with other Movement Disorders,resulting in moderate inter-observer agreement among MovementDisorder professionals. To

  5. Reliability and discriminant validity of ataxia rating scales in early onset ataxia

    NARCIS (Netherlands)

    Brandsma, Rick; Lawerman, Tjitske F; Kuiper, Marieke J; Lunsing, Roelineke J; Burger, Huibert; Sival, Deborah A

    2016-01-01

    AIM: To determine whether ataxia rating scales are reliable disease biomarkers for early onset ataxia (EOA). METHOD: In 40 patients clinically identified with EOA (28 males, 12 females; mean age 15y 3mo [range 5-34y]), we determined interobserver and intraobserver agreement (interclass correlation c

  6. Ataxia telangiectasia-mutated-Rad3-related DNA damage checkpoint signaling pathway triggered by hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    Fan Zhao; Qing-Jun Ma; Hui Zhong; Ning-Bo Hou; Xiao-Li Yang; Xiang He; Yu Liu; Yan-Hong Zhang; Cong-Wen Wei; Ting Song; Li Li

    2008-01-01

    AIM: To explore whether acute cellular DNA damage response is induced upon hepatitis B virus (HBV) infection and the effects of the HBV infection. METHODS: We incubated HL7702 hepatocytes with HBV-positive serum, mimicking a natural HBV infection process. We used immunoblotting to evaluate protein expression levels in HBV-infected cells or in non-infected cells; immunofluorescence to show ATR foci ands Chk1 phosphorylation loci formation; flow cytometry to analyze the cell cycle and apoptosis; ultraviolet (UV) radiation and ionizing radiation (IR)-treated cells to mimic DNA damage; and Trypan blue staining to count the viable cells.RESULTS: We found that HBV infection induced an increased steady state of ATR protein and increased phosphorylation of multiple downstream targets including Chkl, p53 and H2AX. In contrast to ATR and its target, the phosphorylated form of ATM at Ser-1981 and its downstream substrate Chk2 phosphorylation at Thr-68 did not visibly increase upon infection. However, the level of Mre11 and p21 were reduced beginning at 0.5 h after HBV-positive serum addition. Also, HBV infection led to transient cell cycle arrest in the S and the G2 phases without accompanying increased apoptosis. Research on cell survival changes upon radiation following HBV infection showed that survival of UV-treated host cells was greatly increased by HBV infection, owing to the reduced apoptosis. Meanwhile, survival of IR-treated host cells was reduced by HBV infection. CONCLUSION: HBV infection activates ATR DNA damage response to replication stress and abrogates the checkpoint signaling controlled by DNA damage response.

  7. 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.

  8. Gluten-related disorders: gluten ataxia.

    Science.gov (United States)

    Hadjivassiliou, Marios; Sanders, David D; Aeschlimann, Daniel P

    2015-01-01

    The term gluten-related disorders (GRD) refers to a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. They include both intestinal and extraintestinal manifestations. Gluten ataxia (GA) is one of the commonest neurological manifestations of GRD. It was originally defined as otherwise idiopathic sporadic ataxia in the presence of circulating antigliadin antibodies of IgA and/or IgG type. Newer more specific serological markers have been identified but are not as yet readily available. GA has a prevalence of 15% amongst all ataxias and 40% of all idiopathic sporadic ataxias. It usually presents with gait and lower limb ataxia. It is of insidious onset with a mean age at onset of 53 years. Up to 40% of patients have evidence of enteropathy on duodenal biopsy. Gastrointestinal symptoms are seldom prominent and are not a reliable indicator for the presence of enteropathy. Furthermore, the presence of enteropathy does not influence the response to a gluten-free diet. Most patients will stabilise or improve with strict adherence to gluten-free diet depending on the duration of the ataxia prior to the treatment. Up to 60% of patients with GA have evidence of cerebellar atrophy on MR imaging, but all patients have spectroscopic abnormalities primarily affecting the vermis. Recent evidence suggests that patients with newly diagnosed coeliac disease presenting to the gastroenterologists have abnormal MR spectroscopy at presentation associated with clinical evidence of subtle cerebellar dysfunction. The advantage of early diagnosis and treatment (mean age 42 years in patients presenting with gastrointestinal symptoms vs. 53 years in patients presenting with ataxia) may protect the first group from the development and/or progression of neurological dysfunction. © 2015 S. Karger AG, Basel.

  9. A KCNJ10 mutation previously identified in the Russell group of terriers also occurs in Smooth-Haired Fox Terriers with hereditary ataxia and in related breeds.

    Science.gov (United States)

    Rohdin, Cecilia; Gilliam, Douglas; O'Leary, Caroline A; O'Brien, Dennis P; Coates, Joan R; Johnson, Gary S; Jäderlund, Karin Hultin

    2015-05-23

    Hereditary ataxias with similar phenotypes were reported in the Smooth-Haired Fox Terrier, the Jack Russell Terrier and the Parson Russell Terrier. However, segregation analyses showed differing inheritance modes in these breeds. Recently, molecular genetic studies on the Russell group of terriers found independent mutations in KCNJ10 and CAPN1, each associated with a specific clinical subtype of inherited ataxia. The aim of this study was to clarify whether or not Smooth-Haired Fox Terriers with hereditary ataxia and dogs of other related breeds harbor either of the same mutations. A sub goal was to update the results of KCNJ10 genotyping in Russell group terriers. Three Smooth-Haired Fox Terriers with hereditary ataxia and two Toy Fox Terriers with a similar phenotype were all homozygous for the KCNJ10 mutation. The same mutation was also found in a heterozygous state in clinically unaffected Tenterfield Terriers (n = 5) and, in agreement with previous studies, in Jack Russell Terriers, Parson Russell Terriers, and Russell Terriers. A KCNJ10 mutation, previously associated with an autosomal recessive spinocerebellar ataxia in Jack Russell Terriers, Parson Russell Terriers, and Russell Terriers segregates in at least three more breeds descended from British hunting terriers. Ataxic members of two of these breeds, the Smooth-Haired Fox Terrier and the Toy Fox Terrier, were homozygous for the mutation, strengthening the likelihood that this genetic defect is indeed the causative mutation for the disease known as "hereditary ataxia" in Fox Terriers and "spinocerebellar ataxia with myokymia, seizures or both" in the Russell group of terriers.

  10. 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.

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

    Science.gov (United States)

    Albuquerque, Marcus Vinicius Cristino de; Pedroso, José Luiz; Braga Neto, Pedro; Barsottini, Orlando Graziani Povoas

    2015-01-01

    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.

  12. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Twitter Home Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Printable PDF Open All Close All ... the expand/collapse boxes. Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by ...

  13. Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)

    Science.gov (United States)

    ... Resources and Publications Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS): Overview Skip sharing on social media ... this: Page Content Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset condition (occurs ...

  14. Genetics Home Reference: infantile-onset spinocerebellar ataxia

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions IOSCA infantile-onset spinocerebellar ataxia Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Infantile-onset spinocerebellar ataxia ( IOSCA ) is a progressive disorder that affects the ...

  15. 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.

  16. Truncal ataxia from infarction involving the inferior olivary nucleus.

    Science.gov (United States)

    Park, Jae Hyun; Ryoo, Sookyung; Moon, So Young; Seo, Sand Won; Na, Duk L

    2012-08-01

    Truncal ataxia in medullary infarction may be caused by involvement of the lateral part of the medulla; however, truncal ataxia in infarction involving the inferior olivary nucleus (ION) has received comparatively little attention. We report a patient with truncal ataxia due to medial medullary infarction located in the ION. A lesion in the ION could produce a contralateral truncal ataxia due to increased inhibitory input to the contralesional vestibular nucleus from the contralesional flocculus.

  17. Physiologic alterations in ataxia: Channeling changes into novel therapies

    Science.gov (United States)

    Shakkottai, Vikram G.; Paulson, Henry L.

    2009-01-01

    The ataxias constitute a heterogeneous group of diseases in which cerebellar dysfunction typically underlies the major neurologic manifestations. It is increasingly clear that ataxia can result directly from mutations in ion channels or from perturbations in ion channel physiology in the absence of a primary channel defect. Neuronal dysfunction stemming from perturbed channel activity likely explains some motor deficits in episodic and degenerative ataxias. Understanding these pathophysiologic changes may reveal novel therapeutic targets for symptomatic treatment of ataxia. PMID:19822774

  18. The electrophysiology of spinocerebellar ataxias.

    Science.gov (United States)

    Liang, Lipin; Chen, Tao; Wu, Yan

    2016-02-01

    Spinocerebellar Ataxias (SCAs) are a group of autosomal dominantly inherited neurodegenerative diseases, involving the cerebellum and the brainstem. Genetic testing is the most important method of diagnosis. Nowadays, nearly 40 types of SCAs have been identified by genetic analysis. Peripheral nerve impairment is common in SCAs: electrophysiological examination of SCA1, SCA2 and SCA3 usually shows sensorimotor and sensory neuropathy, while pure motor neuropathy is more rare, being seen only in SCA2. The abnormal VEP of SCA1, SCA2 and SCA3 include prolonged P100 latencies and reduced P100 amplitudes. Abnormal BAEP involves prolonged interpeak latency of I-III and III-V. Abnormal SEP usually show absent P40 wave and prolonged P40 latency. The abnormal MEP usually shows prolonged central motor conduction time or absent responses. SCA2 is not associated with gaze-evoked nystagmus and dysmetric saccades. SCA3 usually presents as saccadic intrusions and oscillations. Whether peripheral nerves are involved in SCA6 is uncertain; although abnormal electrophysiology has been reported, neuropathological examinations have not found degenerative changes or reductions in the number of neurons in the anterior horns and/or dorsal root ganglia in SCA6. It is therefore hypothesized that this might be a displayed feature of axonopathy. The clinical presentation of most cases of SCA6 includes spontaneous and positional downbeat nystagmus, and perverted head-shaking nystagmus. Opinion about peripheral nerve involvement in SCA7 varies between authors. Losing P100 is a predominant feature of SCA7, while III and IV/V wave absence is common in SCA17. Electrophysiological study of other types is currently limited, requiring large-scale studies for confirmation. Similar and overlapping clinical features make it difficult to differentiate each type. Electrophysiological testing can therefore play an important role in helping to identify the common phenotypes of SCAs, and determine the extent

  19. 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...... 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...... relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations....

