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Sample records for ataxia telangiectasia cells

  1. Ataxia - telangiectasia

    Science.gov (United States)

    ... 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. 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.

  4. What Is Ataxia-Telangiectasia?

    Science.gov (United States)

    ... 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 ...

  5. Ataxia-Telangiectasia

    OpenAIRE

    J Gordon Millichap

    1990-01-01

    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.

  6. 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 ...

  7. 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.

  8. 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.

  9. Radiosensitive melanoma cell line with mutation of the gene for ataxia telangiectasia.

    OpenAIRE

    Ramsay, J.; Birrell, G.; K. Baumann; Bodero, A.; Parsons, P.; Lavin, M

    1998-01-01

    The human melanoma cell lines MM96L, A2058 and HT144 were examined for sensitivity to ionizing radiation and UVB radiation. HT144 demonstrated a significant increase in sensitivity to ionizing and UVB radiation compared with the MM96L and A2058 cells. Sensitivity to both agents was associated with susceptibility to apoptosis. Using a protein truncation assay, a mutation for the gene for ataxia telangiectasia (ATM) was identified in HT144 cells. This was confirmed to be a homozygous mutation b...

  10. 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).

  11. 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

  12. 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...

  13. 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.

  14. 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.

  15. 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.

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

    OpenAIRE

    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...

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

    Science.gov (United States)

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

    1996-01-01

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

  18. The Functional Role of the Ataxia Telangiectasia Gene

    National Research Council Canada - National Science Library

    Gautier, Jean

    2000-01-01

    Ataxia Telangiectasia (A-T) is an autosomal recessive disease characterized by a progressive cerebellar ataxia, severe immune deficiencies, gonadal atrophy, telangiectases, increased risk for cancer, particularly lymphomas...

  19. The Functional Role of the Ataxia Telangiectasia Gene

    National Research Council Canada - National Science Library

    Gautier, Jean

    1999-01-01

    Ataxia Telangiectasia (A-T) is an autosomal recessive disease characterized by a progressive cerebellar ataxia, severe immune deficiencies, gonadal atrophy, telangiectases, increased risk for cancer, particularly lymphomas...

  20. 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.

  1. Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants

    Science.gov (United States)

    Agathanggelou, Angelo; Weston, Victoria J.; Perry, Tracey; Davies, Nicholas J.; Skowronska, Anna; Payne, Daniel T.; Fossey, John S.; Oldreive, Ceri E.; Wei, Wenbin; Pratt, Guy; Parry, Helen; Oscier, David; Coles, Steve J.; Hole, Paul S.; Darley, Richard L.; McMahon, Michael; Hayes, John D.; Moss, Paul; Stewart, Grant S.; Taylor, A. Malcolm R.; Stankovic, Tatjana

    2015-01-01

    Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumors with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia. PMID:25840602

  2. Establishment of immortal normal and ataxia telangiectasia fibroblast cell lines by introduction of the hTERT gene

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Hideaki; Fukami, Hiroko; Hayashi, Yuko; Kiyono, Tohru; Ishizaki, Kanji [Aichi Cancer Center, Nagoya (Japan). Research Inst.; Nakatsugawa, Shigekazu; Hamaguchi, Michinari [Nagoya Univ. (Japan). School of Medicine

    2002-06-01

    To establish immortal human cells, we introduced the human catalytic subunit of telomerase (hTERT) gene into skin fibroblast cells obtained from normal and ataxia telangiectasia (AT) individuals of Japanese origin. After hTERT introduction, these cells continue to grow beyond a population doubling number of 200 while maintaining their original radiosensitivity. Inductions of p53, phosphorylation of Serl5 in p53, and induction of p21 by X-ray irradiation in immortal cells derived from normal individual were not affected by the hTERT introduction. Both normal and AT immortal cells exhibited an apparent inhibition of growth as original primary cells when they reached confluence. Karyotype analysis has revealed that they are in a diploid range. These results suggest that cells immortalized by hTERT introduction retain their original characteristics except for immortalization, and that they may be useful for analyzing various effects of radiation on human cells. (author)

  3. Biological and molecular mechanisms of sulfur mustard analogue-induced toxicity in JB6 and HaCaT cells: possible role of ataxia telangiectasia-mutated/ataxia telangiectasia-Rad3-related cell cycle checkpoint pathway.

    Science.gov (United States)

    Tewari-Singh, Neera; Gu, Mallikarjuna; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

    2010-06-21

    Effective medical treatment and preventive measures for chemical warfare agent sulfur mustard (HD)-caused incapacitating skin toxicity are lacking, because of limited knowledge of its mechanism of action. The proliferating basal epidermal cells are primary major sites of attack during HD-caused skin injury. Therefore, employing mouse JB6 and human HaCaT epidermal cells, here, we investigated the molecular mechanism of HD analogue 2-chloroethyl ethyl sulfide (CEES)-induced skin cytotoxicity. As compared to the control, up to 1 mM CEES treatment of these cells for 2, 4, and 24 h caused dose-dependent decreases in cell viability and proliferation as measured by DNA synthesis, together with S and G2-M phase arrest in cell cycle progression. Mechanistic studies showed phosphorylation of DNA damage sensors and checkpoint kinases, ataxia telangiectasia-mutated (ATM) at ser1981 and ataxia telangiectasia-Rad3-related (ATR) at ser428 within 30 min of CEES exposure, and modulation of S and G2-M phase-associated cell cycle regulatory proteins, which are downstream targets of ATM and ATR kinases. Hoechst-propidium iodide staining demonstrated that CEES-induced cell death was both necrotic and apoptotic in nature, and the latter was induced at 4 and 24 h of CEES treatment in HaCaT and JB6 cells, respectively. An increase in caspase-3 activity and both caspase-3 and poly(ADP-ribose)polymerase (PARP) cleavage coinciding with CEES-caused apoptosis in both cell lines suggested the involvement of the caspase pathway. Together, our findings suggest a DNA-damaging effect of CEES that activates ATM/ATR cell cycle checkpoint signaling as well as caspase-PARP pathways, leading to cell cycle arrest and apoptosis/necrosis in both JB6 and HaCaT cells. The identified molecular targets, quantitative biomarkers, and epidermal cell models in this study have the potential and usefulness in rapid development of effective prophylactic and therapeutic interventions against HD-induced skin toxicity.

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

    African Journals Online (AJOL)

    TNHJOURNALPH

    Ataxia Telangiectasia - A Report of a case in Port Harcourt. Lucy Yaguo-Ide, Tochi Uchenwa, BalafamaAlex-Hart, Alice Nte, Chidi Ezeani. Department ofPeadiatrics and Child Health, University of Port Harcourt Teaching Hospital, Port. Harcourt, Nigeria. ABSTRACT. BACKGROUND. Ataxia telangiectasia is acomplex multi-.

  5. 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.

  6. 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...

  7. 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

  8. 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.

  9. Cranial MRI in ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Sardanelli, F. [Dept. of Radiology, Univ. of Genoa (Italy); Parodi, R.C. [Dept. of Radiology, Univ. of Genoa (Italy); Ottonello, C. [Dept. of Radiology, Univ. of Genoa (Italy); Renzetti, P. [Dept. of Radiology, Univ. of Genoa (Italy); Saitta, S. [Dept. of Radiology, Univ. of Genoa (Italy); Lignana, E. [G. Gaslini Inst., Genoa (Italy); Mancardi, G.L. [Dept. of Neurology, Univ. of Genoa (Italy)

    1995-01-01

    We examined five males with laboratory-confirmed ataxia-telangiectasia (AT), aged 9-28 years, several times by MRI (9 examinations: 5 at 0.15 T, 3 at 0.5 T, 1 at 1.5 T). Intermediate, T1-, T2- and T2{sup *}-weighted spin-echo and gradient-echo sequences were performed. All patients showed vermian atrophy, enlarged fourth ventricle and cisterna magna; four showed cerebellar hemisphere atrophy; two enlarged infracerebellar subarachnoid spaces and four patients had sinusitis. No focal areas of abnormal signal were seen in the brain, diffuse high signal was found in the central cerebral white matter of the oldest patient. AT is an important human model of inherited cancer susceptibility and multisystem ageing; as in xeroderma pigmentosum and other ``breakage syndromes``, ionising radiation should be avoided. When imaging is necessary, MRI should be preferred to CT in patients known or suspected to have AT and those with undefined paediatric ataxias of nontraumatic origin. If atrophy of only the cerebellum, especially the vermis, is noted, laboratory research should be performed to confirm the diagnosis of AT. (orig.)

  10. Anti-oxidative capacity in patients with ataxia telangiectasia

    Science.gov (United States)

    Reichenbach, J; Schubert, R; Schwan, C; Müller, K; Böhles, H J; Zielen, S

    1999-01-01

    Highly reactive oxygen species (ROS) are involved in T-cell activation and in the defense against environmental pathogens. An imbalance of ROS generation and detoxifying scavenger enzymes could contribute to the increased susceptibility to cancer and infections in ataxia telangiectasia. We studied oxidative status, i.e. plasma total antioxidant capacity (TEAC), retinol, α-tocopherol, ubiquinol, and the number of activated T cells in 10 patients with ataxia telangiectasia (AT) compared to age-matched healthy controls. As expected, patients showed significantly increased levels of activated human leukocyte antigen-DR and CD45RO expressing T cells. TEAC levels as well as the exogenous antioxidants retinol and α-tocopherol were significantly reduced in patients. In addition, patients showed slightly reduced plasma levels of the endogenous ROS scavenger enzyme ubiquinol (Q10). Although no correlation between number of activated T-cells and antioxidant capacity could be demonstrated, an increase in ROS and a diminished reactive oxygen scavenger capacity may be involved in the disease process of patients with AT. PMID:10469059

  11. [Ataxia telangiectasia: what impact in clinical oncology?].

    Science.gov (United States)

    Stoppa-Lyonnet, D; Aurias, A

    1992-01-01

    Ataxia telangiectasia (AT) is a hereditary disease transmitted in a recessive mode and characterized by chromosomal instability and radiosensitivity. AT patients have a 100-fold higher risk of cancer than the general population. Although AT is a rare disease of which the frequency has been estimated to be 1/40,000, the frequency of the heterozygosity status, when assessed with the Hardy-Weinberg equation is high (about 1.4%). Parents of AT children, thus obligate AT carriers, show chromosomal instability and radiosensitivity, but at a lower level than AT patients. Assuming that these AT characteristics deal with the cancer predisposition, it can be hypothesized that AT heterozygote individuals have a higher cancer susceptibility than the general population. To test this hypothesis, M Swift's group compared cancer incidence rates from adult blood relatives of AT patients with controls. The risk of cancer in AT heterozygotes could be increased by 3.5 and, for carrier women, the breast cancer risk could be increased by 5.1. Actually, the diagnosis of the AT heterozygote status is not possible. However, the near cloning of the gene (or genes) for the disease will permit to identify the AT carriers in a population of patients suffering from cancer and to assess precisely the impact of AT heterozygosity in the genetic predisposition to cancer.

  12. 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.

    2014-01-01

    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. PMID:24610783

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

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    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.

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

    Science.gov (United States)

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

    2015-11-05

    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). 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. 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. Caffeine may inhibit IR-related apoptosis of bladder cancer RT4 cells by suppressing activation of the ATM-Chk2-p53-Puma axis.

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

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    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.

  16. 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 cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (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.

  17. 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

  18. 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

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

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    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.

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

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    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.

  1. [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.

  2. 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.

  3. Spontaneous chromosomal aberrations in Fanconi anaemia, ataxia telangiectasia fibroblast and Bloom's syndrome lymphoblastoid cell lines as detected by conventional cytogenetic analysis and fluorescence in situ hybridisation (FISH) technique.

    Science.gov (United States)

    Sakamoto Hojo, E T; van Diemen, P C; Darroudi, F; Natarajan, A T

    1995-02-01

    Several primary and transformed human cell lines derived from cancer prone patients are employed routinely for biochemical and DNA repair studies. Since transformation leads to some chromosomal instability a cytogenetic analysis of spontaneous chromosome aberrations in fibroblast cell lines derived from patients with Fanconi anaemia (FA), ataxia telangiectasia (AT), and in lymphoblastoid cell lines derived from patients with Bloom's syndrome (BS), was undertaken. Unstable aberrations were analysed in Giemsa stained preparations and the chromosome painting technique was used for evaluating the frequencies of stable aberrations (translocations). In addition, the frequency of sister-chromatid exchanges (SCEs) was determined in differentially stained metaphases. The SV40-transformed fibroblasts from these cell lines have higher frequencies of unstable aberrations than the primary fibroblasts. In the four lymphoblastoid cell lines derived from BS patients higher frequencies of spontaneously occurring chromosomal aberrations in comparison to normal TK6wt cells were also evident. The frequency of spontaneously occurring chromosome translocations was determined with fluorescence in situ hybridisation (FISH) and using DNA libraries specific for chromosomes 1, 2, 3, 4, 7, 8, 11, 14, 19, 20 and X. The translocation levels were found to be elevated for primary FA fibroblasts and lymphoblastoid cells derived from BS patients in comparison with control cell lines, hetero- and homozygote BS cell lines not differing in this respect. The SV40-transformed cell lines showed very high frequencies of translocations independent of their origin and almost every cell contained at least one translocation. In addition, clonal translocations were found in transformed control TK6wt and AT cell lines for chromosomes 20 and 14, respectively. The spontaneous frequencies of SCEs were similar in transformed fibroblasts derived from normal individuals and AT patients, whereas in SV40-transformed FA

  4. 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.

  5. Clinical and genetic features of ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Bundey, S. [Birmingham Maternity Hospital (United Kingdom). Clinical Genetics Unit

    1994-12-01

    There are several variants of ataxia-telangiectasia (A-T): classical A-T with marked radiation sensitivity; classical A-T with intermediate levels of radiation sensitivity; mild A-T with intermediate levels of radiation sensitivity; A-T without telangiectasia; A-T without oculomoto apraxia; and A-T with microcephaly. These disorders are probably caused by different allelic mutations, because affected sibs resemble the index patients, and because there is an association of certain haplo-types of 11q22-23 with specific phenotypes. The Nijmegen Breakage Syndrome, with its lack of ataxia, seems on clinical grounds to be a different disorder. Although A-T is almost always inherited as an autosomal recessive, there are some unusual features; an unexpectedly low parental consanguinity rate, an incidence in sibs that is < 0.25, and occurrence of disease in many different races and in the offspring of mixed race unions. Moreover, looking at haplotypes from 63 UK patients, there is a remarkably low incidence of homozygosity. An autosomal recessive condition that is deficient in parental consanguinity, and in homozygosity for the region around the gene, can be explained by J.H. Edwards` hypothesis that homozygosity for alleles at a neighbouring locus are lethal early in embryogenesis. Other possible mechanisms to explain the unusual genetic features are discussed. (author).

  6. 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

  7. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Tavani, F. [Department of Radiology, University of Modena (Italy); Zimmerman, R.A.; Gatti, R.; Bingham, P. [Department of Radiology, Children' s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, PA 19104, Philadelphia (United States); Berry, G.T. [Department of Endocrinology, Children' s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, PA 19104, Philadelphia (United States); Sullivan, K. [Department of Immunology, Children' s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, PA 19104, Philadelphia (United States)

    2003-05-01

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

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

    Science.gov (United States)

    Tomasi, Dardo; Wang, Gene-Jack; Studentsova, Yana; Margus, Brad; Crawford, Thomas O.

    2014-01-01

    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 18F-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 ataxia-telangiectasia also had higher metabolism in globus pallidus (16%, P = 0.05), which correlated negatively with motor performance. Asymptomatic relatives had lower metabolism in anterior vermis (12%; P = 0.01) and hippocampus (19%; P = 0.002) than controls. Our results indicate that, in addition to the expected decrease in cerebellar metabolism, participants with ataxia-telangiectasia had widespread changes in metabolic rates including hyperactivity in globus pallidus indicative of basal ganglia involvement. Changes in basal ganglia metabolism offer potential insight into targeting strategies for therapeutic deep brain stimulation. Our finding of decreased metabolism in vermis and hippocampus of asymptomatic relatives

  10. 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.

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

    Science.gov (United States)

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

    2014-06-01

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

  12. 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

    A 20-month-old girl diagnosed with T-cell acute lymphoblastic leukemia was treated according to the Nordic NOPHO ALL2000 protocol. The patient developed severe immunosuppression and experienced life-threatening adenovirus infection, which was treated with ribavirin and cidofovir. α-fetoprotein wa......A 20-month-old girl diagnosed with T-cell acute lymphoblastic leukemia was treated according to the Nordic NOPHO ALL2000 protocol. The patient developed severe immunosuppression and experienced life-threatening adenovirus infection, which was treated with ribavirin and cidofovir. α...

  13. Lack of mutations in the P53 gene exons 5 to 8 in ataxia-telangiectasia.

    Science.gov (United States)

    Jonveaux, P; Berger, R

    1993-04-01

    Alterations of the TP53 tumor suppressor gene are present in various human malignancies and in the dominantly inherited Li-Fraumeni syndrome. Recently, a cell cycle checkpoint pathway involving p53 and GADD45 has been identified as defective in ataxia-telangiectasia. Using single strand conformation polymorphism analysis of PCR products, we looked for TP53 mutations in DNA of patients with AT. We did not find any mutation in 6 patients, suggesting that TP53 mutations are not directly involved in the cancer susceptibility observed in AT.

  14. 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

    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...

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

    Science.gov (United States)

    Choy, Kay Rui; Watters, Dianne J

    2017-05-22

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

  16. 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

  17. 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

    2014-01-01

    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. 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. 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 pulmonary function testing on two or more occasions over an average of 2 years. 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. © 2013 Wiley Periodicals, Inc.

  18. Characteristic Eye Movements in Ataxia-Telangiectasia-Like Disorder: An Explanatory Hypothesis

    Directory of Open Access Journals (Sweden)

    Pamela Federighi

    2017-11-01

    Full Text Available ObjectiveTo investigate cerebellar dysfunctions and quantitatively characterize specific oculomotor changes in ataxia-telangiectasia-like disorder (ATLD, a rare autosomal recessive disease caused by mutations in the MRE11 gene. Additionally, to further elucidate the pathophysiology of cerebellar damage in the ataxia-telangiectasia (AT spectrum disorders.MethodsSaccade dynamics, metrics, and visual fixation deficits were investigated in two Italian adult siblings with genetically confirmed ATLD. Visually guided saccades were compared with those of 40 healthy subjects. Steady fixation was tested in primary and eccentric positions. Quantitative characterization of saccade parameters, saccadic intrusions (SI, and nystagmus was performed.ResultsPatients showed abnormally hypermetric and fast horizontal saccades to the left and greater inaccuracy than healthy subjects in all saccadic eye movements. Eye movement abnormalities included slow eye movements that preceded the initial saccade. Horizontal and vertical spontaneous jerk nystagmus, gaze-evoked, and rebound nystagmus were evident. Fixation was interrupted by large square-wave jerk SI and macrosaccadic oscillations.ConclusionSlow eye movements accompanying saccades, SI, and cerebellar nystagmus are frequently seen in AT patients, additionally our ATLD patients showed the presence of fast and hypermetric saccades suggesting damage of granule cell-parallel fiber-Purkinje cell synapses of the cerebellar vermis. A dual pathogenetic mechanism involving neurodevelopmental and neurodegenerative changes is hypothesized to explain the peculiar phenotype of this disease.

  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 pdeglutitive airflow increased with age in participants in the comparison group (p=0.006), but not in those with ataxia telangiectasia (p=0.234). With age, mean duration of DIORA decreased in controls (p<0.001) but was unchanged in participants with ataxia 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. 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/.

  1. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1997-03-01

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

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

    Directory of Open Access Journals (Sweden)

    Sam P. Nayler

    2017-10-01

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

  4. Linear growth and endocrine function in children with ataxia telangiectasia

    Directory of Open Access Journals (Sweden)

    Mohammad Ehlayel

    2014-01-01

    Full Text Available Introduction: Ataxia telangiectasia (AT is a rare, genetic, primary immune deficiency disease characterized by immunodeficiency and neurological manifestations, with an increased tendency to infection, malignancy, and autoimmune diseases. Both growth delay and endocrine abnormalities are occasionally reported in these patients. Patients and Methods: We studied growth parameters height (Ht, weight, body mass index (BMI and calculated the Ht standard deviation scores (HtSDS of 13 patients (age 7.7 ± 3.5 years-age range: 3-14.5 years with AT in relation to their mid-parental Ht SDS (MPHtSDS. We measured their serum calcium (Ca, phosphorus (PO4, alkaline phosphatase, alanine transferase (ALT, serum ferritin, creatinine and albumin concentrations. Endocrine investigations included the assessment of serum free thyroxine (FT4, thyrotropin (TSH, insulin-like growth factor-I (IGF-I and morning cortisol. Complete blood count and serum immunoglobulins (IgG, IgM and IgA antibodies were also measured. Growth data were correlated to hormonal and immune data. Results: About 31% of patients with AT had short stature (HtSDS <−2. However, their MPHtSDS denoted that their short stature was familial because four out of 13 had MPHtSDS <−2. They had low BMI, and two of them had low serum albumin and IGF-I, denoting malnutrition or disturbed growth hormone secretion. Elevated serum ALT and ferritin in some patients suggest immune-related inflammation in the liver. 30% of patients had high TSH, two of them had low FT4 diagnosing overt (15% and sub-clinical (15% hypothyroidism. Anti-thyroid peroxidase antibodies were high in two out of 13 patients denoting immune-related thyroid aggression. Eight out of 13 patients had Vitamin D deficiency (<20 ng/ml however, their serum Ca and PO 4 levels were in the normal range. One adolescent girl (14.5 years had hyper-gonadotropic hypogonadism (low estradiol and high follicle stimulating hormone. All patients had normal 8 AM

  5. 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

    2016-01-01

    AIM This cross-sectional investigation aimed to assess the value of non-invasive measures of temporal respiratory–swallow coupling in individuals with ataxic swallowing. METHOD Twenty participants 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). RESULTS 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). INTERPRETATION 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. PMID:27214374

  6. 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.

  7. 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

  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

  9. 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.

  10. 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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Ataxia telangiectasia mutated inhibits oxidative stress-induced apoptosis by regulating heme oxygenase-1 expression.

    Science.gov (United States)

    Yu, Ji Hoon; Cho, Soon Ok; Lim, Joo Weon; Kim, Nanhee; Kim, Hyeyoung

    2015-03-01

    Ataxia telangiectasia (AT) is caused by mutational inactivation of the ataxia telangiectasia mutated (Atm) gene, which is involved in DNA repair. Increased oxidative stress has been shown in human AT cells and neuronal tissues of Atm-deficient mice. Heme oxygenase-1 (HO-1) is an inducible antioxidant enzyme and protects cells against oxidative stress. The purpose of this study is to determine whether ATM induces antioxidant enzyme HO-1 and protects cells from oxidative stress-mediated apoptosis by driving the activation of PKC-δ and NF-κB, by increasing cell viability, and by downregulating DNA fragmentation and apoptotic indicators (apoptosis-inducing factor and cleaved caspase-3). AT fibroblasts stably transfected with human full-length ATM cDNA (YZ5 cells) or the empty vector (MOCK cells) were treated with H2O2 as a source of reactive oxygen species (ROS). As a result, transfection with ATM inhibited ROS-induced cell death and DNA fragmentation in MOCK cells. Transfection with ATM induced expression of HO-1 which was mediated by PKC-δ and NF-κB in H2O2-treated MOCK cells. ZnPP, an HO-1 inhibitor, and transfection with HO-1 siRNA increased ROS levels and apoptosis, whereas hemin, an HO-1 activator, reduced ROS levels and apoptosis in H2O2-treated YZ5 cells. Rottlerin, a PKC-δ inhibitor, inhibited NF-κB activation and HO-1 expression in H2O2-treated YZ5 cells. MOCK cells showed increased cell death, DNA fragmentation, and apoptotic indicators compared to YZ5 cells exposed to H2O2. In addition, transfection with p65 siRNA increased ROS levels and DNA fragmentation, but decreased HO-1 protein levels in H2O2-treated YZ5 cells. In conclusion, ATM induces HO-1 expression via activation of PKC-δ and NF-κB and inhibits oxidative stress-induced apoptosis. A loss of HO-1 induction may explain why AT patients are vulnerable to oxidative stress. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. A high frequency of distinct ATM gene mutations in ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Wright, J.; Teraoka, S.; Concannon, P. [Univ. of Washington School of Medicine, Seattle, WA (United States)] [and others

    1996-10-01

    The clinical features of the autosomal recessive disorder ataxia-telangiectasia (AT) include a progressive cerebellar ataxia, hypersensitivity to ionizing radiation, and an increased susceptibility to malignancies. Epidemiological studies have suggested that AT heterozygotes may also be at increased risk for malignancy, possibly as a consequence of radiation exposure. A gene mutated in AT patients (ATM) has recently been isolated, making mutation screening in both patients and the general population possible. Because of the relatively large size of the ATM gene, the design of screening programs will depend on the types and distribution of mutations in the general population. In this report, we describe 30 mutations identified in a panel of unrelated AT patients and controls. Twenty-five of the 30 were distinct, and most patients were compound heterozygotes. The most frequently detected mutation was found in three different families and had previously been reported in five others. This corresponds to a frequency of 8% of all reported ATM mutations. Twenty-two of the alterations observed would be predicted to lead to protein truncation at sites scattered throughout the molecule. Two fibroblast cell lines, which displayed normal responses to ionizing radiation, also proved to be heterozygous for truncation mutations of ATM. These observations suggest that the carrier frequency of ATM mutations may be sufficiently high to make population screening practical. However, such screening may need to be done prospectively, that is, by searching for new mutations rather than by screening for just those already identified in AT families. 33 refs., 1 fig., 1 tab.

  13. Ocular findings in Norwegian patients with ataxia-telangiectasia: a 5 year prospective cohort study.

    Science.gov (United States)

    Riise, Ruth; Ygge, Jan; Lindman, Carl; Stray-Pedersen, Asbjørg; Bek, Toke; Rødningen, Olaug Kristin; Heiberg, Arvid

    2007-08-01

    To describe the outcome of ophthalmologic examination of 10 Norwegian children with ataxia-telangiectasia (AT) followed through 5 years. Ten Norwegian patients with AT aged 2-22 years (three females, seven males) were examined. The diagnosis was confirmed clinically as well as with molecular genetic studies. Conventional ophthalmologic examination was performed and supplemented by photographs of the conjunctiva, video recordings and registration of eye motility in five consecutive years. Additionally conjunctival biopsies were performed at the end of the follow-up period. General ataxia was usually detected when the child started to walk. All children over the age of 4 years had abnormal saccade movements, a form of ocular motor apraxia. Conjunctival telangiectasias were mostly visible at 4-5 years, primarily within the palpebral fissure. Immunohistochemical examination of conjunctival biopsies showed an increased number of cross-sections of blood vessels and neurons surrounded by glial tissue. There was a tendency to slightly earlier onset of conjunctival telangiectasias in the patients homozygous for a founder mutation compared with the other patients. The diagnosis of AT can be supported at preschool age by the onset of ocular motor apraxia and conjunctival telangiectasias. The findings become more prominent with age. The conjunctival telangiectasias seem to appear slightly earlier in the patients who are homozygous for a Norwegian founder mutation than in the rest of the patients.

  14. Germline Mutations of the Ataxia-Telangiectasia Gene, ATM, as a Risk Factor for Radiation-Associated Breast Cancer

    National Research Council Canada - National Science Library

    Offit, Kenneth

    1998-01-01

    This project is a case-control study designed to determine whether or not the presence of a germline mutation in ATM, the gene responsible for ataxia-telangiectasia, significantly increases the risk...

  15. 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 < 0.001). Mean diffusivity was significantly elevated in anterior tract locations but was reduced within cerebellar peduncle regions of all patient tracts (p < 0.001). Reduced tract streamline number and tract volume in the left and right corticospinal and somatosensory tracts were observed in patients (p < 0.006). In addition, reduced apparent fiber density in the left and right corticospinal and right somatosensory tracts (p < 0.006) occurred in patients. 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.

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

    Science.gov (United States)

    Lin, Zi-Li; Kim, Nam-Hyung

    2015-06-01

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

  17. Ataxia telangiectasia mutated-dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor.

    Science.gov (United States)

    Tamaichi, Hiroyuki; Sato, Masaki; Porter, Andrew C G; Shimizu, Toshiaki; Mizutani, Shuki; Takagi, Masatoshi

    2013-02-01

    Topoisomerase II alpha (TOP2A) has a crucial role in proper chromosome condensation and segregation. Here we report the interaction of TOP2A with ataxia telangiectasia mutated (ATM) and its phosphorylation in an ATM-dependent manner after DNA damage. In vitro kinase assay and site-directed mutagenesis studies revealed that serine 1512 is the target of phosphorylation through ATM. Serine 1512 to Alanine mutation of TOP2A showed increased stability of the protein, retaining TOP2A activity at least with regard to cell survival activity. Ataxia telangiectasia-derived cell lines showed high levels of TOP2A that were associated with hypersensitivity to the TOP2 inhibitor etoposide. These findings suggest that ATM-dependent TOP2A modification is required for proper regulation of TOP2 stability and subsequently of the sensitivity to TOP2 inhibitor. In a lymphoblastoid cell line derived from a patient who developed MLL rearrangement, positive infant leukemia, defective ATM expression, and increased TOP2A expression were shown. It was intriguing that hypersensitivity to TOP2 inhibitor and susceptibility to MLL gene rearrangement were shown by low-dose etoposide exposure in this cell line. Thus, our findings have clinically important implications for the pathogenesis of infantile acute leukemia as well as treatment-associated secondary leukemia following exposure to TOP2 inhibitors. © 2012 Japanese Cancer Association.

  18. 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.

  19. The role of the neuro-astro-vascular unit in the etiology of ataxia telangiectasia.

    Science.gov (United States)

    Meshulam, Leenoy; Galron, Ronit; Kanner, Sivan; De Pittà, Maurizio; Bonifazi, Paolo; Goldin, Miri; Frenkel, Dan; Ben-Jacob, Eshel; Barzilai, Ari

    2012-01-01

    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 neuroglia 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 A-T-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.

  20. 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.

  1. 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.

  2. Antioxidant vitamins intake, ataxia telangiectasia mutated (ATM) genetic polymorphisms, and breast cancer risk.

    Science.gov (United States)

    Lee, Sang-Ah; Lee, Kyoung-Mu; Lee, Seung-Joon; Yoo, Keun-Young; Park, Sue Kyung; Noh, Dong-Young; Ahn, Sei-Hyun; Kang, Daehee

    2010-01-01

    Ataxia telangiectasia mutated (ATM) cells exist under a constant state of oxidative stress with high levels of reactive oxygen species, which are removed by cellular antioxidant vitamins. We investigated the independent and combined effect of antioxidant vitamins intake and the ATM genotype or diplotype on the breast cancer risk. Analyses included 323 cases and age-matched controls who participated in the Korean Breast Cancer Study during 2001-2003 with complete dietary information. The vitamin A (P vitamins including vitamin B(2) (P = 0.01), vitamin C (P intake. No five single nucleotide polymorphisms (ATM-5144A > T (rs228589), IVS21 + 1049T > C (rs664677), IVS33-55T > C (rs664982), IVS34+60G > A (rs664143), and 3393T > G (rs4585)) studied showed significant differences in their allele frequencies between the cases and controls. On the other hand, compared with the diploid of ATTGT/ATTGT, as the number of ATTGT haplotype decreased, the risk of breast cancer increased (P = 0.04). The association between ATM diplotype and the breast cancer risk was predominantly among women with low intake of antioxidant vitamins including vitamin A, vitamin C, and folic acid. This study suggested that some antioxidant vitamins intake may modify the effect of ATM diplotype on the breast cancer risk among Korean women.

  3. 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

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

    Science.gov (United States)

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

    2016-11-04

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

  5. Dano e reparo de dna em indivíduos com ataxia-telangiectasia e em seus pais heterozigotos

    OpenAIRE

    Roberta Passos Palazzo

    2010-01-01

    A presente pesquisa pretende demonstrar evidências capazes de contribuir para o entendimento dos mecanismos envolvidos na ataxia-telangiectasia, bem como oferecer dados que auxiliem na implementação de técnicas complementares ao diagnóstico desta síndrome. Desde a descoberta do gene envolvido na ataxia-telangiectasia (o gene ATM), muito conhecimento tem sido acumulado, especialmente sobre os mecanismos moleculares envolvidos na síndrome, bem como nas respectivas doenças relacionadas. Este est...

  6. Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia

    Directory of Open Access Journals (Sweden)

    Ruth Duecker

    2018-04-01

    Full Text Available Lung failure is responsible for significant morbidity and is a frequent cause of death in ataxia-telangiectasia (A-T. Disturbance in the redox balance of alveolar epithelial cells must be considered as a causal factor for respiratory disease in A-T. To investigate bronchoalveolar sensitivity to reactive oxygen species (ROS and ROS-induced DNA damage, we used bleomycin (BLM to induce experimental inflammation and fibrotic changes in the Atm-deficient mouse model.BLM or saline was administered by oropharyngeal instillation into the lung of Atm-deficient mice and wild-type mice. Mice underwent pulmonary function testing at days 0, 9, and 28, and bronchoalveolar lavage (BAL was analysed for cell distribution and cytokines. Lung tissue was analysed by histochemistry.BLM administration resulted in a tremendous increase in lung inflammation and fibrotic changes in the lung tissue of Atm-deficient mice and was accompanied by irreversible deterioration of lung function. ATM (ataxia telangiectasia mutated deficiency resulted in reduced cell viability, a delay in the resolution of γH2AX expression and a significant increase in intracellular ROS in pulmonary epithelial cells after BLM treatment. This was confirmed in the human epithelial cell line A549 treated with the ATM-kinase inhibitor KU55933.Our results demonstrate high bronchoalveolar sensitivity to ROS and ROS-induced DNA damage in the Atm-deficient mouse model and support the hypothesis that ATM plays a pivotal role in the control of oxidative stress-driven lung inflammation and fibrosis. Keywords: Pulmonary inflammation, Lung fibrosis, Mice, Oxidative stress

  7. Risk for Sporadic Breast Cancer in Ataxia Telangiectasia Heterozygotes

    Science.gov (United States)

    2001-08-01

    6 7 gas 9 a poly p73a poly p73e poly p73N FiG. 1. Endogenous p73 a and P proteins are detectable by various p73-specific antibodies. Immunoblots of...even p73-specific targets. One example may be the Aquaporin 3 gene, a glycerol and solute transporter, which is greatly preferred by the p7313...model in which some DNA damage signals are channeled through c-abl to p73. Hence, one would predict that p73-deficient cells should have defective DNA

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

    National Research Council Canada - National Science Library

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

    2015-01-01

    ...; 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...

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

    NARCIS (Netherlands)

    Reiman, A.; Srinivasan, V.; Barone, G.; Last, J.I.; Wootton, L.L.; Davies, E.G.; Verhagen, M.M.; Willemsen, M.A.A.P.; Weemaes, C.M.R.; 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

  10. Ataxia Telangiectasia

    Science.gov (United States)

    ... Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus on Research Alzheimer's & Related Dementias Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury ...

  11. Ataxia Telangiectasia

    Science.gov (United States)

    ... Español 1-800-4-CANCER Live Chat Publications Dictionary Menu Contact Dictionary Search About Cancer Causes and Prevention Risk Factors ... my chances of getting breast cancer? What about environmental sources of radiation, such as cellular phones? Should ...

  12. A haplotype common to intermediate radiosensitivity variants of ataxia-telangiectasia in the UK

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, A.M.R.; McConville, C.M.; Byrd, P.J. [Birmingham Univ. (United Kingdom). Medical School; Rotman, G.; Shiloh, Y. [Tel Aviv Univ. (Israel). Sackler School of Medicine

    1994-12-01

    In a study of ataxia-telangiectasia (A-T) in the UK, patients in10 out of 60 families were shown to have a much lower level of chromosomal radiosensitivity compared with the majority of patients. In some patients the level of radiosensitivity was hardly distinguishable from normal. Patients in this group, however, could be distinguished clinically from the majority either by the later onset of severe cerebellar features or the slower rate of progress of the disorder. By using highly polymorphic microsatellite repeat markers a chromosome 11q22-23 haplotype common to the majority of these patients, and not occurring in any non-A-T chromosome in 60 families, was identified on one chromosome. The haplotype probably defines the region of the A-T gene in these families and the mutation associated with this haplotype may be much less severe than the second mutation thereby producing the slightly milder phenotype. (author).

  13. 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).

  14. 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.

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

    Science.gov (United States)

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

    2011-01-01

    To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function. Observational case series. Cognitive functioning, language, speech and oral-motor functioning were examined in eight individuals with A-T (six boys, two girls), taking into account the confounding effects of motor functioning on test performance. All patients, except the youngest one, suffered from mild-to-moderate/severe intellectual impairment. Compared to developmental age, patients showed cognitive deficits in attention, (non)verbal memory and verbal fluency. Furthermore, dysarthria and weak oral-motor performance was found. Language was one of the patients' assets. In contrast to the severe deterioration of motor functioning in A-T, cognitive and language functioning appeared to level off with a typical profile of neuropsychological strengths and weaknesses. Based on our experiences with A-T, suggestions are made to determine a valid assessment of the cognitive and speech-language manifestations.

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

    Science.gov (United States)

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

    1999-01-01

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

  17. Ataxia-telangiectasia mutated and the Mre11-Rad50-NBS1 complex: promising targets for radiosensitization.

    Science.gov (United States)

    Kuroda, Shinji; Urata, Yasuo; Fujiwara, Toshiyoshi

    2012-01-01

    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.

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

    Science.gov (United States)

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

    2015-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Crawford Thomas O

    2011-05-01

    Full Text Available Abstract 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.

  20. 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.

  1. Is age a risk factor for liver disease and metabolic alterations in ataxia Telangiectasia patients?

    Science.gov (United States)

    Paulino, Talita Lemos; Rafael, Marina Neto; Hix, Sonia; Shigueoka, David Carlos; Ajzen, Sergio Aron; Kochi, Cristiane; Suano-Souza, Fabíola Isabel; da Silva, Rosangela; Costa-Carvalho, Beatriz T; Sarni, Roseli O S

    2017-08-04

    Ataxia telangiectasia (A-T) is a neurodegenerative disease that leads to mitochondrial dysfunction and oxidative stress. Insulin resistance (IR), type 2 diabetes and the risk for development of cardiovascular disease was recently associated as an extended phenotype of the disease. We aimed to assess IR; liver involvement; carotid intima-media thickness (cIMT) and metabolic alterations associated to cardiovascular risk in A-T patients, and relate them with age. Glucose metabolism alterations were found in 54.6% of the patients. Hepatic steatosis was diagnosed in 11/17 (64.7%) A-T patients. AST/ALT ratio > 1 was observed in 10/17 (58.8%). A strong positive correlation was observed between insulin sum concentrations with ALT (r = 0.782, p < 0.004) and age (r = 0.818, p = 0.002). Dyslipidemia was observed in 55.5% of the patients. The apolipoprotein (Apo-B)/ApoA-I ratio (r = 0.619; p < 0.01), LDL/HDL-c (r = 0.490; p < 0.05) and the Apo-B levels (r = 0.545; p < 0.05) were positively correlated to cIMT. Metabolic disorders implicated in cardiovascular and liver diseases are frequently observed in adolescent A-T patients and those tend to get worse as they become older. Therefore, nutritional intervention and the use of drugs may be necessary.

  2. 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.

  3. 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.

  4. 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.

  5. Genetic, physical and functional analysis of the ataxia-telangiectasia locus on chromosome 11q22-23

    Energy Technology Data Exchange (ETDEWEB)

    Shiloh, Y.; Ziv, Y.; Savitski, K. [Tel Aviv Univ. (Israel)] [and others

    1994-09-01

    Ataxia-telangiectasia (A-T) is an autosomal recessive multisystem disorder featuring cerebellar degeneration, immunodeficiency, chromosomal instability, cancer susceptibility, and radiosensitivity. Four complementation groups have been observed in A-T. The two major groups, A and C, were localized to chromosome 11q22-23, and the other two, D and E, may map to the same chromosomal region. We developed an integrated system of positional and complementation cloning to identify the A-T gene(s). The A-T region was saturated with microsatellite markers by physically mapping markers generated at random by other labs and by identifying new polymorphic CA-repeats in YAC clones obtained from this region. According to recent linkage data based on these markers and linkage disequilibrium analysis in Moroccan Jewish A-T patients, the A-T(A) and A-T(C) mutations are contained within a 2 Mb interval between D11S1819 and D11S1960. This interval was cloned in YAC and cosmid contigs, and transcribed sequences were identified using the following methods: screening of cDNA libraries using cosmid clones; magnetic bead capture using YAC and cosmid clones; direct selection of cDNA clones using YAC clones immobilized on a solid matrix; and 3{prime} exon trapping. Preliminary results indicate that the A-T region is rich in transcribed sequences. Structural and functional analysis of these genes is being carried out by sequence analysis, by physical mapping using the cosmid contigs, and by testing their ability to complement the radiomimetic sensitivity of A-T cells.

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

    Science.gov (United States)

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

    2017-10-01

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

  7. 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...

  8. 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

  9. A YAC contig spanning the ataxia-telangiectasia locus (groups A and C) at 11q22-q23

    Energy Technology Data Exchange (ETDEWEB)

    Rotman, G.; Savitsky, K.; Ziv, Y. [Tel Aviv Univ. Ramat Aviv (Israel)] [and others

    1994-11-15

    Ataxia-telangiectasia (A-T) is an autosomal recessive disease involving cerebellar degeneration, immunodeficiency, cancer predisposition, chromosomal instability and radiosensitivity. A-T is heterogeneous, and the majority of A-T cases are associated with two complementation groups, A and C. The ATA and ATC loci are closely linked at chromosome 11q22-q23. Recombination mapping and linkage disequilibrium analysis have confined both loci between the markers D11S1817 and D11S927. Construction of this contig was expedited by prior generation of a region-specific ICRF sublibrary using Alu-PCR products derived from a radiation hybrid. The contig was expanded further by screening the libraries with Alu-PCR products derived from YAC clones and with STSs from YAC ends. YAC clones were aligned by fingerprinting with moderately repetitive probes. 56 refs., 5 figs., 1 tab.

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

    OpenAIRE

    M. Guzmán

    1994-01-01

    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 incidenci...