  20. POLG-Associated Ataxia Presenting as a Fragile X Tremor/Ataxia Phenocopy Syndrome.

    Science.gov (United States)

    Paucar, Martin; Engvall, Martin; Gordon, Lisa; Tham, Emma; Synofzik, Matthis; Svenningsson, Per

    2016-10-01

    Hyperintensities in the middle cerebellar peduncles (MCP), known as the MCP sign, and progressive late-onset ataxia constitute major characteristics of the fragile X tremor/ataxia syndrome (FXTAS). Here, we describe a 60-year-old male affected by ataxia due to biallelic mutations in the mitochondrial polymerase gamma (POLG) gene in which hyperintensities of the middle cerebellar peduncles (MCP) were found. The initial suspicion of FXTAS was however ruled out by a normal CGG expansion size in the FMR1 gene. We discuss the features of late-onset POLG-A as a phenocopy of FXTAS.

  1. Did Robert Louis Stevenson have hereditary hemorrhagic telangiectasia?

    Science.gov (United States)

    Guttmacher, A E; Callahan, J R

    2000-03-06

    Chronic illness played a major role in the life and literary success of Robert Louis Stevenson. However, the exact nature of his chronic illness remains unclear. It is possible that Stevenson had hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber Syndrome). This would explain his chronic respiratory complaints, recurrent episodes of pulmonary hemorrhage, and his death, at age 44 years, of probable cerebral hemorrhage. It would also explain his mother's hitherto unreported but apparent stroke, at age 38 years. Further support for this hypothesis might come from new details about the health of Stevenson and his relatives or from molecular analysis of tissue specimens remaining from him.

  2. A novel approach for treating cerebellar ataxias.

    Science.gov (United States)

    Manto, Mario; Ben Taib, Nordeyn Oulad

    2008-01-01

    The terminology of cerebellar ataxias encompasses a variety of sporadic and inherited debilitating diseases. Patients exhibit disabling deficits such as dysmetria, kinetic tremor and ataxia of stance/gait. We are currently lacking effective treatments in degenerative cerebellar ataxias. Animal models of cerebellar disorders and studies in ataxic patients have demonstrated that the excitability of the sensorimotor cortex is severely depressed in case of cerebellar lesion. These reduced levels of excitability are associated with learning deficits. Recent experimental data show that transcranial direct current stimulation (tDCS) of the premotor cortex and low-frequency repetitive stimulation of the motor cortex (LFRSM1) restore the excitability of the motor cortex in hemicerebellectomized rats, reinstating the ability of the motor cortex to adapt to sustained peripheral stimulation. The hypothesis is based on the possibility that the combination of tDCS and contralateral LFRSM1 can improve human cerebellar ataxias. The proposed treatment consists of delivering trains of tDCS either in conjunction or in alternance with contralateral LFRSM1, in addition to application of peripheral nerve stimulation to sensitize the sensorimotor cortex. This hypothesis is to be tested in a procedure made of 3 steps in patients exhibiting a sporadic or inherited cerebellar disorder. First, patients are assessed clinically using validated scales of cerebellar ataxias and performing accepted quantified tests. Second, trains of tDCS and LFRSM1 are delivered, using a sham procedure in a cross-over design. Trains of peripheral stimulation are applied at peripheral nerves. Third, patients are re-assessed clinically and with quantified tests. Although grafting of stem cells and gene therapy are being developed, they will not be available soon. A successful treatment of combined neurostimulation would lead to a new and readily available approach in the management of cerebellar ataxias. This new

  3. Paroxysmal movement disorders and episodic ataxias.

    Science.gov (United States)

    Fernández-Alvarez, Emilio; Perez-Dueñas, Belén

    2013-01-01

    This chapter summarizes clinical symptoms of some paroxysmal dyskinesias (PDs) of infancy and childhood, as well as episodic ataxias. PDs refer to a complex group of disorders whose main feature is the occurrence of sudden, intermittent attacks of abnormal postures and involuntary movements. PDs can sometimes be symptomatic (secondary PDs), but usually an underlying cerebral lesion is not present (primary PDs). Some of the primary PDs are transient, such as benign paroxysmal torticollis of infancy. Chronic PDs are subdivided into nonkinesigenic (Mount and Reback type), kinesigenic (Kertesz type), and exercise-induced (Lance type) but cases that overlap with these types are on record. They are autosomal dominant inherited conditions. The myofibrillogenesis regulator-1 gene is responsible for nonkinesigenic PDs. To date, the genetic basis of kinesigenic PDs remains unknown. Several clinical entities associated epilepsy with PDs, such as infantile convulsions and choreoathetosis (ICCA). Exercise-induced PD type can be produced by mutations in the SLC2A1 gene that encodes Glut1 (glucose transporter type1). Episodic ataxias are inherited disorders of intermittent ataxia. The attacks are brief and triggered by abrupt exercise and emotional stimulus. Between attacks, palpebral and hand muscle myokymia is often seen in episodic ataxia type 1 (EA1). In episodic ataxia type 2 (EA2) interictal nystagmus is usually present. Some of these latter patients develop progressive ataxia with vermian atrophy. This disorder is associated with mutations in the human Ca channel alfa 1 subunit CACN1A4 gene. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency

    Science.gov (United States)

    Amor, David J.; Marsh, Ashley P.L.; Storey, Elsdon; Tankard, Rick; Gillies, Greta; Delatycki, Martin B.; Pope, Kate; Bromhead, Catherine; Leventer, Richard J.; Bahlo, Melanie

    2016-01-01

    Objective: To determine the genetic cause of slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism in 5 patients from 3 different families. Methods: The patients comprised 2 sib pairs and 1 sporadic patient. Clinical assessment included history, physical examination, and brain MRI. Linkage analysis was performed separately on the 2 sets of sib pairs using single nucleotide polymorphism microarrays, followed by analysis of the intersection of the regions. Exome sequencing was performed on 1 affected patient with variant filtering and prioritization undertaken using these intersected regions. Results: Using a combination of sequencing technologies, we identified compound heterozygous mutations in HSD17B4 in all 5 affected patients. In all 3 families, peroxisomal D-bifunctional protein (DBP) deficiency was caused by compound heterozygosity for 1 nonsense/deletion mutation and 1 missense mutation. Conclusions: We describe 5 patients with juvenile DBP deficiency from 3 different families, bringing the total number of reported patients to 14, from 8 families. This report broadens and consolidates the phenotype associated with juvenile DBP deficiency.

  5. Spinocerebellar ataxia-10 with paranoid schizophrenia

    OpenAIRE

    Bhavesh Trikamji; Parampreet Singh; Shrikant Mishra

    2015-01-01

    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 ataxi...

  6. 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.

  7. 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

  8. Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3.

    Science.gov (United States)

    Paulson, Henry L

    2007-04-01

    To date, nearly 30 distinct genetic forms of dominantly inherited ataxia are known to exist. Of these, Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is perhaps the most common in many regions of the world including the United States. This article discusses MJD/SCA3 as a paradigm example of the dominant ataxias, which are collectively known as the spinocerebellar ataxias. Using MJD/SCA3 as a starting point, the article reviews common clinical and genetic features of the SCAs and highlights new insights into molecular mechanisms, especially of the SCAs caused by polyglutamine expansion. Also discussed are current and future therapeutic opportunities for MJD/SCA3 in particular, many of which have relevance to other SCAs.

  9. Familial episodic ataxia in lambs.

    Science.gov (United States)

    Mayhew, I G; Jolly, R D; Burnham, D; Ridler, A I; Poff, G J; Blair, H T

    2013-03-01

    A similar episodic neurological disorder occurred in new born lambs on two unrelated properties involving disparate breeds of sheep. Because of the number of lambs born, cross-breeding and the fact it occurred in some mating groups and not others, a dominant mode of inheritance was, initially and separately, suspected in each case. The sires of affected lambs were apparently normal. Whereas one was New Zealand Romney, the other was a composite breed with East Friesian genetics, but both rams originated from the same source property. To investigate the pathogenesis of the disorder these two rams were acquired and mated with unrelated sheep, under experimental conditions in a more controlled environment. A proportion of lambs born to both sires exhibited a similar neurological disorder. Some lambs were noted to be abnormal at birth, both on home properties and in the experimental flock. They tended to adopt a head and neck extended posture and were slow to get to their feet and suckle when they then became more or less normal. When forced to move, they and other more robust lambs elicited an asymmetric gait, base-wide extensor hypertonia (hypometria) of thoracic limbs and flexor hypertonia (hypermetria) of pelvic limbs. In some there was nystagmus. After several metres of asymmetric ataxic gait they would fall to one side, sometimes adopting a sitting position. Recovery usually occurred in one to several minutes. As lambs aged, it became more difficult to elicit the episodes of dysfunction and by 6 months of age they appeared normal. The disorder was diagnosed as a dominant familial episodic cerebellovestibular ataxia inherited as a dominant trait, with incomplete penetration of observed clinical signs and variable expressivity. A proportion of affected lambs are likely to die in the neonatal period so the specific nature of the disorder may go unrecognised. Because of incomplete penetrance and varying expressivity, many of the lambs carrying this mutation will