  11. Ataxia.

    Science.gov (United States)

    Ashizawa, Tetsuo; Xia, Guangbin

    2016-08-01

    This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia. Ataxia is a manifestation of a variety of disease processes, and an underlying etiology needs to be investigated. Pure ataxia is rare in acquired ataxia disorders, and associated symptoms and signs almost always exist to suggest an underlying cause. While the spectrum of hereditary degenerative ataxias is expanding, special attention should be addressed to those treatable and reversible etiologies, especially potentially life-threatening causes. This article summarizes the diseases that can present with ataxia, with special attention given to diagnostically useful features. While emerging genetic tests are becoming increasingly available for hereditary ataxia, they cannot replace conventional diagnostic procedures in most patients with ataxia. Special consideration should be focused on clinical features when selecting a cost-effective diagnostic test. Clinicians who evaluate patients with ataxia should be familiar with the disease spectrum that can present with ataxia. Following a detailed history and neurologic examination, proper diagnostic tests can be designed to confirm the clinical working diagnosis.

  12. Ataxia.

    Science.gov (United States)

    Winchester, Sara; Singh, Piyush K; Mikati, Mohamad A

    2013-01-01

    The approach to the child with ataxia requires a detailed history and careful general and neurological examination as well as selected blood work and brain imaging and increasingly available genetic testing for inherited ataxias that usually have an episodic or progressive presentation. The differential of acute and recurring ataxia covered in this chapter includes intoxication (e.g., antiepileptics, lead, alcohol), postinfectious cerebellitis, hemorrhage, ischemic stroke, tumor (posterior fossa or cerebellum), brainstem encephalitis, occult neuroblastoma, Miller Fisher syndrome, conversion reaction, multiple sclerosis, epileptic pseudoataxia, vasculitis (e.g., Kawasaki), metabolic etiologies (e.g., maple syrup urine disease, pyruvate dehydrogenase deficiency, ornithine transcarbamylase deficiency, biotinidase deficiency, Hartnup disease, and argininosuccinic aciduria), migraine, migraine equivalents (benign paroxysmal positional vertigo), autosomal dominant episodic ataxias (with seven types currently identified), and hypothyroidism. Cooperation with therapists and providers from other specialties including ophthalmology and genetics and metabolism is essential to caring for these children and their families. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Ataxia Telangiectasia-Mutated (ATM) Kinase Activity Is Regulated by ATP-driven Conformational Changes in the Mre11/Rad50/Nbs1 (MRN) Complex*

    Science.gov (United States)

    Lee, Ji-Hoon; Mand, Michael R.; Deshpande, Rajashree A.; Kinoshita, Eri; Yang, Soo-Hyun; Wyman, Claire; Paull, Tanya T.

    2013-01-01

    The 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 and hydrolysis by the Rad50 protein. Here we use an ATP analog-sensitive form of ATM to determine that ATP binding, but not hydrolysis, by Rad50 is essential for MRN stimulation of ATM. Mre11 nuclease activity is dispensable, although some mutations in the Mre11 catalytic domain block ATM activation independent of nuclease function, as does the mirin compound. The coiled-coil domains of Rad50 are important for the DNA binding ability of MRN and are essential for ATM activation, but loss of the zinc hook connection can be substituted by higher levels of the complex. Nbs1 binds to the “closed” form of the MR complex, promoted by the zinc hook and by ATP binding. Thus the primary role of the hook is to tether Rad50 monomers together, promoting the association of the Rad50 catalytic domains into a form that binds ATP and also binds Nbs1. Collectively, these results show that the ATP-bound form of MRN is the critical conformation for ATM activation. PMID:23525106

  14. Ataxia telangiectasia-mutated (ATM) kinase activity is regulated by ATP-driven conformational changes in the Mre11/Rad50/Nbs1 (MRN) complex.

    Science.gov (United States)

    Lee, Ji-Hoon; Mand, Michael R; Deshpande, Rajashree A; Kinoshita, Eri; Yang, Soo-Hyun; Wyman, Claire; Paull, Tanya T

    2013-05-03

    The 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 and hydrolysis by the Rad50 protein. Here we use an ATP analog-sensitive form of ATM to determine that ATP binding, but not hydrolysis, by Rad50 is essential for MRN stimulation of ATM. Mre11 nuclease activity is dispensable, although some mutations in the Mre11 catalytic domain block ATM activation independent of nuclease function, as does the mirin compound. The coiled-coil domains of Rad50 are important for the DNA binding ability of MRN and are essential for ATM activation, but loss of the zinc hook connection can be substituted by higher levels of the complex. Nbs1 binds to the "closed" form of the MR complex, promoted by the zinc hook and by ATP binding. Thus the primary role of the hook is to tether Rad50 monomers together, promoting the association of the Rad50 catalytic domains into a form that binds ATP and also binds Nbs1. Collectively, these results show that the ATP-bound form of MRN is the critical conformation for ATM activation.

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

    Directory of Open Access Journals (Sweden)

    M. Guzmán

    1994-12-01

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

  16. 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

  17. 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

  18. [Progressive disseminated essential telangiectasia with conjunctival involvement].

    Science.gov (United States)

    Swensson, B; Swensson, O; Häring, G

    1998-02-01

    Widespread idiopathic telangiectasia (generalized essential telangiectasia) is a rare skin disorder characterized by the development and gradual spreading of telangiectases. The condition tends to affect women in their midthirties. For no apparent reason telangiectases start to appear to the lower extremities and progress steadily to involve the skin of the trunk, the arms, and the face. General health is not affected by the condition and standard laboratory tests consistently yield normal results. In February 1997 a 78-year-old lady was admitted for treatment of cataracta corticonuclearis of her left eye. Complete ophthalmological and dermatological examinations were performed. She presented marked conjunctival telangiectases of both eyes and widespread cutaneous telangiectases involving her face, trunk, arms, and legs. Complete blanching of lesional skin was observed on diascopy. The Rumpel-Leede-test was normal. Cutaneous and conjunctival changes appeared not to be associated with internal disease or bleeding abnormalities. The patient presented here shows widespread idiopathic telangiectasia with marked conjunctival involvement. Ocular changes rarely have been reported in patients with generalized essential telangiectasia to date. Concomittant conjunctival and cutaneous telangiectases may be seen in other conditions such as hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) and ataxia telangiectasia (Louis-Bar syndrome). The former shows an associated bleeding abnormality and is transmitted autosomal dominantly. The latter presents associated neurological signs such as cerebellar ataxia, strabism, nystagmus, apraxia, and mental retardation.

  19. Modest increased sensitivity to radiation oncogenesis in ATM heterozygous versus wild-type mammalian cells

    Science.gov (United States)

    Smilenov, L. B.; Brenner, D. J.; Hall, E. J.

    2001-01-01

    Subpopulations that are genetically predisposed to radiation-induced cancer could have significant public health consequences. Individuals homozygous for null mutations at the ataxia telangiectasia gene are indeed highly radiosensitive, but their numbers are very small. Ataxia Telangiectasia heterozygotes (1-2% of the population) have been associated with somewhat increased radiosensitivity for some end points, but none directly related to carcinogenesis. Here, intralitter comparisons between wild-type mouse embryo fibroblasts and mouse embryo fibroblasts carrying ataxia telangiectasia mutated (ATM) null mutation indicate that the heterozygous cells are more sensitive to radiation oncogenesis than their normal, litter-matched, counterparts. From these data we suggest that Ataxia Telangiectasia heterozygotes could indeed represent a societally-significant radiosensitive human subpopulation.

  20. Rare forms of autosomal recessive neurodegenerative ataxia.

    Science.gov (United States)

    Koenig, Michel

    2003-09-01

    There has been a recent explosion in knowledge regarding the genetic basis of several autosomal recessive ataxias. This article summarizes current information regarding rare forms of recessive ataxias. Friedreich's ataxia and ataxia telangiectasia are dealt with in other articles in this issue. The rarer recessive ataxias can be clinically classified as sensory and spinocerbellar ataxias, cerebellar ataxia with sensory-motor polyneuropathy, and purely cerebellar ataxias. Examples of the first category include ataxia with isolated vitamin E deficiency, abetalipoproteinemia, Refsum's disease, infantile-onset spinocerebellar ataxia, and ataxia with blindness and deafness. Examples of ataxia with sensory-motor polyneuropathy include ataxia with oculomotor apraxia 1 and 2 and spinocerebellar ataxia with neuropathy 1. Examples of purely cerebellar ataxia include autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with hypogonadotropic hypogonadism. This review summarizes the clinical and genetic features of these entities and concludes that the pathogenic basis of such ataxias at this time appear to involve two broad types of processes: free-radical injury and defects of DNA single- or double-strand break repair.

  1. Response of sensitive human ataxia and resistant T-1 cell lines to accelerated heavy ions

    Energy Technology Data Exchange (ETDEWEB)

    Tobias, C.A.; Blakely, E.A.; Chang, P.Y.; Lommel, L.; Roots, R.

    1983-07-01

    The radiation dose responses of fibroblast from a patient with Ataxia telangiectasis (AT-2SF) and an established line of human T-1 cells were studied. Nearly monoenergetic accelerated neon and argon ions were used at the Berkeley Bevalac with various residual range values. The LET of the particles varied from 30 keV/..mu..m to over 1000 keV/..mu..m. All Ataxia survival curves were exponential functions of the dose. Their radiosensitivity reached peak values at 100 to 200 keV/..mu..m. Human T-1 cells have effective sublethal damage repair as has been evidenced by split dose experiments, and they are much more resistant to low LET than to high LET radiation. The repair-misrepair model has been used to interpret these results. We have obtained mathematical expressions that describe the cross sections and inactivation coefficients for both human cell lines as a function of the LET and the type of particle used. The results suggest either that high-LET particles induce a greater number of radiolesions per track or that heavy-ions at high LET induce lesions that kill cells more effectively and that are different from those produced at low LET. We assume that the lesions induced in T-1 and Ataxia cells are qualitatively similar and that each cell line attempts to repair these lesions. The result in most irradiated Ataxia cells, however, is either lethal misrepair or incomplete repair leading to cell death. 63 references, 10 figures, 1 table.

  2. Treatment of Spinocerebellar Ataxia With Mesenchymal Stem Cells: A Phase I/IIa Clinical Study.

    Science.gov (United States)

    Tsai, Yun-An; Liu, Ren-Shyan; Lirng, Jiing-Feng; Yang, Bang-Hung; Chang, Chin-Hao; Wang, Yi-Chen; Wu, Yu-Shan; Ho, Jennifer Hui-Chun; Lee, Oscar K; Soong, Bing-Wen

    2017-03-13

    Ataxia is one of the most devastating symptoms of many neurodegenerative disorders. As of today, there is not any effective treatment to retard its progression. Mesenchymal stem cells (MSCs) have shown promise in treating neurodegenerative diseases. We hereby report the results of a phase I/IIa clinical study conducted in Taiwan to primarily evaluate the safety, tolerability, and, secondarily, the possible efficacy of intravenous administration of allogeneic adipose tissue-derived MSCs from healthy donors. Six patients with spinocerebellar ataxia type 3 and one with multiple system atrophy-cerebellar type were included in this open-label study with intravenous administration of 106 cells/kg body weight. The subjects were closely monitored for 1 year for safety (vital signs, complete blood counts, serum biochemical profiles, and urinalysis) and possible efficacy (scale for assessment and rating of ataxia and sensory organization testing scores, metabolite ratios on the brain magnetic resonance spectroscopy, and brain glucose metabolism of 18-fluorodeoxyglucose using positron emission tomography). No adverse events related to the injection of MSCs during the 1-year follow-up were observed. The intravenous administration of allogeneic MSCs seemed well tolerated. Upon study completion, all patients wished to continue treatment with the allogeneic MSCs. We conclude that allogeneic MSCs given by intravenous injection seems to be safe and tolerable in patients with spinocerebellar ataxia type 3, thus supporting advancement of the clinical development of allogeneic MSCs for the treatment of spinocerebellar ataxias (SCAs) in a randomized, double-blind, placebo-controlled phase II trials.

  3. Induced pluripotent stem cell - derived neurons for the study of spinocerebellar ataxia type 3

    DEFF Research Database (Denmark)

    Hansen, Susanne Kofoed; Stummann, Tina C.; Madsen, Helena Borland

    2016-01-01

    The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) is caused by a CAG-repeat expansion in the ATXN3 gene. In this study, induced pluripotent stem cell (iPSC) lines were established from two SCA3 patients. Dermal fibroblasts were reprogrammed using an integration-free method...

  4. 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.

  5. Cerebellar Ataxia.

    Science.gov (United States)

    Perlman

    2000-05-01

    urinary tract infections, aspiration, occult respiratory failure, and obstructive sleep apnea, all of which can be life threatening. Depression in the patient and family members is common. Although no cures exist for most of the causes of cerebellar ataxia and there are as yet no proven ways to protect neurons from premature cell death or to restore neuronal populations that have been lost, symptomatic treatment can greatly improve the quality of life of these patients and prevent complications that could hasten death. Supportive interventions should always be offered-- education about the disease itself, genetic counseling, individual and family counseling, referral to support groups and advocacy groups, and guidance to online resources. Misinformation, fear, depression, hopelessness, isolation, and financial and interpersonal stress can often cause more harm to the patient and caregiver than the ataxia itself.

  6. A new Purkinje cell antibody (anti-Ca associated with subacute cerebellar ataxia: immunological characterization

    Directory of Open Access Journals (Sweden)

    Horn Sigrun

    2010-03-01

    Full Text Available Abstract We report on a newly discovered serum and cerebrospinal fluid (CSF reactivity to Purkinje cells (PCs associated with subacute inflammatory cerebellar ataxia. The patient, a previously healthy 33-year-old lady, presented with severe limb and gait ataxia, dysarthria, and diplopia two weeks after she had recovered from a common cold. Immunohistochemical studies on mouse, rat, and monkey brain sections revealed binding of a high-titer (up to 1:10,000 IgG antibody to the cerebellar molecular layer, Purkinje cell (PC layer, and white matter. The antibody is highly specific for PCs and binds to the cytoplasm as well as to the inner side of the membrane of PC somata, dendrites and axons. It is produced by B cell clones within the CNS, belongs to the IgG1 subclass, and activates complement in vitro. Western blotting of primate cerebellum extract revealed binding of CSF and serum IgG to an 80-97 kDa protein. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic antibodies known to be associated with cerebellar ataxia. Screening of >9000 human full length proteins by means of a protein array and additional confirmatory experiments revealed Rho GTPase activating protein 26 (ARHGAP26, GRAF, oligophrenin-1-like protein as the target antigen. Preadsorption of the patient's serum with human ARHGAP26 but not preadsorption with other proteins resulted in complete loss of PC staining. Our findings suggest a role of autoimmunity against ARHGAP26 in the pathogenesis of subacute inflammatory cerebellar ataxia, and extend the panel of diagnostic markers for this devastating disease.

  7. 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.

  8. 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 ...

  9. The defect in the AT-like hamster cell mutants is complemented by mouse chromosome 9 but not by any of the human chromosomes

    NARCIS (Netherlands)

    W. Jongmans; G. Verhaegh (Gerald); N.G.J. Jaspers (Nicolaas); P. Demant (Peter); A.T. Natarajan; Y. Shiloh (Yosef); M. Oshimura (Mitsuo); E.J. Stanbridge (Eric); R.S. Athwal (Raghbir); A.P. Cuthbert (Andrew); R.F. Newbold (Robert); P.H.M. Lohmann (Paul); M.Z. Zdzienicka (Malgorzata)

    1996-01-01

    textabstractX-ray-sensitive Chinese hamster V79 cells mutants, V-C4, V-E5 and V-G8, show an abnormal response to X-ray-induced DNA damage. Like ataxia telangiectasia (AT) cells, they display increased cell killing, chromosomal instability and a diminished inhibition of DNA synthesis following

  10. 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

  11. Induced pluripotent stem cell technology for modelling and therapy of cerebellar ataxia.

    Science.gov (United States)

    Watson, Lauren M; Wong, Maggie M K; Becker, Esther B E

    2015-07-01

    Induced pluripotent stem cell (iPSC) technology has emerged as an important tool in understanding, and potentially reversing, disease pathology. This is particularly true in the case of neurodegenerative diseases, in which the affected cell types are not readily accessible for study. Since the first descriptions of iPSC-based disease modelling, considerable advances have been made in understanding the aetiology and progression of a diverse array of neurodegenerative conditions, including Parkinson's disease and Alzheimer's disease. To date, however, relatively few studies have succeeded in using iPSCs to model the neurodegeneration observed in cerebellar ataxia. Given the distinct neurodevelopmental phenotypes associated with certain types of ataxia, iPSC-based models are likely to provide significant insights, not only into disease progression, but also to the development of early-intervention therapies. In this review, we describe the existing iPSC-based disease models of this heterogeneous group of conditions and explore the challenges associated with generating cerebellar neurons from iPSCs, which have thus far hindered the expansion of this research.

  12. Mesenchymal stem cells ameliorate cerebellar pathology in a mouse model of spinocerebellar ataxia type 1.

    Science.gov (United States)

    Matsuura, Serina; Shuvaev, Anton N; Iizuka, Akira; Nakamura, Kazuhiro; Hirai, Hirokazu

    2014-06-01

    Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disorder caused by the expansion of a polyglutamine tract in the ataxin-1 protein. To date, no fundamental treatments for SCA1 have been elucidated. However, some studies have shown that mesenchymal stem cells (MSCs) are partially effective in other genetic mouse models of cerebellar ataxia. In this study, we tested the efficacy of the intrathecal injection of MSCs in the treatment of SCA1 in transgenic (SCA1-Tg) mice. We found that intrathecal injection of only 3 × 10(3) MSCs greatly mitigated the cerebellar neuronal disorganization observed in SCA1 transgenic mice (SCA1-Tg mice). Although the Purkinje cells (PCs) of 24-week-old nontreated SCA1-Tg mice displayed a multilayer arrangement, SCA1-Tg mice at a similar age injected with MSCs displayed monolayer PCs. Furthermore, intrathecal injection of MSCs suppressed the atrophy of PC dendrites in SCA1-Tg mice. Finally, behavioral tests demonstrated that MSCs normalized deficits in motor coordination in SCA1-Tg mice. Future studies should be performed to develop optimal protocols for intrathecal transplantation of MSCs in SCA1 model primates with the aim of developing applications for SCA1 patients.

  13. Spinocerebellar ataxia: miRNAs expose biological pathways underlying pervasive Purkinje cell degeneration.

    Science.gov (United States)

    van der Stijl, Rogier; Withoff, Sebo; Verbeek, Dineke S

    2017-12-01

    Recent work has demonstrated the importance of miRNAs in the pathogenesis of various brain disorders including the neurodegenerative disorder spinocerebellar ataxia (SCA). This review focuses on the role of miRNAs in the shared pathogenesis of the different SCA types. We examine the novel findings of a recent cell-type-specific RNA-sequencing study in mouse brain and discuss how the identification of Purkinje-cell-enriched miRNAs highlights biological pathways that expose the mechanisms behind pervasive Purkinje cell degeneration in SCA. These key pathways are likely to contain targets for therapeutic development and represent potential candidate genes for genetically unsolved SCAs. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells

    Directory of Open Access Journals (Sweden)

    Ma Wei-Hsien

    2011-08-01

    Full Text Available Abstract Background Spinocerebellar ataxia (SCA refers to a disease entity in which polyglutamine aggregates are over-produced in Purkinje cells (PCs of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions. So far there is no effective neuroprotective treatment for this debilitating disease although numerous efforts have been made. Mesenchymal stem cells (MSCs possess multi-lineage differentiation potentials as well as immuno-modulatory properties, and are theoretically good candidates for SCA treatment. The purpose of this study is to investigate whether transplantation of human MSCs (hMSCs can rescue cerebellar PCs and ameliorate motor function deterioration in SCA in a pre-clinical animal model. Method Transgenic mice bearing poly-glutamine mutation in ataxin-2 gene (C57BL/6J SCA2 transgenic mice were serially transplanted with hMSCs intravenously or intracranially before and after the onset of motor function loss. Motor function of mice was evaluated by an accelerating protocol of rotarod test every 8 weeks. Immunohistochemical stain of whole brain sections was adopted to demonstrate the neuroprotective effect of hMSC transplantation on cerebellar PCs and engraftment of hMSCs into mice brain. Results Intravenous transplantation of hMSCs effectively improved rotarod performance of SCA2 transgenic mice and delayed the onset of motor function deterioration; while intracranial transplantation failed to achieve such neuroprotective effect. Immunohistochemistry revealed that intravenous transplantation was more effective in the preservation of the survival of cerebellar PCs and engraftment of hMSCs than intracranial injection, which was compatible to rotarod performance of transplanted mice. Conclusion Intravenous transplantation of hMSCs can indeed delay the onset as well as improve the motor

  15. Generation of induced pluripotent stem cells from a patient with spinocerebellar ataxia type 3.

    Science.gov (United States)

    Soong, Bing-Wen; Syu, Shih-Han; Wen, Cheng-Hao; Ko, Hui-Wen; Wu, Mei-Ling; Hsieh, Patrick C H; Hwang, Shiaw-Min; Lu, Huai-En

    2017-01-01

    Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a trinucleotide repeat (CAG) expansion in the coding region of ATXN3 gene resulting in production of ataxin-3 with an elongated polyglutamine tract. Here, we generated induced pluripotent stem cells (iPSCs) from the peripheral blood mononuclear cells of a male patient with SCA3 by using the Sendai-virus delivery system. The resulting iPSCs had a normal karyotype, retained the disease-causing ATXN3 mutation, expressed pluripotent markers and could differentiate into the three germ layers. Potentially, the iPSCs could be a useful tool for the investigation of disease mechanisms of SCA3. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  17. Generation of spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cell line SCA3.B11

    DEFF Research Database (Denmark)

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

    2016-01-01

    Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by an expansion of the CAG-repeat in ATXN3. In this study, induced pluripotent stem cells (iPSCs) were generated from SCA3 patient dermal fibroblasts by electroporation with episomal plasmids encoding L...

  18. Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming.

    Science.gov (United States)

    Polak, Urszula; Li, Yanjie; Butler, Jill Sergesketter; Napierala, Marek

    2016-12-01

    Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. This severe neurodegenerative disease is caused by an expansion of guanine-adenine-adenine (GAA) repeats located in the first intron of the frataxin (FXN) gene, which represses its transcription. Although transcriptional silencing is associated with heterochromatin-like changes in the vicinity of the expanded GAAs, the exact mechanism and pathways involved in transcriptional inhibition are largely unknown. As major remodeling of the epigenome is associated with somatic cell reprogramming, modulating chromatin modification pathways during the cellular transition from a somatic to a pluripotent state is likely to generate permanent changes to the epigenetic landscape. We hypothesize that the epigenetic modifications in the vicinity of the GAA repeats can be reversed by pharmacological modulation during somatic cell reprogramming. We reprogrammed FRDA fibroblasts into induced pluripotent stem cells (iPSCs) in the presence of various small molecules that target DNA methylation and histone acetylation and methylation. Treatment of FRDA iPSCs with two compounds, sodium butyrate (NaB) and Parnate, led to an increase in FXN expression and correction of repressive marks at the FXN locus, which persisted for several passages. However, prolonged culture of the epigenetically modified FRDA iPSCs led to progressive expansions of the GAA repeats and a corresponding decrease in FXN expression. Furthermore, we uncovered that differentiation of these iPSCs into neurons also results in resilencing of the FXN gene. Taken together, these results demonstrate that transcriptional repression caused by long GAA repeat tracts can be partially or transiently reversed by altering particular epigenetic modifications, thus revealing possibilities for detailed analyses of silencing mechanism and development of new therapeutic approaches for FRDA.

  19. Selective loss of Purkinje cells in a patient with anti-gliadin-antibody-positive autoimmune cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Hasegawa Akira

    2011-02-01

    Full Text Available Abstract The patient was an 84-year-old woman who had the onset of truncal ataxia at age 77 and a history of Basedow's disease. Her ataxic gait gradually deteriorated. She could not walk without support at age 81 and she was admitted to our hospital at age 83. Gaze-evoked nystagmus and dysarthria were observed. Mild ataxia was observed in all limbs. Her deep tendon reflex and sense of position were normal. IgA anti-gliadin antibody, IgG anti-gliadin antibody, anti-SS-A/Ro antibody, anti-SS-B/La antibody and anti-TPO antibody were positive. A conventional brain MRI did not show obvious cerebellar atrophy. However, MRI voxel based morphometry (VBM and SPECT-eZIS revealed cortical cerebellar atrophy and reduced cerebellar blood flow. IVIg treatment was performed and was moderately effective. After her death at age 85, the patient was autopsied. Neuropathological findings were as follows: selective loss of Purkinje cells; no apparent degenerative change in the efferent pathways, such as the dentate nuclei or vestibular nuclei; no prominent inflammatory reaction. From these findings, we diagnosed this case as autoimmune cerebellar atrophy associated with gluten ataxia. All 3 autopsies previously reported on gluten ataxia have noted infiltration of inflammatory cells in the cerebellum. In this case, we postulated that the infiltration of inflammatory cells was not found because the patient's condition was based on humoral immunity. The clinical conditions of gluten ataxia have not yet been properly elucidated, but are expected to be revealed as the number of autopsied cases increases.

  20. Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich's Ataxia Cells.

    Science.gov (United States)

    Gerhardt, Jeannine; Bhalla, Angela D; Butler, Jill Sergesketter; Puckett, James W; Dervan, Peter B; Rosenwaks, Zev; Napierala, Marek

    2016-08-02

    Friedreich's ataxia (FRDA) is caused by the expansion of GAA repeats located in the Frataxin (FXN) gene. The GAA repeats continue to expand in FRDA patients, aggravating symptoms and contributing to disease progression. The mechanism leading to repeat expansion and decreased FXN transcription remains unclear. Using single-molecule analysis of replicated DNA, we detected that expanded GAA repeats present a substantial obstacle for the replication machinery at the FXN locus in FRDA cells. Furthermore, aberrant origin activation and lack of a proper stress response to rescue the stalled forks in FRDA cells cause an increase in 3'-5' progressing forks, which could enhance repeat expansion and hinder FXN transcription by head-on collision with RNA polymerases. Treatment of FRDA cells with GAA-specific polyamides rescues DNA replication fork stalling and alleviates expansion of the GAA repeats, implicating DNA triplexes as a replication impediment and suggesting that fork stalling might be a therapeutic target for FRDA. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. 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. ...

  2. Buccal Cell Micronucleus Frequency Is Significantly Elevated in Patients with Spinocerebellar Ataxia Type 2.

    Science.gov (United States)

    Cuello-Almarales, Dany A; Almaguer-Mederos, Luis E; Vázquez-Mojena, Yaimé; Almaguer-Gotay, Dennis; Zayas-Feria, Pedro; Laffita-Mesa, José M; González-Zaldívar, Yanetza; Aguilera-Rodríguez, Raúl; Rodríguez-Estupiñán, Annelié; Velázquez-Pérez, Luis

    2017-04-01

    Spinocerebellar ataxia type 2 (SCA2) is part of a group of at least nine dominantly inherited disorders characterized by progressive degeneration of specific neuronal populations and a shared mutational mechanism involving the expansion of a CAG repeat tract in coding regions of novel genes. Efforts have been made to identify biomarkers of disease progression, which would allow timely preventive therapeutic interventions. In the present study was assessed the influence of several genome instability biomarkers on SCA2 clinical severity. A case-control design was applied on exfoliated epithelial buccal cells to determine micronuclei frequency and others nuclear anomalies, using 5% Giemsa stains. The slides were analyzed under 1000X magnification and nuclei morphological anomalies were identified according to Tolbert PE, et al. (1992) and Bolognesi C, et al. (2013) criteria. It was found a highly significant increase in micronuclei frequency in cases related to age and sex-matched healthy controls (p 0.05). Our results are consistent with report previous in similar neurodegenerative diseases, and suggest that micronuclei and binucleated cells constitute potential peripheral biomarkers for SCA2. These results should be validated by other studies. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

  3. Effects of Friedreich's ataxia GAA repeats on DNA replication in mammalian cells.

    Science.gov (United States)

    Chandok, Gurangad S; Patel, Mayank P; Mirkin, Sergei M; Krasilnikova, Maria M

    2012-05-01

    Friedreich's ataxia (FRDA) is a common hereditary degenerative neuro-muscular disorder caused by expansions of the (GAA)n repeat in the first intron of the frataxin gene. The expanded repeats from parents frequently undergo further significant length changes as they are passed on to progeny. Expanded repeats also show an age-dependent instability in somatic cells, albeit on a smaller scale than during intergenerational transmissions. Here we studied the effects of (GAA)n repeats of varying lengths and orientations on the episomal DNA replication in mammalian cells. We have recently shown that the very first round of the transfected DNA replication occurs in the lack of the mature chromatin, does not depend on the episomal replication origin and initiates at multiple single-stranded regions of plasmid DNA. We now found that expanded GAA repeats severely block this first replication round post plasmid transfection, while the subsequent replication cycles are only mildly affected. The fact that GAA repeats affect various replication modes in a different way might shed light on their differential expansions characteristic for FRDA.

  4. No changes in heme synthesis in human Friedreich´s ataxia erythroid progenitor cells.

    Science.gov (United States)

    Steinkellner, Hannes; Singh, Himanshu Narayan; Muckenthaler, Martina U; Goldenberg, Hans; Moganty, Rajeswari R; Scheiber-Mojdehkar, Barbara; Sturm, Brigitte

    2017-07-20

    Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced expression of the protein frataxin. Frataxin is thought to play a role in iron-sulfur cluster biogenesis and heme synthesis. In this study, we used erythroid progenitor stem cells obtained from FRDA patients and healthy donors to investigate the putative role, if any, of frataxin deficiency in heme synthesis. We used electrochemiluminescence and qRT-PCR for frataxin protein and mRNA quantification. We used atomic absorption spectrophotometry for iron levels and a photometric assay for hemoglobin levels. Protoporphyrin IX and Ferrochelatase were analyzed using auto-fluorescence. An "IronChip" microarray analysis followed by a protein-protein interaction analysis was performed. FRDA patient cells showed no significant changes in iron levels, hemoglobin synthesis, protoporphyrin IX levels, and ferrochelatase activity. Microarray analysis presented 11 genes that were significantly changed in all patients compared to controls. The genes are especially involved in oxidative stress, iron homeostasis and angiogenesis. The mystery about the involvement of frataxin on iron metabolism raises the question why frataxin deficiency in primary FRDA cells did not lead to changes in biochemical parameters of heme synthesis. It seems that alternative pathways can circumvent the impact of frataxin deficiency on heme synthesis. We show for the first time in primary FRDA patient cells that reduced frataxin levels are still sufficient for heme synthesis and possibly other mechanisms can overcome reduced frataxin levels in this process. Our data strongly support the fact that so far no anemia in FRDA patients was reported. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Mesenchymal stem cells restore frataxin expression and increase hydrogen peroxide scavenging enzymes in Friedreich ataxia fibroblasts.

    Directory of Open Access Journals (Sweden)

    Kevin Kemp

    Full Text Available Dramatic advances in recent decades in understanding the genetics of Friedreich ataxia (FRDA--a GAA triplet expansion causing greatly reduced expression of the mitochondrial protein frataxin--have thus far yielded no therapeutic dividend, since there remain no effective treatments that prevent or even slow the inevitable progressive disability in affected individuals. Clinical interventions that restore frataxin expression are attractive therapeutic approaches, as, in theory, it may be possible to re-establish normal function in frataxin deficient cells if frataxin levels are increased above a specific threshold. With this in mind several drugs and cytokines have been tested for their ability to increase frataxin levels. Cell transplantation strategies may provide an alternative approach to this therapeutic aim, and may also offer more widespread cellular protective roles in FRDA. Here we show a direct link between frataxin expression in fibroblasts derived from FRDA patients with both decreased expression of hydrogen peroxide scavenging enzymes and increased sensitivity to hydrogen peroxide-mediated toxicity. We demonstrate that normal human mesenchymal stem cells (MSCs induce both an increase in frataxin gene and protein expression in FRDA fibroblasts via secretion of soluble factors. Finally, we show that exposure to factors produced by human MSCs increases resistance to hydrogen peroxide-mediated toxicity in FRDA fibroblasts through, at least in part, restoring the expression of the hydrogen peroxide scavenging enzymes catalase and glutathione peroxidase 1. These findings suggest, for the first time, that stem cells may increase frataxin levels in FRDA and transplantation of MSCs may offer an effective treatment for these patients.

  6. Friedreich ataxia.

    Science.gov (United States)

    Pandolfo, Massimo

    2008-10-01

    Friedreich ataxia is an autosomal recessive degenerative disease that primarily affects the nervous system and the heart. It is named after its original description as a "degenerative atrophy of the posterior columns of the spinal cord" by Nicholaus Friedreich, who was a professor of medicine in Heidelberg in the second half of the 19th century. The full extent of the Friedreich ataxia phenotype and its genetic epidemiology could only be appreciated after a direct genetic test became available in 1996. At the same time, the complex pathogenesis of Friedreich ataxia started to be unraveled. Herein, I review our current knowledge of the disease and how it is contributing to the development of therapeutic approaches.

  7. Induced pluripotent stem cell - derived neurons for the study of spinocerebellar ataxia type 3

    Directory of Open Access Journals (Sweden)

    Susanne K. Hansen

    2016-09-01

    Full Text Available The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3 is caused by a CAG-repeat expansion in the ATXN3 gene. In this study, induced pluripotent stem cell (iPSC lines were established from two SCA3 patients. Dermal fibroblasts were reprogrammed using an integration-free method and the resulting SCA3 iPSCs were differentiated into neurons. These neuronal lines harbored the disease causing mutation, expressed comparable levels of several neuronal markers and responded to the neurotransmitters, glutamate/glycine, GABA and acetylcholine. Additionally, all neuronal cultures formed networks displaying synchronized spontaneous calcium oscillations within 28 days of maturation, and expressed the mature neuronal markers NeuN and Synapsin 1 implying a relatively advanced state of maturity, although not comparable to that of the adult human brain. Interestingly, we were not able to recapitulate the glutamate-induced ataxin-3 aggregation shown in a previously published iPSC-derived SCA3 model. In conclusion, we have generated a panel of SCA3 patient iPSCs and a robust protocol to derive neurons of relatively advanced maturity, which could potentially be valuable for the study of SCA3 disease mechanisms.

  8. 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'.

    Science.gov (United States)

    Abeti, R; Parkinson, M H; Hargreaves, I P; Angelova, P R; Sandi, C; Pook, M A; Giunti, P; Abramov, A Y

    2016-05-26

    Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure.

  9. Purkinje cell-specific ablation of Cav2.1 channels is sufficient to cause cerebellar ataxia in mice.

    Science.gov (United States)

    Todorov, Boyan; Kros, Lieke; Shyti, Reinald; Plak, Petra; Haasdijk, Elize D; Raike, Robert S; Frants, Rune R; Hess, Ellen J; Hoebeek, Freek E; De Zeeuw, Chris I; van den Maagdenberg, Arn M J M

    2012-03-01

    The Cacna1a gene encodes the α(1A) subunit of voltage-gated Ca(V)2.1 Ca(2+) channels that are involved in neurotransmission at central synapses. Ca(V)2.1-α(1)-knockout (α1KO) mice, which lack Ca(V)2.1 channels in all neurons, have a very severe phenotype of cerebellar ataxia and dystonia, and usually die around postnatal day 20. This early lethality, combined with the wide expression of Ca(V)2.1 channels throughout the cerebellar cortex and nuclei, prohibited determination of the contribution of particular cerebellar cell types to the development of the severe neurobiological phenotype in Cacna1a mutant mice. Here, we crossed conditional Cacna1a mice with transgenic mice expressing Cre recombinase, driven by the Purkinje cell-specific Pcp2 promoter, to specifically ablate the Ca(V)2.1-α(1A) subunit and thereby Ca(V)2.1 channels in Purkinje cells. Purkinje cell Ca(V)2.1-α(1A)-knockout (PCα1KO) mice aged without difficulties, rescuing the lethal phenotype seen in α1KO mice. PCα1KO mice exhibited cerebellar ataxia starting around P12, much earlier than the first signs of progressive Purkinje cell loss, which appears in these mice between P30 and P45. Secondary cell loss was observed in the granular and molecular layers of the cerebellum and the volume of all individual cerebellar nuclei was reduced. In this mouse model with a cell type-specific ablation of Ca(V)2.1 channels, we show that ablation of Ca(V)2.1 channels restricted to Purkinje cells is sufficient to cause cerebellar ataxia. We demonstrate that spatial ablation of Ca(V)2.1 channels may help in unraveling mechanisms of human disease.

  10. 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

  11. 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 ...

  12. Palmar Telangiectasias: A Cutaneous Sign for Smoking.

    Science.gov (United States)

    Levi, Assi; Shechter, Ronen; Lapidoth, Moshe; Enk, Claes D

    2017-12-07

    Telangiectasias are permanent dilations of blood capillaries which appear in a variety of medical conditions. Cutaneous palmar telangiectasias have been postulated to be associated with smoking. To determine whether a significant correlation exists between palmar telangiectasias and smoking habits. A total of 124 volunteers participated in this observational study by allowing physical evaluation of their palms and by completing a questionnaire. Palmar telangiectasias were found to be associated with current or past smoking. Neither age nor gender was found to be a co-contributor. Palmar telangiectasias were found to constitute highly specific and sensitive markers for prolonged smoking. © 2017 S. Karger AG, Basel.

  13. MiR-26a enhances the radiosensitivity of glioblastoma multiforme cells through targeting of ataxia–telangiectasia mutated

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Pin; Lan, Jin; Ge, Jianwei; Nie, Quanmin; Guo, Liemei [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Qiu, Yongming, E-mail: qiuzhoub@hotmail.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China); Mao, Qing, E-mail: maoq@netease.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China)

    2014-01-15

    Glioblastoma multiforme (GBM) is notoriously resistant to radiation, and consequently, new radiosensitizers are urgently needed. MicroRNAs are a class of endogenous gene modulators with emerging roles in DNA repair. We found that overexpression of miR-26a can enhance radiosensitivity and reduce the DNA repair ability of U87 cells. However, knockdown miR-26a in U87 cells could act the converse manner. Mechanistically, this effect is mediated by direct targeting of miR-26a to the 3′UTR of ATM, which leads to reduced ATM levels and consequent inhibition of the homologous recombination repair pathway. These results suggest that miR-26a may act as a new radiosensitizer of GBM. - Highlights: ●miR-26a directly target ATM in GBM cells. ●miR-26a enhances the radiosensitivity of GBM cells. ●miR-26a could reduce the DNA repair capacity of GBM cells.

  14. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H196

    DEFF Research Database (Denmark)

    Marthaler, Adele Gabriele; Schmid, Benjamin; Tubsuwan, Alisa

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell...

  15. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H271

    DEFF Research Database (Denmark)

    Marthaler, Adele Gabriele; Schmid, Benjamin; Tubsuwan, Alisa

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell...

  16. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H266

    DEFF Research Database (Denmark)

    Marthaler, Adele Gabriele; Tubsuwan, Alisa; Schmid, Benjamin

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell...

  17. Review of Chromium (VI) Apoptosis, Cell-Cycle-Arrest, and Carcinogenesis

    Science.gov (United States)

    Chiu, A; Shi, J; Lee, WKP; Hill, R; Wakeman, TP; Katz, A; Xu, B; Dalal, NS; Robertson, JD; Chen, C; Chiu, N; Donehower, L

    2014-01-01

    Hexavalent chromium combines with glutathione in chloride intracellular channel carrier to form tetravalent and pentavelent chromium in plasma and organelle membranes. It also combines with NADH/NADPH to form pentavalent chromium in mitochondria. Tetravalent- and pentavalent- chromium (directly and indirectly) mediated DNA double strand breaks activate DNA damage signaling sensors: DNA-dependent-protein-kinase signals p53-dependent intrinsic mitochorndrial apoptosis, and ataxia-telangiectasia-mutated and ataxia-telangiectasia-Rad3-related signal cell-arrest for DNA repair. Tetravalent chromium may be the most potent species since it causes DNA breaks and somatic recombination, but not apoptosis. Upon further failure of apoptosis and senescence/DNA-repair, damaged cells may become immortal with loss-of-heterozygosity and genetic plasticity. PMID:20859824

  18. 'Medusa-head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII.

    Science.gov (United States)

    Jarius, S; Wildemann, B

    2015-09-17

    Serological testing for anti-neural autoantibodies is important in patients presenting with idiopathic cerebellar ataxia, since these autoantibodies may indicate cancer, determine treatment and predict prognosis. While some of them target nuclear antigens present in all or most CNS neurons (e.g. anti-Hu, anti-Ri), others more specifically target antigens present in the cytoplasm or plasma membrane of Purkinje cells (PC). In this series of articles, we provide a detailed review of the clinical and paraclinical features, oncological, therapeutic and prognostic implications, pathogenetic relevance, and differential laboratory diagnosis of the 12 most common PC autoantibodies (often referred to as 'Medusa-head antibodies' due to their characteristic somatodendritic binding pattern when tested by immunohistochemistry). To assist immunologists and neurologists in diagnosing these disorders, typical high-resolution immunohistochemical images of all 12 reactivities are presented, diagnostic pitfalls discussed and all currently available assays reviewed. Of note, most of these antibodies target antigens involved in the mGluR1/calcium pathway essential for PC function and survival. Many of the antigens also play a role in spinocerebellar ataxia. Part 1 focuses on anti-metabotropic glutamate receptor 1-, anti-Homer protein homolog 3-, anti-Sj/inositol 1,4,5-trisphosphate receptor- and anti-carbonic anhydrase-related protein VIII-associated autoimmune cerebellar ataxia (ACA); part 2 covers anti-protein kinase C gamma-, anti-glutamate receptor delta-2-, anti-Ca/RhoGTPase-activating protein 26- and anti-voltage-gated calcium channel-associated ACA; and part 3 reviews the current knowledge on anti-Tr/delta notch-like epidermal growth factor-related receptor-, anti-Nb/AP3B2-, anti-Yo/cerebellar degeneration-related protein 2- and Purkinje cell antibody 2-associated ACA, discusses differential diagnostic aspects and provides a summary and outlook.