  10. Circulatory contributors to the phenotype in hereditary hemorrhagic telangiectasia

    Directory of Open Access Journals (Sweden)

    Claire L Shovlin

    2015-04-01

    Full Text Available Hereditary hemorrhagic telangiectasia (HHT is mechanistically and therapeutically challenging, not only because of the molecular and cellular perturbations that generate vascular abnormalities, but also the modifications to circulatory physiology that result, and are likely to exacerbate vascular injury. First, most HHT patients have visceral arteriovenous malformations (AVMs. Significant visceral AVMs reduce the systemic vascular resistance: supra-normal cardiac outputs are required to maintain arterial blood pressure, and may result in significant pulmonary venous hypertension. Secondly, bleeding from nasal and gastrointestinal telangiectasia leads to iron losses of such magnitude that in most cases, diet is insufficient to meet the ‘hemorrhage adjusted iron requirement.’ Resultant iron deficiency restricts erythropoiesis, leading to anemia and further increases in cardiac output. Low iron levels are also associated with venous and arterial thromboses, elevated Factor VIII, and increased platelet aggregation to circulating 5HT (serotonin. Third, recent data highlight that reduced oxygenation of blood due to pulmonary AVMs results in a graded erythrocytotic response to maintain arterial oxygen content, and higher stroke volumes and/or heart rates to maintain oxygen delivery. Finally, HHT-independent factors such as diet, pregnancy, sepsis and other intercurrent illnesses also influence vascular structures, hemorrhage, and iron handling in HHT patients. These considerations emphasize the complexity of mechanisms that impact on vascular structures in HHT, and also offer opportunities for targeted therapeutic approaches.

  11. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia

    Science.gov (United States)

    Chen, Ying-Hao; Lee, Yi-Chung; Tsai, Yu-Shuen; Guo, Yuh-Cherng; Hsiao, Cheng-Tsung; Tsai, Pei-Chien; Huang, Jin-An

    2017-01-01

    Adrenoleukodystrophy (ALD) is a rare and progressive neurogenetic disease that may manifest disparate symptoms. The present study aims at investigating the role of ataxic variant of ALD (AVALD) in patients with adult-onset cerebellar ataxia, as well as characterizing their clinical features that distinguish AVALD from other cerebellar ataxias. Mutations in the ATP binding cassette subfamily D member 1 gene (ABCD1) were ascertained in 516 unrelated patients with ataxia. The patients were categorized into three groups: molecularly unassigned hereditary ataxia (n = 118), sporadic ataxia with autonomic dysfunctions (n = 296), and sporadic ataxia without autonomic dysfunctions (n = 102). Brain MRIs were scrutinized for white matter hyperintensity (WMH) in the parieto-occipital lobes, frontal lobes, corticospinal tracts, pons, middle cerebellar peduncles and cerebellar hemispheres. Two ABCD1 mutations (p.S108L and p.P623fs) previously linked to cerebral ALD and adrenomyeloneuropathy but not AVALD were identified. ALD accounts for 0.85% (1/118) of the patients with molecularly unassigned hereditary ataxia and 0.34% (1/296) of the patients with sporadic ataxia with autonomic dysfunctions. WMH in the corticospinal tracts and WMH in the cerebellar hemispheres were strongly associated with AVALD rather than other ataxias. To conclude, ALD accounts for approximately 0.39% (2/516) of adult-onset cerebellar ataxias. This study expands the mutational spectrum of AVALD and underscores the importance of considering ALD as a potential etiology of cerebellar ataxia. PMID:28481932

  12. Spinocerebellar ataxia type 2 presenting with cognitive regression in childhood.

    Science.gov (United States)

    Ramocki, Melissa B; Chapieski, Lynn; McDonald, Ryan O; Fernandez, Fabio; Malphrus, Amy D

    2008-09-01

    Spinocerebellar ataxia type 2 typically presents in adulthood with progressive ataxia, dysarthria, tremor, and slow saccadic eye movements. Childhood-onset spinocerebellar ataxia type 2 is rare, and only the infantile-onset form has been well characterized clinically. This article describes a girl who met all developmental milestones until age 3(1/2) years, when she experienced cognitive regression that preceded motor regression by 6 months. A diagnosis of spinocerebellar ataxia type 2 was delayed until she presented to the emergency department at age 7 years. This report documents the results of her neuropsychologic evaluation at both time points. This case broadens the spectrum of spinocerebellar ataxia type 2 presentation in childhood, highlights the importance of considering a spinocerebellar ataxia in a child who presents with cognitive regression only, and extends currently available clinical information to help clinicians discuss the prognosis in childhood spinocerebellar ataxia type 2.

  13. Quantitative evaluation of gait ataxia by accelerometers.

    Science.gov (United States)

    Shirai, Shinichi; Yabe, Ichiro; Matsushima, Masaaki; Ito, Yoichi M; Yoneyama, Mitsuru; Sasaki, Hidenao

    2015-11-15

    An appropriate biomarker for spinocerebellar degeneration (SCD) has not been identified. Here, we performed gait analysis on patients with pure cerebellar type SCD and assessed whether the obtained data could be used as a neurophysiological biomarker for cerebellar ataxia. We analyzed 25 SCD patients, 25 patients with Parkinson's disease as a disease control, and 25 healthy control individuals. Acceleration signals during 6 min of walking and 1 min of standing were measured by two sets of triaxial accelerometers that were secured with a fixation vest to the middle of the lower and upper back of each subject. We extracted two gait parameters, the average and the coefficient of variation of motion trajectory amplitude, from each acceleration component. Then, each component was analyzed by correlation with the Scale for the Assessment and Rating of Ataxia (SARA) and the Berg Balance Scale (BBS). Compared with the gait control of healthy subjects and concerning correlation with severity and disease specificity, our results suggest that the average amplitude of medial-lateral (upper back) of straight gait is a physiological biomarker for cerebellar ataxia. Our results suggest that gait analysis is a quantitative and concise evaluation scale for the severity of cerebellar ataxia.

  14. Friedreich ataxia: dysarthria profile and clinical data.

    Science.gov (United States)

    Brendel, Bettina; Ackermann, Hermann; Berg, Daniela; Lindig, Tobias; Schölderle, Theresa; Schöls, Ludger; Synofzik, Matthis; Ziegler, Wolfram

    2013-08-01

    Friedreich ataxia (FRDA) is the most frequent recessive ataxia in the Western world. Dysarthria is a cardinal feature of FRDA, often leading to severe impairments in daily functioning, but its exact characteristics are only poorly understood so far. We performed a comprehensive evaluation of dysarthria severity and the profile of speech motor deficits in 20 patients with a genetic diagnosis of FRDA based on a carefully selected battery of speaking tasks and two widely used paraspeech tasks, i.e., oral diadochokinesis and sustained vowel productions. Perceptual ratings of the speech samples identified respiration, voice quality, voice instability, articulation, and tempo as the most affected speech dimensions. Whereas vocal instability predicted ataxia severity, tempo turned out as a significant correlate of disease duration. Furthermore, articulation predicted the overall intelligibility score as determined by a systematic speech pathology assessment tool. In contrast, neurologists' ratings of intelligibility--a component of the "Scale for the Assessment and Rating of Ataxia"--were found to be related to perceived speech tempo. Obviously, clinicians are more sensitive to slowness of speech than to any other feature of spoken language during dysarthria evaluation. Our results suggest that different components of speech production and trunk/limb motor functions are differentially susceptible to FRDA pathology. Furthermore, evidence emerged that paraspeech tasks do not allow for an adequate scaling of speech deficits in FRDA.

  15. Spinocerebellar ataxia-10 with paranoid schizophrenia.

    Science.gov (United States)

    Trikamji, Bhavesh; Singh, Parampreet; Mishra, Shrikant

    2015-01-01

    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.

  16. The preclinical stage of spinocerebellar ataxias.

    Science.gov (United States)

    Maas, Roderick P P W M; van Gaalen, Judith; Klockgether, Thomas; van de Warrenburg, Bart P C

    2015-07-07

    The autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of degenerative diseases of the cerebellum and connected regions. The discovery of various SCA genes and the subsequent possibility of predictive testing currently allow a genetic diagnosis to be established years or even decades before the actual appearance of ataxia symptoms. A growing body of evidence, however, indicates that this preclinical stage is subject to the earliest pathophysiologic changes. This review article comprehensively summarizes the studies conducted in preclinical carriers of a mutation in one of the SCA genes. From these data, it can indeed be concluded that the preclinical phase in SCA is already characterized by detectable central and peripheral nervous system changes, which are reflected by subtle abnormalities during a careful clinical examination, changes in structural and functional brain imaging, abnormal neurophysiologic measurements, and/or altered motor learning paradigms. As these may be compensated for a long time, ataxia symptoms probably only appear after a certain threshold of dysfunction or degeneration has been exceeded. Detailed knowledge of this disease stage is of particular relevance for a better understanding of the pathogenesis of SCAs, will allow us to determine the optimal point in time for interventions in future therapeutic trials, and points to objective, valid biomarkers to assess disease progression. Further studies will benefit from a consensus-based definition of the preclinical stage, from using one and the same validated ataxia rating scale with one fixed cutoff value, and from applying similar mathematical models to calculate time to predicted disease onset.

  17. Recent advances in hereditary spinocerebellar ataxias.

    NARCIS (Netherlands)

    Warrenburg, B.P.C. van de; Sinke, R.J.; Kremer, H.P.H.