  19. Time-resolved functional analysis of acute impairment of frataxin expression in an inducible cell model of Friedreich ataxia

    Directory of Open Access Journals (Sweden)

    Dörte Poburski

    2016-05-01

    Full Text Available Friedreich ataxia is a neurodegenerative disease caused by a GAA triplet repeat expansion in the first intron of the frataxin gene, which results in reduced expression levels of the corresponding protein. Despite numerous animal and cellular models, therapeutic options that mechanistically address impaired frataxin expression are lacking. Here, we have developed a new mammalian cell model employing the Cre/loxP recombination system to induce a homozygous or heterozygous frataxin knockout in mouse embryonic fibroblasts. Induction of Cre-mediated disruption by tamoxifen was successfully tested on RNA and protein levels. After loss of frataxin protein, cell division, aconitase activity and oxygen consumption rates were found to be decreased, while ROS production was increased in the homozygous state. By contrast, in the heterozygous state no such changes were observed. A time-resolved analysis revealed the loss of aconitase activity as an initial event after induction of complete frataxin deficiency, followed by secondarily elevated ROS production and a late increase in iron content. Initial impairments of oxygen consumption and ATP production were found to be compensated in the late state and seemed to play a minor role in Friedreich ataxia pathophysiology. In conclusion and as predicted from its proposed role in iron sulfur cluster (ISC biosynthesis, disruption of frataxin primarily causes impaired function of ISC-containing enzymes, whereas other consequences, including elevated ROS production and iron accumulation, appear secondary. These parameters and the robustness of the newly established system may additionally be used for a time-resolved study of pharmacological candidates in a HTS manner.

  20. Genetics Home Reference: hereditary hemorrhagic telangiectasia

    Science.gov (United States)

    ... Osler-Weber-Rendu syndrome Health Topic: Arteriovenous Malformations Genetic and Rare Diseases Information Center (1 link) Hereditary hemorrhagic telangiectasia Additional NIH Resources (1 link) National ...

  1. Cytotoxic CD8+ T cells and CD138+ plasma cells prevail in cerebrospinal fluid in non-paraneoplastic cerebellar ataxia with contactin-associated protein-2 antibodies

    Directory of Open Access Journals (Sweden)

    Melzer Nico

    2012-07-01

    Full Text Available Abstract Objective The purpose of this paper is to report a patient with otherwise unexplained cerebellar ataxia with serum antibodies against contactin-associated protein-2 (CASPR-2 and provide a detailed description of the composition of cellular infiltrates in the cerebrospinal fluid (CSF compared to the peripheral blood (PB. CASPR-2 antibodies strongly labeling axons of cerebellar granule neurons have recently been identified in sera from nine patients with otherwise unexplained progressive cerebellar ataxia with mild to severe cerebellar atrophy. Design This is a report of a single case. Methods The study methods used were neurologic examination, magnetic resonance imaging, fluorodeoxyglucose positron emisson tomography, lumbar puncture and multicolor flow-cytometry. Results A 23-year-old Caucasian male presented with a two-year history of a progressive cerebellar and brainstem syndrome. Magnetic resonance imaging (MRI showed pronounced cerebellar atrophy, especially of the medial parts of the hemispheres and the vermis. Cerebral fluorodeoxyglucose positron emission tomography (FDG-PET showed pronounced hypometabolism of the whole cerebellum. CASPR-2 antibodies were detected in the serum but not the CSF, and none of the staging and laboratory assessments revealed other causes of progressive cerebellar degeneration. Interestingly, flow-cytometry of the CSF as compared to the PB showed increased fractions of CD138+ plasma cells as well as human leukocyte antigen (HLA-DR+ CD8+ T cells suggesting that both B cells and CD8+ T cells were preferentially recruited to and activated within the CSF- (and putatively central nervous system (CNS- compartment. Conclusion We confirm the association of CASPR-2 serum antibodies with cerebellar ataxia and provide the first evidence for a combined humoral and cellular immune response in this novel antibody-associated inflammatory CNS disease.

  2. Lgr4 protein deficiency induces ataxia-like phenotype in mice and impairs long term depression at cerebellar parallel fiber-Purkinje cell synapses.

    Science.gov (United States)

    Guan, Xin; Duan, Yanhong; Zeng, Qingwen; Pan, Hongjie; Qian, Yu; Li, Dali; Cao, Xiaohua; Liu, Mingyao

    2014-09-19

    Cerebellar dysfunction causes ataxia characterized by loss of balance and coordination. Until now, the molecular and neuronal mechanisms of several types of inherited cerebellar ataxia have not been completely clarified. Here, we report that leucine-rich G protein-coupled receptor 4 (Lgr4/Gpr48) is highly expressed in Purkinje cells (PCs) in the cerebellum. Deficiency of Lgr4 leads to an ataxia-like phenotype in mice. Histologically, no obvious morphological changes were observed in the cerebellum of Lgr4 mutant mice. However, the number of PCs was slightly but significantly reduced in Lgr4(-/-) mice. In addition, in vitro electrophysiological analysis showed an impaired long term depression (LTD) at parallel fiber-PC (PF-PC) synapses in Lgr4(-/-) mice. Consistently, immunostaining experiments showed that the level of phosphorylated cAMP-responsive element-binding protein (Creb) was significantly decreased in Lgr4(-/-) PCs. Furthermore, treatment with forskolin, an adenylyl cyclase agonist, rescued phospho-Creb in PCs and reversed the impairment in PF-PC LTD in Lgr4(-/-) cerebellar slices, indicating that Lgr4 is an upstream regulator of Creb signaling, which is underlying PF-PC LTD. Together, our findings demonstrate for first time an important role for Lgr4 in motor coordination and cerebellar synaptic plasticity and provide a potential therapeutic target for certain types of inherited cerebellar ataxia. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Role of mismatch repair enzymes in GAA·TTC triplet-repeat expansion in Friedreich ataxia induced pluripotent stem cells.

    Science.gov (United States)

    Du, Jintang; Campau, Erica; Soragni, Elisabetta; Ku, Sherman; Puckett, James W; Dervan, Peter B; Gottesfeld, Joel M

    2012-08-24

    The genetic mutation in Friedreich ataxia (FRDA) is a hyperexpansion of the triplet-repeat sequence GAA·TTC within the first intron of the FXN gene. Although yeast and reporter construct models for GAA·TTC triplet-repeat expansion have been reported, studies on FRDA pathogenesis and therapeutic development are limited by the availability of an appropriate cell model in which to study the mechanism of instability of the GAA·TTC triplet repeats in the human genome. Herein, induced pluripotent stem cells (iPSCs) were generated from FRDA patient fibroblasts after transduction with the four transcription factors Oct4, Sox2, Klf4, and c-Myc. These cells were differentiated into neurospheres and neuronal precursors in vitro, providing a valuable cell model for FRDA. During propagation of the iPSCs, GAA·TTC triplet repeats expanded at a rate of about two GAA·TTC triplet repeats/replication. However, GAA·TTC triplet repeats were stable in FRDA fibroblasts and neuronal stem cells. The mismatch repair enzymes MSH2, MSH3, and MSH6, implicated in repeat instability in other triplet-repeat diseases, were highly expressed in pluripotent stem cells compared with fibroblasts and neuronal stem cells and occupied FXN intron 1. In addition, shRNA silencing of MSH2 and MSH6 impeded GAA·TTC triplet-repeat expansion. A specific pyrrole-imidazole polyamide targeting GAA·TTC triplet-repeat DNA partially blocked repeat expansion by displacing MSH2 from FXN intron 1 in FRDA iPSCs. These studies suggest that in FRDA, GAA·TTC triplet-repeat instability occurs in embryonic cells and involves the highly active mismatch repair system.

  4. Role of Mismatch Repair Enzymes in GAA·TTC Triplet-repeat Expansion in Friedreich Ataxia Induced Pluripotent Stem Cells*

    Science.gov (United States)

    Du, Jintang; Campau, Erica; Soragni, Elisabetta; Ku, Sherman; Puckett, James W.; Dervan, Peter B.; Gottesfeld, Joel M.

    2012-01-01

    The genetic mutation in Friedreich ataxia (FRDA) is a hyperexpansion of the triplet-repeat sequence GAA·TTC within the first intron of the FXN gene. Although yeast and reporter construct models for GAA·TTC triplet-repeat expansion have been reported, studies on FRDA pathogenesis and therapeutic development are limited by the availability of an appropriate cell model in which to study the mechanism of instability of the GAA·TTC triplet repeats in the human genome. Herein, induced pluripotent stem cells (iPSCs) were generated from FRDA patient fibroblasts after transduction with the four transcription factors Oct4, Sox2, Klf4, and c-Myc. These cells were differentiated into neurospheres and neuronal precursors in vitro, providing a valuable cell model for FRDA. During propagation of the iPSCs, GAA·TTC triplet repeats expanded at a rate of about two GAA·TTC triplet repeats/replication. However, GAA·TTC triplet repeats were stable in FRDA fibroblasts and neuronal stem cells. The mismatch repair enzymes MSH2, MSH3, and MSH6, implicated in repeat instability in other triplet-repeat diseases, were highly expressed in pluripotent stem cells compared with fibroblasts and neuronal stem cells and occupied FXN intron 1. In addition, shRNA silencing of MSH2 and MSH6 impeded GAA·TTC triplet-repeat expansion. A specific pyrrole-imidazole polyamide targeting GAA·TTC triplet-repeat DNA partially blocked repeat expansion by displacing MSH2 from FXN intron 1 in FRDA iPSCs. These studies suggest that in FRDA, GAA·TTC triplet-repeat instability occurs in embryonic cells and involves the highly active mismatch repair system. PMID:22798143

  5. 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.

  6. Dystonia and ataxia progression in spinocerebellar ataxias.

    Science.gov (United States)

    Kuo, Pei-Hsin; Gan, Shi-Rui; Wang, Jie; Lo, Raymond Y; Figueroa, Karla P; Tomishon, Darya; Pulst, Stefan M; Perlman, Susan; Wilmot, George; Gomez, Christopher M; Schmahmann, Jeremy D; Paulson, Henry; Shakkottai, Vikram G; Ying, Sarah H; Zesiewicz, Theresa; Bushara, Khalaf; Geschwind, Michael D; Xia, Guangbin; Subramony, S H; Ashizawa, Tetsuo; Kuo, Sheng-Han

    2017-10-23

    Dystonia is a common feature in spinocerebellar ataxias (SCAs). Whether the presence of dystonia is associated with different rate of ataxia progression is not known. To study clinical characteristics and ataxia progression in SCAs with and without dystonia. We studied 334 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and compared the clinical characteristics of SCAs with and without dystonia. We repeatedly measured ataxia progression by the Scale for Assessment and Rating of Ataxia every 6 months for 2 years. Regression models were employed to study the association between dystonia and ataxia progression after adjusting for age, sex and pathological CAG repeats. We used logistic regression to analyze the impact of different repeat expansion genes on dystonia in SCAs. Dystonia was most commonly observed in SCA3, followed by SCA2, SCA1, and SCA6. Dystonia was associated with longer CAG repeats in SCA3. The CAG repeat number in TBP normal alleles appeared to modify the presence of dystonia in SCA1. The presence of dystonia was associated with higher SARA scores in SCA1, 2, and 3. Although relatively rare in SCA6, the presence of dystonia was associated with slower progression of ataxia. The presence of dystonia is associated with greater severity of ataxia in SCA1, 2, and 3, but predictive of a slower progression in SCA6. Complex genetic interactions among repeat expansion genes can lead to diverse clinical symptoms and progression in SCAs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. 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.

  8. Transplantation of Human Neural Progenitor Cells Reveals Structural and Functional Improvements in the Spastic Han-Wistar Rat Model of Ataxia

    Science.gov (United States)

    Nuryyev, Ruslan L.; Uhlendorf, Toni L.; Tierney, Wesley; Zatikyan, Suren; Kopyov, Oleg; Kopyov, Alex; Ochoa, Jessica; Trigt, William Van; Malone, Cindy S.

    2018-01-01

    The use of regenerative medicine to treat nervous system disorders like ataxia has been proposed to either replace or support degenerating neurons. In this study, we assessed the ability of human neural progenitor cells (hNPCs) to repair and restore the function of dying neurons within the spastic Han-Wistar rat (sHW), a model of ataxia. The sHW rat suffers from neurodegeneration of specific neurons, including cerebellar Purkinje cells and hippocampal CA3 pyramidal cells leading to the observed symptoms of forelimb tremor, hind-leg rigidity, gait abnormality, motor incoordination, and a shortened life span. To alleviate the symptoms of neurodegeneration and to replace or augment dying neurons, neuronal human progenitor cells were implanted into the sHW rats. At 30 d of age, male sHW mutant rats underwent subcutaneous implantation of an Alzet osmotic pump that infused cyclosporine (15 mg/kg/d) used to suppress the rat’s immune system. At 40 d, sHW rats received bilateral injections (500,000 cells in 5 µL media) of live hNPCs, dead hNPCs, live human embryonic kidney cells, or growth media either into the cerebellar cortex or into the hippocampus. To monitor results, motor activity scores (open-field testing) and weights of the animals were recorded weekly. The sHW rats that received hNPC transplantation into the cerebellum, at 60 d of age, displayed significantly higher motor activity scores and sustained greater weights and longevities than control-treated sHW rats or any hippocampal treatment group. In addition, cerebellar histology revealed that the transplanted hNPCs displayed signs of migration and signs of neuronal development in the degenerated Purkinje cell layer. This study revealed that implanted human progenitor cells reduced the ataxic symptoms in the sHW rat, identifying a future clinical use of these progenitor cells against ataxia and associated neurodegenerative diseases. PMID:29338380

  9. 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 ...

  10. Fusion of Human Fetal Mesenchymal Stem Cells with "Degenerating" Cerebellar Neurons in Spinocerebellar Ataxia Type 1 Model Mice.

    Science.gov (United States)

    Huda, Fathul; Fan, Yiping; Suzuki, Mamiko; Konno, Ayumu; Matsuzaki, Yasunori; Takahashi, Nobutaka; Chan, Jerry K Y; Hirai, Hirokazu

    2016-01-01

    Mesenchymal stem cells (MSCs) migrate to damaged tissues, where they participate in tissue repair. Human fetal MSCs (hfMSCs), compared with adult MSCs, have higher proliferation rates, a greater differentiation capacity and longer telomeres with reduced senescence. Therefore, transplantation of quality controlled hfMSCs is a promising therapeutic intervention. Previous studies have shown that intravenous or intracortical injections of MSCs result in the emergence of binucleated cerebellar Purkinje cells (PCs) containing an MSC-derived marker protein in mice, thus suggesting a fusion event. However, transdifferentiation of MSCs into PCs or transfer of a marker protein from an MSC to a PC cannot be ruled out. In this study, we unequivocally demonstrated the fusion of hfMSCs with murine PCs through a tetracycline-regulated (Tet-off) system with or without a Cre-dependent genetic inversion switch (flip-excision; FLEx). In the FLEx-Tet system, we performed intra-cerebellar injection of viral vectors expressing tetracycline transactivator (tTA) and Cre recombinase into either non-symptomatic (4-week-old) or clearly symptomatic (6-8-month-old) spinocerebellar ataxia type 1 (SCA1) mice. Then, the mice received an injection of 50,000 genetically engineered hfMSCs that expressed GFP only in the presence of Cre recombinase and tTA. We observed a significant emergence of GFP-expressing PCs and interneurons in symptomatic, but not non-symptomatic, SCA1 mice 2 weeks after the MSC injection. These results, together with the results obtained using age-matched wild-type mice, led us to conclude that hfMSCs have the potential to preferentially fuse with degenerating PCs and interneurons but not with healthy neurons.

  11. Rapamycin enhances lytic replication of Epstein-Barr virus in gastric carcinoma cells by increasing the transcriptional activities of immediate-early lytic promoters.

    Science.gov (United States)

    Wang, Man; Wu, Wei; Zhang, Yinfeng; Yao, Guoliang; Gu, Bianli

    2017-11-21

    Epstein-Barr virus (EBV), a human herpesvirus, is linked to both epithelial and lymphoid malignancies. Induction of EBV reactivation is a potential therapeutic strategy for EBV-associated tumors. In this study, we assessed the effects of rapamycin on EBV reactivation in gastric carcinoma cells. We found that rapamycin upregulated expression of EBV lytic proteins and increased the viral proliferation triggered by the EBV lytic inducer sodium butyrate. Reverse transcription-qPCR, luciferase activity assays, chromatin immunoprecipitation and western blotting were employed to explore the mechanism by which rapamycin promotes EBV reactivation. Our results showed that rapamycin treatment resulted in increased mRNA levels of EBV immediate-early genes. Rapamycin also enhanced the transcriptional activities of the EBV immediate-early lytic promoters Zp and Rp by strengthening Sp1 binding. Repression of the cellular ataxia telangiectasia-mutated/p53 pathway by siRNA-mediated knockdown of the ataxia telangiectasia-mutated gene significantly abrogated virus reactivation by rapamycin/sodium butyrate treatment, indicating that the ataxia telangiectasia-mutated/p53 pathway is involved in rapamycin-promoted EBV reactivation. Taken together, these findings demonstrate that rapamycin might have the potential to enhance the effectiveness of oncolytic viral therapies developed for EBV-associated malignancies. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Canine hereditary ataxia.

    Science.gov (United States)

    Urkasemsin, Ganokon; Olby, Natasha J

    2014-11-01

    The hereditary ataxias are a group of neurodegenerative diseases that cause a progressive (or episodic) cerebellar ataxia. A large number of different disorders have been described in different breeds of purebred dog, and in some instances, more than one disorder occurs in a single breed, creating a confusing clinical picture. The mutations associated with these disorders are being described at a rapid rate, potentially changing our ability to prevent, diagnose, and treat affected dogs. A breed-related neurodegenerative process should be suspected in any pure bred dog with slowly progressive, symmetric signs of ataxia. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. The diagnostic quandary of hereditary haemorrhagic telangiectasia vs. CREST syndrome.

    Science.gov (United States)

    Lee, J B; Ben-Aviv, D; Covello, S P

    2001-10-01

    The distribution and clinical appearance of the telangiectasia in the CREST syndrome (calcinosis, Raynaud's phenomenon, oesophageal involvement, sclerodactyly, telangiectasia) and hereditary haemorrhagic telangiectasia (HHT) are very similar. Several previously reported cases of the CREST syndrome simulating HHT illustrate this diagnostic quandary. We report a patient who met the diagnostic criteria for both the CREST syndrome and HHT, and discuss the distinguishing features of the two diseases, including the distinctive histopathological findings of telangiectasia in HHT.

  14. Speech in spinocerebellar ataxia.

    Science.gov (United States)

    Schalling, Ellika; Hartelius, Lena

    2013-12-01

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

  15. Spinocerebellar ataxia type 7.

    Science.gov (United States)

    Martin, Jean-Jacques

    2012-01-01

    Spinocerebellar ataxia type 7 (SCA7) is associated with progressive blindness, dominant transmission, and marked anticipation. SCA7 represents one of the polyglutamine expansion diseases with increase of CAG repeats. The gene maps to chromosome 3p12-p21.1. Normal values of CAG repeats range from 4 to 18. The SCA7 gene encodes a protein of largely unknown function, called ataxin-7. SCA7 is reported in many countries and ethnic groups. Its phenotypic expression depends on the number of expanded repeats. The infantile phenotype is very severe, with more than 100 repeats. The classic type has 50 to 55 repeats and is characterized by a combination of visual and ataxic disturbances lasting for 20-40 years.When the number of CAG repeats is between 36 and 43, the evolution is much slower, with few or no retinal abnormalities. A CAG repeat number from 18 to 35 is asymptomatic but predisposes to the development of the disorder when expanding to the pathological range through transmission. The diagnosis is made by molecular genetics. The neuropathology of the disorder includes atrophy of the spinocerebellar pathways, pyramidal tracts, and motor nuclei in the brainstem and spinal cord, a cone-rod sytrophy of the retina, and ataxin-7 immunoreactive neuronal intranuclear inclusions. The neuropathological features vary as a function of the number of CAG repeats. Present research deals mainly with the study of ataxin-7 in transfected neural cells and transgenic mouse models. 2012 Elsevier B.V. All rights reserved.

  16. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H196.

    Science.gov (United States)

    Marthaler, Adele G; Schmid, Benjamin; Tubsuwan, Alisa; Poulsen, Ulla B; Engelbrecht, Alexander F; Mau-Holzmann, Ulrike A; Hyttel, Poul; Nielsen, Jørgen E; Nielsen, Troels T; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H196 clone 7 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line will provide the ideal control to model SCA2 by iPSC technology. Copyright © 2015. Published by Elsevier B.V.

  17. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H271.

    Science.gov (United States)

    Marthaler, Adele G; Schmid, Benjamin; Tubsuwan, Alisa; Poulsen, Ulla B; Engelbrecht, Alexander F; Mau-Holzmann, Ulrike A; Hyttel, Poul; Nielsen, Jørgen E; Nielsen, Troels T; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H271 clone 1 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line will provide the ideal control to model SCA2 by iPSC technology. Copyright © 2015. Published by Elsevier B.V.

  18. Generation of an isogenic, gene-corrected control cell line of the spinocerebellar ataxia type 2 patient-derived iPSC line H266.

    Science.gov (United States)

    Marthaler, Adele G; Tubsuwan, Alisa; Schmid, Benjamin; Poulsen, Ulla B; Engelbrecht, Alexander F; Mau-Holzmann, Ulrike A; Hyttel, Poul; Nielsen, Troels T; Nielsen, Jørgen E; Holst, Bjørn

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. We have successfully generated bona fide induced pluripotent stem cell (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H266 clone 10 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line will provide the ideal control to model SCA2 by iPSC technology. Copyright © 2016. Published by Elsevier B.V.

  19. Increased oxidative stress in AOA3 cells disturbs ATM-dependent DNA damage responses.

    Science.gov (United States)

    Kobayashi, Junya; Saito, Yuichiro; Okui, Michiyo; Miwa, Noriko; Komatsu, Kenshi

    2015-04-01

    Ataxia telangiectasia (AT) is caused by a mutation in the ataxia-telangiectasia-mutated (ATM) gene; the condition is associated with hyper-radiosensitivity, abnormal cell-cycle checkpoints, and genomic instability. AT patients also show cerebellar ataxia, possibly due to reactive oxygen species (ROS) sensitivity in neural cells. The ATM protein is a key regulator of the DNA damage response. Recently, several AT-like disorders have been reported. The genes responsible for them are predicted to encode proteins that interact with ATM in the DNA-damage response. Ataxia with oculomotor apraxia types 1-3 (AOA1, 2, and 3) result in a neurodegenerative and cellular phenotype similar to AT; however, the basis of this phenotypic similarity is unclear. Here, we show that the cells of AOA3 patients display aberrant ATM-dependent phosphorylation and apoptosis following γ-irradiation. The ATM-dependent response to H2O2 treatment was abrogated in AOA3 cells. Furthermore, AOA3 cells had reduced ATM activity. Our results suggest that the attenuated ATM-related response is caused by an increase in endogenous ROS in AOA3 cells. Pretreatment of cells with pyocyanin, which induces endogenous ROS production, abolished the ATM-dependent response. Moreover, AOA3 cells had decreased homologous recombination (HR) activity, and pyocyanin pretreatment reduced HR activity in HeLa cells. These results indicate that excess endogenous ROS represses the ATM-dependent cellular response and HR repair in AOA3 cells. Since the ATM-dependent cell-cycle checkpoint is an important block to carcinogenesis, such inactivation of ATM may lead to tumorigenesis as well as neurodegeneration. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. 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

  1. Brain pathology of spinocerebellar ataxias

    NARCIS (Netherlands)

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

    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.

  2. 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

  3. 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.

  4. Survey of radiosensitivity in a variety of human cell strains

    Energy Technology Data Exchange (ETDEWEB)

    Arlett, C.F.; Harcourt, S.A.

    1980-03-01

    Gamma-ray sensitivity for cell killing was assayed in 54 human cell strains, including some derived from individuals suffering from certain hereditary diseases. The overall range of Do values in this study was 38 to 180 rads, indicating a considerable range of variability in humans. The normal sensitivity was described by a range of Do values of 97 to 180 rads. All ten ataxia telangiectasia cell strains tested proved radiosensitive and gave a mean Do value of 57 +- 15 (S.E.) rads, and these represent the most radiosensitive human skin fibroblasts currently available. Representative cell strains from familial retinoblastoma, Fanconi's anemia, and Hutchinson-Gilford progeria occupied positions of intermediate sensitivity, as did one of two ataxia telangiectasia heterozygotes. Six xeroderma pigmentosum cell strains together with two Cockayne's syndrome cell strains (all known to be sensitive to ultraviolet light) fell into the normal range, indicating an absence of cross-sensitivity between ultraviolet light and gamma-irradiation.

  5. 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.

  6. Purkinje Cell Degeneration and Motor Coordination Deficits in a New Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

    Directory of Open Access Journals (Sweden)

    Man Ding

    2017-05-01

    Full Text Available Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS is an early-onset neurodegenerative disorder. In 2007, a novel locus, SAX2, which is located on chromosome 17p13 and contains 3 genes, ankyrin repeat and FYVE domain-containing 1 (ANKFY1, β-arrestin 2 (ARRB2 and kinesin family member 1C (KIF1C, was linked to ARSACS. We generated Ankfy1 heterozygous (Ankfy1/+ mice to establish an animal model and examine the pathophysiological basis of ARSACS. The transgenic mice displayed an abnormal gait with progressive motor and cerebellar nerve dysfunction that was highly reminiscent of ARSACS. These clinical features were accompanied by an early-onset and progressive loss of Purkinje cells, followed by gliosis. Additionally, the loss of Ankfy1 function resulted in an abnormal expression of neurotrophic factors (NTFs in the Ankfy1/+ mouse cerebellum. Moreover, Purkinje cells cultured from neonatal Ankfy1/+ mice exhibited a shorter dendritic length and decreased numbers of dendritic spines. Importantly, cerebellar Purkinje cells from Ankfy1/+ mice and cells transfected with a lentiviral Ankfy1 shRNA underwent apoptosis. We propose that transgenic Ankfy1/+ mice are a useful model for studying the pathogenesis of ARSACS and for exploring the molecular mechanisms involved in this neurodegenerative disease.

  7. Genetics Home Reference: ataxia-pancytopenia syndrome

    Science.gov (United States)

    ... Baranko PV, Potter NU. Ataxia-pancytopenia: syndrome of cerebellar ataxia, hypoplastic anemia, monosomy 7, and acute myelogenous leukemia. ... A family with acute leukemia, hypoplastic anemia and cerebellar ataxia: association with bone marrow C-monosomy. Am J ...

  8. 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.

  9. 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. 2012 Elsevier B.V. All rights reserved.

  10. 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....

  11. Genetic heterogeneity in hereditary haemorrhagic telangiectasia.

    Science.gov (United States)

    Porteous, M E; Curtis, A; Williams, O; Marchuk, D; Bhattacharya, S S; Burn, J

    1994-01-01

    A locus causing hereditary haemorrhagic telangiectasia (HHT) has recently been mapped to 9q34 in four families and designated HHT1. In this paper, the results of a linkage study showing genetic heterogeneity in four families in whom HHT is segregating are reported. All the previously reported 9q34 linked families contain at least one affected member with a symptomatic pulmonary arteriovenous malformation. We postulate that clinical heterogeneity may also be a feature of HHT with a significantly higher predisposition to symptomatic PAVMs associated with the HHT1 linked families. PMID:7891373

  12. ATM-Deficient Colorectal Cancer Cells Are Sensitive to the PARP Inhibitor Olaparib.

    Science.gov (United States)

    Wang, Chen; Jette, Nicholas; Moussienko, Daniel; Bebb, D Gwyn; Lees-Miller, Susan P

    2017-04-01

    The ataxia telangiectasia mutated (ATM) protein kinase plays a central role in the cellular response to DNA damage. Loss or inactivation of both copies of the ATM gene (ATM) leads to ataxia telangiectasia, a devastating childhood condition characterized by neurodegeneration, immune deficiencies, and cancer predisposition. ATM is also absent in approximately 40% of mantle cell lymphomas (MCLs), and we previously showed that MCL cell lines with loss of ATM are sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Next-generation sequencing of patient tumors has revealed that ATM is altered in many human cancers including colorectal, lung, prostate, and breast. Here, we show that the colorectal cancer cell line SK-CO-1 lacks detectable ATM protein expression and is sensitive to the PARP inhibitor olaparib. Similarly, HCT116 colorectal cancer cells with shRNA depletion of ATM are sensitive to olaparib, and depletion of p53 enhances this sensitivity. Moreover, HCT116 cells are sensitive to olaparib in combination with the ATM inhibitor KU55933, and sensitivity is enhanced by deletion of p53. Together our studies suggest that PARP inhibitors may have potential for treating colorectal cancer with ATM dysfunction and/or colorectal cancer with mutation of p53 when combined with an ATM kinase inhibitor. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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

    Czech Academy of Sciences Publication Activity Database

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

    2016-01-01

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

  14. Ataxia telangiectasia - A report of a case in Port Harcourt | Yaguo ...

    African Journals Online (AJOL)

    She achieved normal early developmental milestones. She is the second child of adoptive parents and was adopted at 2weeks of age. Her biological mother was said to have died immediately after delivery. Her adoptive parents were of high socioeconomic class. The detail of child's family history was not known to the ...

  15. Punicalagin from pomegranate promotes human papillary thyroid carcinoma BCPAP cell death by triggering ATM-mediated DNA damage response.

    Science.gov (United States)

    Yao, Xin; Cheng, Xian; Zhang, Li; Yu, Huixin; Bao, Jiandong; Guan, Haixia; Lu, Rongrong

    2017-11-01

    Punicalagin (PUN), a component derived from pomegranate, is well known for its anticancer activity. Our previous work revealed that PUN induces autophagic cell death in papillary thyroid carcinoma cells. We hypothesized that PUN triggers DNA damage associated with cell death because DNA damage was reported as an inducer of autophagy. Our results showed that PUN treatment caused DNA breaks as evidenced by the significant enhancement in the phosphorylation of H2A.X. However, reactive oxygen species and DNA conformational alteration, 2 common inducing factors in DNA damage, were not involved in PUN-induced DNA damage. The phosphorylation of ataxia-telangiectasia mutated gene-encoded protein (ATM) but not ataxia telangiectasia and Rad3-related protein (ATR) was up-regulated in a time- and dosage-dependent manner after PUN treatment. KU-55933, an inhibitor of ATM, inhibited the phosphorylation of ATM induced by PUN and reversed the decreased cell viability caused by PUN. Thus, we demonstrated that PUN induces cell death of papillary thyroid carcinoma cells by triggering ATM-mediated DNA damage response, which provided novel mechanisms and potential targets for the better understanding of the anticancer actions of PUN. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. 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

  17. Cognition in Friedreich ataxia.

    Science.gov (United States)

    Nieto, Antonieta; Correia, Rut; de Nóbrega, Erika; Montón, Fernando; Hess, Stephany; Barroso, Jose

    2012-12-01

    Friedreich ataxia (FRDA) is the most frequent of the inherited ataxias. However, very few studies have examined the cognitive status of patients with genetically defined FRDA. Our aim was to study cognitive performance of FRDA patients taking into account the motor problems characteristic of this clinical population. Thirty-six FRDA patients were administered a comprehensive neuropsychological battery measuring multiple domains: processing speed, attention, working memory, executive functions, verbal and visual memory, visuoperceptive and visuospatial skills, visuoconstructive functions, and language. Thirty-one gender, age, years of education, and estimated IQ-matched healthy participants served as control subjects. All participants were native Spanish speakers. Patients showed decreased motor and mental speed, problems in conceptual thinking, a diminished verbal fluency, deficits in acquisition of verbal information and use of semantic strategies in retrieval, visuoperceptive and visuoconstructive problems, and poor action naming. Scores on the depression inventory were significantly higher in patients than controls, but depression did not account for group differences in cognitive performance. The observed pattern of neuropsychological impairment is indicative of executive problems and parieto-temporal dysfunction. Neuropathological and neuroimaging studies with FRDA patients have reported only mild anomalies in cerebral hemispheres. Thus, cognitive impairment in FRDA is probably caused by the interruption of the cerebro-cerebellar circuits that have been proposed as the anatomical substrate of the cerebellar involvement in cognition.

  18. Pulmonary vascular complications of hereditary haemorrhagic telangiectasia.

    Science.gov (United States)

    Circo, Sebastian; Gossage, James R

    2014-09-01

    The purpose of this study is to present the latest advances and recommendations in the diagnosis and treatment of pulmonary vascular complications associated with hereditary haemorrhagic telangiectasia (HHT): pulmonary arteriovenous malformations (PAVMs), pulmonary arterial hypertension (PAH), pulmonary hypertension associated with high output cardiac failure or liver vascular malformations, haemoptysis, haemothorax and thromboembolic disease. Transthoracic contrast echocardiography has been validated as a screening tool for PAVM in patients with suspected HHT. Advancements in genetic testing support its use in family members at risk as a cost-effective measure. Therapy with bevacizumab in patients with high output cardiac failure and severe liver AVMs showed promising results. PAH tends to be more aggressive in HHT type 2 patients. Patients suffering from this elusive disease should be referred to HHT specialized centres to ensure a standardized and timely approach to diagnosis and management.

  19. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3.

    NARCIS (Netherlands)

    Verbeek, D.S.; Warrenburg, B.P.C. van de; Wesseling, P.; Pearson, P.L.; Kremer, H.P.H.; Sinke, R.J.

    2004-01-01

    We report upon a Dutch autosomal dominant cerebellar ataxia (ADCA) family, clinically characterized by a late-onset (>40 years), slowly progressive, isolated spinocerebellar ataxia (SCA). Neuropathological examination in one affected subject showed neuronal loss in the Purkinje cell layer,

  20. [Ataxias and hereditary spastic paraplegias].

    Science.gov (United States)

    Schüle, R; Schöls, L

    2017-07-01

    Hereditary ataxias and spastic paraplegias are genetic disorders with age-dependent nearly complete penetrance. The mostly monogenetic etiology allows one to establish the diagnosis, study pathogenesis and to develop new causative therapeutic approaches for these diseases. Both the causative genes as well as the clinical presentation overlap considerably between hereditary ataxias and spastic paraplegias. This strongly argues towards a united classification for these two groups of diseases. Next generation sequencing technologies have greatly expanded the number of genes known to be causative for hereditary ataxias and spastic paraplegias and allow simultaneous time- and cost-effective diagnostic testing of > 200 genes. However, repeat expansions and large genomic deletions must be considered separately. Here, we suggest a pragmatic algorithm for genetic testing in hereditary ataxias and spastic paraplegias that we have developed in our specialized outpatient clinics. Detailed phenotyping remains crucial to interpret the multitude of genetic variants discovered by high throughput sequencing techniques. Despite recent technical advances, a substantial proportion of ataxia and spastic paraplegia families are still without a molecular diagnosis. Beside new and so far undetected ataxia and spasticity genes, unusual mutation types including noncoding variants and polygenic inheritance patterns may contribute. Because of these clinical, genetic, and technological challenges, patients with hereditary ataxias and spastic paraplegias should be referred to specialized centers offering research and clinical studies. This will also help to recruit representative patient cohorts for upcoming interventional trials.

  1. Optimal management of hereditary hemorrhagic telangiectasia

    Directory of Open Access Journals (Sweden)

    Garg N

    2014-10-01

    Full Text Available Neetika Garg,1 Monica Khunger,2 Arjun Gupta,3 Nilay Kumar4 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Department of Medicine, All India Institute of Medical Sciences, New Delhi, India; 3Department of Medicine, UT Southwestern Medical Center, Dallas, TX, USA; 4Department of Medicine, Cambridge Health Alliance/Harvard Medical School, Cambridge, MA, USA Abstract: Hereditary hemorrhagic telangiectasia (HHT, also known by the eponym Osler–Weber–Rendu syndrome, is a group of related disorders inherited in an autosomal dominant fashion and characterized by the development of arteriovenous malformations (AVM in the skin, mucous membranes, and/or internal organs such as brain, lungs, and liver. Its prevalence is currently estimated at one in 5,000 to 8,000. Most cases are due to mutations in the endoglin (HHT1 or ACVRLK1 (HHT2 genes. Telangiectasias in nasal and gastrointestinal mucosa generally present with recurrent/chronic bleeding and iron deficiency anemia. Larger AVMs occur in lungs (~40%–60% of affected individuals, liver (~40%–70%, brain (~10%, and spine (~1%. Due to the devastating and potentially fatal complications of some of these lesions (for example, strokes and brain abscesses with pulmonary AVMs, presymptomatic screening and treatment are of utmost importance. However, due to the rarity of this condition, many providers lack an appreciation for the whole gamut of its manifestations and complications, age-dependent penetrance, and marked intrafamilial variation. As a result, HHT remains frequently underdiagnosed and many families do not receive the appropriate screening and treatments. This article provides an overview of the clinical features of HHT, discusses the clinical and genetic diagnostic strategies, and presents an up-to-date review of literature and detailed considerations regarding screening for visceral AVMs, preventive modalities, and treatment options. Keywords: arteriovenous

  2. Ciliary neurotrophic factor for macular telangiectasia type 2: results from a phase 1 safety trial.

    Science.gov (United States)

    Chew, Emily Y; Clemons, Traci E; Peto, Tunde; Sallo, Ferenc B; Ingerman, Avner; Tao, Weng; Singerman, Lawrence; Schwartz, Steven D; Peachey, Neal S; Bird, Alan C

    2015-04-01

    To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. An open-label safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. The participant's more severely affected eye (worse baseline visual acuity) received the high-dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy. Published by Elsevier Inc.

  3. Radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector.

    Science.gov (United States)

    Zhang, Chao; Wang, Bing; Li, Lei; Li, Yawei; Li, Pengzhi; Lv, Guohua

    2017-09-01

    Surgery followed by radiotherapy is the standard treatment for chordomas, which are a rare but low-grade type of bone cancer arising from remnants of the embryonic notochord. However, disease recurrence following radiotherapy is common, most likely due to endogenous DNA repair mechanisms that promote cell survival upon radiation strikes. The ataxia telangiectasia mutated/ataxia telangiectasia mutated and Rad3 related (ATM/ATR)-mediated pathway has a critical role in DNA repair mechanisms; however, it has rarely been investigated in chordomas. In the present study, the expression of signal molecules related to the ATM/ATR pathway in chordoma tissues and adjacent normal tissues were initially examined using immunohistochemistry and western blot analysis. Chordoma U-CH1 and U-CH2 cells were subsequently used to investigate cell responses to ionizing radiation and the potential protective actions mediated by the ATM/ATR pathway. Phosphorylated (p)-ATM, p-ATR, γ-H2A histone family, member X (H2AX) and RAD51 were significantly upregulated in chordoma tissues relative to adjacent normal tissues (PATM, γ-H2AX and RAD51 expression in U-CH1 cells (PATM, p-ATR and RAD51 levels in U-CH2 cells (PATM/ATR pathway, in which RAD51 serves as an important downstream effector. Thus, RAD51 presents a promising therapeutic target for improving the outcome of radiotherapy treatment in chordomas.

  4. Redefining cerebellar ataxia in degenerative ataxias: lessons from recent research on cerebellar systems.

    Science.gov (United States)

    Tada, Masayoshi; Nishizawa, Masatoyo; Onodera, Osamu

    2015-08-01

    Recent advances in our understanding of neurophysiological functions in the cerebellar system have revealed that each region involved in degenerative ataxias contributes differently. To regulate voluntary movements, the cerebellum forms internal models within its neural circuits that mimic the behaviour of the sensorimotor system and objects in the external environment. The cerebellum forms two different internal models: forward and inverse. The forward model is formed by efference copy signals conveyed by the corticopontocerebellar system, and it derives the estimated consequences for action. The inverse model describes sequences of motor commands to accomplish an aim. During motor learning, we improve internal models by comparing the estimated consequence of an action from the forward model with the actual consequence of the action produced by the inverse model. The functions of the cerebellum encompass the formation, storage and selection of internal models. Considering the neurophysiological properties of the cerebellar system, we have classified degenerative ataxias into four types depending on which system is involved: Purkinje cells, the corticopontocerebellar system, the spinocerebellar system and the cerebellar deep nuclei. With regard to their respective contributions to the internal models, we speculate that loss of Purkinje cells leads to malformation of the internal models, whereas disturbance of the afferent system, corticopontocerebellar system or spinocerebellar system leads to mis-selection of the proper internal model. An understanding of the pathophysiological properties of ataxias in each degenerative ataxia enables the development of new methods to evaluate ataxias. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  5. Proteomic profiling of ATM kinase proficient and deficient cell lines upon blockage of proteasome activity.

    Science.gov (United States)

    Marzano, Valeria; Santini, Simonetta; Rossi, Claudia; Zucchelli, Mirco; D'Alessandro, Annamaria; Marchetti, Carlo; Mingardi, Michele; Stagni, Venturina; Barilà, Daniela; Urbani, Andrea

    2012-08-03

    Ataxia Telangiectasia Mutated (ATM) protein kinase is a key effector in the modulation of the functionality of some important stress responses, including DNA damage and oxidative stress response, and its deficiency is the hallmark of Ataxia Telangiectasia (A-T), a rare genetic disorder. ATM modulates the activity of hundreds of target proteins, essential for the correct balance between proliferation and cell death. The aim of this study is to evaluate the phenotypic adaptation at the protein level both in basal condition and in presence of proteasome blockage in order to identify the molecules whose level and stability are modulated through ATM expression. We pursued a comparative analysis of ATM deficient and proficient lymphoblastoid cells by label-free shotgun proteomic experiments comparing the panel of proteins differentially expressed. Through a non-supervised comparative bioinformatic analysis these data provided an insight on the functional role of ATM deficiency in cellular carbohydrate metabolism's regulation. This hypothesis has been demonstrated by targeted metabolic fingerprint analysis SRM (Selected Reaction Monitoring) on specific thermodynamic checkpoints of glycolysis. This article is part of a Special Issue entitled: Translational Proteomics. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Proteomic profiling of ATM kinase proficient and deficient cell lines upon blockage of proteasome activity☆

    Science.gov (United States)

    Marzano, Valeria; Santini, Simonetta; Rossi, Claudia; Zucchelli, Mirco; D'Alessandro, Annamaria; Marchetti, Carlo; Mingardi, Michele; Stagni, Venturina; Barilà, Daniela; Urbani, Andrea

    2012-01-01

    Ataxia Telangiectasia Mutated (ATM) protein kinase is a key effector in the modulation of the functionality of some important stress responses, including DNA damage and oxidative stress response, and its deficiency is the hallmark of Ataxia Telangiectasia (A-T), a rare genetic disorder. ATM modulates the activity of hundreds of target proteins, essential for the correct balance between proliferation and cell death. The aim of this study is to evaluate the phenotypic adaptation at the protein level both in basal condition and in presence of proteasome blockage in order to identify the molecules whose level and stability are modulated through ATM expression. We pursued a comparative analysis of ATM deficient and proficient lymphoblastoid cells by label-free shotgun proteomic experiments comparing the panel of proteins differentially expressed. Through a non-supervised comparative bioinformatic analysis these data provided an insight on the functional role of ATM deficiency in cellular carbohydrate metabolism's regulation. This hypothesis has been demonstrated by targeted metabolic fingerprint analysis SRM (Selected Reaction Monitoring) on specific thermodynamic checkpoints of glycolysis. This article is part of a Special Issue entitled: Translational Proteomics. PMID:22641158

  7. Cerebellar ataxia induced by 3-AP affects immunological function.

    Science.gov (United States)

    Jiang, Yong-Ying; Cao, Bei-Bei; Wang, Xiao-Qin; Peng, Yu-Ping; Qiu, Yi-Hua

    2015-01-01

    We previously showed that the cerebellum modulates the immune system. Here we determined whether cerebellar ataxia alters immunological function to further demonstrate an involvement of the cerebellum in immune modulation. Neurotoxin 3-acetylpyridine (3-AP) was intraperitoneally injected in rats to induce cerebellar ataxia. Behavior and motor coordination were tested on day 7 following 3-AP injection. Nissl staining and high-performance liquid chromatography (HPLC) were used to determine neuronal loss and neurotransmitter contents, respectively, in all the three cerebellar nuclei, fastigial nucleus (FN), interposed nucleus (IN) and dentate nucleus (DN). T and B lymphocyte differentiation and function were measured by flow cytometry, Western blot and ELISA. 3-AP induced motor discoordination and locomotor reduction. In all the three cerebellar nuclei, FN, IN and DN, there was a neuronal loss and a decrease in contents of glutamate and GABA (but not glycine) after 3-AP injection. Importantly, CD4+ T cells, but not CD8+ T cells, were increased by the 3-AP treatment. Moreover, interferon (IFN)-γ-producing cells and interleukin (IL)-17-producing cells were decreased in cerebellar ataxia rats, but IL-4-producing cells and CD25-expressing cells were increased. Expression of the T helper (Th)1- and Th17-related cytokines, IFN-γ, IL-2, IL-17 and IL-22, was downregulated in CD4+ cells in cerebellar ataxia rats, while expression of the Th2 and regulatory T (Treg)-related cytokines, IL-4, IL-5, IL-10 and transforming growth factor (TGF)-β, was upregulated. Furthermore, B lymphocyte number and anti-bovine serum albumin (BSA) IgM and IgG antibody levels were elevated in cerebellar ataxia. Cerebellar ataxia alters cellular and humoral immunity.