    2005-01-01

    In recent years, molecular genetic research has unraveled a major part of the genetic background of autosomal dominant and recessive spinocerebellar ataxias. These advances have also allowed insight in (some of) the pathophysiologic pathways assumed to be involved in these diseases. For the clinicia

  18. Recent advances in hereditary spinocerebellar ataxias

    NARCIS (Netherlands)

    van de Warrenburg, Bart P C; Sinke, Richard J; Kremer, Berry

    2005-01-01

    In recent years, molecular genetic research has unraveled a major part of the genetic background of autosomal dominant and recessive spinocerebellar ataxias. These advances have also allowed insight in (some of) the pathophysiologic pathways assumed to be involved in these diseases. For the clinicia

  19. Peripheral nerve involvement in spinocerebellar ataxias

    NARCIS (Netherlands)

    van de Warrenburg, Bart P C; Notermans, Nicolette C; Schelhaas, Helenius J; van Alfen, Nens; Sinke, Richard J; Knoers, Nine V A M; Zwarts, Machiel J; Kremer, Berry P H

    2004-01-01

    BACKGROUND: In autosomal dominant cerebellar ataxias (ADCAs), it is unclear whether the associated peripheral nerve involvement is always a typical length-dependent axonopathy rather than primary neuronopathy due to neuronal degeneration in the spinal anterior horns and/or dorsal root ganglia. OBJEC

  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. Genetic and clinical analysis in a Chinese parkinsonism-predominant spinocerebellar ataxia type 2 family.

    Science.gov (United States)

    Sun, Hao; Satake, Wataru; Zhang, Changjun; Nagai, Yoshitaka; Tian, Youyong; Fu, Shouzhi; Yu, Jiankun; Qian, Yaping; Qian, Yuan; Chu, Jiayou; Toda, Tatsushi

    2011-04-01

    Parkinson's disease is a degenerative central nervous system disorder that often impairs motor skills, speech and other functions. We discovered a large Chinese family showing primarily parkinsonism symptoms with autosomal dominant inheritance. Six affected individuals in the family showed typical parkinsonism symptoms, including pill-rolling tremor. Two other affected individuals showed cerebellar ataxia symptoms. A whole-genome scan using the 50K single nucleotide polymorphism array with three different linkage methods detected two positive regions on chromosome 12q24.1 and 5q13.3. The ATXN2 gene, responsible for spinocerebellar ataxia type 2 (SCA2) was located precisely in the center of the positive region on chromosome 12. Further analysis of SCA2 revealed heterozygous pathological CAG expansions in the family. The affected individuals' symptoms were typical of parkinsonism, but complex. Inverse correlation between CAG repeat size and age of onset is not obvious in this pedigree. This parkinsonism-predominant SCA2 family shared the same disease gene locus with other 'standard' SCA2 families, but it is possible that variations in one or more modifier genes might account for the parkinsonism-predominant SCA2 predisposition observed in this pedigree.

  2. Roles of inositol 1,4,5-trisphosphate receptors in spinocerebellar ataxias.

    Science.gov (United States)

    Tada, Masayoshi; Nishizawa, Masatoyo; Onodera, Osamu

    2016-03-01

    Modulation of the intracellular calcium concentration is a ubiquitous signaling system involved in the control of numerous biological processes in a wide variety of cells. Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which act as calcium release channels in the ER membrane, play a key role in the regulation of intracellular calcium concentration. IP3R type 1 (IP3R1) is the major neuronal IP3R isoform in the central nervous system and particularly abundant in cerebellar Purkinje cells. Heterozygous deletions or missense mutations in ITPR1, which encodes IP3R1, result in autosomal dominantly inherited spinocerebellar ataxias (SCAs), including SCA types 15 (SCA15) and 29 (SCA29). In addition, homozygous missense mutations in carbonic anhydrase-related protein VIII (CARP), which suppresses the ability of IP3 to bind to IP3R1, cause a recessively inherited ataxia with mild cognitive impairment with/without quadrupedal gait. Moreover, cytosolic calcium overload with excessive IP3R1 activity has been implicated in the pathogenesis of other SCAs, including SCA types 2 (SCA2) and 3 (SCA3). These facts indicate that dysregulation of IP3R-mediated calcium signaling is linked to the pathogenesis of SCAs. Here, we focus on the molecular basis of SCA15 and SCA29, which are caused by mutations in ITPR1. In addition, we discuss other SCAs whose pathogenesis may be linked to aberrant activation of IP3R-mediated Ca(2+) signaling.

  3. A Gain-of-Function Mutation in NALCN in a Child with Intellectual Disability, Ataxia, and Arthrogryposis.

    Science.gov (United States)

    Aoyagi, Kyota; Rossignol, Elsa; Hamdan, Fadi F; Mulcahy, Ben; Xie, Lin; Nagamatsu, Shinya; Rouleau, Guy A; Zhen, Mei; Michaud, Jacques L

    2015-08-01

    NALCN and its homologues code for the ion channel responsible for half of background Na(+) -leak conductance in vertebrate and invertebrate neurons. Recessive mutations in human NALCN cause intellectual disability (ID) with hypotonia. Here, we report a de novo heterozygous mutation in NALCN affecting a conserved residue (p.R1181Q) in a girl with ID, episodic and persistent ataxia, and arthrogryposis. Interestingly, her episodes of ataxia were abolished by the administration of acetazolamide, similar to the response observed in episodic ataxia associated with other ion channels. Introducing the analogous mutation in the Caenorhabditis elegans homologue nca-1 induced a coiling locomotion phenotype, identical to that obtained with previously characterized C. elegans gain-of-function nca alleles, suggesting that p.R1181Q confers the same property to NALCN. This observation thus suggests that dominant mutations in NALCN can cause a neurodevelopmental phenotype that overlaps with, while being mostly distinct from that associated with recessive mutations in the same gene. © 2015 WILEY PERIODICALS, INC.

  4. 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.

  5. Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1.

    Science.gov (United States)

    Tomlinson, Susan Elizabeth; Rajakulendran, Sanjeev; Tan, Stella Veronica; Graves, Tracey Dawn; Bamiou, Doris-Eva; Labrum, Robyn W; Burke, David; Sue, Carolyn M; Giunti, Paola; Schorge, Stephanie; Kullmann, Dimitri M; Hanna, Michael G

    2013-10-01

    Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations. 15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry. Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of K(v)1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia. The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of K(v)1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between K(v)1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1.

  6. Prevalence of ataxia in children: a systematic review.

    Science.gov (United States)

    Musselman, Kristin E; Stoyanov, Cristina T; Marasigan, Rhul; Jenkins, Mary E; Konczak, Jürgen; Morton, Susanne M; Bastian, Amy J

    2014-01-07

    To estimate the prevalence of childhood ataxia resulting from both genetic and acquired causes. A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Five databases were searched for articles reporting a frequency measure (e.g., prevalence, incidence) of ataxia in children. Included articles were first grouped according to the World Health Organization (WHO) regions and subsequently classified according to etiology (genetic, acquired, or mixed). Each article was assessed for its risk of bias on the domains of sampling, measurement, and analysis. Incidence values were converted to prevalence estimates whenever possible. European prevalence estimates for different etiologies of ataxia were summed to gauge the overall prevalence of childhood ataxia. One hundred fifteen articles were included in the review. More than 50% of the data originated from the Europe WHO region. Data from this region also showed the least susceptibility to bias. Little data were available for Africa and Southeast Asia. The prevalence of acquired ataxias was found to vary more greatly across regions than the genetic ataxias. Ataxic cerebral palsy was found to be a significant contributor to the overall prevalence of childhood ataxia across WHO regions. The prevalence of childhood ataxias in Europe was estimated to be ∼26/100,000 children and likely reflects a minimum prevalence worldwide. The findings show that ataxia is a common childhood motor disorder with a higher prevalence than previously assumed. More research concerning the epidemiology, assessment, and treatment of childhood ataxia is warranted.

  7. 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...... and compared to normative data. In 30 patients, we measured the BT before laser treatment 1.5 and 6.5 months after treatment. The Short form 36 (SF-36), a validated health questionnaire, was completed before and 6.5 months after treatment. Compared to preoperative value, BT was significantly reduced 1.5 and 6...

  8. Filaggrin compound heterozygous patients carry mutations in trans position

    DEFF Research Database (Denmark)

    Carlsen, Berit C; Meldgaard, Michael; Johansen, Jeanne D

    2013-01-01

    ; however, this has not been scientifically investigated. Two different FLG null mutations in the same individual may be in trans position, meaning that each mutation locates to a different allele functionally equivalent to homozygosity, or may be in cis position, meaning that both mutations locate...... to the same allele functionally equivalent to heterozygosity. To experimentally investigate allelic in cis versus in trans configuration of the two most common filaggrin (FLG) mutations (R501X and 2282del4) in compound heterozygous individuals. Testing for in cis or in trans allele configuration was performed...... compound heterozygous individuals were found to carry the two mutations in trans position. FLG null mutation compound heterozygous individuals can be considered functionally equivalent to FLG null mutation homozygosity for any of the two mutations....

  9. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients

    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 d...

  10. Pulmonary arteriovenous malformations: screening procedures and pulmonary angiography in patients with hereditary hemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, A D; Oxhøj, H; Andersen, P E

    1999-01-01

    Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited disease with a high prevalence of pulmonary arteriovenous malformations (PAVMs). The first symptom of HHT may be stroke or fatal hemoptysis associated with the presence of PAVM....

  11. ‘Costa da Morte’ ataxia is spinocerebellar ataxia 36: clinical and genetic characterization

    Science.gov (United States)

    García-Murias, María; Quintáns, Beatriz; Arias, Manuel; Seixas, Ana I.; Cacheiro, Pilar; Tarrío, Rosa; Pardo, Julio; Millán, María J.; Arias-Rivas, Susana; Blanco-Arias, Patricia; Dapena, Dolores; Moreira, Ramón; Rodríguez-Trelles, Francisco; Sequeiros, Jorge; Carracedo, Ángel; Silveira, Isabel

    2012-01-01

    Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ∼0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5–14 hexanucleotide repeats, expanded alleles range from ∼650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ∼1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia

  12. 'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization.

    Science.gov (United States)

    García-Murias, María; Quintáns, Beatriz; Arias, Manuel; Seixas, Ana I; Cacheiro, Pilar; Tarrío, Rosa; Pardo, Julio; Millán, María J; Arias-Rivas, Susana; Blanco-Arias, Patricia; Dapena, Dolores; Moreira, Ramón; Rodríguez-Trelles, Francisco; Sequeiros, Jorge; Carracedo, Angel; Silveira, Isabel; Sobrido, María J

    2012-05-01

    Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ~0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5-14 hexanucleotide repeats, expanded alleles range from ~650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ~1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is

  13. 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.

  14. Specific cerebellar and cortical degeneration correlates with ataxia severity in spinocerebellar ataxia type 7.

    Science.gov (United States)

    Hernandez-Castillo, Carlos R; Galvez, Victor; Diaz, Rosalinda; Fernandez-Ruiz, Juan

    2016-03-01

    Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder that is accompanied by loss of motor control and macular degeneration. Previous studies have shown cerebellar and pons atrophy as well as functional connectivity changes across the whole brain. Although different MRI modalities have been used to study the degenerative process, little is known about the relationship between the motor symptoms and cerebral atrophy. Twenty-four patients with molecular diagnosis of SCA7 where invited to participate in this study. Ataxia severity was evaluated using the scale for the assessment and rating of ataxia (SARA). Structural magnetic resonance imaging (MRI) brain images were used to obtain the grey matter volume of each participant. As expected, we found a significant negative correlation between the SARA score and the grey matter volume in distinct regions of the cerebellum in the patient group. Additionally, we found significant correlations between the ataxia degree and the degeneration of specific cortical areas in these patients. These findings provide a better understanding of the relationship between gray matter atrophy and ataxia related symptoms that result from the SCA7 mutation.

  15. Hereditary hemorrhagic telangiectasia with oral manifestations. Report of periodontal treatment in two cases.

    Science.gov (United States)

    Austin, G B; Quart, A M; Novak, B

    1981-03-01

    The periodontal conditions of two patients with hereditary hemorrhagic telangiectasia were successfully treated by a two-phase plan. The first phase of treatment eliminated inflammation from local etiologic factors by removing plaque and plaque-retaining factors. The second phase eliminated the residual anatomic defects of periodontal disease. Gingival bleeding has been indicated as a symptomatic factor of hereditary hemorrhagic telangiectasia, but such bleeding is more likely the result of periodontal inflammation.

  16. Novel Diagnostic Paradigms for Friedreich Ataxia

    Science.gov (United States)

    Brigatti, Karlla W.; Deutsch, Eric C.; Lynch, David R.; Farmer, Jennifer M.

    2013-01-01

    Friedreich ataxia is the most common inherited ataxia, with a wide phenotypic spectrum. It is generally caused by GAA expansions on both alleles of FXN, but a small percentage of patients are compound heterozygotes for a pathogenic expansion and a point mutation. Two recent diagnostic innovations are further characterizing individuals with the phenotype but without the classic genotypes. First, lateral-flow immunoassay is able to quantify the frataxin protein, thereby further characterizing these atypical individuals as likely affected or not affected, and providing some correlation to phenotype. It also holds promise as a biomarker for clinical trials in which the investigative agent increases frataxin. Second, gene dosage analysis and the identification of affected individuals with gene deletions introduce a novel genetic mechanism of disease. Both tests are now clinically available and suggest a new diagnostic paradigm for the disorder. Genetic counseling issues and future diagnostic testing approaches are considered as well. PMID:22752491

  17. Episodic Ataxias: Clinical and Genetic Features

    Science.gov (United States)

    Choi, Kwang-Dong; Choi, Jae-Hwan

    2016-01-01

    Episodic ataxia (EA) is a clinically heterogeneous group of disorders that are characterized by recurrent spells of truncal ataxia and incoordination lasting minutes to hours. Most have an autosomal dominant inheritance pattern. To date, 8 subtypes have been defined according to clinical and genetic characteristics, and five genes are known to be linked to EAs. Both EA1 and EA2, which are caused by mutations in KCNA1 and CACNA1A, account for the majority of EA, but many patients with no identified mutations still exhibit EA-like clinical features. Furthermore, genetically confirmed EAs have mostly been identified in Caucasian families. In this article, we review the current knowledge on the clinical and genetic characteristics of EAs. Additionally, we summarize the phenotypic features of the genetically confirmed EA2 families in Korea. PMID:27667184

  18. Machado-Joseph disease and other rare spinocerebellar ataxias.

    Science.gov (United States)

    Matilla-Dueñas, Antoni

    2012-01-01

    The spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases characterised by progressive lack of motor coordination leading to major disability. SCAs show high clinical, genetic, molecular and epidemiological variability. In the last one decade, the intensive scientific research devoted to the SCAs is resulting in clear advances and a better understanding on the genetic and nongenetic factors contributing to their pathogenesis which are facilitating the diagnosis, prognosis and development of new therapies. The scope of this chapter is to provide an updated information on Machado-Joseph disease (MJD), the most frequent SCA subtype worldwide and other rare spinocerebellar ataxias including dentatorubral-pallidoluysian atrophy (DRPLA), the X-linked fragile X tremor and ataxia syndrome (FXTAS) and the nonprogressive episodic forms of inherited ataxias (EAs). Furthermore, the different therapeutic strategies that are currently being investigated to treat the ataxia and non-ataxia symptoms in SCAs are also described.

  19. Case of infantile onset spinocerebellar ataxia type 5.

    Science.gov (United States)

    Jacob, Francois-Dominique; Ho, Eugenia S; Martinez-Ojeda, Mayra; Darras, Basil T; Khwaja, Omar S

    2013-10-01

    Dominant spinocerebellar ataxias are a rare clinically and genetically heterogeneous group of neurodegenerative disorders. They are characterized by progressive cerebellar ataxia resulting in unsteady gait, clumsiness, dysarthria, and swallowing difficulty. The onset of symptoms is usually in the third or fourth decade of life; however, more subtle clinical manifestations can start in early childhood. Spinocerebellar ataxia type 5, a dominant spinocerebellar ataxia associated with mutations involving β-III spectrin (SPTBN2), has been described in 3 families. It typically consists of a slowly progressive spinocerebellar ataxia with onset in the third decade. The authors present the first case of infantile-onset spinocerebellar ataxia associated with a novel SPTBN2 mutation (transition C>T at nucleotide position 1438), the proband having a much more severe phenotype with global developmental delay, hypotonia, tremor, nystagmus, and facial myokymia.

  20. Automatic detection of basal cell carcinoma using telangiectasia analysis in dermoscopy skin lesion images.

    Science.gov (United States)

    Cheng, Beibei; Erdos, David; Stanley, Ronald J; Stoecker, William V; Calcara, David A; Gómez, David D

    2011-08-01

    Telangiectasia, dilated blood vessels near the surface of the skin of small, varying diameter, are critical dermoscopy structures used in the detection of basal cell carcinoma (BCC). Distinguishing these vessels from other telangiectasia, that are commonly found in sun-damaged skin, is challenging. Image analysis techniques are investigated to find vessels structures in BCC automatically. The primary screen for vessels uses an optimized local color drop technique. A noise filter is developed to eliminate false-positive structures, primarily bubbles, hair, and blotch and ulcer edges. From the telangiectasia mask containing candidate vessel-like structures, shape, size and normalized count features are computed to facilitate the discrimination of benign skin lesions from BCCs with telangiectasia. Experimental results yielded a diagnostic accuracy as high as 96.7% using a neural network classifier for a data set of 59 BCCs and 152 benign lesions for skin lesion discrimination based on features computed from the telangiectasia masks. In current clinical practice, it is possible to find smaller BCCs by dermoscopy than by clinical inspection. Although almost all of these small BCCs have telangiectasia, they can be short and thin. Normalization of lengths and areas helps to detect these smaller BCCs. © 2011 John Wiley & Sons A/S.

  1. 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

  2. Substantia nigra echogenicity in Friedreich's ataxia patients.

    Science.gov (United States)

    Sierra, María; Infante, Jon; Berciano, José

    2013-08-01

    The aim of this study is to assess the presence of substantia nigra (SN) hypoechogenicity in a cohort of Friedreich's ataxia (FRDA) patients and its possible association with restless syndrome (RLS). Fourteen genetically confirmed FRDA patients and 14 sex- and age-matched healthy controls underwent transcranial sonography examination to evaluate the area of echogenicity of the SN. Both groups were clinically assessed with the essential and additional diagnostic criteria for RLS established by the International RLS Study Group. Ataxia was evaluated using the Scale for the Assessment and Rating of Ataxia. We did not find significant differences between the mean sum area of SN echogenicity in FRDA patients and in controls. Only one patient in the FDRA group and two control subjects showed SN hypoechogenicity. Two out of the 14 FDRA patients and one of the controls fulfilled diagnostic criteria for RLS. The areas of SN echogenicity in the two FRDA patients with RLS were the lowest found in this group. We conclude that our data do not support the notion that SN hypoechogenicity is related to FRDA itself, although it might be associated with RLS.