  8. Purkinje Cell Compartmentation in the Cerebellum of the Lysosomal Acid Phosphatase 2 Mutant Mouse (Nax - Naked-Ataxia Mutant Mouse)

    Science.gov (United States)

    Bailey, Karen; Rahimi Balaei, Maryam; Mannan, Ashraf; Del Bigio, Marc R.; Marzban, Hassan

    2014-01-01

    The Acp2 gene encodes the beta subunit of lysosomal acid phosphatase, which is an isoenzyme that hydrolyzes orthophosphoric monoesters. In mice, a spontaneous mutation in Acp2 results in severe cerebellar defects. These include a reduced size, abnormal lobulation, and an apparent anterior cerebellar disorder with an absent or hypoplastic vermis. Based on differential gene expression in the cerebellum, the mouse cerebellar cortex can normally be compartmentalized anteroposteriorly into four transverse zones and mediolaterally into parasagittal stripes. In this study, immunohistochemistry was performed using various Purkinje cell compartmentation markers to examine their expression patterns in the Acp2 mutant. Despite the abnormal lobulation and anterior cerebellar defects, zebrin II and PLCβ4 showed similar expression patterns in the nax mutant and wild type cerebellum. However, fewer stripes were found in the anterior zone of the nax mutant, which could be due to a lack of Purkinje cells or altered expression of the stripe markers. HSP25 expression was uniform in the central zone of the nax mutant cerebellum at around postnatal day (P) 18–19, suggesting that HSP25 immunonegative Purkinje cells are absent or delayed in stripe pattern expression compared to the wild type. HSP25 expression became heterogeneous around P22–23, with twice the number of parasagittal stripes in the nax mutant compared to the wild type. Aside from reduced size and cortical disorganization, both the posterior zone and nodular zone in the nax mutant appeared less abnormal than the rest of the cerebellum. From these results, it is evident that the anterior zone of the nax mutant cerebellum is the most severely affected, and this extends beyond the primary fissure into the rostral central zone/vermis. This suggests that ACP2 has critical roles in the development of the anterior cerebellum and it may regulate anterior and central zone compartmentation. PMID:24722417

  9. Adult-onset cerebellar Ataxia: a clinical and genetic Survey

    NARCIS (Netherlands)

    E. Brusse (Esther)

    2011-01-01

    textabstractCerebellar ataxias represent a heterogeneous group of neurodegenerative disorders. Two main categories are distinguished: hereditary and sporadic ataxias. Sporadic ataxias may be symptomatic or idiopathic. The clinical classification of hereditary ataxias is nowadays being replaced by

  10. Susceptibility of ATM-deficient pancreatic cancer cells to radiation.

    Science.gov (United States)

    Ayars, Michael; Eshleman, James; Goggins, Michael

    2017-05-19

    Ataxia telangiectasia mutated (ATM) is inactivated in a significant minority of pancreatic ductal adenocarcinomas and may be predictor of treatment response. We determined if ATM deficiency renders pancreatic cancer cells more sensitive to fractionated radiation or commonly used chemotherapeutics. ATM expression was knocked down in three pancreatic cancer cell lines using ATM-targeting shRNA. Isogenic cell lines were tested for sensitivity to several chemotherapeutic agents and radiation. DNA repair kinetics were analyzed in irradiated cells using the comet assay. We find that while rendering pancreatic cancer cells ATM-deficient did not significantly change their sensitivity to several chemotherapeutics, it did render them exquisitely sensitized to radiation. Pancreatic cancer ATM status may help predict response to radiotherapy.

  11. 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.

  12. ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion.

    Science.gov (United States)

    Chen, Wei-Ta; Ebelt, Nancy D; Stracker, Travis H; Xhemalce, Blerta; Van Den Berg, Carla L; Miller, Kyle M

    2015-06-01

    Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer-promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion. Transcription analyses identified a gene network, including the chemokine IL-8, regulated by ATM. IL-8 expression required ATM and was regulated by oxidative stress. IL-8 was validated as an ATM target by its ability to rescue cell migration and invasion defects in ATM-depleted cells. Finally, ATM-depletion in human breast cancer cells reduced lung tumors in a mouse xenograft model and clinical data validated IL-8 in lung metastasis. These findings provide insights into how ATM activation by oxidative stress regulates IL-8 to sustain cell migration and invasion in cancer cells to promote metastatic potential. Thus, in addition to well-established roles in tumor suppression, these findings identify a role for ATM in tumor progression.

  13. Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias.

    Science.gov (United States)

    Gan, Shi-Rui; Wang, Jie; Figueroa, Karla P; Pulst, Stefan M; Tomishon, Darya; Lee, Danielle; Perlman, Susan; Wilmot, George; Gomez, Christopher M; Schmahmann, Jeremy; Paulson, Henry; Shakkottai, Vikram G; Ying, Sarah H; Zesiewicz, Theresa; Bushara, Khalaf; Geschwind, Michael D; Xia, Guangbin; Subramony, S H; Ashizawa, Tetsuo; Kuo, Sheng-Han

    2017-01-01

    Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known. We studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012. Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ± 3.12 vs. 70.42 ± 3.96, p = 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, β = -0.91, p < 0.001; SCA6, β = -1.28, p = 0.025), while SCA2 patients with postural tremor had a faster rate of ataxia progression (β = 1.54, p = 0.034). We also found that the presence of postural tremor in SCA2 patients could be influenced by repeat expansions of ATXN1 (β = -1.53, p = 0.037) and ATXN3 (β = 0.57, p = 0.018), whereas postural tremor in SCA3 was associated with repeat lengths in TBP (β = 0.63, p = 0.041) and PPP2R2B (β = -0.40, p = 0.032). Postural tremor could be a clinical feature of SCAs, and the presence of postural tremor could be associated with different rates of ataxia progression. Genetic interactions between ataxia genes might influence the brain circuitry and thus affect the clinical presentation of postural tremor.

  14. 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...

  15. 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 ...

  16. 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 ...

  17. 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 ...

  18. Genetics Home Reference: spinocerebellar ataxia type 6

    Science.gov (United States)

    ... Email Facebook Twitter Home Health Conditions SCA6 Spinocerebellar ataxia type 6 Printable PDF Open All Close All ... to view the expand/collapse boxes. Description Spinocerebellar ataxia type 6 ( SCA6 ) is a condition characterized by ...

  19. Familial cerebellar ataxia and diabetes insipidus.

    OpenAIRE

    Robinson, I C; O'Malley, B P; Young, I D

    1988-01-01

    Two sisters are reported who both developed partial cranial diabetes insipidus in their 4th decade, followed by progressive cerebellar ataxia. This appears to be the first report of cerebellar ataxia and diabetes insipidus occurring together as a genetic entity.

  20. Ataxias cerebelares hereditárias: do martelo ao gen Hereditary cerebellar ataxias from neurological hammer to genetics

    Directory of Open Access Journals (Sweden)

    Walter Oleschko Arruda

    1997-09-01

    (SCA1 to SCA7, including Machado-Joseph disease / SCA3, probably the most common form of ADCA in South Brazil, and Friedreich ataxia (GAA expansion - chromosome 9p. Familial alpha-tocopherol deficiency (chromosome 8q may have a Friedreich ataxia phenotype and responds to the oral supplementaion with vitamin E. Familial episodic ataxias with (EA1 - chromosome 12p and without (chromosome 19p - EA2 myokimia were identified, the first one caused by point mutations in the gene encoding the KCNA1 potassium voltage-gated channel. The gene responsible for ataxia-teleangiectasia (chromosome 1 lq was found to encode a putative DNA binding protein kinase (ATM, related to the cell cycle control. One to 3% of the population are heterozygotic ATM gen carry and pose a higher risk of cancer when exposed to ionizing radiation. Molecular biology has provided us with useful tools to diagnosis and genetic counseling and, hopefully, will provide us with a better understanding of the pathogenesis and eventual treatment of the several forms of hereditary ataxias.

  1. 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.

  2. Friedreich Ataxia: From the Eye of a Molecular Biologist.

    Science.gov (United States)

    Muthuswamy, Srinivasan; Agarwal, Sarita

    2015-09-01

    Friedreich ataxia (FRDA) is caused by the expansion of a GAA triplet repeat in the first intron of the FXN gene. This disease was named after Nicholaus Friedreich, Germany, who depicted the essential finding. Among ataxias, FRDA is the most common hereditary ataxia. It has the autosomal recessive pattern of inheritance. The expansion of the GAA triplet repeat hinders the transcription, thereby reducing the level of the FXN transcript and consequently reducing the level of frataxin, a 210-amino acid protein. The disease pathogenesis is fundamentally due to a lack of frataxin, which is claimed to play a role in iron-sulfur cluster synthesis. Oxidative stress builds up as a result of Fe accumulation in the mitochondria, causing degeneration of the cells, which primarily occurs in the neurons and later in the cardiac tissues, and to some extent in the pancreas. The therapeutic interventions are at infancy; however, current treatments are targeted toward the reduction of iron overload and its effects.

  3. Acute cerebellar ataxia and consecutive cerebellitis produced by glutamate receptor delta2 autoantibody.

    Science.gov (United States)

    Shiihara, Takashi; Kato, Mitsuhiro; Konno, Akihiro; Takahashi, Yukitoshi; Hayasaka, Kiyoshi

    2007-05-01

    Acute cerebellar ataxia is usually a self-limited benign disease, which may develop in children after certain viral infections or vaccinations. There are several reports of acute cerebellar ataxia associated with autoantibodies. Glutamate receptor delta2, a member of the glutamate receptor family, is predominantly expressed in cerebellar Purkinje cells and plays a crucial role in cerebellar functions. To date anti-GluRdelta2 autoantibody was detected in a patient with chronic cerebellitis. Herein, an 18-month-old boy presented with cerebellar ataxia 9 days following a mild respiratory tract infection. Although cerebellar ataxia gradually improved, it worsened yet again following mumps and varicella virus infection. Cerebro-spinal fluid examination and magnetic resonance imaging of the brain demonstrated pleocytosis and meningeal enhancement, respectively. Furthermore, glutamate receptor delta2 autoantibody was detected in serum and cerebro-spinal fluid. Thus, we believe that the glutamate receptor delta2 autoantibody may play a role in cerebellar ataxia and consecutive cerebellitis.

  4. A case of human immunodeficiency virus infection with cerebellar ataxia that suggested by an association with autoimmunity.

    Science.gov (United States)

    Nagao, Shigeto; Kondo, Takayuki; Nakamura, Takashi; Nakagawa, Tomokazu; Matsumoto, Sadayuki

    2016-04-28

    We report a case of human immunodeficiency virus (HIV) infection that showed subacute progressive cerebellar ataxia without HIV encephalopathy or other encephalopathies, including progressive multifocal leukoencephalopathy or encephalitis of other human herpes virus (HHV) infections. A 43-year-old man exhibited unsteady gait. Neurological examination disclosed ataxia of the trunk and lower extremities. Personality change and dementia were absent. Magnetic resonance imaging did not reveal any abnormal finding, including of the cerebellum. The serum HIV-1-RNA was 1.2 × 10(5) copies/ml, and the absolute CD4 lymphocyte count was 141 cells/ml. Remarkably, the serum anti-Yo antibody, as an anti-cerebellar antibody of paraneoplastic syndrome, and anti-gliadin antibody, associated with celiac disease or gluten ataxia, were positive. The cerebrospinal fluid (CSF) immunoglobulin G index was 1.2 (ataxia, cerebellar ataxia associated with anti-glutamic acid decarboxylase antibody, and Hashimoto's encephalopathy might manifest as autoimmune cerebellar ataxia. As regards the association of HIV infection and autoimmune cerebellar ataxia, a previous report suggested that anti-gliadin antibody was detected in about 30% of HIV-infected children, though there is no reference to an association with cerebellar ataxia. Moreover, to our knowledge, detection of anti-Yo antibody in an HIV-infected patient with cerebellar ataxia has not been reported. These findings suggest that, although it is extremely rare, clinicians need to consider HIV infection in a patient exhibiting autoimmune cerebellar ataxia.

  5. miR-30a can inhibit DNA replication by targeting RPA1 thus slowing cancer cell proliferation.

    Science.gov (United States)

    Zou, Zhenyou; Ni, Mengjie; Zhang, Jing; Chen, Yongfeng; Ma, Hongyu; Qian, Shihan; Tang, Longhua; Tang, Jiamei; Yao, Hailun; Zhao, Chengbin; Lu, Xiongwen; Sun, Hongyang; Qian, Jue; Mao, Xiaoting; Lu, Xulin; Liu, Qun; Zen, Juping; Wu, Hanbing; Bao, Zhaosheng; Lin, Shudan; Sheng, Hongyu; Li, Yunlong; Liang, Yong; Chen, Zhiqiang; Zong, Dan

    2016-07-15

    Cell proliferation was inhibited following forced over-expression of miR-30a in the ovary cancer cell line A2780DX5 and the gastric cancer cell line SGC7901R. Interestingly, miR-30a targets the DNA replication protein RPA1, hinders the replication of DNA and induces DNA fragmentation. Furthermore, ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2) were phosphorylated after DNA damage, which induced p53 expression, thus triggering the S-phase checkpoint, arresting cell cycle progression and ultimately initiating cancer cell apoptosis. Therefore, forced miR-30a over-expression in cancer cells can be a potential way to inhibit tumour development. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  6. Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich ataxia.

    Science.gov (United States)

    Ouellet, D L; Cherif, K; Rousseau, J; Tremblay, J P

    2017-05-01

    The Friedreich ataxia is a monogenic disease due to a hyperexpanded GAA triplet located within the first intron of the frataxin gene that causes transcriptional issues. The resulting frataxin protein deficiency leads to a Fe-S cluster biosynthesis dysfunction in the mitochondria and to oxidative stress and cell death. Here we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo. Nevertheless, our results suggest the YG8sR as a better and more suitable model for the study of the CRISPR-Cas9 edition of the mutated frataxin gene.

  7. 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

  8. 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

  9. Speech Prosody in Cerebellar Ataxia

    Science.gov (United States)

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

    2007-01-01

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

  10. Spectrum of centrosome autoantibodies in childhood varicella and post-varicella acute cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Stinton Laura M

    2003-09-01

    Full Text Available Abstract Background Sera from children with post-varicella infections have autoantibodies that react with centrosomes in brain and tissue culture cells. We investigated the sera of children with infections and post-varicella ataxia and related conditions for reactivity to five recombinant centrosome proteins: γγ-enolase, pericentrin, ninein, PCM-1, and Mob1. Methods Sera from 12 patients with acute post-varicella ataxia, 1 with post-Epstein Barr virus (EBV ataxia, 5 with uncomplicated varicella infections, and other conditions were tested for reactivity to cryopreserved cerebellum tissue and recombinant centrosome proteins. The distribution of pericentrin in the cerebellum was studied by indirect immunofluorescence (IIF using rabbit antibodies to the recombinant protein. Antibodies to phospholipids (APL were detected by ELISA. Results Eleven of 12 children with post-varicella ataxia, 4/5 children with uncomplicated varicella infections, 1/1 with post-EBV ataxia, 2/2 with ADEM, 1/2 with neuroblastoma and ataxia, and 2/2 with cerebellitis had antibodies directed against 1 or more recombinant centrosome antigens. Antibodies to pericentrin were seen in 5/12 children with post-varicella ataxia but not in any of the other sera tested. IIF demonstrated that pericentrin is located in axons and centrosomes of cerebellar cells. APL were detected in 75% of the sera from children with post-varicella ataxia and 50% of children with varicella without ataxia and in none of the controls. Conclusion This is the first study to show the antigen specificity of anti-centrosome antibodies in children with varicella. Our data suggest that children with post-varicella ataxia have unique autoantibody reactivity to pericentrin.

  11. 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.

  12. 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.

  13. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, A D; Kjeldsen, J

    2000-01-01

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

  14. Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.

    Science.gov (United States)

    Aspatwar, Ashok; Tolvanen, Martti E E; Jokitalo, Eija; Parikka, Mataleena; Ortutay, Csaba; Harjula, Sanna-Kaisa E; Rämet, Mika; Vihinen, Mauno; Parkkila, Seppo

    2013-02-01

    Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans.

  15. Friedreich's Ataxia (FA)

    Science.gov (United States)

    ... the heart and parts of the nervous sys- tem involved in muscle control and coordination. What Is ... Genes are recipes for making proteins, which provide structure to our cells and drive the chemical reactions ...

  16. [IOSCA - Infantile onset spinocerebellar ataxia].

    Science.gov (United States)

    Lönnqvist, Tuula

    2011-01-01

    IOSCA is a difficult, progressive degenerative disease causing damage to the peripheral and central nervous system. All known 24 patients are Finnish. Initial symptoms include ataxia, athetosis, ophthalmoplegia, hearing disability and muscular hypotonia. Sensory axonal neuropathy and associated optic atrophy are typical of the disease, as well as primary hypergonadotropic hypogonadism in girls. The patients are progressively severely disabled from the age of approx. eighteen months. The pathogenesis is unknown and there is no curative treatment for the disease.

  17. Ciliary Neurotrophic Factor (CNTF) for Macular Telangiectasia Type 2 (MacTel): Results from a phase I safety trial

    Science.gov (United States)

    Chew, Emily Y.; Clemons, Traci E.; Peto, Tunde; Sallo, Ferenc B.; Ingerman, Avner; Tao, Weng; Singerman, Lawrence; Schwartz, Steven D.; Peachey, Neal S.; Bird, Alan C.

    2015-01-01

    PURPOSE To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. DESIGN An open-labeled safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. METHODS The participant’s more severely affected eye (worse baseline visual acuity) received the high dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. RESULTS The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. CONCLUSIONS The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy. PMID:25528956

  18. 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 ...

  19. 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 ...

  20. Hepatic mitochondrial dysfunction in Friedreich Ataxia

    Directory of Open Access Journals (Sweden)

    Stüwe Sven H

    2011-11-01

    Full Text Available Abstract Background Mitochondrial dysfunction due to respiratory chain impairment is a key feature in pathogenesis of Friedreich ataxia. Friedreich ataxia affects the nervous system, heart and pancreas. Methods We assessed hepatic mitochondrial function by 13C-methionine-breath-test in 16 Friedreich ataxia patients and matched healthy controls. Results Patients exhaled significantly smaller amounts of 13CO2 over 90 minutes. Maximal exhaled percentage dose of 13CO2 recovery was reduced compared to controls. Conclusions 13C-methionine-breath-test indicates subclinical hepatic mitochondrial dysfunction in Friedreich ataxia but did not correlate with GAA repeat lengths, disease duration or disease severity.

  1. hiPSC Disease Modeling of Rare Hereditary Cerebellar Ataxias.

    Science.gov (United States)

    Lukovic, Dunja; Moreno-Manzano, Victoria; Rodriguez-Jimenez, Francisco Javier; Vilches, Angel; Sykova, Eva; Jendelova, Pavla; Stojkovic, Miodrag; Erceg, Slaven

    2016-10-01

    Cerebellar ataxias are clinically and genetically heterogeneous diseases affecting primary cerebellar cells. The lack of availability of affected tissue from cerebellar ataxias patients is the main obstacle in investigating the pathogenicity of these diseases. The landmark discovery of human-induced pluripotent stem cells (hiPSC) has permitted the derivation of patient-specific cells with an unlimited self-renewing capacity. Additionally, their potential to differentiate into virtually any cell type of the human organism allows for large amounts of affected cells to be generated in culture, converting this hiPSC technology into a revolutionary tool in the study of the mechanisms of disease, drug discovery, and gene correction. In this review, we will summarize the current studies in which hiPSC were utilized to study cerebellar ataxias. Describing the currently available 2D and 3D hiPSC-based cellular models, and due to the fact that extracerebellar cells were used to model these diseases, we will discuss whether or not they represent a faithful cellular model and whether they have contributed to a better understanding of disease mechanisms.

  2. Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Ariza, Jeanelle; Rogers, Hailee; Hartvigsen, Anna; Snell, Melissa; Dill, Michael; Judd, Derek; Hagerman, Paul; Martínez-Cerdeño, Verónica

    2017-04-01

    Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome pathology includes dystrophic white matter and intranuclear inclusions in neurons and astrocytes. We previously demonstrated that the transport of iron into the brain is altered in fragile X-associated tremor/ataxia syndrome; therefore, we also expect an alteration of iron metabolism in brain areas related to motor control. Iron is essential for cell metabolism, but uncomplexed iron leads to oxidative stress and contributes to the development of neurodegenerative diseases. We investigated a potential iron modification in the putamen - a structure that participates in motor learning and performance - in fragile X-associated tremor/ataxia syndrome. We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome and 9 control cases to study iron localization using Perl's method, and iron-binding proteins using immunostaining. We found increased iron deposition in neuronal and glial cells in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron. Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  3. Multimodality imaging in macular telangiectasia 2: A clue to its pathogenesis

    Directory of Open Access Journals (Sweden)

    Lihteh Wu

    2015-01-01

    Full Text Available Macular telangiectasia type 2 also known as idiopathic perifoveal telangiectasia and juxtafoveolar retinal telangiectasis type 2A is an acquired bilateral neurodegenerative macular disease that manifests itself during the fifth or sixth decades of life. It is characterized by minimal dilatation of the parafoveal capillaries with graying of the retinal area involved, a lack of lipid exudation, right-angled retinal venules, refractile deposits in the superficial retina, hyperplasia of the retinal pigment epithelium, foveal atrophy, and subretinal neovascularization (SRNV. Our understanding of the disease has paralleled advances in multimodality imaging of the fundus. Optical coherence tomography (OCT images typically demonstrate the presence of intraretinal hyporeflective spaces that are usually not related to retinal thickening or fluorescein leakage. The typical fluorescein angiographic (FA finding is a deep intraretinal hyperfluorescent staining in the temporal parafoveal area. With time, the staining may involve the whole parafoveal area but does not extend to the center of the fovea. Long-term prognosis for central vision is poor, because of the development of SRNV or macular atrophy. Its pathogenesis remains unclear but multimodality imaging with FA, spectral domain OCT, adaptive optics, confocal blue reflectance and short wave fundus autofluorescence implicate Müller cells and macular pigment. Currently, there is no known treatment for this condition.

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    carry mutations in the ENG, ACVRL1 or SMAD4 genes. Here, we report on the genetic heterogeneity in the Danish national HHT population and address the prevalence of pulmonary arteriovenous malformations (PAVM). Probands of 107 apparently unrelated families received genetic testing, including sequencing....... Large deletions were identified in ENG and ACVRL1. The prevalence of PAVM was 52.3% in patients with an ENG mutation and 12.9% in the ACVRL1 mutation carriers. We diagnosed 80% of the patients clinically, fulfilling the Curaçao criteria, and those remaining were diagnosed by genetic testing......Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominantly inherited vascular disease characterized by the presence of mucocutaneous telangiectasia and visceral arteriovenous malformations (AVM). The clinical diagnosis of HHT is based on the Curaçao criteria. About 85% of HHT patients...

  5. Hereditary Hemorrhagic Telangiectasia: A Primer for Critical Care Nurses.

    Science.gov (United States)

    Sacco, Kathleen M; Barkley, Thomas W

    2016-06-01

    Hereditary hemorrhagic telangiectasia is a rare, autosomal dominant genetic disease that causes abnormal growth of blood vessels and, subsequently, life-threatening arteriovenous malformations in vital organs. Epistaxis may be one of the initial clues that a patient has more serious, generalized arteriovenous malformations. Recommended treatment involves careful evaluation to determine the severity and risk of spontaneous rupture of the malformations and the management of various signs and symptoms. The disease remains undiagnosed in many patients, and health care providers may miss the diagnosis until catastrophic events happen in multiple family members. Prompt recognition of hereditary hemorrhagic telangiectasia and early intervention can halt the dangerous course of the disease. Critical care nurses can assist with early diagnosis within families with this genetic disease, thus preventing early death and disability. ©2016 American Association of Critical-Care Nurses.

  6. Research progress of spinocerebellar ataxia type 1

    Directory of Open Access Journals (Sweden)

    Lin-wei ZHANG

    2014-05-01

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

  7. Thalidomide Effects in Patients with Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic Zebrafish Model.

    Science.gov (United States)

    Peng, Hong-Ling; Yi, Yi-Fang; Zhou, Shun-Ke; Xie, Si-Si; Zhang, Guang-Sen

    2015-11-20

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasia, and arteriovenous malformations. The efficacy of traditional treatments for HHT is very limited. The aim of this study was to investigate the therapeutic role of thalidomide in HHT patients and the effect in FLI-EGFP transgenic zebrafish model. HHT was diagnosed according to Shovlin criteria. Five HHT patients were treated with thalidomide (100 mg/d). The Epistaxis Severity Score (ESS), telangiectasia spots, and hepatic computed tomography angiography (CTA) were used to assess the clinical efficacy of thalidomide. The Fli-EGFP zebrafish model was investigated for the effect of thalidomide on angiogenesis. Dynamic real-time polymerase chain reaction assay, ELISA and Western blotting from patient's peripheral blood mononuclear cells and plasma were used to detect the expression of transforming growth factor beta 3 (TGF-β3) messenger RNA (mRNA) and vascular endothelial growth factor (VEGF) protein before and after 6 months of thalidomide treatment. The average ESS before and after thalidomide were 6.966 ± 3.093 and 1.799 ± 0.627, respectively (P = 0.009). The "telangiectatic spot" on the tongue almost vanished; CTA examination of case 2 indicated a smaller proximal hepatic artery and decreased or ceased hepatic artery collateral circulation. The Fli-EGFP zebrafish model manifested discontinuous vessel development and vascular occlusion (7 of 10 fishes), and the TGF-β3 mRNA expression of five patients was lower after thalidomide therapy. The plasma VEGF protein expression was down-regulated in HHT patients. Thalidomide reverses telangiectasia and controls nosebleeds by down-regulating the expression of TGF-β3 and VEGF in HHT patients. It also leads to vascular remodeling in the zebrafish model.

  8. The first knockin mouse model of episodic ataxia type 2.

    Science.gov (United States)

    Rose, Samuel J; Kriener, Lisa H; Heinzer, Ann K; Fan, Xueliang; Raike, Robert S; van den Maagdenberg, Arn M J M; Hess, Ellen J

    2014-11-01

    Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca(2+) channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ~70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/- mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/- mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. MACULAR TELANGIECTASIA TYPE 2: Quantitative Analysis of a Novel Phenotype and Implications for the Pathobiology of the Disease.

    Science.gov (United States)

    Okada, Mali; Egan, Catherine A; Heeren, Tjebo F C; Tufail, Adnan; Fruttiger, Marcus; Maloca, Peter M

    2018-01-01

    To investigate retinal microcystoid spaces in macular telangiectasia type 2 with spectral domain optical coherence tomography. Retrospective review of 135 patients enrolled in the MacTel Natural History Observation and Registry Study at Moorfields Eye Hospital, United Kingdom. One hundred seventy-two eyes from 86 patients who had a comparable scan protocol of at least 30 μm interval were included for analysis. Retinal microcystoid spaces were identified and segmented and metrics analyzed. From 172 eyes of 86 patients, microcystoid spaces were found in 11 eyes (6.4%) from 8 patients (9.3%). The mean number of microcystoid spaces per eye was 12.9 ± 18.2. Most were located in the inner nuclear layer. The inferonasal quadrant of the macula was the least commonly affected region. Microcystoid spaces were distributed entirely within the assumed macular telangiectasia area on blue light reflectance in all but 2 eyes (4 of 142 microcysts). The median diameter of the microcystoid spaces was 31 μm (range 15 μm-80 μm). Microcystoid spaces as a phenotype of macular telangiectasia should be considered in the differentials for microcystic edema. Understanding the pathogenesis of these lesions may provide further insight into the role of Müller cell dysfunction in this disorder.

  10. Pediatric retinal detachment in cutis aplasia and cutis marmorata telangiectasia.

    Science.gov (United States)

    Lagan, Maeve; Brennan, Rosie; McLoone, Eibhlin

    2012-01-01

    This is a report of 2 cases of cutis aplasia and cutis marmorata telangiectasia with associated retinal detachment. Retrospective case report. Illustration of ophthalmic associations of the rare congenital dermatologic presentations and description of successful treatment with laser photocoagulation. Awareness of the association between retinal detachment and cutis aplasia and cutis marmorata should be acted upon as laser photocoagulation has been shown in this case report to successfully treat the associated retinal detachment.

  11. Study of ATM Phosphorylation by Cdk5 in Neuronal Cells.

    Science.gov (United States)

    She, Hua; Mao, Zixu

    2017-01-01

    The phosphatidylinositol-3-kinase-like kinase ATM (ataxia-telangiectasia mutated) plays a central role in coordinating the DNA damage responses including cell cycle checkpoint control, DNA repair, and apoptosis. Mutations of ATM cause a spectrum of defects ranging from neurodegeneration to cancer predisposition. We previously showed that Cdk5 (cyclin-dependent kinase 5) is activated by DNA damage and directly phosphorylates ATM at serine 794 in postmitotic neurons. Phosphorylation at serine 794 precedes and is required for ATM autophosphorylation at serine 1981, and activates ATM kinase activity. Cdk5-ATM pathway plays a crucial role in DNA damage-induced neuronal injury. This chapter describes protocols used in analyzing ATM phosphorylation by Cdk5 in CGNs (cerebellar granule neurons) and its effects on neuronal survival.

  12. 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.

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

    DEFF Research Database (Denmark)

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

    2000-01-01

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

  14. 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.

  15. [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.

  16. 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.

  17. Emerging therapies in Friedreich's ataxia

    Science.gov (United States)

    Aranca, Tanya V; Jones, Tracy M; Shaw, Jessica D; Staffetti, Joseph S; Ashizawa, Tetsuo; Kuo, Sheng-Han; Fogel, Brent L; Wilmot, George R; Perlman, Susan L; Onyike, Chiadi U; Ying, Sarah H; Zesiewicz, Theresa A

    2016-01-01

    Friedreich's ataxia (FRDA) is an inherited, progressive neurodegenerative disease that typically affects teenagers and young adults. Therapeutic strategies and disease insight have expanded rapidly over recent years, leading to hope for the FRDA population. There is currently no US FDA-approved treatment for FRDA, but advances in research of its pathogenesis have led to clinical trials of potential treatments. This article reviews emerging therapies and discusses future perspectives, including the need for more precise measures for detecting changes in neurologic symptoms as well as a disease-modifying agent. PMID:26782317

  18. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.

    Directory of Open Access Journals (Sweden)

    Joyce van de Leemput

    2007-06-01

    Full Text Available We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1(Delta18/Delta18, encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15, a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5' part of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in three studied families, underlies SCA15 in humans.

  19. Germline Mutations of the Ataxia-Telangiectasia Gene, ATM, as a Risk Factor for Radiation-Associated Breast Cancer

    National Research Council Canada - National Science Library

    Offit, Kenneth

    1998-01-01

    ... of breast cancer after exposure to a defined dose of therapeutic irradiation. The study population will be comprised of women who have developed breast cancer after treatment for Hodgkin's Disease...

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

    Science.gov (United States)

    1999-09-01

    G, Itnyre J (1997) Prevalence and contribution of BRCA1 mutations in breast and ovarian cancer: results from three U.S. population-based case-control...GTTAAGAA two of these cases, AT1ILA and AT119LA, the families were consanguineous , and the mutations were homo- zygous, simplifying the interpretation...screening efficiency and expand significantly the number of cases to be screened. Assessment of the prevalence of ATM mutations in breast cancer

  1. 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

  2. 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.

  3. 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.

  4. Synthetic dural graft septoplasty in epistaxis from hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Burckhardt B, Wilfred; Guerra, Claudia Patricia

    2013-07-01

    It is an autosomal dominant vascular disorder, which has a variety of clinical manifestations, with epistaxis being one of the most common. Many treatment options exist for epistaxis, but with no consensus on which is the method of choice. We describe the case of a patient with hereditary hemorrhagic telangiectasia (HHT) secondary epistaxis with septoplasty managed with synthetic hard graft, which improved intensity and frequency of bleeding episodes. This technique is a variant of the septodermoplasty described by several authors, but the use of synthetic dura can help in obtaining better results and avoid taking skin grafts from other sites different from the surgical site.

  5. [Ataxia-opsoclonus-myoclonus syndrome].

    Science.gov (United States)

    Pinsard, N; Pons-Cerdan, C; Mancini, J; Livet, M O; Bernard, R

    The ataxia-opsoclonus-myoclonus syndrome that was well individualized by Kinsbourne is mostly observed in young children (less than three years old in 90 percent of the cases). From six personal cases, and from a review of ninety cases of the literature, the clinical and etiological features, as well as the evolution of the syndrome, are studied. Prodromes (infectious and digestive manifestations) and comportmental changes usually precede the sudden onset of the clinical triad. Neurologic complementary investigations are typically normal during the acute phase. The frequent association (46 percent of the cases) of this syndrome to a neuroblastoma (usually thoracic) makes it very particular from the etiological point of view. The evolution is identical whatever the type ("isolated" or "tumoral"). Corticotherapy (ACTH or corticoids) is efficient in 60 percent of the cases. But recurrences and cerebral sequelae (mental deficiency and speech disorders) are frequent.

  6. ATM mutants

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. ATM mutants. ATM (Ataxia Telangiectasia Mutated). AT2BE and AT5B1 cells – fibroblast cell lines from Ataxia telangiectasia patients. Deletion mutants expressing truncated ATM protein which is inactive. Have been used in studies looking at the role of ATM in DNA damage ...

  7. Chronic Replication Problems Impact Cell Morphology and Adhesion of DNA Ligase I Defective Cells.

    Directory of Open Access Journals (Sweden)

    Paolo Cremaschi

    Full Text Available Moderate DNA damage resulting from metabolic activities or sub-lethal doses of exogenous insults may eventually lead to cancer onset. Human 46BR.1G1 cells bear a mutation in replicative DNA ligase I (LigI which results in low levels of replication-dependent DNA damage. This replication stress elicits a constitutive phosphorylation of the ataxia telangiectasia mutated (ATM checkpoint kinase that fails to arrest cell cycle progression or to activate apoptosis or cell senescence. Stable transfection of wild type LigI, as in 7A3 cells, prevents DNA damage and ATM activation. Here we show that parental 46BR.1G1 and 7A3 cells differ in important features such as cell morphology, adhesion and migration. Comparison of gene expression profiles in the two cell lines detects Bio-Functional categories consistent with the morphological and migration properties of LigI deficient cells. Interestingly, ATM inhibition makes 46BR.1G1 more similar to 7A3 cells for what concerns morphology, adhesion and expression of cell-cell adhesion receptors. These observations extend the influence of the DNA damage response checkpoint pathways and unveil a role for ATM kinase activity in modulating cell biology parameters relevant to cancer progression.

  8. Acute cerebellar ataxia in enteric fever.

    Science.gov (United States)

    Sawhney, I M; Prabhakar, S; Dhand, U K; Chopra, J S

    1986-01-01

    Acute cerebellar ataxia as an isolated neurological manifestation of enteric fever is very rare. Three cases of acute cerebellar ataxia associated with enteric fever are reported. The diagnosis of enteric fever was confirmed by positive blood culture, strongly positive Widal test and rising antibody titres. The major clinical features were rapid development of gait ataxia, limb ataxia and dysarthria. None of the patients had altered sensorium. The cerebellar involvement was noticed on the second or third day of fever which progressed for one to two days. The symptoms remained static for one to two weeks and thereafter all the patients showed gradual recovery in a few weeks. Acute onset of cerebellar lesion, self limiting course and cerebrospinal fluid pleocytosis suggest par- or post-infectious demyelinating pathology in these patients, who were not related to each other.

  9. Dysarthria in Friedreich's Ataxia: A Perceptual Analysis

    National Research Council Canada - National Science Library

    Folker, Joanne; Murdoch, Bruce; Cahill, Louise; Delatycki, Martin; Corben, Louise; Vogel, Adam

    2010-01-01

    The aims of this study were to: (1) evaluate the perceptual speech dimensions, speech intelligibility and dysarthria severity of a group of individuals diagnosed with Friedreich's ataxia (FRDA); (2...

  10. Ataxias and Cerebellar or Spinocerebellar Degeneration

    Science.gov (United States)

    ... Division of Neuroscience Director, NIH BRAIN Initiative® Health Scientist Administrator Channels Synapses Circuits Cluster Scientific Director, Division of Intramural Research Featured Director's Message menu search Enter Search Term Submit Search Ataxias and Cerebellar ...

  11. 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

  12. Vestibular ataxia and its measurement in man

    Science.gov (United States)

    Fregly, A. R.

    1974-01-01

    Methods involved in and results obtained with a new comprehensive ataxia test battery are described, and definitions of spontaneous and induced vestibular ataxia in man are given in terms of these findings. In addition, the topic of alcohol-induced ataxia in relation to labyrinth function is investigated. Items in the test battery comprise a sharpened Romberg test, in which the subject stands on the floor with eyes closed and arms folded against his chest, feet heel-to-toe, for 60 seconds; an eyes-open walking test; an eyes-open standing test; an eyes-closed standing test; an eyes-closed on-leg standing test; an eyes-closed walk a line test; an eyes-closed heel-to-toe walking test; and supplementary ataxia tests such as the classical Romberg test.

  13. Acute Cerebellar Ataxia and Lyme Disease

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-06-01

    Full Text Available Child neurologists at Baskent University Faculty of Medicine, Turkey, report the case of a 5-year-old girl from the Mediterranean region of Anatolia with a 4-day history of progressive ataxia.

  14. Ataxia and cranial neuropathies from subcutaneously injected elemental mercury.

    Science.gov (United States)

    Malkani, Roneil; Weinstein, Jill M; Kumar, Neeraj; Victor, Thomas A; Bernstein, Lawrence

    2011-04-01

    CONTEXT. Although neurological toxicity from elemental mercury vapor and organic mercury exposure has been commonly reported in the literature, it is rarely reported from soft tissue injection of elemental mercury. We present a case of neurological dysfunction from subcutaneous injection of elemental mercury. CASE DETAILS. A 35-year-old Latin American man subacutely developed gait ataxia, diplopia, and vomiting 1 year after subcutaneous injection of elemental mercury, a practice common in Afro-Caribbean and Latin-American cultures. Physical examination showed an indurated plaque on his right shoulder at the injection site, left third nerve and bilateral sixth nerve palsies, nystagmus, dysarthria, and gait and limb ataxia. The patient's serum and 24-h urine mercury levels were significantly elevated; he underwent excision of the mercury reservoir and chelation with dimercaptosuccinic acid but experienced only mild improvement after 1 year. DISCUSSION. Neurological sequelae from elemental mercury, specifically cognitive dysfunction, tremor, cortical myoclonus, and peripheral neuropathy, have been reported but cranial neuropathies, ataxia, cerebrospinal fluid pleocytosis, and the presence of anti-Purkinje cell type-Tr antibody have not. Treatment involves removal of any existing mercury reservoir and chelation; however, improvement in neurological dysfunction after treatment has rarely been reported in the literature.

  15. Disease: H00848 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00848 Ataxia with ocular apraxia (AOA), including: Ataxia telangiectasia (AT); Ata...xia telangiectasia like disorder (ATLD); Ataxia oculomotor apraxia type 1 (AOA1); Ataxia oculomotor apraxia ...type 2 (AOA2) Ataxia with oculomotor apraxia (AOA) is a group of autosomal recessive cerebellar ataxias main...ly characterized by ataxia, oculomotor apraxia and choreoathetosis. AOA includes ...ataxia telangiectasia (AT), ataxia telangiectasia like disorder (ATLD), ataxia oculomotor apraxia type 1 (AO

  16. A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells

    DEFF Research Database (Denmark)

    Ahuja, Akshay K.; Jodkowska, Karolina; Teloni, Federico

    2016-01-01

    phosphorylation is dependent on Ataxia telangiectasia and Rad3 related (ATR) and is associated with chromatin loading of the ssDNA-binding proteins RPA and RAD51. Single-molecule analysis of replication intermediates reveals massive ssDNA gap accumulation, reduced fork speed and frequent fork reversal. All...... these marks of replication stress do not impair the mitotic process and are rapidly lost at differentiation onset. Delaying the G1/S transition in ESCs allows formation of 53BP1 nuclear bodies and suppresses ssDNA accumulation, fork slowing and reversal in the following S-phase. Genetic inactivation of fork...... slowing and reversal leads to chromosomal breakage in unperturbed ESCs. We propose that rapid cell cycle progression makes ESCs dependent on effective replication-coupled mechanisms to protect genome integrity....