  3. The ever expanding spinocerebellar ataxias. Editorial.

    Science.gov (United States)

    Matilla-Dueñas, Antoni

    2012-12-01

    The spinocerebellar ataxias (SCAs) are a clinically, genetically, and neuropathologically heterogeneous group of neurological disorders defined by variable degrees of cerebellar ataxia often accompanied by additional cerebellar and non-cerebellar symptoms that, in many cases,defy differentiation based on clinical characterisation alone. The clinical symptoms are triggered by neurodegeneration of the cerebellum and its relay connexions. The current identification of at least 43 SCA subtypes and the causative molecular defects in 27 of them refine the clinical diagnosis,provide molecular testing of at risk, a/pre-symptomatic, prenatal or pre-implantation and facilitate genetic counselling. The recent discovery of new causative SCA genes along with the respective scientific advances is uncovering high complexity and altered molecular pathways involved in the mechanisms by which the mutant gene products cause pathogenesis. Fortunately, the intensive ongoing clinical and neurogenetic research together with the applied molecular approaches is sure to yield scientific advances that will be translated into developing effective treatments for the spinocerebellar ataxias and other similar neurological conditions.

  4. Coenzyme Q10 and spinocerebellar ataxias.

    Science.gov (United States)

    Lo, Raymond Y; Figueroa, Karla P; Pulst, Stefan M; Lin, Chi-Ying; Perlman, Susan; Wilmot, George; Gomez, Christopher; Schmahmann, Jeremy; Paulson, Henry; Shakkottai, Vikram G; Ying, Sarah; Zesiewicz, Theresa; Bushara, Khalaf; Geschwind, Michael; Xia, Guangbin; Subramony, S H; Ashizawa, Tetsuo; Kuo, Sheng-Han

    2015-02-01

    The aim of this study was to investigate the association between drug exposure and disease severity in SCA types 1, 2, 3 and 6. The Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) enrolled 319 participants with SCA1, 2, 3, and 6 from 12 medical centers in the United States and repeatedly measured clinical severity by the Scale for Assessment and Rating of Ataxia (SARA), the Unified Huntington's Disease Rating Scale part IV (UHDRS-IV), and the 9-item Patient Health Questionnaire during July 2009 to May 2012. We employed generalized estimating equations in regression models to study the longitudinal effects of coenzyme Q10 (CoQ10), statin, and vitamin E on clinical severity of ataxia after adjusting for age, sex, and pathological CAG repeat number. Cross-sectionally, exposure to CoQ10 was associated with lower SARA and higher UHDRS-IV scores in SCA1 and 3. No association was found between statins, vitamin E, and clinical outcome. Longitudinally, CoQ10, statins, and vitamin E did not change the rates of clinical deterioration indexed by SARA and UHDRS-IV scores within 2 years. CoQ10 is associated with better clinical outcome in SCA1 and 3. These drug exposures did not appear to influence clinical progression within 2 years. Further studies are warranted to confirm the association.

  5. Genetics Home Reference: PRICKLE1-related progressive myoclonus epilepsy with ataxia

    Science.gov (United States)

    ... with ataxia PRICKLE1-related progressive myoclonus epilepsy with ataxia Printable PDF Open All Close All Enable Javascript ... boxes. Description PRICKLE1 -related progressive myoclonus epilepsy with ataxia is a rare inherited condition characterized by recurrent ...

  6. Gluten Sensitivity in Japanese Patients with Adultonset Cerebellar Ataxia

    National Research Council Canada - National Science Library

    Ihara, Masafumi; Makino, Fumi; Sawada, Hideyuki; Mezaki, Takahiro; Mizutani, Kotaro; Nakase, Hiroshi; Matsui, Makoto; Tomimoto, Hidekazu; Shimohama, Shun

    2006-01-01

    Objective: Gluten sensitivity is associated with multiple neurological abnormalities including gluten ataxia, motor neuron diseaselike neuropathy, small fiber type neuropathy, cognitive impairment, and even parkinsonism...

  7. 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

  8. Risk of asthma in heterozygous carriers for cystic fibrosis

    DEFF Research Database (Denmark)

    Nielsen, Anne Orholm; Qayum, Sadaf; Bouchelouche, Pierre Nourdine;

    2016-01-01

    BACKGROUND: Patients with cystic fibrosis (CF) have a higher prevalence of asthma than the background population, however, it is unclear whether heterozygous CF carriers are susceptible to asthma. Given this, a meta-analysis is necessary to determine the veracity of the association of CF...

  9. Risk of asthma in heterozygous carriers for cystic fibrosis

    DEFF Research Database (Denmark)

    Nielsen, Anne Orholm; Qayum, Sadaf; Bouchelouche, Pierre Nourdine

    2016-01-01

    Background Patients with cystic fibrosis (CF) have a higher prevalence of asthma than the background population, however, it is unclear whether heterozygous CF carriers are susceptible to asthma. Given this, a meta-analysis is necessary to determine the veracity of the association of CF...

  10. Compound heterozygous ASPM mutations in Pakistani MCPH families

    DEFF Research Database (Denmark)

    Muhammad, Farooq; Mahmood Baig, Shahid; Hansen, Lars;

    2009-01-01

    confirmed compound heterozygosity in two and homozygous mutations in 20 families, respectively, showing that up to 10% of families with MCPH caused by ASPM are compound heterozygous. In total we identified 16 different nonsense or frameshift mutations of which 12 were novel thereby increasing the number...

  11. Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia

    Science.gov (United States)

    Kahle, Juliette J.; Gulbahce, Natali; Shaw, Chad A.; Lim, Janghoo; Hill, David E.; Barabási, Albert-László; Zoghbi, Huda Y.

    2011-01-01

    Spinocerebellar ataxias 6 and 7 (SCA6 and SCA7) are neurodegenerative disorders caused by expansion of CAG repeats encoding polyglutamine (polyQ) tracts in CACNA1A, the alpha1A subunit of the P/Q-type calcium channel, and ataxin-7 (ATXN7), a component of a chromatin-remodeling complex, respectively. We hypothesized that finding new protein partners for ATXN7 and CACNA1A would provide insight into the biology of their respective diseases and their relationship to other ataxia-causing proteins. We identified 118 protein interactions for CACNA1A and ATXN7 linking them to other ataxia-causing proteins and the ataxia network. To begin to understand the biological relevance of these protein interactions within the ataxia network, we used OMIM to identify diseases associated with the expanded ataxia network. We then used Medicare patient records to determine if any of these diseases co-occur with hereditary ataxia. We found that patients with ataxia are at 3.03-fold greater risk of these diseases than Medicare patients overall. One of the diseases comorbid with ataxia is macular degeneration (MD). The ataxia network is significantly (P= 7.37 × 10−5) enriched for proteins that interact with known MD-causing proteins, forming a MD subnetwork. We found that at least two of the proteins in the MD subnetwork have altered expression in the retina of Ataxin-7266Q/+ mice suggesting an in vivo functional relationship with ATXN7. Together these data reveal novel protein interactions and suggest potential pathways that can contribute to the pathophysiology of ataxia, MD, and diseases comorbid with ataxia. PMID:21078624

  12. Spinocerebellar ataxia type 1 and Machado-Joseph disease: Incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia

    Energy Technology Data Exchange (ETDEWEB)

    Ranum, L.P.W.; Gomez, C.; Orr, H.T. [Univ. of Minnesota, Minneapolis, MN (United States)] [and others

    1995-09-01

    The ataxias are a complex group of diseases with both environmental and genetic causes. Among the autosomal dominant forms of ataxia the genes for two, spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD), have been isolated. In both of these disorders the molecular basis of disease is the expansion of an unstable CAG trinucleotide repeat. To assess the frequency of the SCA1 and MJD trinucleotide repeat expansions among individuals diagnosed with ataxia, we have collected DNA from individuals representing 311 families with adult-onset ataxia of unknown etiology and screened these samples for trinucleotide repeat expansions within the SCA1 and MJD genes. Within this group there are 149 families with dominantly inherited ataxia. Of these, 3% have SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. Thus, together SCA1 and MJD represent 24% of the autosomal dominant ataxias in our group, and the frequency of MJD is substantially greater than that of SCA1. For the 57 patients with MJD trinucleotide repeat expansions, a strong inverse correlation between CAG repeat size and age at onset was observed (r = -.838). Among the MJD patients, the normal and affected ranges of CAG repeat size are 14-40 and 68-82 repeats, respectively. For SCA1 the normal and affected ranges are much closer, containing 19-38 and 40-81 CAG repeats, respectively. 30 refs., 1 fig., 3 tabs.

  13. Friedreich's ataxia--a case of aberrant transcription termination?

    Science.gov (United States)

    Butler, Jill Sergesketter; Napierala, Marek

    2015-01-01

    Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia. We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia.

  14. Meningococcal meningitis presenting with bilateral deafness and ataxia.

    OpenAIRE

    Sandyk, R; Brennan, M J

    1984-01-01

    A 50-year-old man presented with bilateral deafness and ataxia of sudden onset and without constitutional symptoms or signs of meningeal irritation. He was subsequently proved to have meningococcal meningitis, and the deafness and ataxia resolved following appropriate antibiotic therapy.