  17. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3

    NARCIS (Netherlands)

    Verbeek, D S; van de Warrenburg, B P; Wesseling, P; Pearson, P L; Kremer, H P; Sinke, R J

    2004-01-01

    We report upon a Dutch autosomal dominant cerebellar ataxia (ADCA) family, clinically characterized by a late-onset (>40 years), slowly progressive, isolated spinocerebellar ataxia (SCA). Neuropathological examination in one affected subject showed neuronal loss in the Purkinje cell layer, dentate

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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.

  3. Brief Report: Late Efavirenz-Induced Ataxia and Encephalopathy: A Case Series.

    Science.gov (United States)

    Variava, Ebrahim; Sigauke, Farai R; Norman, Jennifer; Rakgokong, Modiehi; Muchichwa, Petudzai; Mochan, Andre; Maartens, Gary; Martinson, Neil A

    2017-08-15

    WHO treatment guidelines recommend efavirenz in first-line antiretroviral therapy (ART). Efavirenz commonly causes early transient neuropsychiatric adverse events. We present 20 cases with severe encephalopathy accompanied by ataxia due to efavirenz toxicity. Consecutive HIV-infected adults taking efavirenz-containing ART admitted to Tshepong hospital, Klerksdorp, South Africa with ataxia and encephalopathy were included in this case series. We identified 20 women admitted to hospital with severe ataxia. All received efavirenz-based ART for a median of 2 years. All had severe ataxia and none had nystagmus. Eleven had features of encephalopathy. Median weight was 34 kg [interquartile range (IQR): 29.7-35.3]; median CD4 count 299 cells/mm (IQR: 258-300) and most (18 of 19) were virally suppressed. Eight patients had a record of prior weights and 7 of 8 showed significant weight loss with a median weight loss of 10.8 kg (IQR: 8-11.6). All cases had plasma efavirenz assays, 19 were supratherapeutic (more than twice the upper level of therapeutic range), and 15 had concentrations above the upper limit of assay detection. Ataxia resolved after withdrawal of efavirenz at a median time of 2 months (IQR: 1.25-4) and recurred in 2 of 3 patients when rechallenged. Admissions before diagnosis were frequent with 10 cases admitted previously. Three women died. Efavirenz toxicity may present with severe reversible ataxia often with encephalopathy years after its initiation, likely in genetic slow metabolizers. We recommend that patients whose weight is ataxia. Eight patients had a record of prior subsequent weights and 7 of 8 showed significant weight loss gain; median gain of 10.8 kg (IQR: 8-11.6).

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

    DEFF Research Database (Denmark)

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

    2018-01-01

    BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder caused by mutations in ENG, ACVRL1, or SMAD4. Around 90% of HHT patients present with a heterozygous pathogenic genetic variation. Almost all cases of HHT have a family history. Very few cases are de......, and the flanking sequences of the genes were sequenced by NGS. RESULTS: The proband had clinical HHT fulfilling the Curaçao criteria and genetic testing identified a frameshift mutation in ENG. The mother of the proband, also with clinical HHT, was found negative when analyzing DNA from blood for the familial...... mutation using Sanger sequencing. Analyzing her DNA by NGS HHT panel sequencing when extracted from both peripheral blood leukocytes, and cheek swabs, identified the familial ENG mutation at low levels. CONCLUSION: We provide evidence of ENG mutational mosaicism in an individual presenting with clinical...

  5. 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.

  6. Life expextancy of parents with Hereditary Haemorrhagic Telangiectasia.

    Science.gov (United States)

    de Gussem, E M; Edwards, C P; Hosman, A E; Westermann, C J J; Snijder, R J; Faughnan, M E; Mager, J J

    2016-04-22

    Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disease associated with epistaxis, arteriovenous malformations and telangiectasias. Disease complications may result in premature death. We investigated life-expectancies of parents of HHT patients compared with their non-HHT partners using self- or telephone-administered questionnaires sent to their children. Patients were extracted from the databases of 2 participating HHT Centres: the Toronto HHT Database (Toronto, Canada) and the St. Antonius Hospital HHT Database (Nieuwegein, The Netherlands). Two hundred twenty five/407 (55%) of respondents were included creating HHT- (n = 225) and control groups (n = 225) of equal size. Two hundred thirteen/225 (95%) of the HHT group had not been screened for organ involvement of the disease prior to death. The life expectancy in parents with HHT was slightly lower compared to parents without (median age at death 73.3 years in patients versus 76.6 years in controls, p0.018). Parents with ACVRL 1 mutations had normal life expectancies, whereas parents with Endoglin mutations died 7.1 years earlier than controls (p = 0.024). Women with Endoglin mutations lived a median of 9.3 years shorter than those without (p = 0.04). Seven/123 (5%) of deaths were HHT related with a median age at death of 61.5 years (IQ range 54.4-67.7 years). Our study showed that the life expectancy of largely unscreened HHT patients was lower than people without HHT. Female patients with Endoglin mutations were most strikingly at risk of premature death from complications. These results emphasize the importance of referring patients with HHT for screening of organ involvement and timely intervention to prevent complications.

  7. 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 ...

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

    Science.gov (United States)

    ... Twitter Home Health Conditions ADCADN Autosomal dominant cerebellar ataxia, deafness, and narcolepsy Printable PDF Open All Close ... the expand/collapse boxes. Description Autosomal dominant cerebellar ataxia, deafness, and narcolepsy ( ADCADN ) is a nervous system ...

  9. T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice.

    Science.gov (United States)

    Gupta, Arun; Hunt, Clayton R; Pandita, Raj K; Pae, Juhee; Komal, K; Singh, Mayank; Shay, Jerry W; Kumar, Rakesh; Ariizumi, Kiyoshi; Horikoshi, Nobuo; Hittelman, Walter N; Guha, Chandan; Ludwig, Thomas; Pandita, Tej K

    2013-05-01

    Ataxia telangiectasia patients develop lymphoid malignancies of both B- and T-cell origin. Similarly, ataxia telangiectasia mutated (Atm)-deficient mice exhibit severe defects in T-cell maturation and eventually develop thymomas. The function of ATM is known to be influenced by the mammalian orthologue of the Drosophila MOF (males absent on the first) gene. Here, we report the effect of T-cell-specific ablation of the mouse Mof (Mof) gene on leucocyte trafficking and survival. Conditional Mof(Flox/Flox) (Mof (F/F)) mice expressing Cre recombinase under control of the T-cell-specific Lck proximal promoter (Mof(F/F)/Lck-Cre(+)) display a marked reduction in thymus size compared with Mof(F/F)/Lck-Cre(-) mice. In contrast, the spleen size of Mof(F/F)/Lck-Cre(+) mice was increased compared with control Mof(F/F)/Lck-Cre(-) mice. The thymus of Mof(F/F)/Lck-Cre(+) mice contained significantly reduced T cells, whereas thymic B cells were elevated. Within the T-cell population, CD4(+)CD8(+) double-positive T-cell levels were reduced, whereas the immature CD4(-)CD8(-) double-negative (DN) population was elevated. Defective T-cell differentiation is also evident as an increased DN3 (CD44(-)CD25(+)) population, the cell stage during which T-cell receptor rearrangement takes place. The differentiation defect in T cells and reduced thymus size were not rescued in a p53-deficient background. Splenic B-cell distributions were similar between Mof(F/F)/Lck-Cre(+) and Mof(F/F)/Lck-Cre(-) mice except for an elevation of the κ light-chain population, suggestive of an abnormal clonal expansion. T cells from Mof(F/F)/Lck-Cre(+) mice did not respond to phytohaemagglutinin (PHA) stimulation, whereas LPS-stimulated B cells from Mof(F/F)/Lck-Cre(+) mice demonstrated spontaneous genomic instability. Mice with T-cell-specific loss of MOF had shorter lifespans and decreased survival following irradiation than did Mof(F/F)/Lck-Cre(-) mice. These observations suggest that Mof plays a critical

  10. 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.

  11. PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia.

    Science.gov (United States)

    Jobling, Rebekah K; Assoum, Mirna; Gakh, Oleksandr; Blaser, Susan; Raiman, Julian A; Mignot, Cyril; Roze, Emmanuel; Dürr, Alexandra; Brice, Alexis; Lévy, Nicolas; Prasad, Chitra; Paton, Tara; Paterson, Andrew D; Roslin, Nicole M; Marshall, Christian R; Desvignes, Jean-Pierre; Roëckel-Trevisiol, Nathalie; Scherer, Stephen W; Rouleau, Guy A; Mégarbané, André; Isaya, Grazia; Delague, Valérie; Yoon, Grace

    2015-06-01

    Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Clinical characteristics of patients with cerebellar ataxia associated with anti-GAD antibodies

    Directory of Open Access Journals (Sweden)

    Tiago Silva Aguiar

    Full Text Available ABSTRACT The enzyme glutamic acid decarboxylase (GAD, present in GABAergic neurons and in pancreatic beta cells, catalyzes the conversion of gamma-aminobutyric acid (GABA. The cerebellum is highly susceptible to immune-mediated mechanisms, with the potentially treatable autoimmune cerebellar ataxia associated with the GAD antibody (CA-GAD-ab being a rare, albeit increasingly detected condition. Few cases of CA-GAD-ab have been described. Methods This retrospective and descriptive study evaluated the clinical characteristics and outcomes of patients with CA-GAD-ab. Result Three patients with cerebellar ataxia, high GAD-ab titers and autoimmune endocrine disease were identified. Patients 1 and 2 had classic stiff person syndrome and insidious-onset cerebellar ataxia, while Patient 3 had pure cerebellar ataxia with subacute onset. Patients received intravenous immunoglobulin therapy with no response in Patients 1 and 3 and partial recovery in Patient 2. Conclusion CA-GAD-ab is rare and its clinical presentation may hamper diagnosis. Clinicians should be able to recognize this potentially treatable autoimmune cerebellar ataxia.

  13. 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

  14. 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....

  15. Differential responses to high- and low-dose ultraviolet-B stress in tobacco Bright Yellow-2 cells

    Directory of Open Access Journals (Sweden)

    Shinya eTakahashi

    2015-04-01

    Full Text Available Ultraviolet (UV-B irradiation leads to DNA damage, cell cycle arrest, growth inhibition, and cell death. To evaluate the UV-B stress–induced changes in plant cells, we developed a model system based on tobacco Bright Yellow-2 (BY-2 cells. Both low-dose UV-B (low UV-B: 740 J m−2 and high-dose UV-B (high UV-B: 2960 J m−2 inhibited cell proliferation and induced cell death; these effects were more pronounced at high UV-B. Flow cytometry showed cell cycle arrest within 1 day after UV-B irradiation; neither low- nor high-UV-B–irradiated cells entered mitosis within 12 h. Cell cycle progression was gradually restored in low-UV-B–irradiated cells but not in high-UV-B–irradiated cells. UV-A irradiation, which activates cyclobutane pyrimidine dimer (CPD photolyase, reduced inhibition of cell proliferation by low but not high UV-B and suppressed high-UV-B–induced cell death. UV-B induced CPD formation in a dose-dependent manner. The amounts of CPDs decreased gradually within 3 days in low-UV-B–irradiated cells, but remained elevated after 3 days in high-UV-B–irradiated cells. Low UV-B slightly increased the number of DNA single-strand breaks detected by the comet assay at 1 day after irradiation, and then decreased at 2 and 3 days after irradiation. High UV-B increased DNA fragmentation detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay 1 and 3 days after irradiation. Caffeine, an inhibitor of ataxia telangiectasia mutated (ATM and ataxia telangiectasia and Rad3-related (ATR checkpoint kinases, reduced the rate of cell death in high-UV-B–irradiated cells. Our data suggest that low-UV-B–induced CPDs and/or DNA strand-breaks inhibit DNA replication and proliferation of BY-2 cells, whereas larger contents of high-UV-B–induced CPDs and/or DNA strand-breaks lead to cell death.

  16. 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.

  17. 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.

  18. Hereditary Hemorrhagic Telangiectasia, a Vascular Dysplasia Affecting the TGF-β Signaling Pathway

    Science.gov (United States)

    Fernández-L, Africa; Sanz-Rodriguez, Francisco; Blanco, Francisco J.; Bernabéu, Carmelo; Botella, Luisa M.

    2006-01-01

    Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in endoglin (ENG; HHT1) or ACVRL1/ALK1 (HHT2) genes and is an autosomal dominant vascular dysplasia. Clinically, HHT is characterized by epistaxis, telangiectases and arteriovenous malformations in some internal organs such as the lung, brain or liver. Endoglin and ALK1 proteins are specific endothelial receptors of the transforming growth factor (TGF)-β superfamily that are essential for vascular integrity. Genetic studies in mice and humans have revealed the pivotal role of TGF-β signaling during angiogenesis. Through binding to the TGF-β type II receptor, TGF-β can activate two distinct type I receptors (ALK1 and ALK5) in endothelial cells, each one leading to opposite effects on endothelial cell proliferation and migration. The recent isolation and characterization of circulating endothelial cells from HHT patients has revealed a decreased endoglin expression, impaired ALK1- and ALK5-dependent TGF-β signaling, disorganized cytoskeleton and the failure to form cord-like structures which may lead to the fragility of small vessels with bleeding characteristic of HHT vascular dysplasia or to disrupted and abnormal angiogenesis after injuries and may explain the clinical symptoms associated with this disease. PMID:16595794

  19. The ataxia (axJ mutation causes abnormal GABAA receptor turnover in mice.

    Directory of Open Access Journals (Sweden)

    Corinna Lappe-Siefke

    2009-09-01

    Full Text Available Ataxia represents a pathological coordination failure that often involves functional disturbances in cerebellar circuits. Purkinje cells (PCs characterize the only output neurons of the cerebellar cortex and critically participate in regulating motor coordination. Although different genetic mutations are known that cause ataxia, little is known about the underlying cellular mechanisms. Here we show that a mutated ax(J gene locus, encoding the ubiquitin-specific protease 14 (Usp14, negatively influences synaptic receptor turnover. Ax(J mouse mutants, characterized by cerebellar ataxia, display both increased GABA(A receptor (GABA(AR levels at PC surface membranes accompanied by enlarged IPSCs. Accordingly, we identify physical interaction of Usp14 and the GABA(AR alpha1 subunit. Although other currently unknown changes might be involved, our data show that ubiquitin-dependent GABA(AR turnover at cerebellar synapses contributes to ax(J-mediated behavioural impairment.

  20. Ataxia in children: think about vitamin E deficiency ! (comment on: ataxia in children: early recognition and clinical evaluation).

    Science.gov (United States)

    Rahmoune, H; Boutrid, N; Amrane, M; Chekkour, M C; Bioud, B

    2017-07-19

    A recent article from Pavone et al. published in the Italian Journal of Pediatrics entitled «Ataxia in children: early recognition and clinical evaluation» made an exhaustive overview of the large spectrum of pediatric ataxias. However, we would underline the importance of considering hereditary ataxia due to isolated vitamin E deficiency as a specific and treatable cause of child ataxia. We present a short clinical and therpeutic synopsis of this peculiar genetic etiology, frequently encountred in the mediterranean region.

  1. 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

  2. ELOVL5 mutations cause spinocerebellar ataxia 38.

    Science.gov (United States)

    Di Gregorio, Eleonora; Borroni, Barbara; Giorgio, Elisa; Lacerenza, Daniela; Ferrero, Marta; Lo Buono, Nicola; Ragusa, Neftj; Mancini, Cecilia; Gaussen, Marion; Calcia, Alessandro; Mitro, Nico; Hoxha, Eriola; Mura, Isabella; Coviello, Domenico A; Moon, Young-Ah; Tesson, Christelle; Vaula, Giovanna; Couarch, Philippe; Orsi, Laura; Duregon, Eleonora; Papotti, Mauro Giulio; Deleuze, Jean-François; Imbert, Jean; Costanzi, Chiara; Padovani, Alessandro; Giunti, Paola; Maillet-Vioud, Marcel; Durr, Alexandra; Brice, Alexis; Tempia, Filippo; Funaro, Ada; Boccone, Loredana; Caruso, Donatella; Stevanin, Giovanni; Brusco, Alfredo

    2014-08-07

    Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  3. Generation of spinocerebellar ataxia type 2 patient-derived iPSC line H271

    DEFF Research Database (Denmark)

    Marthaler, Adele Gabriele; Tubsuwan, Alisa; Schmid, Benjamin

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. Here, we demonstrate the generation of an induced pluripotent stem cell...

  4. Generation of spinocerebellar ataxia type 2 patient-derived iPSC line H196

    DEFF Research Database (Denmark)

    Marthaler, Adele Gabriele; Schmid, Benjamin; Tubsuwan, Alisa

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. Here, we demonstrate the generation of an induced pluripotent stem cell...

  5. Generation of spinocerebellar ataxia type 2 patient-derived iPSC line H266

    DEFF Research Database (Denmark)

    Marthaler, Adele Gabriele; Schmid, Benjamin; Tubsuwan, Alisa

    2016-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease primarily affecting the cerebellum. Very little is known about the molecular mechanisms underlying the disease and, to date, no cure or treatment is available. Here, we demonstrate the generation of an induced pluripotent stem cell...

  6. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.

    Science.gov (United States)

    Ruano, Luis; Melo, Claudia; Silva, M Carolina; Coutinho, Paula

    2014-01-01

    Hereditary cerebellar ataxias (HCA) and hereditary spastic paraplegias (HSP) are two groups of neurodegenerative disorders that usually present with progressive gait impairment, often leading to permanent disability. Advances in genetic research in the last decades have improved their diagnosis and brought new possibilities for prevention and future treatments. Still, there is great uncertainty regarding their global epidemiology. Our objective was to assess the global distribution and prevalence of HCA and HSP by a systematic review and meta-analysis of prevalence studies. The MEDLINE, ISI Web of Science and Scopus databases were searched (1983-2013) for studies performed in well-defined populations and geographical regions. Two independent reviewers assessed the studies and extracted data and predefined methodological parameters. Overall, 22 studies were included, reporting on 14,539 patients from 16 countries. Multisource population-based studies yielded higher prevalence values than studies based primarily on hospitals or genetic centres. The prevalence range of dominant HCA was 0.0-5.6/10(5), with an average of 2.7/10(5) (1.5-4.0/10(5)). Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease was the most common dominant ataxia, followed by SCA2 and SCA6. The autosomal recessive (AR) HCA (AR-HCA) prevalence range was 0.0-7.2/10(5), the average being 3.3/10(5) (1.8-4.9/10(5)). Friedreich ataxia was the most frequent AR-HCA, followed by ataxia with oculomotor apraxia or ataxia-telangiectasia. The prevalence of autosomal dominant (AD) HSP (AD-HSP) ranged from 0.5 to 5.5/10(5) and that of AR-HSP from 0.0 to 5.3/10(5), with pooled averages of 1.8/10(5) (95% CI: 1.0-2.7/10(5)) and 1.8/10(5) (95% CI: 1.0-2.6/10(5)), respectively. The most common AD-HSP form in every population was spastic paraplegia, autosomal dominant, type 4 (SPG4), followed by SPG3A, while SPG11 was the most frequent AR-HSP, followed by SPG15. In population-based studies, the number of

  7. Disease: H00064 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H00064 Ataxia telangiectasia (AT); Ataxia telangiectasia like disorder (ATLD); Lou...is-Bar syndrome; Boder-Sedgwick syndrome Ataxia-telangiectasia (AT) is an autosomal recessive disorder with

  8. Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38).

    Science.gov (United States)

    Borroni, Barbara; Di Gregorio, Eleonora; Orsi, Laura; Vaula, Giovanna; Costanzi, Chiara; Tempia, Filippo; Mitro, Nico; Caruso, Donatella; Manes, Marta; Pinessi, Lorenzo; Padovani, Alessandro; Brusco, Alfredo; Boccone, Loredana

    2016-07-01

    SCA38 (MIM 611805) caused by mutations within the ELOVL5 gene, which encodes an enzyme involved in the synthesis of long-chain fatty acids with a high and specific expression in Purkinje cells, has recently been identified. The present study was aimed at describing the clinical and neuroimaging features, and the natural history of SCA38. We extended our clinical and brain neuroimaging data on SCA38 including 21 cases from three Italian families. All had the ELOVL5 c.689G > T (p.Gly230Val) missense mutation. Age at disease onset was in the fourth decade of life. The presenting features were nystagmus (100% of cases) and slowly progressive gait ataxia (95%). Frequent signs and symptoms included pes cavus (82%) and hyposmia (76%); rarer symptoms were hearing loss (33%) and anxiety disorder (33%). The disease progressed with cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and ophtalmoparesis followed in the later stages by ophtalmoplegia. Peripheral nervous system involvement was present in the last phase of disease with sensory loss. Dementia or extrapyramidal signs were not detected. Significant loss of abilities of daily living was reported only after 20 years of the disease. Brain imaging documented cerebellar atrophy with sparing of cerebral cortex and no white matter disease. SCA38 is a rare form of inherited ataxia with characteristic clinical features, including pes cavus and hyposmia, that may guide genetic screening and prompt diagnosis in light of possible future therapeutic interventions. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Mutations in KCND3 cause spinocerebellar ataxia type 22

    Science.gov (United States)

    Lee, Yi-chung; Durr, Alexandra; Majczenko, Karen; Huang, Yen-hua; Liu, Yu-chao; Lien, Cheng-chang; Tsai, Pei-chien; Ichikawa, Yaeko; Goto, Jun; Monin, Marie-Lorraine; Li, Jun Z.; Chung, Ming-yi; Mundwiller, Emeline; Shakkottai, Vikram; Liu, Tze-tze; Tesson, Christelle; Lu, Yi-chun; Brice, Alexis; Tsuji, Shoji; Burmeister, Margit; Stevanin, Giovanni; Soong, Bing-wen

    2014-01-01

    Objective To identify the causative gene in SCA22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23. Subjects and Methods We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all three families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and co-segregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions. Results We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame three-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified three mutations, c.1034G>T p.G345V, c.1013T>C p.V338E and c.1130C>T p.T377M, in three Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K+ channel conductance in whole-cell patch-clamp recordings. Interpretation Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration. PMID:23280837

  10. Recent advances in hereditary spinocerebellar ataxias

    NARCIS (Netherlands)

    van de Warrenburg, Bart P C; Sinke, Richard J; Kremer, Berry

    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

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

    Indian Academy of Sciences (India)

    Mahesh

    Yichuanxue Zazhi = Chinese Journal of Medical Genetics 27(5): 501–505. Wu, Y. R., H. Y. Lin, C. M. Chen, et al. 2004 Genetic Testing in Spinocerebellar Ataxia in Taiwan: Expansions of Trinucleotide Repeats in SCA8 and SCA17 Are Associated with Typical Parkinson's Disease. Clinical Genetics 65(3): 209–214.

  12. 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.

  13. 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...

  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. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia.

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    Ying-Hao Chen

    Full Text Available 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.

  16. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia.

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    Chen, Ying-Hao; Lee, Yi-Chung; Tsai, Yu-Shuen; Guo, Yuh-Cherng; Hsiao, Cheng-Tsung; Tsai, Pei-Chien; Huang, Jin-An; Liao, Yi-Chu; Soong, Bing-Wen

    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.

  17. Spinocerebellar ataxia type 2 presenting with cognitive regression in childhood.

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    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.

  18. Radiotherapy induces cell cycle arrest and cell apoptosis in nasopharyngeal carcinoma via the ATM and Smad pathways.

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    Li, Ming-Yi; Liu, Jin-Quan; Chen, Dong-Ping; Li, Zhou-Yu; Qi, Bin; He, Lu; Yu, Yi; Yin, Wen-Jin; Wang, Meng-Yao; Lin, Ling

    2017-09-02

    Nasopharyngeal carcinoma (NPC) is a common malignant neoplasm of the head and neck which is harmful to human's health. Radiotherapy is commonly used in the treatment of NPC and it induces immediate cell cycle arrest and cell apoptosis. However, the mechanism remains unknown. Evidences suggested the activation of Ataxia telangiectasia mutated (ATM) pathway and Smad pathway are 2 of the important crucial mediators in the function of radiotherapy. In this study, we performed in vitro assays with human nasopharyngeal carcinoma CNE-2 cells and in vivo assays with nude mice to investigate the role of the ATM and Smad pathways in the treatment of nasopharyngeal carcinoma with radiotherapy. The results suggested that radiation induced activation of ATM pathway by inducing expression of p-ATM, p-CHK1, p-CHK2, p15 and inhibiting expression of p-Smad3. In addition, Caspase3 expression was increased while CDC25A was decreased, leading to cell cycle arrest and cell apoptosis. On the other hand, activation of Smad3 can inhibited the ATM pathway and attenuated the efficacy of radiation. In summary, we suggest that both ATM and Smad pathways contribute to the cell cycle arrest and cell apoptosis during nasopharyngeal carcinoma cells treated with radiation.

  19. Sun1 deficiency leads to cerebellar ataxia in mice

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    Jing-Ya Wang

    2015-08-01

    Full Text Available Migration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC complex. Regardless, Syne1-mutant mice present with normal cerebellar development. The Sad1-Unc-84 homology (SUN-domain proteins are located at the inner nuclear membrane and recruit Syne proteins through the KASH domain to the outer nuclear membrane. Here, we report an unrecognized contribution of Sun1 and Sun2 to the postnatal development of murine cerebellum. Mice depleted of Sun1 showed a marked reduction in the cerebellar volume, and this phenotype is exacerbated with additional loss of a Sun2 allele. Consistent with these histological changes, Sun1−/− and Sun1−/−Sun2+/− mice exhibited defective motor coordination. Results of immunohistochemical analyses suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the periphery of the nucleus. Approximately 33% of Purkinje cells in Sun1−/− mice and 66% of Purkinje cells in Sun1−/−Sun2+/− mice were absent from the surface of the internal granule layer (IGL, whereas the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1−/−Sun2+/− Purkinje cells exhibited retarded primary dendrite specification, reduced dendritic complexity and aberrant patterning of synapses. Our findings reveal a cell-type-specific role for Sun1 and Sun2 in nucleokinesis during cerebellar development, and we propose the use of Sun-deficient mice as a model for studying cerebellar ataxia that is associated with mutation of human SYNE genes or loss of Purkinje cells.

  20. Ethanol-Induced Cerebellar Ataxia: Cellular and Molecular Mechanisms.

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    Dar, M Saeed

    2015-08-01

    The cerebellum is an important target of ethanol toxicity given that cerebellar ataxia is the most consistent physical manifestation of acute ethanol consumption. Despite the significance of the cerebellum in ethanol-induced cerebellar ataxia (EICA), the cellular and molecular mechanisms underlying EICA are incompletely understood. However, two important findings have shed greater light on this phenomenon. First, ethanol-induced blockade of cerebellar adenosine uptake in rodent models points to a role for adenosinergic A1 modulation of EICA. Second, the consistent observation that intracerebellar administration of nicotine in mice leads to antagonism of EICA provides evidence for a critical role of cerebellar nitric oxide (NO) in EICA reversal. Based on these two important findings, this review discusses the potential molecular events at two key synaptic sites (mossy fiber-granule cell-Golgi cell (MGG synaptic site) and granule cell parallel fiber-Purkinje cell (GPP synaptic site) that lead to EICA. Specifically, ethanol-induced neuronal NOS inhibition at the MGG synaptic site acts as a critical trigger for Golgi cell activation which leads to granule cell deafferentation. Concurrently, ethanol-induced inhibition of adenosine uptake at the GPP synaptic site produces adenosine accumulation which decreases glutamate release and leads to the profound activation of Purkinje cells (PCs). These molecular events at the MGG and GPP synaptic sites are mutually reinforcing and lead to cerebellar dysfunction, decreased excitatory output of deep cerebellar nuclei, and EICA. The critical importance of PCs as the sole output of the cerebellar cortex suggests normalization of PC function could have important therapeutic implications.

  1. Sun1 deficiency leads to cerebellar ataxia in mice.

    Science.gov (United States)

    Wang, Jing-Ya; Yu, I-Shing; Huang, Chien-Chi; Chen, Chia-Yen; Wang, Wan-Ping; Lin, Shu-Wha; Jeang, Kuan-Teh; Chi, Ya-Hui

    2015-08-01

    Migration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Regardless, Syne1-mutant mice present with normal cerebellar development. The Sad1-Unc-84 homology (SUN)-domain proteins are located at the inner nuclear membrane and recruit Syne proteins through the KASH domain to the outer nuclear membrane. Here, we report an unrecognized contribution of Sun1 and Sun2 to the postnatal development of murine cerebellum. Mice depleted of Sun1 showed a marked reduction in the cerebellar volume, and this phenotype is exacerbated with additional loss of a Sun2 allele. Consistent with these histological changes, Sun1(-/-) and Sun1(-/-)Sun2(+/-) mice exhibited defective motor coordination. Results of immunohistochemical analyses suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the periphery of the nucleus. Approximately 33% of Purkinje cells in Sun1(-/-) mice and 66% of Purkinje cells in Sun1(-/-)Sun2(+/-) mice were absent from the surface of the internal granule layer (IGL), whereas the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1(-/-)Sun2(+/-) Purkinje cells exhibited retarded primary dendrite specification, reduced dendritic complexity and aberrant patterning of synapses. Our findings reveal a cell-type-specific role for Sun1 and Sun2 in nucleokinesis during cerebellar development, and we propose the use of Sun-deficient mice as a model for studying cerebellar ataxia that is associated with mutation of human SYNE genes or loss of Purkinje cells. © 2015. Published by The Company of Biologists Ltd.

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

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    Bassam R Ali

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

  3. Crystalline deposits in the macula - tamoxifen maculopathy or macular telangiectasia?

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    Rijal, Roshija Khanal; Nakhwa, Chinmay; Sindal, Manavi D

    2014-01-01

    Tamoxifen citrate is an anti-estrogen agent used in the treatment of breast carcinoma. Crystalline maculopathy is a rare complication of tamoxifen therapy. The clinical picture resembles that of idiopathic macular telangiectasia (IMT) Type 2, which is a more common clinical entity. To report a case of crystalline maculopathy secondary to tamoxifen and highlight the importance of the medical history and investigations in differentiating it from IMT Type 2. A diabetic female with a past history of breast carcinoma treated with tamoxifen came to the hospital for a routine eye check-up. Crystalline deposits were seen in the parafoveal region in both the eyes.The spectral domain optical coherence tomography (SD-OCT) showed foveal cysts in the inner retinal layer and fundus autofluorescence (FAF) and fundus fluorescein angiography (FFA) were within normal limits. While tamoxifen maculopathy is reversible on stopping the therapy, IMT needs a long-term follow-up to monitor the potential risk of loss of vision due to choroidal neovascularization, hence necessitating the distinction between these two different clinical entities.

  4. Mutation study of Spanish patients with Hereditary Hemorrhagic Telangiectasia

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    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.

  5. Research on Potential Biomarkers in Hereditary Haemorrhagic Telangiectasia

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    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.

  6. 5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia

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    Damjanovich Kristy

    2011-12-01

    Full Text Available Abstract Background 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. Methods and Results 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. Conclusions Our results emphasize the need for the inclusion of the 5'UTR region of ENG in clinical testing for HHT.

  7. Dose - response relationship of bevacizumab in hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Azzopardi, Nicolas; Dupuis-Girod, Sophie; Ternant, David; Fargeton, Anne-Emmanuelle; Ginon, Isabelle; Faure, Frédéric; Decullier, Evelyne; Roux, Adeline; Carette, Marie-France; Gilbert-Dussardier, Brigitte; Hatron, Pierre-Yves; Lacombe, Pascal; Leguy-Seguin, Vanessa; Rivière, Sophie; Corre, Romain; Bailly, Sabine; Paintaud, Gilles

    2015-01-01

    Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI <4 L/min/m(2) at 24 months, respectively. The fraction of patients with <20 min epistaxis per month was predicted to be 34%, 43% and 60%, with infusion every 3, 2 or one months, respectively. Simulations of the effects of different maintenance dosing regimens predict that monthly 5 mg/kg infusions of bevacizumab should allow sustained control of both cardiac index and epistaxis.

  8. Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia.

    Science.gov (United States)

    Zarrabeitia, Roberto; Ojeda-Fernandez, Luisa; Recio, Lucia; Bernabéu, Carmelo; Parra, Jose A; Albiñana, Virginia; Botella, Luisa M

    2016-06-02

    Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients' quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).

  9. Early Cerebellar Network Shifting in Spinocerebellar Ataxia Type 6.

    Science.gov (United States)

    Falcon, M I; Gomez, C M; Chen, E E; Shereen, A; Solodkin, A

    2016-07-01

    Spinocerebellar ataxia 6 (SCA6), an autosomal dominant degenerative disease, is characterized by diplopia, gait ataxia, and incoordination due to severe progressive degeneration of Purkinje cells in the vestibulo- and spinocerebellum. Ocular motor deficits are common, including difficulty fixating on moving objects, nystagmus and disruption of smooth pursuit movements. In presymptomatic SCA6, there are alterations in saccades and smooth-pursuit movements. We sought to assess functional and structural changes in cerebellar connectivity associated with a visual task, hypothesizing that gradual changes would parallel disease progression. We acquired functional magnetic resonance imaging and diffusion tensor imaging data during a passive smooth-pursuit task in 14 SCA6 patients, representing a range of disease duration and severity, and performed a cross-sectional comparison of cerebellar networks compared with healthy controls. We identified a shift in activation from vermis in presymptomatic individuals to lateral cerebellum in moderate-to-severe cases. Concomitantly, effective connectivity between regions of cerebral cortex and cerebellum was at its highest in moderate cases, and disappeared in severe cases. Finally, we noted structural differences in the cerebral and cerebellar peduncles. These unique results, spanning both functional and structural domains, highlight widespread changes in SCA6 and compensatory mechanisms associated with cerebellar physiology that could be utilized in developing new therapies. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Prevalence of ataxia in children: a systematic review.

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    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.

  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, 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

  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, 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

  13. 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.

  14. Caffeine markedly sensitizes human mesothelioma cell lines to pemetrexed

    Science.gov (United States)

    Min, Sang Hee; Goldman, I. David; Zhao, Rongbao

    2013-01-01

    Pemetrexed is a new generation antifolate approved for the treatment of mesothelioma and non-small cell lung cancer. Caffeine is known to augment radiation or chemotherapeutic drug-induced cell killing. The current study addresses the impact of caffeine on the activity of pemetrexed in mesothelioma cell lines. Caffeine enhanced pemetrexed activity in all four mesothelioma cell lines tested (H2052, H2373, H28 and MSTO-211H). Caffeine sensitized H2052 cells in a dose- and schedule-dependent manner, and was associated with a markedly decreased clonogenic survival. Caffeine sensitization occurred only in cells subjected to pulse, but not continuous, exposure to pemetrexed. Similar pemetrexed sensitization was also observed with the clinically better tolerated caffeine analog, theobromine. Pemetrexed sensitization by caffeine was associated with an increase in pemetrexed-induced phosphorylation of ataxia-telangiectasia-mutated (ATM) and Chk1. These data indicate that caffeine and its analog, theobromine, may be a useful approach to enhance pemetrexed-based chemotherapy. PMID:17594092

  15. Cancer incidence in patients with hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Duarte, Christine W; Black, Adam W; Lucas, F Lee; Vary, Calvin P H

    2017-02-01

    Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by deficiency in endoglin, an angiogenic protein. We previously showed that HHT, in which systemic endoglin expression is reduced, was associated with better survival outcomes in cancer patients (Duarte et al. in Cancer Epidemiol Biomarkers Prev 23:117-125, 2014). Here, we evaluated whether HHT was associated with reduced cancer incidence. A matched case-control analysis using SEER Medicare was conducted to evaluate the effect of HHT on diagnosis with breast, colorectal, lung, or prostate cancer between 2000 and 2007 (n = 633,162). Cancer and non-cancer patients were matched on age, sex, SEER registry region, and length of the ascertainment period for HHT. We assessed crude association using a McNemar's test and then adjusted for demographic variables, cancer type, cancer stage, comorbidities, and ascertainment period with a conditional logistic regression model for cancer incidence. The McNemar's test showed no significant association between HHT and cancer incidence (p = 0.74). Adjusting for covariates with the conditional logistic regression model did not change the result [HHT odds ratio 0.978; 95 % CI (0.795, 1.204)]. The lack of association between HHT and cancer incidence is unexpected given the previously discovered significant association between HHT and improved survival outcomes (Duarte et al. in Cancer Epidemiol Biomarkers Prev 23:117-125, 2014). We conclude that the protective effect of reduced systemic endoglin expression in cancer is specific to cancer progression through its effect on vascularization and other stromal effects but does not extend to cancer initiation.

  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. Inhibition of DNA-PKcs enhances radiosensitivity and increases the levels of ATM and ATR in NSCLC cells exposed to carbon ion irradiation.

    Science.gov (United States)

    Yang, Lina; Liu, Yuanyuan; Sun, Chao; Yang, Xinrui; Yang, Zhen; Ran, Juntao; Zhang, Qiuning; Zhang, Hong; Wang, Xinyu; Wang, Xiaohu

    2015-11-01

    Non-small cell lung cancer (NSCLC) exhibits radioresistance to conventional rays, due to its DNA damage repair systems. NSCLC may potentially be sensitized to radiation treatment by reducing those factors that continuously enhance the repair of damaged DNA. In the present study, normal lung fibroblast MRC-5 and lung cancer A549 cells were treated with NU7026 and CGK733, which are inhibitors of the DNA-dependent protein kinase catalytic subunit (PKcs) and ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), respectively, followed by exposure to X-rays and carbon ion irradiation. The cytotoxic activity, cell survival rate, DNA damage repair ability, cell cycle arrest and apoptosis rate of the treated cells were analyzed with MTT assay, colony formation assay, immunofluorescence and flow cytometry, respectively. The transcription and translation levels of the ATM, ATR and DNA-PKcs genes were detected by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results indicated that the radiosensitivity and DNA repair ability of A549 cells were reduced, and the percentages of apoptotic cells and those arrested at the G2/M phase of the cell cycle were significantly increased, following ionizing radiation with inhibitor-pretreatment. The expression levels of ATM, ATR, DNA-PKcs and phosphorylated histone H2AX, a biomarker for DNA double-strand breaks, were all upregulated at the transcriptional or translational level in A549 cells treated with carbon ion irradiation, compared with the control and X-rays-treated cells. In addition, the treatment with 5-50 µM NU7026 or CGK733 did not produce any obvious cytotoxicity in MRC-5 cells, and the effect of the DNA-PKcs-inhibitor on enhancing the radiosensitivity of A549 cells was stronger than that observed for the ATM and ATR-inhibitor. These findings demonstrated a minor role for ATM and ATR in radiation-induced cell death, since the upregulation of

  18. Targeting Ongoing DNA Damage in Multiple Myeloma: Effects of DNA Damage Response Inhibitors on Plasma Cell Survival

    Directory of Open Access Journals (Sweden)

    Ana Belén Herrero

    2017-05-01

    Full Text Available Human myeloma cell lines (HMCLs and a subset of myeloma patients with poor prognosis exhibit high levels of replication stress (RS, leading to DNA damage. In this study, we confirmed the presence of DNA double-strand breaks (DSBs in several HMCLs by measuring γH2AX and RAD51 foci and analyzed the effect of various inhibitors of the DNA damage response on MM cell survival. Inhibition of ataxia telangiectasia and Rad3-related protein (ATR, the main kinase mediating the response to RS, using the specific inhibitor VE-821 induced more cell death in HMCLs than in control lymphoblastoid cells and U266, an HMCL with a low level of DNA damage. The absence of ATR was partially compensated by ataxia telangiectasia-mutated protein (ATM, since chemical inhibition of both kinases using VE-821 and KU-55933 significantly increased the death of MM cells with DNA damage. We found that ATM and ATR are involved in DSB repair by homologous recombination (HR in MM. Inhibition of both kinases resulted in a stronger inhibition that may underlie cell death induction, since abolition of HR using two different inhibitors severely reduced survival of HMCLs that exhibit DNA damage. On the other hand, inhibition of the other route involved in DSB repair, non-homologous end joining (NHEJ, using the DNA-PK inhibitor NU7441, did not affect MM cell viability. Interestingly, we found that NHEJ inhibition did not increase cell death when HR was simultaneously inhibited with the RAD51 inhibitor B02, but it clearly increased the level of cell death when HR was inhibited with the MRE11 inhibitor mirin, which interferes with recombination before DNA resection takes place. Taken together, our results demonstrate for the first time that MM cells with ongoing DNA damage rely on an intact HR pathway, which thereby suggests therapeutic opportunities. We also show that inhibition of HR after the initial step of end resection might be more appropriate for inducing MM cell death, since it

  19. Targeting Ongoing DNA Damage in Multiple Myeloma: Effects of DNA Damage Response Inhibitors on Plasma Cell Survival.

    Science.gov (United States)

    Herrero, Ana Belén; Gutiérrez, Norma Carmen

    2017-01-01

    Human myeloma cell lines (HMCLs) and a subset of myeloma patients with poor prognosis exhibit high levels of replication stress (RS), leading to DNA damage. In this study, we confirmed the presence of DNA double-strand breaks (DSBs) in several HMCLs by measuring γH2AX and RAD51 foci and analyzed the effect of various inhibitors of the DNA damage response on MM cell survival. Inhibition of ataxia telangiectasia and Rad3-related protein (ATR), the main kinase mediating the response to RS, using the specific inhibitor VE-821 induced more cell death in HMCLs than in control lymphoblastoid cells and U266, an HMCL with a low level of DNA damage. The absence of ATR was partially compensated by ataxia telangiectasia-mutated protein (ATM), since chemical inhibition of both kinases using VE-821 and KU-55933 significantly increased the death of MM cells with DNA damage. We found that ATM and ATR are involved in DSB repair by homologous recombination (HR) in MM. Inhibition of both kinases resulted in a stronger inhibition that may underlie cell death induction, since abolition of HR using two different inhibitors severely reduced survival of HMCLs that exhibit DNA damage. On the other hand, inhibition of the other route involved in DSB repair, non-homologous end joining (NHEJ), using the DNA-PK inhibitor NU7441, did not affect MM cell viability. Interestingly, we found that NHEJ inhibition did not increase cell death when HR was simultaneously inhibited with the RAD51 inhibitor B02, but it clearly increased the level of cell death when HR was inhibited with the MRE11 inhibitor mirin, which interferes with recombination before DNA resection takes place. Taken together, our results demonstrate for the first time that MM cells with ongoing DNA damage rely on an intact HR pathway, which thereby suggests therapeutic opportunities. We also show that inhibition of HR after the initial step of end resection might be more appropriate for inducing MM cell death, since it prevents the

  20. Friedreich's Ataxia – A Clinical Diagnosis

    Directory of Open Access Journals (Sweden)

    Md. Fekarul Islam

    2015-01-01

    Full Text Available Friedreich's ataxia (FA is an autosomal recessive spinocerebellar degenerative disease characterized by hyperexpansion of GAA triplets in Frataxin gene. The hallmark of this disorder is ataxic gait, areflexia, Babinski's sign and positive Romberg test. We report a 9 year old child who presented with all these features and was diagnosed with FA on the basis of these clinical features. There are few case reports of FA where the diagnosis was made so early

  1. Epigenetic-based therapies for Friedreich ataxia

    OpenAIRE

    Sandi, C; Sandi, M; Virmouni, SA; Al-Mahdawi, S; Pook, MA

    2014-01-01

    This article has been made available through the Brunel Open Access Publishing Fund. Friedreich ataxia (FRDA) is a lethal autosomal recessive neurodegenerative disorder caused primarily by a homozygous GAA repeat expansion mutation within the first intron of the FXN gene, leading to inhibition of FXN transcription and thus reduced frataxin protein expression. Recent studies have shown that epigenetic marks, comprising chemical modifications of DNA and histones, are associated with FXN gene...