  15. Longitudinal Cerebral Blood Flow Changes during Speech in Hereditary Ataxia

    Science.gov (United States)

    Sidtis, John J.; Strother, Stephen C.; Naoum, Ansam; Rottenberg, David A.; Gomez, Christopher

    2010-01-01

    The hereditary ataxias constitute a group of degenerative diseases that progress over years or decades. With principal pathology involving the cerebellum, dysarthria is an early feature of many of the ataxias. Positron emission tomography was used to study regional cerebral blood flow changes during speech production over a 21 month period in a…

  16. Drug-induced cerebellar ataxia: a systematic review

    NARCIS (Netherlands)

    Gaalen, J. van; Kerstens, F.G.; Maas, R.P.P.W.M.; Harmark, L.; Warrenburg, B.P.C. van de

    2014-01-01

    BACKGROUND AND OBJECTIVES: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR). METHODS: We performed a systematic literature search in Pubmed (1966 to January 2014) and

  17. 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

  18. 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.

    2014-01-01

    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

  19. Dysarthria and Friedreich's Ataxia: What Can Intelligibility Assessment Tell Us?

    Science.gov (United States)

    Blaney, Bronagh; Hewlett, Nigel

    2007-01-01

    Background: Friedreich's ataxia is one of the most common hereditary disorders of the nervous system. Dysarthria is a pervasive symptom of Friedreich's ataxia, yet the clinical presentation of speech symptoms remains poorly understood, leaving clinicians without the evidence required to develop therapy interventions. Aims: The research reported…

  20. A case of spinocerebellar ataxia type 6 mimicking olivopontocerebellar atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Nakagawa, N.; Katayama, T.; Makita, Y.; Kuroda, K.; Aizawa, H.; Kikuchi, K. [First Dept. of Internal Medicine, Asahikawa Medical Coll. (Japan)

    1999-07-01

    Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant, slowly progressive cerebellar ataxia without multisystem involvement. We report a 57-year-old woman with genetically confirmed SCA6 who showed clinical features of olivopontocerebellar atrophy. Conventional T2-weighted and FLAIR MRI demonstrated high signal in the middle cerebellar peduncles, in addition to mild atrophy of the pons and cerebellum. (orig.)

  1. Drug-induced cerebellar ataxia: a systematic review

    NARCIS (Netherlands)

    Gaalen, J. van; Kerstens, F.G.; Maas, R.P.P.W.M.; Harmark, L.; Warrenburg, B.P.C. van de

    2014-01-01

    BACKGROUND AND OBJECTIVES: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR). METHODS: We performed a systematic literature search in Pubmed (1966 to January 2014) and EMB

  2. Longitudinal Cerebral Blood Flow Changes during Speech in Hereditary Ataxia

    Science.gov (United States)

    Sidtis, John J.; Strother, Stephen C.; Naoum, Ansam; Rottenberg, David A.; Gomez, Christopher

    2010-01-01

    The hereditary ataxias constitute a group of degenerative diseases that progress over years or decades. With principal pathology involving the cerebellum, dysarthria is an early feature of many of the ataxias. Positron emission tomography was used to study regional cerebral blood flow changes during speech production over a 21 month period in a…

  3. Meningococcal meningitis presenting with bilateral deafness and ataxia.

    OpenAIRE

    Sandyk, R; Brennan, M.J.

    1984-01-01

    A 50-year-old man presented with bilateral deafness and ataxia of sudden onset and without constitutional symptoms or signs of meningeal irritation. He was subsequently proved to have meningococcal meningitis, and the deafness and ataxia resolved following appropriate antibiotic therapy.

  4. Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia.

    Science.gov (United States)

    Koutsis, Georgios; Pemble, Sally; Sweeney, Mary G; Paudel, Reema; Wood, Nicholas W; Panas, Marios; Kladi, Athina; Houlden, Henry

    2012-07-15

    The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified.

  5. Treatment of essential telangiectasia: effects of increasing concentrations of polidocanol.

    Science.gov (United States)

    Norris, M J; Carlin, M C; Ratz, J L

    1989-04-01

    A double-blind, double-paired comparison study was performed to evaluate the effects of increasing concentrations of polidocanol in the sclerotherapy of essential telangiectasias of the legs. Polidocanol 0.25%, 0.50%, 0.75%, and 1.0% were compared with regard to clinical effectiveness, safety, and patient acceptance. All dosages were well tolerated by the patients. There were no allergic reactions to polidocanol and no cases of superficial ulceration nor necrosis. Among those whose veins cleared, there was little difference in time to clearing for the four concentrations, which averaged three to four treatment sessions. No statistically significant differences existed among the four dosages with respect to level of improvement, itching, or neovascularization. Polidocanol 0.75% and 1.0%, however, caused more side effects noted by patients and induced more hyperpigmentation than did the lower concentrations. Polidocanol 0.25% yielded the lowest percentage of patients whose veins cleared. The 0.50% solution was the most effective concentration for total overall clearing of the types of vessels treated in this study. From this information it appears that 0.50% polidocanol may be the sclerosing agent of choice.

  6. Anti-angiogenic therapeutic strategies in hereditary hemorrhagic telangiectasia

    Directory of Open Access Journals (Sweden)

    Daniela S. Ardelean

    2015-02-01

    Full Text Available Hereditary hemorrhagic telangiectasia (HHT is an autosomal dominant vascular dysplastic disorder, characterized by recurrent nosebleeds (epistaxis, multiple telangiectases and arteriovenous malformations (AVMs in major organs. Mutations in Endoglin (ENG or CD105 and Activin receptor-like kinase 1 (ACVRL1 or ALK1 genes of the TGF-β superfamily receptors are responsible for HHT1 and HHT2 respectively and account for the majority of HHT cases. Haploinsufficiency in ENG and ALK1 is recognized at the underlying cause of HHT. However, the mechanisms responsible for the predisposition to and generation of AVMs, the hallmark of this disease, are poorly understood. Recent data suggest that dysregulated angiogenesis contributes to the pathogenesis of HHT and that the vascular endothelial growth factor, VEGF, may be implicated in this disease, by modulating the angiogenic balance in the affected tissues. Hence, anti-angiogenic therapies that target the abnormal vessels and restore the angiogenic balance are candidates for treatment of HHT. Here we review the experimental evidence for dysregulated angiogenesis in HHT, the anti-angiogenic therapeutic strategies used in animal models and some patients with HHT and the potential benefit of the anti-angiogenic treatment for ameliorating this severe, progressive vascular disease.

  7. 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.

  8. 5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Damjanovich, Kristy; Langa, Carmen; Blanco, Francisco J; McDonald, Jamie; Botella, Luisa M; Bernabeu, Carmelo; Wooderchak-Donahue, Whitney; Stevenson, David A; Bayrak-Toydemir, Pinar

    2011-12-22

    Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by epistaxis, arteriovenous malformations, and telangiectases. The majority of the patients have a mutation in the coding region of the activin A receptor type II-like 1 (ACVRL1) or Endoglin (ENG) gene. However, in approximately 15% of cases, sequencing analysis and deletion/duplication testing fail to identify mutations in the coding regions of these genes. Knowing its vital role in transcription and translation control, we were prompted to investigate the 5'untranslated region (UTR) of ENG. We sequenced the 5'UTR of ENG for 154 HHT patients without mutations in ENG or ACVRL1 coding regions. We found a mutation (c.-127C > T), which is predicted to affect translation initiation and alter the reading frame of endoglin. This mutation was found in a family with linkage to the ENG, as well as in three other patients, one of which had an affected sibling with the same mutation. In vitro expression studies showed that a construct with the c.-127C > T mutation alters the translation and decreases the level of the endoglin protein. In addition, a c.-9G > A mutation was found in three patients, one of whom was homozygous for this mutation. Expression studies showed decreased protein levels suggesting that the c.-9G > A is a hypomorphic mutation. Our results emphasize the need for the inclusion of the 5'UTR region of ENG in clinical testing for HHT.

  9. Hereditary hemorrhagic telangiectasia: two distinct ENG deletions in one family.

    Science.gov (United States)

    Wooderchak, W; Gedge, F; McDonald, M; Krautscheid, P; Wang, X; Malkiewicz, J; Bukjiok, C J; Lewis, T; Bayrak-Toydemir, P

    2010-11-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by aberrant vascular development. Mutations in endoglin (ENG) or activin A receptor type II-like 1 (ACVRL1) account for around 90% of HHT patients, 10% of those are large deletions or duplications. We report here the first observation of two distinct, large ENG deletions segregating in one pedigree. An ENG exon 4-7 deletion was observed in a patient with HHT. This deletion was identified in several affected family members. However, some affected family members had an ENG exon 3 deletion instead. These deletions were detected by multiplex ligation-dependent probe amplification and confirmed by mRNA sequencing and an oligo-CGH array. Linkage analysis revealed that one individual with the exon 3 deletion inherited the same chromosome from his mother who has the exon 4-7 deletion. This finding has important clinical implications because it shows that targeted family-specific mutation analysis for exon deletions could have led to the misdiagnosis of some affected family members. © 2010 John Wiley & Sons A/S.

  10. Mutation study of Spanish patients with Hereditary Hemorrhagic Telangiectasia

    Directory of Open Access Journals (Sweden)

    Blanco Francisco J

    2008-08-01

    Full Text Available Abstract Background Hereditary Hemorrhagic Telangiectasia (HHT is an autosomal dominant and age-dependent vascular disorder characterised mainly by mutations in the Endoglin (ENG or activin receptor-like kinase-1 (ALK1, ACVRL1 genes. Methods Here, we have identified 22 ALK1 mutations and 15 ENG mutations, many of which had not previously been reported, in independent Spanish families afflicted with HHT. Results We identified mutations in thirty-seven unrelated families. A detailed analysis of clinical symptoms was recorded for each patient analyzed, with a higher significant presence of pulmonary arteriovenous malformations (PAVM in HHT1 patients over HHT2. Twenty-two mutations in ALK1 and fifteen in ENG genes were identified. Many of them, almost half, represented new mutations in ALK1 and in ENG. Missense mutations in ENG and ALK1 were localized in a tridimensional protein structure model. Conclusion Overall, ALK1 mutations (HHT2 were predominant over ENG mutations (HHT1 in our Spanish population, in agreement with previous data from our country and other Mediterranean countries (France, Italy, but different to Northern Europe or North America. There was a significant increase of PAVM associated with HHT1 over HHT2 in these families.