  2. 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....

  3. 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.

  4. Acute cerebellar ataxia, acute cerebellitis, and opsoclonus-myoclonus syndrome.

    Science.gov (United States)

    Desai, Jay; Mitchell, Wendy G

    2012-11-01

    Acute cerebellar ataxia and acute cerebellitis represent a process characterized by parainfectious, postinfectious, or postvaccination cerebellar inflammation. There is considerable overlap between these entities. The mildest cases of acute cerebellar ataxia represent a benign condition that is characterized by acute truncal and gait ataxia, variably with appendicular ataxia, nystagmus, dysarthria, and hypotonia. It occurs mostly in young children, presents abruptly, and recovers over weeks. Neuroimaging is normal. Severe cases of cerebellitis represent the other end of the spectrum, presenting with acute cerebellar signs often overshadowed by alteration of consciousness, focal neurological deficits, raised intracranial pressure, hydrocephalus, and even herniation. Neuroimaging is abnormal and the prognosis is less favorable than in acute cerebellar ataxia. Acute disseminated encephalomyelitis may be confused with acute cerebellitis when the clinical findings are predominantly cerebellar, but lesions on neuroimaging are usually widespread. Paraneoplastic opsoclonus-myoclonus syndrome is often initially misdiagnosed as acute cerebellar ataxia, but has very specific features, course, and etiopathogensis.

  5. Acute cerebellar ataxia following meningococcal group C conjugate vaccination.

    Science.gov (United States)

    Cutroneo, Paola Maria; Italiano, Domenico; Trifirò, Gianluca; Tortorella, Gaetano; Russo, Alessandra; Isola, Stefania; Caputi, Achille Patrizio; Spina, Edoardo

    2014-01-01

    Acute cerebellar ataxia is the most common cause of childhood ataxia, usually resulting from infections or vaccinations. Cases of acute cerebellar ataxia have been reported as a consequence of several viral and bacterial infections as well as immunizing agents, such as varicella, influenza, hepatitis B, and diphtheria-pertussis-tetanus vaccines. Although immunization with meningococcal group C conjugate vaccines has been associated with several neurological side effects, acute cerebellar ataxia has not been previously reported. The authors describe a case of a 12-year-old girl exhibiting acute cerebellar ataxia following meningococcal group C conjugate vaccination. In this patient, cerebellar symptoms started within 24 hours from the vaccination, and infective causes have been ruled out by serum and liquoral analyses. Magnetic resonance imaging findings were normal. Progressive clinical improvement was obtained after corticosteroid treatment. This case increases the small number of postvaccinal ataxias and contributes to further clarifying the complex pathogenesis of this disorder.

  6. Helichrysetin Induces DNA Damage that Triggers JNK-Mediated Apoptosis in Ca Ski Cells.

    Science.gov (United States)

    Fong, Ho Yen; Abd Malek, Sri Nurestri; Yee, Hui Shin; Karsani, Saiful Anuar

    2017-01-01

    Cervical cancer has become one of the most common cancers in women and currently available treatment options for cervical cancer are very limited. Naturally occurring chalcones and its derivatives have been studied extensively as a potential anticancer agent in different types of cancer and helichrysetin is naturally occurring chalcone that possess potent antiproliferative activity toward human cancer cells. Inhibitory activity of helichrysetin was evaluated at different concentrations. Ability of helichrysetin to induce apoptosis and its relation with c-Jun N-terminal kinase (JNK)-mediated mechanism of apoptosis was assessed using flow cytometry and Western blotting. Helichrysetin inhibited Ca Ski cells at half maximal inhibitory concentration 30.62 ± 0.38 μM. This compound has the ability to induce DNA damage, mitochondrial membrane disruption, and loss of cell membrane integrity. We have shown that apoptosis was induced through the activation of JNK-mediated apoptosis by DNA damage in the cells then triggering p53-downstream apoptotic pathway with increased expression of pro-apoptotic proteins, Bax and caspase 3, and suppression of Bcl-2 anti-apoptotic protein. DNA damage in the cells also caused phosphorylation of protein ataxia-telangiectasia mutated, an activator of DNA damage response. We conclude that helichrysetin can inhibit Ca Ski cells through DNA damage-induced JNK-mediated apoptotic pathway highlighting the potential of this compound as anticancer agent for cervical cancer. Helichrysetin induced DNA damage in Ca Ski cellsDNA damage caused JNK-mediated phosphorylation of p53 resulting in p53-mediated apoptosisHelichrysetin is a potential DNA damage inducing agent through JNK activation to kill human cervical carcinoma cells. Abbreviations used: ATM: Ataxia-telangiectasia mutated, DAPI: 4',6-diamidino-2-phenylindole, DMSO: Dimethyl sulfoxide, FITC: Fluorescein isothiocyanate, IC 50 : Half maximal inhibitory concentration, JC1-5,5',6,6'-Tetrachloro: 1

  7. Infantile spinocerebellar ataxia type 6: relationship to episodic ataxia type 6.

    Science.gov (United States)

    Gosalakkal, Jayaprakash A; Swamy, Puttamadaiah Mallikarjuna

    2006-04-01

    Spinocerebellar ataxia type 6 is one of the hereditary progressive cerebellar ataxias first described in 1997. Genetic studies have identified the defect as abnormal expansion of CAG trinucleotide repeat in 1 alpha subunit of the calcium channel gene located on chromosome 19p13. The symptomatic individuals have 20 or 23 repeats in contrast to normal individuals who manifest 19 or less CAG repeats. Most of the earlier reports indicate the age of onset of symptoms to be after the third decade. This report presents a patient with episodic symptoms soon after birth, which is unusual, and to our knowledge this is the youngest reported case. The clinical features of spinocerebellar ataxia type 6 are variable. The mode of inheritance and the common symptoms of this condition are also discussed.

  8. Differential responses of neuronal and spermatogenic cells to the doppel cytotoxicity.

    Directory of Open Access Journals (Sweden)

    Kefeng Qin

    Full Text Available Although structurally and biochemically similar to the cellular prion (PrP(C, doppel (Dpl is unique in its biological functions. There are no reports about any neurodegenerative diseases induced by Dpl. However the artificial expression of Dpl in the PrP-deficient mouse brain causes ataxia with Purkinje cell death. Abundant Dpl proteins have been found in testis and depletion of the Dpl gene (Prnd causes male infertility. Therefore, we hypothesize different regulations of Prnd in the nerve and male productive systems. In this study, by electrophoretic mobility shift assays we have determined that two different sets of transcription factors are involved in regulation of the Prnd promoter in mouse neuronal N2a and GC-1 spermatogenic (spg cells, i.e., upstream stimulatory factors (USF in both cells, Brn-3 and Sp1 in GC-1 spg cells, and Sp3 in N2a cells, leading to the expression of Dpl in GC-1 spg but not in N2a cells. We have further defined that, in N2a cells, Dpl induces oxidative stress and apoptosis, which stimulate ataxia-telangiectasia mutated (ATM-modulating bindings of transcription factors, p53 and p21, to Prnp promoter, resulting the PrP(C elevation for counteraction of the Dpl cytotoxicity; in contrast, in GC-1 spg cells, phosphorylation of p21 and N-terminal truncated PrP may play roles in the control of Dpl-induced apoptosis, which may benefit the physiological function of Dpl in the male reproduction system.

  9. Differential Responses of Neuronal and Spermatogenic Cells to the Doppel Cytotoxicity

    Science.gov (United States)

    Qin, Kefeng; Ding, Tianbing; Xiao, Yi; Ma, Wenyu; Wang, Zhen; Gao, Jimin; Zhao, Lili

    2013-01-01

    Although structurally and biochemically similar to the cellular prion (PrPC), doppel (Dpl) is unique in its biological functions. There are no reports about any neurodegenerative diseases induced by Dpl. However the artificial expression of Dpl in the PrP-deficient mouse brain causes ataxia with Purkinje cell death. Abundant Dpl proteins have been found in testis and depletion of the Dpl gene (Prnd) causes male infertility. Therefore, we hypothesize different regulations of Prnd in the nerve and male productive systems. In this study, by electrophoretic mobility shift assays we have determined that two different sets of transcription factors are involved in regulation of the Prnd promoter in mouse neuronal N2a and GC-1 spermatogenic (spg) cells, i.e., upstream stimulatory factors (USF) in both cells, Brn-3 and Sp1 in GC-1 spg cells, and Sp3 in N2a cells, leading to the expression of Dpl in GC-1 spg but not in N2a cells. We have further defined that, in N2a cells, Dpl induces oxidative stress and apoptosis, which stimulate ataxia-telangiectasia mutated (ATM)-modulating bindings of transcription factors, p53 and p21, to Prnp promoter, resulting the PrPC elevation for counteraction of the Dpl cytotoxicity; in contrast, in GC-1 spg cells, phosphorylation of p21 and N-terminal truncated PrP may play roles in the control of Dpl-induced apoptosis, which may benefit the physiological function of Dpl in the male reproduction system. PMID:24339999

  10. 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 ...

  11. ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress*

    Science.gov (United States)

    Kemp, Michael G.; Sancar, Aziz

    2016-01-01

    ATR (ataxia telangiectasia and Rad-3-related) is a protein kinase that maintains genome stability and halts cell cycle phase transitions in response to DNA lesions that block DNA polymerase movement. These DNA replication-associated features of ATR function have led to the emergence of ATR kinase inhibitors as potential adjuvants for DNA-damaging cancer chemotherapeutics. However, whether ATR affects the genotoxic stress response in non-replicating, non-cycling cells is currently unknown. We therefore used chemical inhibition of ATR kinase activity to examine the role of ATR in quiescent human cells. Although ATR inhibition had no obvious effects on the viability of non-cycling cells, inhibition of ATR partially protected non-replicating cells from the lethal effects of UV and UV mimetics. Analyses of various DNA damage response signaling pathways demonstrated that ATR inhibition reduced the activation of apoptotic signaling by these agents in non-cycling cells. The pro-apoptosis/cell death function of ATR is likely due to transcription stress because the lethal effects of compounds that block RNA polymerase movement were reduced in the presence of an ATR inhibitor. These results therefore suggest that whereas DNA polymerase stalling at DNA lesions activates ATR to protect cell viability and prevent apoptosis, the stalling of RNA polymerases instead activates ATR to induce an apoptotic form of cell death in non-cycling cells. These results have important implications regarding the use of ATR inhibitors in cancer chemotherapy regimens. PMID:26940878

  12. 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

  13. Cancer cells with alternative lengthening of telomeres do not display a general hypersensitivity to ATR inhibition

    Directory of Open Access Journals (Sweden)

    Katharina I Deeg

    2016-08-01

    Full Text Available Telomere maintenance is a hallmark of cancer as it provides cancer cells with cellular immortality. A significant fraction of tumors uses the alternative lengthening of telomeres (ALT pathway to elongate their telomeres and to gain an unlimited proliferation potential. Since the ALT pathway is unique to cancer cells, it represents a potentially valuable, currently unexploited target for anticancer therapies. Recently, it was proposed that ALT renders cells hypersensitive to ataxia telangiectasia- and RAD3-related (ATR protein inhibitors (Flynn et al., Science 347, 273. Here, we measured the response of various ALT or telomerase positive cell lines to the ATR inhibitor VE-821. In addition, we compared the effect of the inhibitor on cell viability in isogenic cell lines, in which ALT was active or suppressed. In these experiments a general ATR inhibitor sensitivity of cells with ALT could not be confirmed. We rather propose that the observed variations in sensitivity reflect differences between cell lines that are unrelated to ALT.

  14. Dose rate effect on low-dose hyper-radiosensitivity with cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Geon-Min; Kim, Eun-Hee [Seoul National University, Seoul (Korea, Republic of)

    2016-10-15

    Low-dose hyper-radiosensitivity (HRS) is the phenomenon that mammalian cells exhibit higher sensitivity to radiation at low doses (< 0.5 Gy) than expected by the linear-quadratic model. At doses above 0.5Gy, the cellular response is recovered to the level expected by the linear-quadratic model. This transition is called the increased radio-resistance (IRR). HRS was first verified using Chinese hamster V79 cells in vitro by Marples and has been confirmed in studies with other cell lines including human normal and tumor cells. HRS is known to be induced by inactivation of ataxia telangiectasia-mutated (ATM), which plays a key role in repairing DNA damages. Considering the connection between ATM and HRS, one can infer that dose rate may affect cellular response regarding HRS at low doses. In this study, we quantitated the effect of dose rate on HRS by clonogenic assay with normal and tumor cells. The HRS of cells at low dose exposures is a phenomenon already known. In this study, we observed HRS of rat normal diencephalon cells and rat gliosarcoma cells at doses below 1 Gy. In addition, we found that dose rate mattered. HRS occurred at low doses, but only when total dose was delivered at a rate below certain level.

  15. Analysis of Chromatin Opening in Heterochromatic Non-Small Cell Lung Cancer Tumor-Initiating Cells in Relation to DNA-Damaging Antitumor Treatment.

    Science.gov (United States)

    Eriksson, Mina; Hååg, Petra; Brzozowska, Beata; Lipka, Magdalena; Lisowska, Halina; Lewensohn, Rolf; Wojcik, Andrzej; Viktorsson, Kristina; Lundholm, Lovisa

    2018-01-01

    We previously reported that sphere-forming non-small cell lung cancer (NSCLC) tumor-initiating cells (TICs) have an altered activation of DNA damage response- and repair proteins and are refractory to DNA-damaging treatments. We analyzed whether chromatin organization plays a role in the observed refractoriness. Bulk cells and TICs from the NSCLC H23 and H1299 cell lines were examined using cell viability, clonogenic survival, Western blot, short interfering RNA analysis, and micronucleus assay. NSCLC TICs displayed elevated heterochromatin markers trimethylated lysine 9 of histone H3 and heterochromatin protein 1γ relative to bulk cells and reduced cell viability upon histone deacetylase inhibition (HDACi). Vorinostat and trichostatin A increased the euchromatin markers acetylated lysine 9/14 of histone H3 and lysine 8 of histone H4, and HDACi pretreatment increased the phosphorylation of the DNA damage response proteins ataxia telangiectasia mutated and DNA-dependent protein kinase, catalytic subunit, upon irradiation in TICs. HDACi sensitized TICs to cisplatin and to some extent to ionizing irradiation. The protectiveness of a dense chromatin structure was indicated by an enhanced frequency of micronuclei in TICs following irradiation, after knockdown of heterochromatin protein 1γ. Although confirmatory studies in additional NSCLC model systems and with respect to analyses of other DNA damage response proteins are needed, our data point toward a heterochromatic structure of NSCLC TICs, such that HDACi can sensitize TICs to DNA damage. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion.

    Science.gov (United States)

    Hakonen, Anna H; Goffart, Steffi; Marjavaara, Sanna; Paetau, Anders; Cooper, Helen; Mattila, Kimmo; Lampinen, Milla; Sajantila, Antti; Lönnqvist, Tuula; Spelbrink, Johannes N; Suomalainen, Anu

    2008-12-01

    Infantile-onset spinocerebellar ataxia (IOSCA) is a severe neurodegenerative disorder caused by the recessive mutation in PEO1, leading to an Y508C change in the mitochondrial helicase Twinkle, in its helicase domain. However, no mitochondrial dysfunction has been found in this disease. We studied here the consequences of IOSCA for the central nervous system, as well as the in vitro performance of the IOSCA mutant protein. The results of the mtDNA analyses were compared to findings in a similar juvenile or adult-onset ataxia syndrome, mitochondrial recessive ataxia syndrome (MIRAS), caused by the W748S mutation in the mitochondrial DNA polymerase (POLG). We show here that IOSCA brain does not harbor mtDNA deletions or increased amount of mtDNA point mutations, whereas MIRAS brain shows multiple deletions of mtDNA. However, IOSCA, and to a lesser extent also MIRAS, show mtDNA depletion in the brain and the liver. In both diseases, especially large neurons show respiratory chain complex I (CI) deficiency, but also CIV is decreased in IOSCA. Helicase activity, hexamerization and nucleoid structure of the IOSCA mutant were, however, unaffected. The lack of in vitro helicase defect or cell culture phenotype suggest that Twinkle-Y508C dysfunction affects mtDNA maintenance in a highly context and cell-type specific manner. Our results indicate that IOSCA is a new member of the mitochondrial DNA depletion syndromes.

  17. Long intronic GAA repeats causing Friedreich ataxia impede transcription elongation.

    Science.gov (United States)

    Punga, Tanel; Bühler, Marc

    2010-04-01

    Friedreich ataxia is a degenerative disease caused by deficiency of the protein frataxin (FXN). An intronic expansion of GAA triplets in the FXN-encoding gene, FXN, causes gene silencing and thus reduced FXN protein levels. Although it is widely assumed that GAA repeats block transcription via the assembly of an inaccessible chromatin structure marked by methylated H3K9, direct proof for this is lacking. In this study, we analysed different histone modification patterns along the human FXN gene in FRDA patient-derived lymphoblastoid cell lines. We show that FXN mRNA synthesis, but not turnover rates are affected by an expanded GAA repeat tract. Importantly, rather than preventing transcription initiation, long GAA repeat tracts affect transcription at the elongation step and this can occur independently of H3K9 methylation. Our data demonstrate that finding novel strategies to overcome the transcription elongation problem may develop into promising new treatments for FRDA.

  18. JS-K, a nitric oxide prodrug, induces DNA damage and apoptosis in HBV-positive hepatocellular carcinoma HepG2.2.15 cell.

    Science.gov (United States)

    Liu, Zhengyun; Li, Guangmin; Gou, Ying; Xiao, Dongyan; Luo, Guo; Saavedra, Joseph E; Liu, Jie; Wang, Huan

    2017-08-01

    Hepatocellular carcinoma (HCC) is the most important cause of cancer-related death, and 85% of HCC is caused by chronic HBV infection, the prognosis of patients and the reduction of HBV DNA levels remain unsatisfactory. JS-K, a nitric oxide-releasing diazeniumdiolates, is effective against various tumors, but little is known on its effects on HBV positive HCC. We found that JS-K reduced the expression of HBsAg and HBeAg in HBV-positive HepG2.2.15 cells. This study aimed to further examine anti-tumor effects of JS-K on HepG2.2.15 cells. The MTT assay and colony forming assay were used to study the cell growth inhibition of JS-K; scratch assay and transwell assay were performed to detect cell migration. The cell cycle was detected by flow cytometry. The immunofluorescence, flow cytometry analysis, and western blot were used to study DNA damage and cell apoptosis. JS-K inhibited HepG2.2.15 cell growth in a dose-dependent manner, suppressed cell colony formation and migration, arrested cells gather in the G2 phase. JS-K (1-20μM) increased the expression of DNA damage-associated protein phosphorylation H2AX (γH2AX), phosphorylation of checkpoint kinase 1 (p-Chk1), phosphorylation of checkpoint kinase 2 (p-Chk2), ataxia-telangiectasia mutated (ATM), phosphorylation of ataxia-telangiectasia mutated rad3-related (p-ATR) and apoptotic-associated proteins cleaved caspase-3, cleaved caspase-7, cleaved poly ADP-ribose polymerase (cleaved PARP). The study demonstrated JS-K is effective against HBV-positive HepG2.2.15 cells, the mechanisms are not only related to inhibition of HBsAg and HBeAg secretion, but also related with induction of DNA damage and apoptosis. JS-K is a promising anti-cancer candidate against HBV-positive HCC. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. The reciprocal cerebellar circuitry in human hereditary ataxia.

    Science.gov (United States)

    Koeppen, Arnulf H; Ramirez, R Liane; Bjork, Sarah T; Bauer, Peter; Feustel, Paul J

    2013-08-01

    Clinicoanatomic correlation in the spinocerebellar ataxias (SCA) and Friedreich's ataxia (FRDA) is difficult as these diseases differentially affect multiple sites in the central and peripheral nervous systems. A new way to study cerebellar ataxia is the systematic analysis of the "reciprocal cerebellar circuitry" that consists of tightly organized reciprocal connections between Purkinje cells, dentate nuclei (DN), and inferior olivary nuclei (ION). This circuitry is similar to but not identical with the "cerebellar module" in experimental animals. Neurohumoral transmitters operating in the circuitry are both inhibitory (γ-aminobutyric acid in corticonuclear and dentato-olivary fibers) and excitatory (glutamate in olivocerebellar or climbing fibers). Glutamatergic climbing fibers also issue collaterals to the DN. The present study applied five immunohistochemical markers in six types of SCA (1, 2, 3, 6, 7, 17), genetically undefined SCA, FRDA, and FRDA carriers to identify interruptions within the circuitry: calbindin-D28k, neuron-specific enolase, glutamic acid decarboxylase, and vesicular glutamate transporters 1 and 2. Lesions of the cerebellar cortex, DN, and ION were scored according to a guide as 0 (normal), 1 (mild), 2 (moderate), and 3 (severe). Results of each of the five immunohistochemical stains were examined separately for each of the three regions. Combining scores of each anatomical region and each stain yielded a total score as an indicator of pathological severity. Total scores ranged from 16 to 38 in SCA-1 (nine cases); 22 to 39 in SCA-2 (six cases); 9 to 15 in SCA-3 (four cases); and 13 and 25 in SCA-6 (two cases). In single cases of SCA-7 and SCA-17, scores were 16 and 31, respectively. In two genetically undefined SCA, scores were 36 and 37, respectively. In nine cases of FRDA, total scores ranged from 11 to 19. The low scores in SCA-3 and FRDA reflect selective atrophy of the DN. The FRDA carriers did not differ from normal controls. These

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-09-15

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

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  3. Breast cancer stem cell-like cells are more sensitive to ionizing radiation than non-stem cells: role of ATM.

    Directory of Open Access Journals (Sweden)

    Seog-Young Kim

    Full Text Available There are contradictory observations about the different radiosensitivities of cancer stem cells and cancer non-stem cells. To resolve these contradictory observations, we studied radiosensitivities by employing breast cancer stem cell (CSC-like MDA-MB231 and MDA-MB453 cells as well as their corresponding non-stem cells. CSC-like cells proliferate without differentiating and have characteristics of tumor-initiating cells [1]. These cells were exposed to γ-rays (1.25-8.75 Gy and survival curves were determined by colony formation. A final slope, D(0, of the survival curve for each cell line was determined to measure radiosensitivity. The D(0 of CSC-like and non-stem MDA-MB-453 cells were 1.16 Gy and 1.55 Gy, respectively. Similar results were observed in MDA-MB-231 cells (0.94 Gy vs. 1.56 Gy. After determination of radiosensitivity, we investigated intrinsic cellular determinants which influence radiosensitivity including cell cycle distribution, free-radical scavengers and DNA repair. We observed that even though cell cycle status and antioxidant content may contribute to differential radiosensitivity, differential DNA repair capacity may be a greater determinant of radiosensitivity. Unlike non-stem cells, CSC-like cells have little/no sublethal damage repair, a low intracellular level of ataxia telangiectasia mutated (ATM and delay of γ-H2AX foci removal (DNA strand break repair. These results suggest that low DNA repair capacity is responsible for the high radiosensitivity of these CSC-like cells.

  4. The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation

    Directory of Open Access Journals (Sweden)

    Sunnerhagen Per

    2009-11-01

    Full Text Available Abstract The ataxia telangiectasia mutated (ATM and the ATM- related (ATR kinases play a central role in facilitating the resistance of cancer cells to genotoxic treatment regimens. The components of the ATM and ATR regulated signaling pathways thus provide attractive pharmacological targets, since their inhibition enhances cellular sensitivity to chemo- and radiotherapy. Caffeine as well as more specific inhibitors of ATM (KU55933 or ATM and ATR (CGK733 have recently been shown to induce cell death in drug-induced senescent tumor cells. Addition of these agents to cancer cells previously rendered senescent by exposure to genotoxins suppressed the ATM mediated p21 expression required for the survival of these cells. The precise molecular pharmacology of these agents however, is not well characterized. Herein, we report that caffeine, CGK733, and to a lesser extent KU55933, inhibit the proliferation of otherwise untreated human cancer and non-transformed mouse fibroblast cell lines. Exposure of human cancer cell lines to caffeine and CGK733 was associated with a rapid decline in cyclin D1 protein levels and a reduction in the levels of both phosphorylated and total retinoblastoma protein (RB. Our studies suggest that observations based on the effects of these compounds on cell proliferation and survival must be interpreted with caution. The differential effects of caffeine/CGK733 and KU55933 on cyclin D1 protein levels suggest that these agents will exhibit dissimilar molecular pharmacological profiles.

  5. HMGA2 Inhibits Apoptosis through Interaction with ATR-CHK1 Signaling Complex in Human Cancer Cells

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    Suchitra Natarajan

    2013-03-01

    Full Text Available The non-histone chromatin binding protein high mobility group AT-hook 2 (HMGA2 is expressed in stem cells and many cancer cells, including tumor initiating cells, but not translated in normal human somatic cells. The presence of HMGA2 is correlated with advanced neoplastic disease and poor prognosis for patients. We had previously demonstrated a role of HMGA2 in DNA repair pathways. In the present study, we employed different human tumor cell models with endogenous and exogenous expression of HMGA2 and show that upon DNA damage, the presence of HMGA2 caused an increased and sustained phosphorylation of the ataxia telangiectasia and Rad3-related kinase (ATR and its downstream target checkpoint kinase 1 (CHK1. The presence of activated pCHK1Ser296 coincided with prolonged G2/M block and increased tumor cell survival, which was enhanced further in the presence of HMGA2. Our study, thus, identifies a novel relationship between the ATR-CHK1 DNA damage response pathway and HMGA2, which may support the DNA repair function of HMGA2 in cancer cells. Furthermore, our data provide a rationale for the use of inhibitors to ATR or CHK1 and HMGA2 in the treatment of HMGA2-positive human cancer cells.

  6. Fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Hoem, Gry; Koht, Jeanette

    2017-10-31

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

  7. 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

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

    African Journals Online (AJOL)

    Abstract: Introduction: Seasonal ataxia is a clinical syndrome of acute cerebellar ataxia which follows ingestion of roasted larvae of. Anaphe venata Butler, an alternative protein source consumed in western Nigeria. It was first reported in the 1950s in west- ern Nigeria when it caused a wave of epidemics. This is the first ...

  9. Seasonal ataxia: a case report of a disappearing disease | Moyo ...

    African Journals Online (AJOL)

    Introduction: Seasonal ataxia is a clinical syndrome of acute cerebellar ataxia which follows ingestion of roasted larvae of Anaphe venata Butler, an alternative protein source consumed in western Nigeria. It was first reported in the 1950s in western Nigeria when it caused a wave of epidemics. This is the first case report of ...

  10. 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…

  11. 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

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

    NARCIS (Netherlands)

    Wolf, N.I.; Koenig, M.; Dulac, O.L.M.; Sarnat, H.B.

    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

  13. Autosomal recessive cerebellar ataxia with bull's-eye macular dystrophy.

    NARCIS (Netherlands)

    Cruysberg, J.R.M.; Eerola, K.U.; Vrijland, H.R.; Aandekerk, A.L.; Kremer, H.P.H.; Deutman, A.F.

    2002-01-01

    PURPOSE: In 1980, we published in the American Journal of Ophthalmology two siblings with hereditary ataxia and atrophic maculopathy. The report is cited in the literature as autosomal dominant cerebellar ataxia with retinal degeneration. The purpose of the present study is to document the

  14. 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.)

  15. Spinocerebellar ataxia 17: Inconsistency between phenotype and neuroimage findings

    Directory of Open Access Journals (Sweden)

    Jin Zhang

    2013-01-01

    Full Text Available Spinocerebellar ataxia 17 (SCA17 is an autosomal dominant neurodegenerative disease clinically characterized by the presence of cerebellar ataxia in combination with variable neurological symptoms. Here we report a Chinese SCA17 family which proband′s clinical manifestation was inconsistent with the neuroimage findings.

  16. 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…

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

    Science.gov (United States)

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

    2017-01-01

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

  18. The Moonwalker mouse: new insights into TRPC3 function, cerebellar development, and ataxia.

    Science.gov (United States)

    Becker, Esther B E

    2014-10-01

    The Moonwalker (Mwk) mouse is a recent model of dominantly inherited cerebellar ataxia. The motor phenotype of the Mwk mouse is due to a gain-of-function mutation in the gene encoding the cation-permeable transient receptor potential channel (TRPC3). This mutation converts a threonine into an alanine in the highly conserved cytoplasmic S4-S5 linker of the channel, affecting channel gating. TRPC3 is highly expressed in cerebellar Purkinje cells and type II unipolar brush cells that both degenerate in the Mwk mouse. Studies of the Mwk mouse have provided new insights into the role of TRPC3 in cerebellar development and disease, which could not have been predicted from the Trpc3 knockout phenotype. Here, the genetic, behavioral, histological, and functional characterization of the Mwk mouse is reviewed. Moreover, the relationship of the Mwk mutant to other cerebellar mouse models and its relevance as a model for cerebellar ataxia are discussed.

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

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    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.

  20. Mouse Models of Hereditary Haemorrhagic Telangiectasia: Recent Advances and Future Challenges

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    Simon eTual-Chalot

    2015-02-01

    Full Text Available Hereditary Haemorrhagic Telangiectasia (HHT is a genetic disorder characterised by a multi-systemic vascular dysplasia and haemorrhage. The precise factors leading to these vascular malformations are not yet understood and robust animal models of HHT are essential to gain a detailed understanding of the molecular and cellular events that lead to clinical symptoms, as well as to test new therapeutic modalities. Most cases of HHT are caused by mutations in either endoglin (ENG or activin receptor like kinase 1 (ACVRL1, also known as ALK1. Both genes are associated with TGFβ/BMP signalling, and loss of function mutations in the co-receptor ENG are causal in HHT1, whilst HHT2 is associated with mutations in the signalling receptor ACVRL1. Significant advances in mouse genetics have provided powerful ways to study the function of Eng and Acvrl1 in vivo, and to generate mouse models of HHT disease. Mice that are null for either Acvrl1 or Eng genes show embryonic lethality due to major defects in angiogenesis. However mice that are heterozygous for mutations in either of these genes develop to adulthood with no effect on survival. Although these heterozygous mice exhibit selected vascular phenotypes relevant to the clinical pathology of HHT, the phenotypes are variable and generally quite mild. An alternative approach using conditional knockout mice allows us to study the effects of specific inactivation of either Eng or Acvrl1 at different times in development and in different cell types. These conditional knockout mice provide robust and reproducible models of arteriovenous malformations, and they are currently being used to unravel the causal factors in HHT pathologies. In this review, we will summarize the strengths and limitations of current mouse models of HHT, discuss how knowledge obtained from these studies has already informed clinical care and explore the potential of these models for developing improved treatments for HHT patients in the

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

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    Emmanuelle eTillet

    2015-01-01

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

  2. Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model.

    Science.gov (United States)

    Ferro, Austin; Carbone, Emily; Zhang, Jenny; Marzouk, Evan; Villegas, Monica; Siegel, Asher; Nguyen, Donna; Possidente, Thomas; Hartman, Jessilyn; Polley, Kailen; Ingram, Melissa A; Berry, Georgia; Reynolds, Thomas H; Possidente, Bernard; Frederick, Kimberley; Ives, Stephen; Lagalwar, Sarita

    2017-01-01

    Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.

  3. FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia.

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    Yogesh K Chutake

    Full Text Available Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues.The humanized mouse model of Friedreich ataxia (YG8sR, which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R. We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse.Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.

  4. Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia.

    Directory of Open Access Journals (Sweden)

    Eun-Jung Choi

    Full Text Available Endoglin (ENG is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1. HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng(2fl/2fl mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl mice: R26CreER (all cell types after tamoxifen treatment, SM22α-Cre (smooth muscle and endothelial cell and LysM-Cre (lysozyme M-positive macrophage. An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF was injected into the brain to induce focal angiogenesis. We found that SM22α-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.

  5. Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice.

    Science.gov (United States)

    Liu, Chunyi; Mei, Mei; Li, Qiuling; Roboti, Peristera; Pang, Qianqian; Ying, Zhengzhou; Gao, Fei; Lowe, Martin; Bao, Shilai

    2017-01-10

    The Golgi apparatus lies at the heart of the secretory pathway where it is required for secretory trafficking and cargo modification. Disruption of Golgi architecture and function has been widely observed in neurodegenerative disease, but whether Golgi dysfunction is causal with regard to the neurodegenerative process, or is simply a manifestation of neuronal death, remains unclear. Here we report that targeted loss of the golgin GM130 leads to a profound neurological phenotype in mice. Global KO of mouse GM130 results in developmental delay, severe ataxia, and postnatal death. We further show that selective deletion of GM130 in neurons causes fragmentation and defective positioning of the Golgi apparatus, impaired secretory trafficking, and dendritic atrophy in Purkinje cells. These cellular defects manifest as reduced cerebellar size and Purkinje cell number, leading to ataxia. Purkinje cell loss and ataxia first appear during postnatal development but progressively worsen with age. Our data therefore indicate that targeted disruption of the mammalian Golgi apparatus and secretory traffic results in neuronal degeneration in vivo, supporting the view that Golgi dysfunction can play a causative role in neurodegeneration.

  6. AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells.

    Science.gov (United States)

    Min, Ahrum; Im, Seock-Ah; Jang, Hyemin; Kim, Seongyeong; Lee, Miso; Kim, Debora Keunyoung; Yang, Yaewon; Kim, Hee-Jun; Lee, Kyung-Hun; Kim, Jin Won; Kim, Tae-Yong; Oh, Do-Youn; Brown, Jeff; Lau, Alan; O'Connor, Mark J; Bang, Yung-Jue

    2017-04-01

    Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect. The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer.In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis.These findings suggest synthetic lethality between ATR inhibition and ATM deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM deficiency are warranted to develop novel treatment strategies for gastric cancer. Mol Cancer Ther; 16(4); 566-77. ©2017 AACR. ©2017 American Association for Cancer Research.

  7. Personality and Neuropsychological Profiles in Friedreich Ataxia.

    Science.gov (United States)

    Sayah, Sabrina; Rotgé, Jean-Yves; Francisque, Hélène; Gargiulo, Marcela; Czernecki, Virginie; Justo, Damian; Lahlou-Laforet, Khadija; Hahn, Valérie; Pandolfo, Massimo; Pelissolo, Antoine; Fossati, Philippe; Durr, Alexandra

    2017-10-30

    Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited ataxia. Many studies have attempted to identify cognitive and affective changes associated with the disease, but conflicting results have been obtained, depending on the tests used and because many of the samples studied were very small. We investigated personality and neuropsychological characteristics in a cohort of 47 patients with genetically confirmed disease. The neuropsychological battery assessed multiple cognition domains: processing speed, attention, working memory, executive functions, verbal memory, vocabulary, visual reasoning, emotional recognition, and social cognition. Personality was assessed with the Temperament and Character Inventory, and depressive symptoms were assessed with the Beck Depression Inventory. We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Visual reasoning, memory, and learning were preserved. Emotional processes and social cognition were unimpaired. We also detected a change in automatic processes, such as reading. Personality traits were characterized by high persistence and low self-transcendence. The mild cognitive impairment observed may be a developmental rather than degenerative problem, due to early cerebellum dysfunction, with the impairment of cognitive and emotional processing. Disease manifestations at crucial times for personality development may also have an important impact on personality traits.

  8. The Saccharomyces cerevisiae MEC1 gene, which encodes a homolog of the human ATM gene product, is required for G1 arrest following radiation treatment.

    OpenAIRE

    Siede, W.; Allen, J B; Elledge, S. J.; Friedberg, E C

    1996-01-01

    The Saccharomyces cerevisiae gene MEC1 represents a structural homolog of the human gene ATM mutated in ataxia telangiectasia patients. Like human ataxia telangiectasia cell lines, mec1 mutants are defective in G2 and S-phase cell cycle checkpoints in response to radiation treatment. Here we show an additional defect in G1 arrest following treatment with UV light or gamma rays and map a defective arrest stage at or upstream of START in the yeast cell cycle.

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

    Science.gov (United States)

    Wang, Yubin; Hersheson, Joshua; Lopez, Dulce; Hammer, Monia; Liu, Yan; Lee, Ka-Hung; Pinto, Vanessa; Seinfeld, Jeff; Wiethoff, Sarah; Sun, Jiandong; Amouri, Rim; Hentati, Faycal; Baudry, Neema; Tran, Jennifer; Singleton, Andrew B; Coutelier, Marie; Brice, Alexis; Stevanin, Giovanni; Durr, Alexandra; Bi, Xiaoning; Houlden, Henry; Baudry, Michel

    2016-06-28

    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. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. 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,

  11. Superoxide dismutase activity and chromosome damage in cultured chromosome instability syndrome cells.

    Science.gov (United States)

    Lee, K H; Abe, S; Yanabe, Y; Matsuda, I; Yoshida, M C

    1990-07-01

    The basal levels of superoxide dismutase (SOD) activity and chromosome aberration (CA) and sister-chromatid exchange (SCE) frequencies were examined in cultured fibroblasts or Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs). These cells were derived from patients with chromosome instability syndromes (CISs) including Bloom's syndrome (BS), Fanconi's anemia (FA) and ataxia telangiectasia (AT). Embryonal fibroblasts and LCLs from normal subjects served as controls. Although LCLs tended to exhibit a higher SOD level than fibroblasts due to an elevation of Cu/Zn-SOD activity, BS and FA fibroblasts with increased frequencies of CAs and/or SCEs showed abnormally elevated SOD activity due to the manifold increase of Mn-SOD levels compared with control cells. However, BS and AT LCLs with almost control levels of CA and SCE frequencies showed no, or a slightly elevated, SOD activity, suggesting a possible selection of such cells during EBV transformation. The observed parallelism between the SOD activity and the cytogenetic manifestation may imply an involvement of active oxygen species, especially superoxide radicals, in the increased chromosome damage of CIS cells.

  12. Activation of ATM by DNA Damaging Agents

    National Research Council Canada - National Science Library

    Kurz, Ebba U; Lees-Miller, Susan P

    2005-01-01

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

  13. Activation of ATM by DNA Damaging Agents

    National Research Council Canada - National Science Library

    Kurz, Ebba U; Lees-Miller, Susan P

    2004-01-01

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

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

    Science.gov (United States)

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

    2014-06-01

    To investigate ataxia rating scales in children for reliability and the effect of age and sex. Three independent neuropaediatric observers cross-sectionally scored a set of paediatric ataxia rating scales in a group of 52 healthy children (26 males, 26 females) aged 4 to 16 years (mean age 10y 5mo SD 3y 11mo). The investigated scales involved the commonly applied International Cooperative Ataxia Rating Scale (ICARS), the Scale for Assessment and Rating of Ataxia (SARA), the Brief Ataxia Rating Scale (BARS), and PEG-board tests. We investigated the interrelatedness between individual ataxia scales, the influence of age and sex, inter- and intra-observer agreement, and test-retest reliability. Spearman's rank correlations revealed strong correlations between ICARS, SARA BARS, and PEG-board test (all pataxia rating scales are reliable, but should include age-dependent interpretation in children up to 12 years of age. To enable longitudinal interpretation of quantitative ataxia rating scales in children, European paediatric normative values are necessary. © 2014 Mac Keith Press.

  15. Update on the Pharmacotherapy of Cerebellar Ataxia and Nystagmus.

    Science.gov (United States)

    Feil, Katharina; Bremova, Tatiana; Muth, Carolin; Schniepp, Roman; Teufel, Julian; Strupp, Michael

    2016-02-01

    Pharmacological treatment of cerebellar ataxias and cerebellar nystagmus still remains difficult. The efficacy of most of the agents recommended in the past for symptomatic or even causative therapy could not be proven in larger state-of-the art clinical trials. Exceptions are (a) 4-aminopyridine (4-AP) for episodic ataxia type 2 (EA2): one observational and one randomized controlled trial showed a significant effect on the number of attacks of ataxia and quality of life; (b) aminopyridines in cerebellar downbeat nystagmus (DBN): two randomized controlled trials and several observational studies demonstrate a significant improvement of the intensity of DBN, visual acuity, and postural imbalance. In both diseases the sustained-release form is evidently also efficient; (c) 4-AP in cerebellar gait ataxia: evidence comes from two observational studies. (d) chlorzoxazone in DBN which, however, was so far demonstrated in only one observational study; (e) the modified amino acid acetyl-DL-leucine: evidently effective in cerebellar ataxias, shown in three observational studies, one on patients with Niemann-Pick type C; its mode of action has to be evaluated in animal models and on a cellular/electrophysiological level. There are ongoing randomized placebo-controlled trials on EA2 with 4-AP versus acetazolamide (EAT-2-TREAT), cerebellar gait ataxia with 4-AP (FACEG), and a multinational trial on cerebellar ataxia with acetyl-DL-leucine (ALCAT).

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

    Directory of Open Access Journals (Sweden)

    Valeriana Moura Ribeiro

    1968-03-01

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

  17. Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death

    DEFF Research Database (Denmark)

    Cheng, Wen-Hsing; Wu, Ryan T Y; Wu, Min

    2012-01-01

    , but promoted recovery from the MSeA-induced DNA damage. Taken together, WRN protects U-2 OS osteosarcoma cells against MSeA-induced cytotoxicity, suggesting that oxidative DNA repair pathway is a promising target for improving the efficacy of selenium on tumor suppression....... in mouse models of cancer. To test the hypothesis that targeting WRN can potentiate selenium toxicity in cancer cells, isogenic WRN small hairpin RNA (shRNA) and control shRNA U-2 OS osteosarcoma cells were treated with MSeA for 2d, followed by recovery for up to 7d. WRN deficiency sensitized U-2 OS cells...... to MSeA-induced necrotic death. Co-treatment with the ataxia-telangiectasia mutated (ATM) kinase inhibitor KU55933 desensitized the control shRNA cells, but not WRN shRNA cells, to MSeA treatment. WRN did not affect MSeA-induced ATM phosphorylation on Ser-1981 or H2A.X phosphorylation on Ser-139...

  18. Autopsy case of spinocerebellar ataxia type 31 with severe dementia at the terminal stage.

    Science.gov (United States)

    Adachi, Tadashi; Kitayama, Michio; Nakano, Toshiya; Adachi, Yoshiki; Kato, Shinsuke; Nakashima, Kenji

    2015-06-01

    Spinocerebellar ataxia type 31 (SCA31) is an autosomal dominant cerebellar ataxia commonly observed in Japan. However, few neuropathological examinations have been conducted. Here we report the case of a 76-year-old Japanese male SCA31 patient. He noticed dysarthria and difficulty walking at 65 years old. His symptoms subsequently deteriorated, although he could still walk with assistance at 70 years. At 73 years, when he could no longer walk, he was admitted to our hospital. He showed severe limb and truncal ataxia. His father and older brother had shown the same symptoms. Brain magnetic resonance imaging showed cerebellar atrophy of the anterior lobe and white matter hyperintensities. He was diagnosed with SCA31 by genetic analysis. Gradually, his cognitive functions and ability to communicate declined. He died of respiratory failure at the age of 76. Neuropathological examination revealed severe Purkinje cell loss that was accentuated in the anterior lobe of the cerebellum. Furthermore, the remaining Purkinje cells showed abnormal processes (that is, halo-like amorphous materials), as has been reported previously. Severe deposition of hyperphosphorylated tau-positive neurites, many senile plaques and amyloid angiopathy were observed in the neocortex. Our findings suggest that in SCA31, accelerated tau and amyloid pathology in the neocortex might induce dementia at the terminal stage. © 2014 Japanese Society of Neuropathology.

  19. NPRL-Z-1, as a new topoisomerase II poison, induces cell apoptosis and ROS generation in human renal carcinoma cells.

    Science.gov (United States)

    Wu, Szu-Ying; Pan, Shiow-Lin; Xiao, Zhi-Yan; Hsu, Jui-Ling; Chen, Mei-Chuan; Lee, Kuo-Hsiung; Teng, Che-Ming

    2014-01-01

    NPRL-Z-1 is a 4β-[(4"-benzamido)-amino]-4'-O-demethyl-epipodophyllotoxin derivative. Previous reports have shown that NPRL-Z-1 possesses anticancer activity. Here NPRL-Z-1 displayed cytotoxic effects against four human cancer cell lines (HCT 116, A549, ACHN, and A498) and exhibited potent activity in A498 human renal carcinoma cells, with an IC50 value of 2.38 µM via the MTT assay. We also found that NPRL-Z-1 induced cell cycle arrest in G1-phase and detected DNA double-strand breaks in A498 cells. NPRL-Z-1 induced ataxia telangiectasia-mutated (ATM) protein kinase phosphorylation at serine 1981, leading to the activation of DNA damage signaling pathways, including Chk2, histone H2AX, and p53/p21. By ICE assay, the data suggested that NPRL-Z-1 acted on and stabilized the topoisomerase II (TOP2)-DNA complex, leading to TOP2cc formation. NPRL-Z-1-induced DNA damage signaling and apoptotic death was also reversed by TOP2α or TOP2β knockdown. In addition, NPRL-Z-1 inhibited the Akt signaling pathway and induced reactive oxygen species (ROS) generation. These results demonstrated that NPRL-Z-1 appeared to be a novel TOP2 poison and ROS generator. Thus, NPRL-Z-1 may present a significant potential anticancer candidate against renal carcinoma.

  20. Ataxia espinocerebelar tipo 6: relato de caso

    Directory of Open Access Journals (Sweden)

    Bianca Simone Zeigelboim

    2014-10-01

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

  1. 1H MR Spectroscopy in Friedreich's Ataxia and Ataxia with Oculomotor Apraxia Type 2

    Science.gov (United States)

    Iltis, Isabelle; Hutter, Diane; Bushara, Khalaf O.; Clark, H. Brent; Gross, Myron; Eberly, Lynn E.; Gomez, Christopher M.; Öz, Gülin

    2010-01-01

    Background and aim Friedreich's ataxia (FRDA) and ataxia with oculomotor apraxia type 2 (AOA2) are the two most frequent forms of autosomal recessive cerebellar ataxias. However, brain metabolism in these disorders is poorly characterized and biomarkers of the disease progression are lacking. We aimed at assessing the neurochemical profile of the pons, the cerebellar hemisphere and the vermis in patients with FRDA and AOA2 to identify potential biomarkers of these diseases. Methods Short-echo, single voxel proton (1H) magnetic resonance spectroscopy data were acquired from 8 volunteers with FRDA, 9 volunteers with AOA2, and 38 control volunteers at 4T. Disease severity was assessed by the Friedreich's Ataxia Rating Scale (FARS). Results Neuronal loss/dysfunction was indicated in the cerebellar vermis and hemispheres in both diseases by lower total N-acetylaspartate levels than controls. The putative gliosis marker myo-inositol was higher than controls in the vermis and pons in AOA2 and in the vermis in FRDA. Total creatine, another potential gliosis marker, was higher in the cerebellar hemispheres in FRDA relative to controls. Higher glutamine in FRDA and lower glutamate in AOA2 than controls were observed in the vermis, indicating different mechanisms possibly leading to altered glutamatergic neurotransmission. In AOA2, total N-acetylaspartate levels in the cerebellum strongly correlated with the FARS score (p < 0.01). Conclusion Distinct neurochemical patterns were observed in the two patient populations, warranting further studies with larger patient populations to determine if the alterations in metabolite levels observed here may be utilized to monitor disease progression and treatment. PMID:20713024

  2. Ataxia crónica en pediatría

    OpenAIRE

    Ricardo Erazo Torricelli

    2013-01-01

    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 ...

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

    Science.gov (United States)

    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

    2011-10-01

    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, and the genetic heterogeneity often complicate the clinical management of such patients. Despite the steady increase in newly discovered ARCA genes, many patients with a putative ARCA cannot be genotyped yet, proving that more genes must be involved. This review presents an updated overview of the various ARCAs. The clinical and genetic characteristics of those forms with a known molecular genetic defect are discussed, along with the emerging insights in the underlying pathophysiological mechanisms.

  4. Ataxia with vitamin E deficiency associated with deafness.

    Science.gov (United States)

    Kara, Bülent; Uzümcü, Abdullah; Uyguner, Oya; Rosti, Rasim Ozgür; Koçbaş, Ayça; Ozmen, Meral; Kayserili, Hülya

    2008-01-01

    Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive disorder, usually with a phenotype resembling Friedreich ataxia, caused by selective impairment of gastrointestinal vitamin E absorption. Vitamin E supplementation improves symptoms and prevents disease progress. In North Africa and Southern Europe, AVED is as common as Friedreich ataxia. There are no reported cases from Turkey. We herein report a 16-year-old Turkish girl with AVED, who was found to have total deletion of the TTPA gene as well as sensorineural deafness, and we present her follow-up data after vitamin E therapy.

  5. Ataxia crónica en pediatría

    National Research Council Canada - National Science Library

    Ricardo Erazo Torricelli

    2013-01-01

    ... 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...

  6. Ataxia heredo-degenerativa associada a hipoacusia

    Directory of Open Access Journals (Sweden)

    José Antonio Levy

    1964-06-01

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

  7. Epigenetic-based therapies for Friedreich ataxia

    Directory of Open Access Journals (Sweden)

    Chiranjeevi eSandi

    2014-06-01

    Full Text Available Friedreich ataxia (FRDA is a lethal autosomal recessive neurodegenerative disorder caused primarily by a homozygous GAA repeat expansion mutation within the first intron of the FXN gene, leading to inhibition of FXN transcription and thus reduced frataxin protein expression. Recent studies have shown that epigenetic marks, comprising chemical modifications of DNA and histones, are associated with FXN gene silencing. Such epigenetic marks can be reversed, making them suitable targets for epigenetic-based therapy. Furthermore, since FRDA is caused by insufficient, but functional, frataxin protein, epigenetic-based transcriptional re-activation of the FXN gene is an attractive therapeutic option. In this review we summarise our current understanding of the epigenetic basis of FXN gene silencing and we discuss current epigenetic-based FRDA therapeutic strategies.

  8. Activation of Holliday junction recognizing protein involved in the chromosomal stability and immortality of cancer cells.

    Science.gov (United States)

    Kato, Tatsuya; Sato, Nagato; Hayama, Satoshi; Yamabuki, Takumi; Ito, Tomoo; Miyamoto, Masaki; Kondo, Satoshi; Nakamura, Yusuke; Daigo, Yataro

    2007-09-15

    We identified a novel gene HJURP (Holliday junction-recognizing protein) whose activation seemed to play a pivotal role in the immortality of cancer cells. HJURP was considered a possible downstream target for ataxia telangiectasia mutated signaling, and its expression was increased by DNA double-strand breaks (DSB). HJURP was involved in the homologous recombination pathway in the DSB repair process through interaction with hMSH5 and NBS1, which is a part of the MRN protein complex. HJURP formed nuclear foci in cells at S phase and those subjected to DNA damage. In vitro assays implied that HJURP bound directly to the Holliday junction and rDNA arrays. Treatment of cancer cells with small interfering RNA (siRNA) against HJURP caused abnormal chromosomal fusions and led to genomic instability and senescence. In addition, HJURP overexpression was observed in a majority of lung cancers and was associated with poor prognosis as well. We suggest that HJURP is an indispensable factor for chromosomal stability in immortalized cancer cells and is a potential novel therapeutic target for the development of anticancer drugs.

  9. Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest.

    Science.gov (United States)

    Sarin, Navin; Engel, Florian; Kalayda, Ganna V; Mannewitz, Mareike; Cinatl, Jindrich; Rothweiler, Florian; Michaelis, Martin; Saafan, Hisham; Ritter, Christoph A; Jaehde, Ulrich; Frötschl, Roland

    2017-01-01

    The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

  10. Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest.

    Directory of Open Access Journals (Sweden)

    Navin Sarin

    Full Text Available The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2, xeroderma pigmentosum complementation group C (XPC, stress inducible protein (SIP and p21 compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

  11. ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy.

    Science.gov (United States)

    Antonelli, Martina; Strappazzon, Flavie; Arisi, Ivan; Brandi, Rossella; D'Onofrio, Mara; Sambucci, Manolo; Manic, Gwenola; Vitale, Ilio; Barilà, Daniela; Stagni, Venturina

    2017-03-28

    The efficacy of Ataxia-Telangiectasia Mutated (ATM) kinase signalling inhibition in cancer therapy is tempered by the identification of new emerging functions of ATM, which suggests that the role of this protein in cancer progression is complex. We recently demonstrated that this tumor suppressor gene could act as tumor promoting factor in HER2 (Human Epidermal Growth Factor Receptor 2) positive breast cancer. Herein we put in evidence that ATM expression sustains the proportion of cells with a stem-like phenotype, measured as the capability to form mammospheres, independently of HER2 expression levels. Transcriptomic analyses revealed that, in mammospheres, ATM modulates the expression of cell cycle-, DNA repair- and autophagy-related genes. Among these, the silencing of the autophagic gene, autophagy related 4C cysteine peptidase (ATG4C), impairs mammosphere formation similarly to ATM depletion. Conversely, ATG4C ectopic expression in cells silenced for ATM expression, rescues mammospheres growth. Finally, tumor array analyses, performed using public data, identify a significant correlation between ATM and ATG4C expression levels in all human breast cancer subtypes, except for the basal-like one.Overall, we uncover a new connection between ATM kinase and autophagy regulation in breast cancer. We demonstrate that, in breast cancer cells, ATM and ATG4C are essential drivers of mammosphere formation, suggesting that their targeting may improve current approaches to eradicate breast cancer cells with a stem-like phenotype.

  12. Methacryloxylethyl Cetyl Ammonium Chloride Induces DNA Damage and Apoptosis in Human Dental Pulp Cells via Generation of Oxidative Stress.

    Science.gov (United States)

    Jiao, Yang; Ma, Sai; Wang, Yirong; Li, Jing; Shan, Lequn; Sun, Jinlong; Chen, Jihua

    2016-01-01

    The polymerizable antibacterial monomer methacryloxylethyl cetyl ammonium chloride (DMAE-CB) has provided an effective strategy to combat dental caries. However, the application of such material raises the question about the biological safety and the question remains open. The mechanism of this toxic action, however, is not yet clearly understood. The present study aims at providing novel insight into the possible causal link between cellular oxidative stress and DNA damage, as well as apoptosis in human dental pulp cells exposed to DMAE-CB. The enhanced formation of reactive oxygen species and depletion of glutathione, as well as differential changes in activities of superoxide dismutase, glutathione peroxidase, and catalase in DMAE-CB-treated cells indicated oxidative stress. By using substances that can alter GSH synthesis, we found that GSH was the key component in the regulation of cell response towards oxidative stress induced by DMAE-CB. The increase in oxidative stress-sensitive 8-Oxo-2'-deoxyguanosine (8-OHdG) content, formation of γ-H2AX and cell cycle G1 phase arrest indicated that DNA damage occurred as a result of the interaction between DNA base and ROS beyond the capacities of antioxidant mechanisms in cells exposed to DMAE-CB. Such oxidative DNA damage thus triggers the activation of ataxia telangiectasia-mutated (ATM) signaling, the intrinsic apoptotic pathway, and destruction of mitochondrial morphology and function.

  13. Evaluation of ATM heterozygous mutations underlying individual differences in radiosensitivity using genome editing in human cultured cells.

    Science.gov (United States)

    Royba, Ekaterina; Miyamoto, Tatsuo; Natsuko Akutsu, Silvia; Hosoba, Kosuke; Tauchi, Hiroshi; Kudo, Yoshiki; Tashiro, Satoshi; Yamamoto, Takashi; Matsuura, Shinya

    2017-07-20

    Ionizing radiation (IR) induces DNA double-strand breaks (DSBs), which are an initial step towards chromosomal aberrations and cell death. It has been suggested that there are individual differences in radiosensitivity within human populations, and that the variations in DNA repair genes might determine this heterogeneity. However, it is difficult to quantify the effect of genetic variants on the individual differences in radiosensitivity, since confounding factors such as smoking and the diverse genetic backgrounds within human populations affect radiosensitivity. To precisely quantify the effect of a genetic variation on radiosensitivity, we here used the CRISPR-ObLiGaRe (Obligate Ligation-Gated Recombination) method combined with the CRISPR/Cas9 system and a nonhomologous end joining (NHEJ)-mediated knock-in technique in human cultured cells with a uniform genetic background. We generated ATM heterozygous knock-out (ATM +/- ) cell clones as a carrier model of a radiation-hypersensitive autosomal-recessive disorder, ataxia-telangiectasia (A-T). Cytokinesis-blocked micronucleus assay and chromosome aberration assay showed that the radiosensitivity of ATM +/- cell clones was significantly higher than that of ATM +/+ cells, suggesting that ATM gene variants are indeed involved in determining individual radiosensitivity. Importantly, the differences in radiosensitivity among the same genotype clones were small, unlike the individual differences in fibroblasts derived from A-T-affected family members.

  14. Aplicación del drenaje linfático: manual en Telangiectasias

    OpenAIRE

    Tripodi, Melanie

    2015-01-01

    Las telangiectasias son conocidas vulgarmente como arañas vasculares o derrames que simplemente representan un problema estético, estas se hallan dentro del grupo de las enfermedades venosas. Ciertos factores como antecedentes genéticos, alteraciones hormonales, posturas estáticas de bipedestación por largo tiempo predisponen su formación. Objetivo: Determinar la efectividad del tratamiento con drenaje linfático, con respecto a la presoterapia, en el tratamiento de telangiec...

  15. Chromosomal Aberrations in Normal and AT Cells Exposed to High Dose of Low Dose Rate Irradiation

    Science.gov (United States)

    Kawata, T.; Shigematsu, N.; Kawaguchi, O.; Liu, C.; Furusawa, Y.; Hirayama, R.; George, K.; Cucinotta, F.

    2011-01-01

    Ataxia telangiectasia (A-T) is a human autosomally recessive syndrome characterized by cerebellar ataxia, telangiectases, immune dysfunction, and genomic instability, and high rate of cancer incidence. A-T cell lines are abnormally sensitive to agents that induce DNA double strand breaks, including ionizing radiation. The diverse clinical features in individuals affected by A-T and the complex cellular phenotypes are all linked to the functional inactivation of a single gene (AT mutated). It is well known that cells deficient in ATM show increased yields of both simple and complex chromosomal aberrations after high-dose-rate irradiation, but, less is known on how cells respond to low-dose-rate irradiation. It has been shown that AT cells contain a large number of unrejoined breaks after both low-dose-rate irradiation and high-dose-rate irradiation, however sensitivity for chromosomal aberrations at low-dose-rate are less often studied. To study how AT cells respond to low-dose-rate irradiation, we exposed confluent normal and AT fibroblast cells to up to 3 Gy of gamma-irradiation at a dose rate of 0.5 Gy/day and analyzed chromosomal aberrations in G0 using fusion PCC (Premature Chromosomal Condensation) technique. Giemsa staining showed that 1 Gy induces around 0.36 unrejoined fragments per cell in normal cells and around 1.35 fragments in AT cells, whereas 3Gy induces around 0.65 fragments in normal cells and around 3.3 fragments in AT cells. This result indicates that AT cells can rejoin breaks less effectively in G0 phase of the cell cycle? compared to normal cells. We also analyzed chromosomal exchanges in normal and AT cells after exposure to 3 Gy of low-dose-rate rays using a combination of G0 PCC and FISH techniques. Misrejoining was detected in the AT cells only? When cells irradiated with 3 Gy were subcultured and G2 chromosomal aberrations were analyzed using calyculin-A induced PCC technique, the yield of unrejoined breaks decreased in both normal and AT

  16. Seasonal ataxia: A case report of a disappearing disease.

    Science.gov (United States)

    Ayoade Moyo, Adebiyi; Michael Bimbo, Fawale; Morenikeji Adeyoyin, Komolafe; Valentine Nnaemeka, Amadi; Oluwatoyin, Ganiyu; Victor Oladeji, Adeyeye

    2014-09-01

    Seasonal ataxia is a clinical syndrome of acute cerebellar ataxia which follows ingestion of roasted larvae of Anaphe venata Butler, an alternative protein source consumed in western Nigeria. It was first reported in the 1950s in western Nigeria when it caused a wave of epidemics. This is the first case report of this condition in the literature since 1993. We present the case of a 35 year old woman from western Nigeria who was admitted in October 2012 with acute onset of gait instability and bilateral hand tremors, preceded by several episodes of vomiting. She had ingested a meal containing roasted larvae of the African silkworm, 2 hours before the onset of vomiting. Seasonal ataxia is an important differential diagnosis of acute cerebellar ataxia among the indigenous ethnic population of western Nigeria.It is non-fatal and treatable, with complete resolution of symptoms usually following thiamine therapy.

  17. Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination

    DEFF Research Database (Denmark)

    Margolin, David H.; Kousi, Maria; Chan, Yee-Ming

    2013-01-01

    The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive. METHODS We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly...... in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed...... in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis. CONCLUSIONS The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia...

  18. Ataxia with Vitamin E Deficiency May Present with Cervical Dystonia

    Directory of Open Access Journals (Sweden)

    Andrew E. Becker

    2016-05-01

    Full Text Available Background: Ataxia with vitamin E deficiency (AVED is an autosomal recessive disorder that usually presents with ataxia, areflexia, and proprioceptive and vibratory sensory loss. Dystonia has been reported rarely. Case Report: An 11‐year‐old female presented with dystonic head tremor and cervical and bilateral arm dystonia. Her 14‐year‐old older brother had dystonic head tremor and generalized dystonia. One year later, the brother developed dysarthria, limb dysmetria, and gait ataxia. Compound heterozygous mutations in TTPA were detected, confirming the diagnosis of AVED. Discussion: AVED may present with dystonia rather than ataxia, and should be considered in the differential diagnosis of progressive dystonia. 

  19. 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 respect to the disease etiology.

  20. Proteomic Characterization of Cerebrospinal Fluid from Ataxia-Telangiectasia (A-T Patients Using a LC/MS-Based Label-Free Protein Quantification Technology

    Directory of Open Access Journals (Sweden)

    Monika Dzieciatkowska

    2011-01-01

    Full Text Available Cerebrospinal fluid (CSF has been used for biomarker discovery of neurodegenerative diseases in humans since biological changes in the brain can be seen in this biofluid. Inactivation of A-T-mutated protein (ATM, a multifunctional protein kinase, is responsible for A-T, yet biochemical studies have not succeeded in conclusively identifying the molecular mechanism(s underlying the neurodegeneration seen in A-T patients or the proteins that can be used as biomarkers for neurologic assessment of A-T or as potential therapeutic targets. In this study, we applied a high-throughput LC/MS-based label-free protein quantification technology to quantitatively characterize the proteins in CSF samples in order to identify differentially expressed proteins that can serve as potential biomarker candidates for A-T. Among 204 identified CSF proteins with high peptide-identification confidence, thirteen showed significant protein expression changes. Bioinformatic analysis revealed that these 13 proteins are either involved in neurodegenerative disorders or cancer. Future molecular and functional characterization of these proteins would provide more insights into the potential therapeutic targets for the treatment of A-T and the biomarkers that can be used to monitor or predict A-T disease progression. Clinical validation studies are required before any of these proteins can be developed into clinically useful biomarkers.

  1. Fluorescein-guided intraoperative endoscopy in patients with hereditary hemorrhagic telangiectasia: first impressions.

    Science.gov (United States)

    Pagella, Fabio; Pusateri, Alessandro; Zaccari, Dario; Bongetta, Daniele; Zoia, Cesare; Spinozzi, Giuseppe; Olivieri, Carla; Matti, Elina

    2017-03-01

    Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease that results in mucocutaneous telangiectasias and arteriovenous visceral malformations. Nasal telangiectasias lead to recurrent epistaxis, which affects up to 96% of patients. Different morphologic classifications and methods of visualization of nasal lesions have been described in the literature. We developed a new method of intraoperative endoscopy based on the intravenous administration of fluorescein. Preliminary data of this technique are reported. After the intravenous administration of sodium fluorescein, an intraoperative fluorescein-guided endoscopy was carried out using photographic customized yellow filters on top of a 0-degree, 4-mm endoscope. In 2015, 65 HHT patients underwent surgery for their epistaxis in our institution, and in 7 patients (3 males, 4 females; mean age, 54 years) an intraoperative fluorescein-guided intraoperative nasal endoscopy was performed. No adverse events or complications were observed. First impressions regarding the usage of this technique in HHT patients seem to be promising and positive in terms of efficacy and safety. However, further studies with larger cohorts of patients should be performed in order to better investigate the use of this method for diagnostic and surgical purposes in HHT. © 2016 ARS-AAOA, LLC.

  2. EFFECT OF DARK ADAPTATION AND BLEACHING ON BLUE LIGHT REFLECTANCE IMAGING IN MACULAR TELANGIECTASIA TYPE 2.

    Science.gov (United States)

    Okada, Mali; Heeren, Tjebo F C; Egan, Catherine A; Rocco, Vincent; Bonelli, Roberto; Fruttiger, Marcus

    2017-06-26

    In patients with macular telangiectasia Type 2, blue light reflectance imaging reveals an oval, parafoveal area in the macula that has increased reflectance compared with its surrounding. Here, we examine how dark adaptation and photobleaching can affect the blue light reflectance imaging pattern. Prospective study of patients with macular telangiectasia enrolled in the MacTel Natural History Observation Study. After dark adaptation, a sequence of images was obtained with a confocal scanning laser ophthalmoscope at 488 nm. Change of reflectance patterns was analyzed over time. Eighteen eyes from 16 patients were analyzed. Initially, increased reflectivity in the parafoveal area resulted in higher gray values compared with the paramacular surrounding on blue light reflectance imaging. The difference between parafoveal and paramacular reflectance intensity decreased steadily during imaging, from 17.7 gray-value units (95% confidence interval: 12.1-23.2) down to 2.8 (95% confidence interval: -0.8 to 6.5) after around 30 seconds, and recovered after 5 minutes of dark adaptation. A bleaching effect was evident in our study. Understanding these changes is important for both diagnosis and assessment of blue light reflectance phenotype in patients with macular telangiectasia and could also provide further insights into the pathophysiology of this disease.

  3. Host cell reactivation of uv- and X-ray-damaged herpes simplex virus by Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Henderson, E.E. (Temple Univ. School of Medicine, Philadelphia, PA); Long, W.K.

    1981-12-01

    The efficacy of using an infected centers assay, employing herpes simplex virus-infected, Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) as components, to study host cell reactivation has been explored. Herpes simplex virus type 1 (HSV-1) was shown through the infected centers assay to have detectable but varying ability to lytically infect LCLs established from chromosomal breakage syndromes or closely related genetic disorders. The rate of HSV inactivation by ultraviolet (uv) irradiation was faster in LCLs established from Cockaynes's syndrome than in normal LCLs, and faster still in LCLs established from xeroderma pigmentosum. These results indicate that Cockayne's syndrome, while having what appears to be quantitatively normal levels of uv-induced DNA repair replication, shows decreased ability to host cell reactivated uv-damaged HSV. In direct contrast, X-irradiated HSV showed identical survival when assayed on normal LCLs or LCLs established from ataxia telangiectasia showing increased sensitivity to X irradiation as measured by colony formation. Through the infected centers assay, it has also been possible to demonstrate low levels of multiplicity reactivation of mutagen-damaged HSV in permanently proliferating LCLs.

  4. Kv3.3 potassium channels and spinocerebellar ataxia.

    Science.gov (United States)

    Zhang, Yalan; Kaczmarek, Leonard K

    2016-08-15

    The voltage-dependent potassium channel subunit Kv3.3 is expressed at high levels in cerebellar Purkinje cells, in auditory brainstem nuclei and in many other neurons capable of firing at high rates. In the cerebellum, it helps to shape the very characteristic complex spike of Purkinje cells. Kv3.3 differs from other closely related channels in that human mutations in the gene encoding Kv3.3 (KCNC3) result in a unique neurodegenerative disease termed spinocerebellar ataxia type 13 (SCA13). This primarily affects the cerebellum, but also results in extracerebellar symptoms. Different mutations produce either early onset SCA13, associated with delayed motor and impaired cognitive skill acquisition, or late onset SCA13, which typically produces cerebellar degeneration in middle age. This review covers the localization and physiological function of Kv3.3 in the central nervous system and how the normal function of the channel is altered by the disease-causing mutations. It also describes experimental approaches that are being used to understand how Kv3.3 mutations are linked to neuronal survival, and to develop strategies for treatment. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  5. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.

    Science.gov (United States)

    Hoch, Nicolas C; Hanzlikova, Hana; Rulten, Stuart L; Tétreault, Martine; Komulainen, Emilia; Ju, Limei; Hornyak, Peter; Zeng, Zhihong; Gittens, William; Rey, Stephanie A; Staras, Kevin; Mancini, Grazia M S; McKinnon, Peter J; Wang, Zhao-Qi; Wagner, Justin D; Yoon, Grace; Caldecott, Keith W

    2017-01-05

    XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.

  6. Spinocerebellar ataxia 35: novel mutations in TGM6 with clinical and genetic characterization.

    Science.gov (United States)

    Guo, Yuh-Cherng; Lin, Juei-Jueng; Liao, Yi-Chu; Tsai, Pei-Chien; Lee, Yi-Chung; Soong, Bing-Wen

    2014-10-21

    To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type 35 (SCA35), which is caused by mutations in the TGM6 gene encoding transglutaminase 6 (TG6), in a Taiwanese cohort. Mutations in TGM6 were ascertained in 109 unrelated probands of Chinese descent with molecularly unassigned SCA from 512 pedigrees, in whom mutations responsible for 15 other ataxia syndromes had been excluded. The clinical features of all patients with a TGM6 mutation were systematically analyzed. The biological consequences of the newly identified TGM6 mutations were investigated in HEK293 cells transfected with mutant complementary DNA constructs. Two missense mutations (p.R111C and p.D510H) and one 3-base pair deletion (p.E574del) in TGM6 were identified. Among them, p.R111C and p.E574del were novel. The common features of SCA35 include a slowly progressive clinical course, trunk/limb ataxia, and hand tremors. The age at onset varies from adolescence to the fifth decade. Torticollis and intellectual impairment are rare manifestations. Brain MRI reveals diffuse cerebellar atrophy without involvement of the cerebral hemispheres or brainstem. The 3 mutations identified here attenuated the protein stability and catalytic activities of TG6. SCA35 is an uncommon ataxia syndrome, accounting for 0.6% (3/512) of SCAs among the Han-Chinese descent in Taiwan. This study broadens the mutational spectrum of SCA35 and stresses the importance of TG6 in cerebellar functions. © 2014 American Academy of Neurology.

  7. Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia

    OpenAIRE

    Iqbal, Zafar; Rydning, Siri L.; Wedding, Iselin M.; Koht, Jeanette; Pihlstr?m, Lasse; Rengmark, Aina H.; Henriksen, Sandra P.; Tallaksen, Chantal M. E.; Toft, Mathias

    2017-01-01

    Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%)...

  8. Myoclonus epilepsy and ataxia due to KCNC1 mutation

    DEFF Research Database (Denmark)

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

    2017-01-01

    OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. METHODS: We analyzed clinical, electroclinical, and neuroimaging.......5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed...

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

    Directory of Open Access Journals (Sweden)

    Breno José Alencar Pires Barbosa

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

  10. p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Shi-Wei [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Wu, Chun-Ying [Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Wang, Yen-Ting [Department of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan (China); Kao, Jun-Kai [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Pediatrics, Children' s Hospital, Changhua Christian Hospital, Changhua, Taiwan (China); Lin, Chi-Chen; Chang, Chia-Che; Mu, Szu-Wei; Chen, Yu-Yu [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Chiu, Husan-Wen [Institute of Biotechnology, National Cheng-Kung University, Tainan, Taiwan (China); Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan (China); Chang, Chuan-Hsun [Department of Surgical Oncology, Cheng Hsin General Hospital, Taipei, Taiwan (China); Department of Nutrition Therapy, Cheng Hsin General Hospital, Taipei, Taiwan (China); School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan (China); Liang, Shu-Mei [Institute of Biotechnology, National Cheng-Kung University, Tainan, Taiwan (China); Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan (China); Chen, Yi-Ju [Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan (China); Huang, Jau-Ling [Department of Bioscience Technology, Chang Jung Christian University, Tainan, Taiwan (China); Shieh, Jeng-Jer, E-mail: shiehjj@vghtc.gov.tw [Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan (China); Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan (China)

    2013-02-15

    Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell's p53 status. - Highlights: ► Compound C caused more apoptosis in p53 wildtype than p53-mutant skin cancer cells. ► Compound C can upregulate p53 expression and induce p53 activation. ► Compound C induced p53 effects were dependent on ROS induced DNA damage pathway. ► p53-knockdown attenuated compound C-induced apoptosis but not autophagy. ► Compound C-induced apoptosis in skin cancer cells was dependent on p53 status.

  11. Harry Lee Parker and paroxysmal dysarthria and ataxia.

    Science.gov (United States)

    Klaas, James P; Burkholder, David B; Singer, Wolfgang; Boes, Christopher J

    2013-01-15

    To review descriptions of paroxysmal dysarthria and ataxia in multiple sclerosis (MS), with special attention given to Parker and his 1946 case series. Evaluation of original publications describing paroxysmal dysarthria and ataxia, bibliographic information, writings, and unpublished letters from the Mayo Clinic Historical Unit. In 1940, Störring described a patient with MS with paroxysmal symptoms that included dizziness and trouble speaking, but also unilateral extremity weakness. In 1946, Parker published a series of 11 patients with paroxysmal dysarthria and ataxia. Six of these patients had MS, and he recognized this phenomenon as a manifestation of the disease. The term "paroxysmal dysarthria and ataxia" was first used in 1959 by Andermann and colleagues. Since that time, paroxysmal dysarthria and ataxia has become a well-recognized phenomenon in MS. More recent reports have suggested that the responsible lesion is located in the midbrain, near or involving the red nucleus. Parker was the first to accurately describe paroxysmal dysarthria and ataxia in patients with MS.

  12. Early-Onset Friedreich's Ataxia With Oculomotor Apraxia

    Directory of Open Access Journals (Sweden)

    Amene Saghazadeh

    2017-02-01

    Full Text Available Friedreich’s ataxia (FRDA is a rare autosomal recessive spinocerebellar ataxia which in the majority of cases is associated with a GAA-trinucleotide repeat expansion in the first intron of Frataxin gene located on chromosome 9. The clinical features include progressive gait and limb ataxia, cerebellar dysarthria, neuropathy, optic atrophy, and loss of vibration and proprioception. Ataxia with ocular motor apraxia type 1 (AOA1 is another autosomal recessive cerebellar ataxia which is associated with oculomotor apraxia, hypoalbuminaemia, and hypercholesterolemia. Here we describe two siblings (13- and 10-year-old display overlapping clinical features of both early-onset FRDA and AOA1. Almost all of laboratory test (including urinary analysis/culture, biochemistry, peripheral blood smear, C-reactive protein level, erythrocyte sedimentation rate-1h results were within the normal range for both patients. Due to the normal laboratory test results; we concluded that the diagnosis was more likely to be FRDA than AOA1. Therefore, neurologists should bear in mind that clinical presentations of FRDA may vary widely from the classical phenotype of gait and limb ataxia to atypical manifestations such as oculomotor apraxia.

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

    Science.gov (United States)

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

    2014-10-28

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

  14. Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells.

    Science.gov (United States)

    Rass, Emilie; Grabarz, Anastazja; Plo, Isabelle; Gautier, Jean; Bertrand, Pascale; Lopez, Bernard S

    2009-08-01

    Here we have used an intrachromosomal substrate to monitor the end joining of distant ends, which leads to DNA rearrangements in mammalian cells. We show that silencing Mre11 reduces the efficiency of nonhomologous end joining (NHEJ), affecting both the canonical and alternative pathways, partly in a manner that is independent of the ataxia-telangiectasia mutated kinase (ATM). Silencing of Rad50 or CtIP decreases end-joining efficiency in the same pathway as Mre11. In cells defective for Xrcc4, the MRE11-RAD50-NBS1 (MRN) complex inhibitor MIRIN decreases end-joining frequencies, demonstrating a role for MRN in alternative NHEJ. Consistently, MIRIN sensitizes both complemented and NHEJ-defective cells to ionizing radiation. Conversely, overexpression of Mre11 stimulates the resection of single-stranded DNA and increases alternative end joining, through a mechanism that requires Mre11's nuclease activity, but in an ATM-independent manner. These data demonstrate that, in addition to its role in ATM activation, Mre11 can favor alternative NHEJ through its nuclease activity.

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

    Directory of Open Access Journals (Sweden)

    Jinyoung Youn

    2012-05-01

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

  16. Identification of signaling pathways mediating cell cycle arrest and apoptosis induced by Porphyromonas gingivalis in human trophoblasts.

    Science.gov (United States)

    Inaba, Hiroaki; Kuboniwa, Masae; Sugita, Hideyuki; Lamont, Richard J; Amano, Atsuo

    2012-08-01

    Epidemiological and interventional studies of humans have revealed a close association between periodontal diseases and preterm delivery of low-birth-weight infants. Porphyromonas gingivalis, a periodontal pathogen, can translocate to gestational tissues following oral-hematogenous spread. We previously reported that P. gingivalis invades extravillous trophoblast cells (HTR-8) derived from the human placenta and inhibits proliferation through induction of arrest in the G(1) phase of the cell cycle. The purpose of the present study was to identify signaling pathways mediating cellular impairment caused by P. gingivalis. Following P. gingivalis infection, the expression of Fas was induced and p53 accumulated, responses consistent with response to DNA damage. Ataxia telangiectasia- and Rad3-related kinase (ATR), an essential regulator of DNA damage checkpoints, was shown to be activated together with its downstream signaling molecule Chk2, while the p53 degradation-related protein MDM2 was not induced. The inhibition of ATR prevented both G(1) arrest and apoptosis caused by P. gingivalis in HTR-8 cells. In addition, small interfering RNA (siRNA) knockdown of p53 abrogated both G(1) arrest and apoptosis. The regulation of apoptosis was associated with Ets1 activation. HTR-8 cells infected with P. gingivalis exhibited activation of Ets1, and knockdown of Ets1 with siRNA diminished both G(1) arrest and apoptosis. These results suggest that P. gingivalis activates cellular DNA damage signaling pathways that lead to G(1) arrest and apoptosis in trophoblasts.

  17. Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiang-Yuan; Wang, Zhen [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Li, Bei [Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zhang, Ying-Jian, E-mail: yjzhang111@aliyun.com [Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Li, Ying-Yi, E-mail: liyingyi@fudan.edu.cn [Cancer Research Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China)

    2016-04-22

    Resistance of cancer cells to chemoradiotherapy is a major clinical problem in pancreatic cancer treatment. Therefore, understanding the molecular basis of cellular resistance and identifying novel targets are essential for improving treatment efficacy for pancreatic cancer patients. Previous studies have demonstrated a significant role for Pim-3 in pancreatic cancer survival against gemcitabine-induced genotoxic stress. Here, we observed that radiation treatment enhanced Pim-3 expression in human pancreatic cancer cells in vitro. Stable overexpression of Pim-3 in pancreatic cancer cells significantly protected cells against radiation treatment by attenuating G2/M phase cell cycle arrest and DNA damage response. Silencing of Pim-3 expression significantly elevated the phosphorylation of histone variant H2AX, a marker of DNA double strand breaks, and decreased the activation of ataxia-telangiectasia-mutated (ATM) kinase, along with its downstream targets, eventually enhancing the radiosensitivity of human pancreatic cancer cells in vitro and in vivo. Hence, we demonstrated a novel function for Pim-3 in human pancreatic cancer cell survival against radiation. Targeting Pim-3 may be a promising way to improve treatment efficacy in combination with radiotherapy in human pancreatic cancer. - Highlights: • This is first study to demonstrate that Pim-3 is endogenously induced by ionizing radiation in pancreatic cancer cells, and Pim-3 overexpression enhanced radioresistance of pancreatic cancer cells both in vitro and in vivo. • This is first study to provide evidence that radioresistance induced by Pim-3 is mainly attributed to Pim-3 induces activation of ATM, which subsequently activates checkpoint 1, leading to amplification of DNA repair through cell cycle arrest and DNA repair pathways. • This is first study to indicate that targeting Pim-3 may be a promising strategy to provide better treatment efficacy in combination with radiotherapy in human pancreatic

  18. Piperine causes G1 phase cell cycle arrest and apoptosis in melanoma cells through checkpoint kinase-1 activation.

    Directory of Open Access Journals (Sweden)

    Neel M Fofaria

    Full Text Available In this study, we determined the cytotoxic effects of piperine, a major constituent of black and long pepper in melanoma cells. Piperine treatment inhibited the growth of SK MEL 28 and B16 F0 cells in a dose and time-dependent manner. The growth inhibitory effects of piperine were mediated by cell cycle arrest of both the cell lines in G1 phase. The G1 arrest by piperine correlated with the down-regulation of cyclin D1 and induction of p21. Furthermore, this growth arrest by piperine treatment was associated with DNA damage as indicated by phosphorylation of H2AX at Ser139, activation of ataxia telangiectasia and rad3-related protein (ATR and checkpoint kinase 1 (Chk1. Pretreatment with AZD 7762, a Chk1 inhibitor not only abrogated the activation of Chk1 but also piperine mediated G1 arrest. Similarly, transfection of cells with Chk1 siRNA completely protected the cells from G1 arrest induced by piperine. Piperine treatment caused down-regulation of E2F1 and phosphorylation of retinoblastoma protein (Rb. Apoptosis induced by piperine was associated with down-regulation of XIAP, Bid (full length and cleavage of Caspase-3 and PARP. Furthermore, our results showed that piperine treatment generated ROS in melanoma cells. Blocking ROS by tiron protected the cells from piperine mediated cell cycle arrest and apoptosis. These results suggest that piperine mediated ROS played a critical role in inducing DNA damage and activation of Chk1 leading to G1 cell cycle arrest and apoptosis.

  19. Piperine causes G1 phase cell cycle arrest and apoptosis in melanoma cells through checkpoint kinase-1 activation.

    Science.gov (United States)

    Fofaria, Neel M; Kim, Sung-Hoon; Srivastava, Sanjay K

    2014-01-01

    In this study, we determined the cytotoxic effects of piperine, a major constituent of black and long pepper in melanoma cells. Piperine treatment inhibited the growth of SK MEL 28 and B16 F0 cells in a dose and time-dependent manner. The growth inhibitory effects of piperine were mediated by cell cycle arrest of both the cell lines in G1 phase. The G1 arrest by piperine correlated with the down-regulation of cyclin D1 and induction of p21. Furthermore, this growth arrest by piperine treatment was associated with DNA damage as indicated by phosphorylation of H2AX at Ser139, activation of ataxia telangiectasia and rad3-related protein (ATR) and checkpoint kinase 1 (Chk1). Pretreatment with AZD 7762, a Chk1 inhibitor not only abrogated the activation of Chk1 but also piperine mediated G1 arrest. Similarly, transfection of cells with Chk1 siRNA completely protected the cells from G1 arrest induced by piperine. Piperine treatment caused down-regulation of E2F1 and phosphorylation of retinoblastoma protein (Rb). Apoptosis induced by piperine was associated with down-regulation of XIAP, Bid (full length) and cleavage of Caspase-3 and PARP. Furthermore, our results showed that piperine treatment generated ROS in melanoma cells. Blocking ROS by tiron protected the cells from piperine mediated cell cycle arrest and apoptosis. These results suggest that piperine mediated ROS played a critical role in inducing DNA damage and activation of Chk1 leading to G1 cell cycle arrest and apoptosis.