  11. Approach to acute ataxia in childhood: diagnosis and evaluation.

    Science.gov (United States)

    Sivaswamy, Lalitha

    2014-04-01

    Ataxia refers to motor incoordination that is usually most prominent during movement or when a child is attempting to maintain a sitting posture. The first part of the review focuses on the anatomic localization of ataxia--both within the nervous system and without--using a combination of historical features and physical findings. The remainder of the review discusses etiological considerations that vary depending on the age group under consideration. In infancy, certain specific diseases, such as opsoclonus myoclonus ataxia syndrome, must receive special mention because the underlying disease process may be amenable to surgical intervention. In the toddler- and school-age groups, certain conditions (such as stroke and acute cerebellitis) require immediate recognition and imaging, whereas others (such as post-infectious ataxia and concussion) require close follow-up. Finally, mention must be made of diseases outside of the central nervous system that can present with ataxia, such as Guillain-Barré syndrome. Copyright 2014, SLACK Incorporated.

  12. Familial episodic ataxia: a model for migrainous vertigo.

    Science.gov (United States)

    Jen, Joanna C; Baloh, Robert W

    2009-05-01

    Familial episodic ataxias are inherited channelopathies that manifest as episodes of vertigo and ataxia triggered by emotional stress and physical exertion. Mutations in two neuronal ion-channel genes KCNA1 and CACNA1A abundantly expressed in the cerebellum account for the majority of the identified cases of episodic ataxia. Overlapping features between episodic ataxia and the more common recurrent vertigo and ataxia syndromes, particularly those associated with migraine, suggest shared underlying mechanisms. Altered neuronal excitability in the brain and inner ear could contribute to the central and peripheral features of migrainous vertigo. Given the familial aggregation of migraine and migrainous vertigo, our objective was to identify predisposing genetic factors. Preliminary findings demonstrate that migrainous vertigo is genetically heterogeneous and complex. Efforts are ongoing to perform genomewide association studies to identify risk alleles for migrainous vertigo, which may also be relevant to migraine in general.

  13. Long-pulsed dye laser vs. intense pulsed light for the treatment of facial telangiectasias: a randomized controlled trial

    DEFF Research Database (Denmark)

    Nymann, Peter; Hedelund, Lene; Haedersdal, M

    2010-01-01

    This study aims to compare the efficacy and adverse effects of long-pulsed dye laser (LPDL) and intense pulsed light (IPL) in the treatment of facial telangiectasias.......This study aims to compare the efficacy and adverse effects of long-pulsed dye laser (LPDL) and intense pulsed light (IPL) in the treatment of facial telangiectasias....

  14. Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT)

    DEFF Research Database (Denmark)

    Kjeldsen, A D; Oxhøj, H; Andersen, P E;

    2000-01-01

    Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease. HHT is characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs) and neurological symptoms.......Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease. HHT is characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs) and neurological symptoms....

  15. Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.

    Science.gov (United States)

    Haack, Tobias B; Ignatius, Erika; Calvo-Garrido, Javier; Iuso, Arcangela; Isohanni, Pirjo; Maffezzini, Camilla; Lönnqvist, Tuula; Suomalainen, Anu; Gorza, Matteo; Kremer, Laura S; Graf, Elisabeth; Hartig, Monika; Berutti, Riccardo; Paucar, Martin; Svenningsson, Per; Stranneheim, Henrik; Brandberg, Göran; Wedell, Anna; Kurian, Manju A; Hayflick, Susan A; Venco, Paola; Tiranti, Valeria; Strom, Tim M; Dichgans, Martin; Horvath, Rita; Holinski-Feder, Elke; Freyer, Christoph; Meitinger, Thomas; Prokisch, Holger; Senderek, Jan; Wredenberg, Anna; Carroll, Christopher J; Klopstock, Thomas

    2016-09-01

    SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases.

  16. Genome-wide association study for hereditary ataxia in the Parson Russell Terrier and DNA-testing for ataxia-associated mutations in the Parson and Jack Russell Terrier.

    Science.gov (United States)

    Gast, Alana Christina; Metzger, Julia; Tipold, Andrea; Distl, Ottmar

    2016-10-10

    Spinocerebellar ataxia also referred to as hereditary ataxia comprises different forms of progressive neurodegenerative diseases. A complex mode of inheritance was most likely in Parson Russell Terriers (PRT) and in Jack Russell Terriers (JRT). Recently, the missense mutation KCNJ10:c.627C > G was shown to be associated with the spinocerebellar ataxia (SCA) in JRT and related Russell group of terriers, whereas the missense mutation CAPN1:c.344G > A was associated with late onset ataxia (LOA) in PRT. We performed a genome-wide association study (GWAS) in PRT including 15 cases and 29 controls and found a statistically strong signal in the genomic region on dog chromosome 38 (CFA38) where KCNJ10 is located. We tested the CAPN1:c.344G > A and KCNJ10:c.627C > G (Transcript XM_545752.4) mutations in a sample of 77 PRT and 9 JRT from Germany as well as further 179 controls from 20 different dog breeds. All cases and controls genotyped carried the wild-type for the CAPN1:c.344G > A mutation. Among the PRT, 17/77 (22.1 %) dogs were homozygous for the mutant KCNJ10 allele and 22/77 (28.6 %) dogs were heterozygous. Three cases of PRT had the homozygous KCNJ10 wild-type. In JRT, 1/3 cases did show the mutant KCNJ10 allele homozygous. Thus, we sequenced the KCNJ10 exons with their adjacent regions from 10 PRT and 3 JRT including the animals with imperfect co-segregation of the c.627C > G mutation. We identified a total of 45 genetic variants within KCNJ10. The most likely variant explaining the cases appeared a 1-bp-insertion in a C-stretch within exon 3 (KCNJ10:g.22141027insC). In silico analysis showed that this indel may influence the regulation of gene expression. In the present study, 16/21 cases of hereditary ataxia perfectly co-segregated with the KCNJ10:c.627C > G mutation. The CAPN1:c.344G > A mutation could not be validated and seems to be a rare variant in the samples screened. Screening KCNJ10 for further mutations did result in a

  17. Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences.

    Science.gov (United States)

    Labate, Angelo; Tarantino, Patrizia; Viri, Maurizio; Mumoli, Laura; Gagliardi, Monica; Romeo, Antonino; Zara, Federico; Annesi, Grazia; Gambardella, Antonio

    2012-12-01

    Heterozygous mutations of PRRT2, which encodes proline-rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6-44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD--mental retardation, episodic ataxia, and absences--who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

  18. Assessment of speech in early-onset ataxia : a pilot study

    NARCIS (Netherlands)

    Kuiper, Marieke J.; Brandsma, Rick; Lawerman, T.F.; Lunsing, Roelineke J.; Keegstra, Anne L.; Burger, Huibert; De Koning, Tom J.; Tijssen, Marina A. J.; Sival, Deborah A.

    2014-01-01

    AIM: The aim of the study was to determine whether paediatric ataxia speech subscores are reliably applicable for international early-onset ataxia (EOA) databases. If so, we reasoned that ataxia speech subscores should be associated with ataxia scores and involve high interobserver agreement,

  19. Assessment of speech in early-onset ataxia : a pilot study

    NARCIS (Netherlands)

    Kuiper, Marieke J.; Brandsma, Rick; Lawerman, T.F.; Lunsing, Roelineke J.; Keegstra, Anne L.; Burger, Huibert; De Koning, Tom J.; Tijssen, Marina A. J.; Sival, Deborah A.

    2014-01-01

    AIM: The aim of the study was to determine whether paediatric ataxia speech subscores are reliably applicable for international early-onset ataxia (EOA) databases. If so, we reasoned that ataxia speech subscores should be associated with ataxia scores and involve high interobserver agreement, includ

  20. Orofacial hereditary haemorrhagic telangiectasia: high power diode laser in early and advanced lesion treatment

    Science.gov (United States)

    Tempesta, Angela; Franco, Simonetta; Miccoli, Simona; Suppressa, Patrizia; De Falco, Vincenzo; Crincoli, Vito; Lacaita, Mariagrazia; Giuliani, Michele; Favia, Gianfranco

    2014-01-01

    Hereditary Haemorrhagic Telangiectasia (HHT) is a muco-cutaneous inherited disease. Symptoms are epistaxis, visceral arterio-venous malformations, multiple muco-cutaneous telangiectasia with the risk of number increasing enlargement, bleeding, and super-infection. The aim of this work is to show the dual Diode Laser efficacy in preventive treatment of Early Lesions (EL < 2mm) and therapeutic treatment of Advanced Lesions (AL < 2mm). 21 patients affected by HHT with 822 muco-cutaneous telangiectatic nodules have been treated in several sessions with local anaesthesia and cooling of treated sites. EL preventive treatment consists of single Laser impulse (fibre 320) in ultrapulsed mode (2 mm single point spot). AL therapeutic treatment consists of repeated Laser impulses in pulsed mode (on 200ms / off 400ms). According to the results, Diode Laser used in pulsed and ultra-pulsed mode is very effective as noninvasive treatment both in early and advanced oral and perioral telangiectasia.