  20. ATM/ATR-related checkpoint signals mediate arsenite-induced G{sub 2}/M arrest in primary aortic endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Tsou, Tsui-Chun; Tsai, Feng-Yuan; Yeh, Szu-Ching; Chang, Louis W. [National Health Research Institutes, Division of Environmental Health and Occupational Medicine, Miaoli County (Taiwan)

    2006-12-15

    Epidemiological studies have demonstrated a high association of inorganic arsenic exposure with vascular disease. Our recent in vitro studies have linked this vascular damage to vascular endothelial dysfunction induced by arsenic exposure. However, cell-cycle arrest induced by arsenic and its involvement in vascular dysfunction remain to be clarified. In this study, we employed primary porcine aortic endothelial cells to investigate regulatory mechanisms of G{sub 2}/M phase arrest induced by arsenite. Our study revealed that lower concentrations of arsenite (1 and 3 {mu}M) increased cell proliferation, whereas higher concentrations of arsenite (10, 20, and 30 {mu}M) inhibited cell proliferation together with correlated increases in G{sub 2}/M phase arrest. We found that this arsenite-induced G{sub 2}/M phase arrest was accompanied by accumulation and/or phosphorylation of checkpoint-related molecules, including p53, Cdc25B, Cdc25C, and securin. Inhibition of activations of these checkpoint-related molecules by caffeine significantly attenuated the 30-{mu}M arsenite-induced G{sub 2}/M phase arrest by 93%. Our data suggest that the DNA damage responsive kinases ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related) play critical roles in arsenite-induced G{sub 2}/M phase arrest in aortic endothelial cells possibly via regulation of checkpoint-related signaling molecules including p53, Cdc25B, Cdc25C, and securin. (orig.)

  1. Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One-Step Strategy to Overcome Stem Cell-Based Gene Therapy Limitations

    Directory of Open Access Journals (Sweden)

    Seo-Young Lee

    2016-01-01

    Full Text Available The recent advent of induced pluripotent stem cells (iPSCs and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. In addition, as genetic etiology of Parkinson’s disease, it has been well known that induced neural stem cells (iNSCs were progressively depleted by LRRK2 gene mutation, LRRK2 (G2019S. Thus, to maintain the induced NSCs directly derived from PD patient cells harboring LRRK2 (G2019S, it would be ideal to simultaneously treat the LRRK2 (G2019S fibroblast during the process of TD. Therefore, simultaneous reprogramming (or TD and gene therapy would provide the solution for therapeutic limitation caused by vulnerability of reprogramming or TD, in addition to being suitable for general application to the generation of autologous cell-therapy products for patients with genetic defects, thereby obviating the need for the arduous processes currently required.

  2. Radioprotection and Cell Cycle Arrest of Intestinal Epithelial Cells by Darinaparsin, a Tumor Radiosensitizer

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Junqiang; Doi, Hiroshi [Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, California (United States); Saar, Matthias; Santos, Jennifer [Department of Urology, School of Medicine, Stanford University, Stanford, California (United States); Li, Xuejun; Peehl, Donna M. [Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, California (United States); Knox, Susan J., E-mail: sknox@stanford.edu [Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, California (United States)

    2013-12-01

    Purpose: It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs. Methods and Materials: The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry. Results: In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest. Conclusions: DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy.

  3. Radioprotection and cell cycle arrest of intestinal epithelial cells by darinaparsin, a tumor radiosensitizer.

    Science.gov (United States)

    Tian, Junqiang; Doi, Hiroshi; Saar, Matthias; Santos, Jennifer; Li, Xuejun; Peehl, Donna M; Knox, Susan J

    2013-12-01

    It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs. The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry. In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest. DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Acquired progressive ataxia and palatal tremor: importance of MRI evidence of hemosiderin deposition and vascular malformations.

    Science.gov (United States)

    Kumar, Neeraj; Eggers, Scott D Z; Milone, Margherita; Keegan, B Mark

    2011-08-01

    Oculopalatal tremor is frequently accompanied by progressive ataxia. In symptomatic oculopalatal tremor the ataxia frequently is delayed in onset. Progressive ataxia is a defining clinical feature of superficial siderosis. We report 5 cases with palatal tremor and ataxia. Four cases had evidence of intraparenchymal hemosiderin deposition on T2-gradient-echo imaging. Three cases had a brainstem vascular malformation. In two cases the hemosiderin deposition was likely due to prior trauma. The significance of these associations and possible similarities between ataxia related to superficial siderosis and ataxia and intraparenchymal hemosiderin is discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

    DEFF Research Database (Denmark)

    Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten

    2013-01-01

    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective...

  6. Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Castro, Hoanna; Kul, Emre; Buijsen, Ronald A M; Severijnen, Lies-Anne W F M; Willemsen, Rob; Hukema, Renate K; Stork, Oliver; Santos, Mónica

    2017-06-01

    A CGG-repeat expansion in the premutation range in the Fragile X mental retardation 1 gene (FMR1) has been identified as the genetic cause of Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that manifests with action tremor, gait ataxia and cognitive impairments. In this study, we used a bigenic mouse model, in which expression of a 90CGG premutation tract is activated in neural cells upon doxycycline administration-P90CGG mouse model. We, here, demonstrate the behavioural manifestation of clinically relevant features of FXTAS patients and premutation carrier individuals in this inducible mouse model. P90CGG mice display heightened anxiety, deficits in motor coordination and impaired gait and represent the first FXTAS model that exhibits an ataxia phenotype as observed in patients. The behavioural phenotype is accompanied by the formation of ubiquitin/FMRpolyglycine-positive intranuclear inclusions, as another hallmark of FXTAS, in the cerebellum, hippocampus and amygdala. Strikingly, upon cessation of transgene induction the anxiety phenotype of mice recovers along with a reduction of intranuclear inclusions in dentate gyrus and amygdala. In contrast, motor function deteriorates further and no reduction in intranuclear inclusions can be observed in the cerebellum. Our data thus demonstrate that expression of a 90CGG premutation expansion outside of the FMR1 context is sufficient to evoke an FXTAS-like behavioural phenotype. Brain region-specific neuropathology and (partial) behavioural reversibility make the inducible P90CGG a valuable mouse model for testing pathogenic mechanisms and therapeutic intervention methods. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2.

    Science.gov (United States)

    Park, Sung O; Lee, Young Jae; Seki, Tsugio; Hong, Kwon-Ho; Fliess, Naime; Jiang, Zhigang; Park, Alice; Wu, Xiaofang; Kaartinen, Vesa; Roman, Beth L; Oh, S Paul

    2008-01-15

    ALK1 belongs to the type I receptor family for transforming growth factor-beta family ligands. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia type 2 (HHT2), a multisystemic vascular disorder. Based largely on in vitro studies, TGF-beta1 has been considered as the most likely ALK1 ligand related to HHT, yet the identity of the physiologic ALK1 ligand remains controversial. In cultured endothelial cells, ALK1 and another TGF-beta type I receptor, ALK5, regulate angiogenesis by controlling TGF-beta signal transduction, and ALK5 is required for ALK1 signaling. However, the extent to which such interactions between these 2 receptors play a role in pathogenesis of HHT is unknown. We directly addressed these issues in vivo by comparing the phenotypes of mice in which the Alk1, Alk5, or Tgfbr2 gene was conditionally deleted in restricted vascular endothelia using a novel endothelial Cre transgenic line. Alk1-conditional deletion resulted in severe vascular malformations mimicking all pathologic features of HHT. Yet Alk5- or Tgfbr2-conditional deletion in mice, or Alk5 inhibition in zebrafish, did not affect vessel morphogenesis. These data indicate that neither ALK5 nor TGFBR2 is required for ALK1 signaling pertinent to the pathogenesis of HHT and suggest that HHT might not be a TGF-beta subfamily disease.

  8. Excision of Expanded GAA Repeats Alleviates the Molecular Phenotype of Friedreich's Ataxia.

    Science.gov (United States)

    Li, Yanjie; Polak, Urszula; Bhalla, Angela D; Rozwadowska, Natalia; Butler, Jill Sergesketter; Lynch, David R; Dent, Sharon Y R; Napierala, Marek

    2015-06-01

    Friedreich's ataxia (FRDA) is an autosomal recessive neurological disease caused by expansions of guanine-adenine-adenine (GAA) repeats in intron 1 of the frataxin (FXN) gene. The expansion results in significantly decreased frataxin expression. We report that human FRDA cells can be corrected by zinc finger nuclease-mediated excision of the expanded GAA repeats. Editing of a single expanded GAA allele created heterozygous, FRDA carrier-like cells and significantly increased frataxin expression. This correction persisted during reprogramming of zinc finger nuclease-edited fibroblasts to induced pluripotent stem cells and subsequent differentiation into neurons. The expression of FRDA biomarkers was normalized in corrected patient cells and disease-associated phenotypes, such as decreases in aconitase activity and intracellular ATP levels, were reversed in zinc finger nuclease corrected neuronal cells. Genetically and phenotypically corrected patient cells represent not only a preferred disease-relevant model system to study pathogenic mechanisms, but also a critical step towards development of cell replacement therapy.

  9. Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

    Science.gov (United States)

    Perkins, Emma; Suminaite, Daumante

    2016-01-01

    Abstract Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar degeneration. Animal and in vitro models have revealed β‐III spectrin, a cytoskeletal protein present throughout the soma and dendritic tree of cerebellar Purkinje cells, to be required for the maintenance of dendritic architecture and for the trafficking and/or stabilisation of several membrane proteins: ankyrin‐R, cell adhesion molecules, metabotropic glutamate receptor‐1 (mGluR1), voltage‐gated sodium channels (Nav) and glutamate transporters. This scaffold of interactions connects β‐III spectrin to a wide variety of proteins implicated in the pathology of many SCAs. Heterozygous mutations in the gene encoding β‐III spectrin (SPTBN2) underlie SCA type‐5 whereas homozygous mutations cause spectrin associated autosomal recessive ataxia type‐1 (SPARCA1), an infantile form of ataxia with cognitive impairment. Loss‐of β‐III spectrin function appears to underpin cerebellar dysfunction and degeneration in both diseases resulting in thinner dendrites, excessive dendritic protrusion with loss of planarity, reduced resurgent sodium currents and abnormal glutamatergic neurotransmission. The initial physiological consequences are a decrease in spontaneous activity and excessive excitation, likely to be offsetting each other, but eventually hyperexcitability gives rise to dark cell degeneration and reduced cerebellar output. Similar molecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting alterations to intrinsic Purkinje cell activity, dendritic architecture and glutamatergic transmission as possible common mechanisms downstream of various loss‐of‐function primary genetic defects. A key question for future research is whether similar mechanisms underlie progressive cerebellar decline in normal ageing. PMID:26821241

  10. Responses to and Outcomes of Treatment of Autoimmune Cerebellar Ataxia in Adults.

    Science.gov (United States)

    Jones, Amy L; Flanagan, Eoin P; Pittock, Sean J; Mandrekar, Jay N; Eggers, Scott D; Ahlskog, J Eric; McKeon, Andrew

    2015-11-01

    Classic Purkinje cell cytoplasmic antibody type 1 (PCA-1, or anti-Yo) paraneoplastic cerebellar ataxia has a poor prognosis, yet little has been published otherwise regarding treatment responses and outcomes among patients with autoimmune cerebellar ataxia. To investigate treatment responses and outcomes in adults with autoimmune cerebellar ataxia. A cohort study conducted at Mayo Clinic, Rochester, Minnesota, included 118 patients who had ataxia, were 18 years or older, were seropositive for at least 1 neural autoantibody, had received at least 1 immunotherapy or cancer therapy, and had neurologist-reported outcomes documented from January 1, 1989, through December 31, 2013. Data were collected from May 14, 2013, through August 9, 2014, and analyzed from August 9, 2014, through April 27, 2015. Responses to immunotherapy (corticosteroids, intravenous immunoglobulin, plasma exchange, and immunosuppressants) and ambulatory outcomes were compared between different subgroups. Subgroups were classified as paraneoplastic vs nonparaneoplastic disorders; neuronal nuclear and/or cytoplasmic (NNC) antibody positivity vs plasma membrane protein (PMP) antibody positivity; and glutamic acid decarboxylase 65-kDa isoform (GAD65) antibody positivity vs PMP antibody positivity. Response to therapy and ambulatory ability, with univariate logistic regression and Kaplan-Meier analyses. Inclusion criteria were met by 118 patients. Median age at onset of neurologic symptoms was 58 (range, 27-83) years, and 87 patients (73.7%) were women. Median duration from symptom onset to last follow-up was 25 (range, 2-223) months. Sixty-three patients had paraneoplastic and 55 patients had nonparaneoplastic ataxic disorders. Eighty-one patients were seropositive for NNC antibodies (most commonly PCA-1 [anti-Yo], antineuronal nuclear antibody type 1 [anti-Hu], and GAD65 antibody); 22 patients, for neural PMP receptor or ion channel antibodies (most commonly targeting P/Q- or N-type voltage

  11. Activation of eNOS in endothelial cells exposed to ionizing radiation involves components of the DNA damage response pathway

    Energy Technology Data Exchange (ETDEWEB)

    Nagane, Masaki; Yasui, Hironobu; Sakai, Yuri; Yamamori, Tohru [Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818 (Japan); Niwa, Koichi [Laboratory of Biochemistry, Department of Food and Cosmetic Science, Faculty of Bioindustry, Tokyo University of Agriculture, Abashiri 099-2493 (Japan); Hattori, Yuichi [Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 (Japan); Kondo, Takashi [Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194 (Japan); Inanami, Osamu, E-mail: inanami@vetmed.hokudai.ac.jp [Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818 (Japan)

    2015-01-02

    Highlights: • eNOS activity is increased in BAECs exposed to X-rays. • ATM is involved in this increased eNOS activity. • HSP90 modulates the radiation-induced activation of ATM and eNOS. - Abstract: In this study, the involvement of ataxia telangiectasia mutated (ATM) kinase and heat shock protein 90 (HSP90) in endothelial nitric oxide synthase (eNOS) activation was investigated in X-irradiated bovine aortic endothelial cells. The activity of nitric oxide synthase (NOS) and the phosphorylation of serine 1179 of eNOS (eNOS-Ser1179) were significantly increased in irradiated cells. The radiation-induced increases in NOS activity and eNOS-Ser1179 phosphorylation levels were significantly reduced by treatment with either an ATM inhibitor (Ku-60019) or an HSP90 inhibitor (geldanamycin). Geldanamycin was furthermore found to suppress the radiation-induced phosphorylation of ATM-Ser1181. Our results indicate that the radiation-induced eNOS activation in bovine aortic endothelial cells is regulated by ATM and HSP90.

  12. Nature and role of high sister chromatid exchanges in Bloom syndrome cells. Some cytogenetic and immunological aspects.

    Science.gov (United States)

    Shiraishi, Y

    1990-12-01

    The phenomenon of sister chromatid exchange (SCE) is an interesting genetic event in metaphase chromosomes, even though its exact mechanism remains unknown. The fact that SCE can take place, whether "spontaneously" or induced by various agents, is in itself important, for such an event, involving damage and possible repair of bilateral loci in chromosomes, presents opportunities for modification of the chromosomal structure and/or function (e.g., oncogene activation). It has been assumed that under "normal" circumstances, SCE does not lead to any change in the functional genome, although this may not apply to abnormal conditions. The latter may be produced by a number of chemical agents (including various carcinogens) that lead to a significantly increased incidence of SCE in normal and malignant cells either in vitro or in vivo. In fact, SCE has been recognized and advocated as a most sensitive test for potentially mutagenic and/or carcinogenic agents. Thus, the broad field of SCE studies becomes of direct interest for and subject to exploration by those involved with cancer causation and biology. In this review, a synopsis of our experiences with high SCE mechanisms in Bloom syndrome cell lines will be presented, in connection with high SCE mutant cell line derived from ataxia telangiectasia (AT) and/or malignant transformation.

  13. Modulation of proteostasis counteracts oxidative stress and affects DNA base excision repair capacity in ATM-deficient cells.

    Science.gov (United States)

    Poletto, Mattia; Yang, Di; Fletcher, Sally C; Vendrell, Iolanda; Fischer, Roman; Legrand, Arnaud J; Dianov, Grigory L

    2017-09-29

    Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

    National Research Council Canada - National Science Library

    Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten; Skovby, Flemming; Hjermind, Lena E; Nielsen, Jørgen E; Nielsen, Troels Tolstrup

    2013-01-01

    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms...

  15. Host cell reactivation by fibroblasts from patients with pigmentary degeneration of the retina

    Energy Technology Data Exchange (ETDEWEB)

    Lytle, C.D. (Food and Drug Administration, Rockville, MD (USA)); Tarone, R.E.; Barrett, S.F.; Robbins, J.H. (National Cancer Inst., Bethesda, MD (USA)); Wirtschafter, J.D. (Minnesota Univ., Minneapolis (USA). Hospitals); Dupuy, J.M. (Quebec Univ., Laval-des-Rapides (Canada). Inst. Armand-Frappier)

    1983-05-01

    Cockayne syndrome (CS) is an autosomal recessive disease characterized by numerous clinical abnormalities including acute sun sensitivity and primary pigmentary degeneration of the retina. Cultured fibroblasts from CS patients are hypersensitive to ultraviolet radiation. Host cell reactivation of irradiated virus was studied in CS and in other diseases with retinal degeneration to evaluate repair. The survival of UV-irradiated Herpes simplex virus type 1 was determined in fibroblast lines from four normal donors, two patients with CS, one with both xeroderma pigmentosum (XP) and CS, and from several other patients with (Usher syndrome, olivopontocerebellar atrophy, retinitis pigmentosa) and without (XP, ataxia telangiectasia) primary pigmentary degeneration of the retina. The viral survival curves in all cell lines showed two components: a very sensitive initial component followed by an exponential, less sensitive component. The exponential component had greater sensitivity than normal in the case of the CS patients, the patient with both XP and CS, and the XP patient. It was proposed that patients with CS have defective repair of DNA which may be the cause of their retinal degeneration.

  16. ATM facilitates mouse gammaherpesvirus reactivation from myeloid cells during chronic infection.

    Science.gov (United States)

    Kulinski, Joseph M; Darrah, Eric J; Broniowska, Katarzyna A; Mboko, Wadzanai P; Mounce, Bryan C; Malherbe, Laurent P; Corbett, John A; Gauld, Stephen B; Tarakanova, Vera L

    2015-09-01

    Gammaherpesviruses are cancer-associated pathogens that establish life-long infection in most adults. Insufficiency of Ataxia-Telangiectasia mutated (ATM) kinase leads to a poor control of chronic gammaherpesvirus infection via an unknown mechanism that likely involves a suboptimal antiviral response. In contrast to the phenotype in the intact host, ATM facilitates gammaherpesvirus reactivation and replication in vitro. We hypothesized that ATM mediates both pro- and antiviral activities to regulate chronic gammaherpesvirus infection in an immunocompetent host. To test the proposed proviral activity of ATM in vivo, we generated mice with ATM deficiency limited to myeloid cells. Myeloid-specific ATM deficiency attenuated gammaherpesvirus infection during the establishment of viral latency. The results of our study uncover a proviral role of ATM in the context of gammaherpesvirus infection in vivo and support a model where ATM combines pro- and antiviral functions to facilitate both gammaherpesvirus-specific T cell immune response and viral reactivation in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Spinocerebellar ataxia types 1, 2, 3 and 6: the clinical spectrum of ataxia and morphometric brainstem and cerebellar findings.

    Science.gov (United States)

    Jacobi, Heike; Hauser, Till-Karsten; Giunti, Paola; Globas, Christoph; Bauer, Peter; Schmitz-Hübsch, Tanja; Baliko, László; Filla, Alessandro; Mariotti, Caterina; Rakowicz, Maria; Charles, Perine; Ribai, Pascale; Szymanski, Sandra; Infante, Jon; van de Warrenburg, Bart P C; Dürr, Alexandra; Timmann, Dagmar; Boesch, Sylvia; Fancellu, Roberto; Rola, Rafal; Depondt, Chantal; Schöls, Ludger; Zdzienicka, Elzbieta; Kang, Jun-Suk; Ratzka, Susanne; Kremer, Berry; Stephenson, Dennis A; Melegh, Béla; Pandolfo, Massimo; Tezenas du Montcel, Sophie; Borkert, Johannes; Schulz, Jörg B; Klockgether, Thomas

    2012-03-01

    To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1-3), speech (item 4) and the limb kinetic subscore (items 5-8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose-finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

  18. Vascular Risk Factors and Clinical Progression in Spinocerebellar Ataxias

    Directory of Open Access Journals (Sweden)

    Raymond Y. Lo

    2015-02-01

    Full Text Available Background: The contributions of vascular risk factors to spinocerebellar ataxia (SCA are not known.Methods: We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account.Results: Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. Discussion: Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression.

  19. Low-titer anti-GAD-antibody-positive cerebellar ataxia.

    Science.gov (United States)

    Nanri, Kazunori; Niwa, Hisayoshi; Mitoma, Hiroshi; Takei, Asako; Ikeda, Junko; Harada, Toshihide; Okita, Mitsunori; Takeguchi, Masafumi; Taguchi, Takeshi; Mizusawa, Hidehiro

    2013-04-01

    The majority of cases of anti-glutamic acid decarboxylase (GAD)-antibody-positive cerebellar ataxia are reported to have high levels of anti-GAD antibody, and the diagnostic value of low titers of anti-GAD antibody in a patient with cerebellar ataxia is still unknown. The purpose of this study was to verify the characteristics of low-titer-anti-GAD-antibody-positive cerebellar ataxia patients and the diagnostic value of low titers of anti-GAD antibody in patients with cerebellar ataxia. The subjects were six patients positive for low-titer GAD antibody (cerebellar atrophy. The GAD antibody index in three of the five patients reviewed was >1.0. Two of the six patients were thyroid antibody-positive, and one was both antinuclear- and anti-SS-A antibody-positive. After the administration of immunotherapy to three patients, two showed clear effectiveness, and one, transient effectiveness. Effectiveness was greatest in the two patients with familial occurrence of the disease. In cerebellar ataxia, regardless of family history or isolated illness, it is critical to measure the GAD antibody level, and, even with a low titer level, if the result is positive, immunotherapy should be considered.

  20. Clinical and genetic abnormalities in patients with Friedreich's ataxia.

    Science.gov (United States)

    Dürr, A; Cossee, M; Agid, Y; Campuzano, V; Mignard, C; Penet, C; Mandel, J L; Brice, A; Koenig, M

    1996-10-17

    Friedreich's ataxia, the most common inherited ataxia, is associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9, which encodes a protein of unknown function. We studied 187 patients with autosomal recessive ataxia, determined the size of the GAA expansions, and analyzed the clinical manifestations in relation to the number of GAA repeats and the duration of disease. One hundred forty of the 187 patients, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1700 repeats of the trinucleotides. About one quarter of the patients, despite being homozygous, had atypical Friedreich's ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair) was associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs. The GAA repeats were unstable during transmission. The clinical spectrum of Friedreich's ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion on chromosome 9 is useful for diagnosis, determination of prognosis, and genetic counseling.

  1. A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability.

    Science.gov (United States)

    Kawarai, Toshitaka; Tajima, Atsushi; Kuroda, Yukiko; Saji, Naoki; Orlacchio, Antonio; Terasawa, Hideo; Shimizu, Hirotaka; Kita, Yasushi; Izumi, Yuishin; Mitsui, Takao; Imoto, Issei; Kaji, Ryuji

    2016-06-01

    Hereditary cerebellar ataxia constitutes a heterogeneous group of neurodegenerative disorders, occasionally accompanied by other neurological features. Genetic defects remain to be elucidated in approximately 40% of hereditary cerebellar ataxia cases in Japan. We attempted to identify the gene responsible for autosomal recessive cerebellar ataxia with intellectual disability. The present study involved three patients in a consanguineous Japanese family. Neurological examination and gene analyses were performed in all family members. We performed genome-wide linkage analysis including single nucleotide polymorphism arrays, copy-number variation analysis and whole exome sequencing. To clarify the functional alteration resulting from the identified mutation, we performed cell viability assay of cultured cells expressing mutant protein. One homozygous region shared among the three patients on chromosomes 2p16.1-2q12.3 was identified. Using whole exome sequencing, six homozygous variants in genes in the region were detected. Only one variant, VWA3B c.A1865C, results in a change of a highly conserved amino acid (p.K622T) and was not present in control samples. VWA3B encodes a von Willebrand Factor A Domain-Containing Protein 3B with ubiquitous expression, including the cerebellum. The viability of cultured cells expressing the specific K622T mutation was proved to decrease through the activation of apoptotic pathway. Mutated VWA3B was found to be likely associated with cerebellar degeneration with intellectual disability. Although a rare cause of cerebellar degeneration, these findings indicate a critical role for VWA3B in the apoptosis pathway in neuronal tissues. 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/

  2. Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia.

    Science.gov (United States)

    Morral, Jennifer A; Davis, Ashley N; Qian, Jiang; Gelman, Benjamin B; Koeppen, Arnulf H

    2010-07-01

    Friedreich's ataxia (FRDA) causes a complex neuropathological phenotype with characteristic lesions of dorsal root ganglia (DRG); dorsal spinal roots; dorsal nuclei of Clarke; spinocerebellar and corticospinal tracts; dentate nuclei; and sensory nerves. This report presents a systematic morphological analysis of sural nerves obtained by autopsy of six patients with genetically confirmed FRDA. The outstanding lesion consisted of lack of myelinated fibers whereas axons were present in normal numbers. On cross-sections, only 11% of all class III-beta-tubulin-positive axons were myelinated in FRDA, contrasting with 36% in normal control nerves. Despite their paucity, thin myelinated fibers assembled compact sheaths containing the peripheral myelin proteins PMP-22, P(0), and myelin basic protein. The nerves displayed major modifications in Schwann cells that were apparent by laminin 2 and S100alpha immunocytochemistry. Few S100alpha-immunoreactive cells remained detectable whereas laminin 2 reaction product was abundant. The normal honeycomb-like distribution of laminin 2 around myelinated fibers was replaced by confluent regions of reaction product that enveloped clusters of closely apposed thin axons. Electron microscopy not only confirmed the lack of myelin but also showed abnormal Schwann cells and axons. Ferritin localized to normal Schwann cell cytoplasm. In the sensory nerves of patients with FRDA, the distribution of this protein strongly resembled laminin 2, but there was no net increase of the total ferritin-reactive area. Ferroportin reaction product occurred in all axons of sural nerves in FRDA, which was at variance with dorsal spinal roots. In the pathogenesis of sensory neuropathy in FRDA, two mechanisms are likely: hypomyelination due to faulty interaction between axons and Schwann cells; and slow axonal degeneration. Neurons of DRG, satellite cells, Schwann cells, and axons of sensory nerves and dorsal spinal roots derive from the neural crest, and

  3. Non-progressive cerebellar ataxia and previous undetermined acute cerebellar injury: a mysterious clinical condition

    Directory of Open Access Journals (Sweden)

    Wladimir Bocca Vieira de Rezende Pinto

    2015-01-01

    Full Text Available Cerebellar ataxias represent a wide group of neurological diseases secondary to dysfunctions of cerebellum or its associated pathways, rarely coursing with acute-onset acquired etiologies and chronic non-progressive presentation. We evaluated patients with acquired non-progressive cerebellar ataxia that presented previous acute or subacute onset. Clinical and neuroimaging characterization of adult patients with acquired non-progressive ataxia were performed. Five patients were identified with the phenotype of acquired non-progressive ataxia. Most patients presented with a juvenile to adult-onset acute to subacute appendicular and truncal cerebellar ataxia with mild to moderate cerebellar or olivopontocerebellar atrophy. Establishing the etiology of the acute triggering events of such ataxias is complex. Non-progressive ataxia in adults must be distinguished from hereditary ataxias.

  4. Non-progressive cerebellar ataxia and previous undetermined acute cerebellar injury: a mysterious clinical condition

    Directory of Open Access Journals (Sweden)

    Wladimir Bocca Vieira de Rezende Pinto

    2015-10-01

    Full Text Available Cerebellar ataxias represent a wide group of neurological diseases secondary to dysfunctions of cerebellum or its associated pathways, rarely coursing with acute-onset acquired etiologies and chronic non-progressive presentation. We evaluated patients with acquired non-progressive cerebellar ataxia that presented previous acute or subacute onset. Clinical and neuroimaging characterization of adult patients with acquired non-progressive ataxia were performed. Five patients were identified with the phenotype of acquired non-progressive ataxia. Most patients presented with a juvenile to adult-onset acute to subacute appendicular and truncal cerebellar ataxia with mild to moderate cerebellar or olivopontocerebellar atrophy. Establishing the etiology of the acute triggering events of such ataxias is complex. Non-progressive ataxia in adults must be distinguished from hereditary ataxias.

  5. New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease)

    NARCIS (Netherlands)

    Rueb, Udo; Brunt, Ewout R.; Deller, Thomas

    Purpose of review This review summarizes recent neuropathological findings in spinocerebellar ataxia type 3 and discusses their relevance for clinical neurology. Recent findings The extent of the spinocerebellar ataxia type 3 related central nervous neurodegenerative changes has been recently

  6. 2 SISTERS WITH MENTAL-RETARDATION, CATARACT, ATAXIA, PROGRESSIVE HEARING-LOSS, AND POLYNEUROPATHY

    NARCIS (Netherlands)

    BEGEER, JH; SCHOLTE, FA; VANESSEN, AJ

    1991-01-01

    Two sisters are described with a disorder characterised by mental retardation, congenital cataract, progressive spinocerebellar ataxia, sensorineural deafness, and signs of peripheral neuropathy. Progressive hearing loss, ataxia, and polyneuropathy became evident in the third decade. The

  7. Genetics Home Reference: autosomal recessive spastic ataxia of Charlevoix-Saguenay

    Science.gov (United States)

    ... Twitter Home Health Conditions ARSACS Autosomal recessive spastic ataxia of Charlevoix-Saguenay Printable PDF Open All Close ... the expand/collapse boxes. Description Autosomal recessive spastic ataxia of Charlevoix-Saguenay , more commonly known as ARSACS , ...

  8. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

    NARCIS (Netherlands)

    Nibbeling, Esther A. R.; Duarri, Anna; Verschuuren-Bemelmans, Corien C.; Fokkens, Michiel R.; Karjalainen, Juha M; Smeets, Cleo J L M; de Boer-Bergsma, Jelkje J; van der Vries, Gerben; Dooijes, Dennis; Bampi, Giovana B; Van Diemen, Cleo C.; Brunt, Ewout R; Ippel, Elly; Kremer, Berry P. H.; Vlak, Monique H M; Adir, Noam; Wijmenga, Cisca; van de Warrenburg, Bart P. C.; Franke, Lude; Sinke, Richard J.; Verbeek, Dineke S.

    2017-01-01

    The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of

  9. Non-progressive cerebellar ataxia and previous undetermined acute cerebellar injury: a mysterious clinical condition.

    Science.gov (United States)

    Pinto, Wladimir Bocca Vieira de Rezende; Pedroso, José Luiz; Souza, Paulo Victor Sgobbi de; Albuquerque, Marcus Vinícius Cristino de; Barsottini, Orlando Graziani Povoas

    2015-10-01

    Cerebellar ataxias represent a wide group of neurological diseases secondary to dysfunctions of cerebellum or its associated pathways, rarely coursing with acute-onset acquired etiologies and chronic non-progressive presentation. We evaluated patients with acquired non-progressive cerebellar ataxia that presented previous acute or subacute onset. Clinical and neuroimaging characterization of adult patients with acquired non-progressive ataxia were performed. Five patients were identified with the phenotype of acquired non-progressive ataxia. Most patients presented with a juvenile to adult-onset acute to subacute appendicular and truncal cerebellar ataxia with mild to moderate cerebellar or olivopontocerebellar atrophy. Establishing the etiology of the acute triggering events of such ataxias is complex. Non-progressive ataxia in adults must be distinguished from hereditary ataxias.

  10. Spinal anaesthesia for a caesarean section in a patient with paraneoplastic cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Ayca Tas Tuna

    2017-01-01

    Full Text Available Paraneoplastic cerebellar ataxia (PCA is most frequently observed in gynaecological cancers, small cell lung cancer, breast cancer, Hodgkin's lymphoma, cancer testis or malignant thymoma. In the literature, there is no data related to the effects of PCA during pregnancy or reports on the effects of anaesthesia in patients with PCA. We present management of a pregnant woman with PCA who was suddenly unable to walk with PCA and for whom effective spinal anaesthesia was performed for an elective caesarean section with no complications.

  11. Is Friedreich ataxia an epigenetic disorder?

    Directory of Open Access Journals (Sweden)

    Kumari Daman

    2012-01-01

    Full Text Available Abstract Friedreich ataxia (FRDA is a debilitating and frequently fatal neurological disorder that is recessively inherited. It belongs to the group of genetic disorders known as the Repeat Expansion Diseases, in which pathology arises from the deleterious consequences of the inheritance of a tandem repeat array whose repeat number exceeds a critical threshold. In the case of FRDA, the repeat unit is the triplet GAA•TTC and the tandem array is located in the first intron of the frataxin (FXN gene. Pathology arises because expanded alleles make lower than normal levels of mature FXN mRNA and thus reduced levels of frataxin, the FXN gene product. The repeats form a variety of unusual DNA structures that have the potential to affect gene expression in a number of ways. For example, triplex formation in vitro and in bacteria leads to the formation of persistent RNA:DNA hybrids that block transcription. In addition, these repeats have been shown to affect splicing in model systems. More recently, it has been shown that the region flanking the repeats in the FXN gene is enriched for epigenetic marks characteristic of transcriptionally repressed regions of the genome. However, exactly how repeats in an intron cause the FXN mRNA deficit in FRDA has been the subject of much debate. Identifying the mechanism or mechanisms responsible for the FXN mRNA deficit in FRDA is important for the development of treatments for this currently incurable disorder. This review discusses evidence for and against different models for the repeat-mediated mRNA deficit.

  12. Anesthetic management of a patient with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome): case report

    OpenAIRE

    Goulart, Alexandre Palmeira; Moro, Eduardo Toshiyuki; Guasti, Valter Moreno; Colares, Régis Faria

    2009-01-01

    JUSTIFICATIVA E OBJETIVOS: A telangiectasia hemorrágica hereditária (THH), também conhecida como síndrome de Rendu-Osler-Weber, é uma doença autossômica dominante, caracterizada por displasia vascular mucocutânea e visceral associada a episódios freqüentes de epistaxe e sangramentos gastrintestinais. O objetivo do presente relato foi descrever a anestesia em paciente portador dessa síndrome. RELATO DO CASO: Paciente do sexo masculino, 25 anos, submetido à correção cirúrgica de fratura de órbi...

  13. Long non-coding RNA expression profiles in hereditary haemorrhagic telangiectasia

    DEFF Research Database (Denmark)

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

    2014-01-01

    to the TGF-β signalling pathway. The exact mechanism of how haploinsufficiency of ENG and ACVRL1 leads to HHT manifestations remains to be identified. As long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression and constitute a sizable fraction of the human......RNAs are enriched for genomic loci involved in key pathways concerning HHT. Our study identified lncRNAs that are aberrantly expressed in HHT telangiectasia and indicates that lncRNAs may contribute to regulate protein-coding loci in HHT. These results suggest that the lncRNA component of the transcriptome deserves...

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder with three disease-causing genes identified to date: ENG, ACVRL1, and SMAD4. We report an HHT patient with allelic dropout that on routine sequence analysis for a known mutation in the family (c.817......-3T>G in ENG) initially seemed to be homozygous for the mutation. Aim: To explore the possibility of allelic dropout causing a false result in this patient. Methods: Mutation analysis of additional family members was performed and haplotype analysis carried out. New primers were designed to reveal...

  15. Infantile childhood onset of spinocerebellar ataxia type 2.

    Science.gov (United States)

    Di Fabio, Roberto; Santorelli, Filippo; Bertini, Enrico; Balestri, Martina; Cursi, Laura; Tessa, Alessandra; Pierelli, Francesco; Casali, Carlo

    2012-06-01

    Spinocerebellar ataxia type 2 (SCA2) is a late-onset autosomal dominant cerebellar ataxia caused by triplet CAG/CTG expansion in the ATX2 gene. The initial symptoms usually appear when subjects are in their 30s.Pediatric onset is less common and usually associated with larger triplet expansions. We here report the case of a 1-year-old girl who presented with facial dysmorphism,dystonic features, developmental delay, and retinitis pigmentosa.She was diagnosed as carrying an expanded CAG/CTG tract (92 repeats) before a molecular diagnosis of SCA2 was made in her father. Facial dysmorphism associated with developmental delay and retinitis pigmentosa in early childhood should prompt a careful family investigation for ataxia and study of ATX2.

  16. Diabetes mellitus as the presenting feature of Friedreich's ataxia

    Directory of Open Access Journals (Sweden)

    Meenal Garg

    2017-01-01

    Full Text Available Patients with Friedreich's ataxia (FA are at an increased risk of developing diabetes mellitus and glucose intolerance. Diabetes usually develops many years after the initial presentation. We report an 8-year-old girl who initially presented with diabetic ketoacidosis and was treated as a case of insulin-dependent diabetes mellitus. Around a year later, she developed gait problems and ataxia. Cardiac involvement was detected on echocardiography. Genetic testing confirmed the diagnosis of FA. FA should be a diagnostic consideration in children presenting with diabetes and neurological issues, even with early presentation of the former. Early occurrence of diabetes and rapid progression of ataxia in this patient needs a better understanding of underlying genetic mechanisms.

  17. An unusual cause of adult onset cerebellar ataxia with hypogonadism

    Directory of Open Access Journals (Sweden)

    Menon Ramshekhar

    2009-01-01

    Full Text Available We report an unusual case of sporadic adult onset cerebellar ataxia with hypogonadism. A 40-year-old unmarried man presented with progressive ataxia and dysarthria along with complaints of non-development of secondary sexual characteristics and erectile dysfunction. There were complaints of intermittent diarrhea. Clinical examination revealed a pan-cerebellar syndrome with features of hypoandrogenism. No eye movement abnormalities were evident. There were signs of malabsorption. Investigations confirmed the presence of auto-antibodies found in celiac disease, and a duodenal biopsy confirmed the same. Hypoandrogenism was postulated to be due to hypergonadotropic hypogonadism which has been mentioned in a few patients of celiac disease. However, the pattern seen in our patient was of a hypogonadotropic hypogonadism. This is probably secondary to an autoimmune hypophysitis seen in some patients in the absence of other clinical manifestations. Autoantibody testing should be a diagnostic necessity in any adult with a sporadic cerebellar ataxia.

  18. Deficits in peripheral visual attention in patients with optic ataxia.

    Science.gov (United States)

    Striemer, Christopher; Blangero, Annabelle; Rossetti, Yves; Boisson, Dominique; Rode, Gilles; Vighetto, Alain; Pisella, Laure; Danckert, James

    2007-07-16

    Earlier research has suggested that optic ataxia, a deficit in reaching in peripheral vision, can be isolated from Balint's syndrome as it is primarily a visuomotor disorder, independent of perceptual or attentional deficits. Yet almost no research has examined the attentional abilities of these patients. We examined peripheral visual attention in two patients with unilateral optic ataxia. Results indicated that both patients were slower to respond to targets in their ataxic visual field, irrespective of cuing condition (i.e. validly, invalidly, and no cue conditions), consistent with an overall decrease in the salience of stimuli in the ataxic field. Attentional deficits in peripheral vision are therefore an important factor to consider when examining visuomotor control deficits in optic ataxia.

  19. AT cells are not radiosensitive for simple chromosomal exchanges at low dose

    Energy Technology Data Exchange (ETDEWEB)

    Hada, Megumi; Huff, Janice L.; Patel, Zarana S. [USRA Division of Life Sciences, Houston, TX 77058 (United States); Kawata, Tetsuya [Department of Radiology, School of Medicine, Keio University, Tokyo (Japan); Pluth, Janice M. [Lawrence Berkeley National Laboratory, Life Sciences Division, One Cyclotron Road, Building 74, Berkeley, CA 94720 (United States); George, Kerry A. [Wyle, 1290 Hercules Drive, Houston, TX 77058 (United States); Cucinotta, Francis A., E-mail: Francis.A.Cucinotta@nasa.gov [NASA, Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, TX 77058 (United States)

    2011-11-01

    Cells deficient in ATM (product of the gene that is mutated in ataxia telangiectasia patients) or NBS (product of the gene mutated in the Nijmegen breakage syndrome) show increased yields of both simple and complex chromosomal aberrations after high doses (>0.5 Gy) of ionizing radiation (X-rays or {gamma}-rays), however less is known on how these cells respond at low dose. Previously we had shown that the increased chromosome aberrations in ATM and NBS defective lines was due to a significantly larger quadratic dose-response term compared to normal fibroblasts for both simple and complex exchanges. The linear dose-response term for simple exchanges was significantly higher in NBS cells compared to wild type cells, but not for AT cells. However, AT cells have a high background level of exchanges compared to wild type or NBS cells that confounds the understanding of low dose responses. To understand the sensitivity differences for high to low doses, chromosomal aberration analysis was first performed at low dose-rates (0.5 Gy/d), and results provided further evidence for the lack of sensitivity for exchanges in AT cells below doses of 1 Gy. Normal lung fibroblast cells treated with KU-55933, a specific ATM kinase inhibitor, showed increased numbers of exchanges at a dose of 1 Gy and higher, but were similar to wild type cells at 0.5 Gy or below. These results were confirmed using siRNA knockdown of ATM. The present study provides evidence that the increased radiation sensitivity of AT cells for chromosomal exchanges found at high dose does not occur at low dose.

  20. Common Data Elements for Clinical Research in Friedreich Ataxia

    Science.gov (United States)

    Lynch, David R.; Pandolfo, Massimo; Schulz, Jorg B.; Perlman, Susan; Delatycki, Martin B.; Payne, R. Mark; Shaddy, Robert; Fischbeck, Kenneth H.; Farmer, Jennifer; Kantor, Paul; Raman, Subha V.; Hunegs, Lisa; Odenkirchen, Joanne; Miller, Kristy; Kaufmann, Petra

    2012-01-01

    Background To reduce study start-up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreich ataxia, a neurological disorder that involves multiple organ systems. Methods To develop Friedreich’s ataxia common data elements, Friedreich’s ataxia experts formed a working group and subgroups to define elements in: Ataxia and Performance Measures; Biomarkers; Cardiac and Other Clinical Outcomes; and Demographics, Laboratory Tests and Medical History. The basic development process included: Identification of international experts in Friedreich’s ataxia clinical research; Meeting via teleconference to develop a draft of standardized common data elements recommendations; Vetting of recommendations across the subgroups; Dissemination of recommendations to the research community for public comment. Results The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx. The Subgroups’ recommendations are classified as core, supplemental or exploratory. Template case report forms were created for many of the core tests. Conclusions The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new and ongoing studies will be assessed in an ongoing fashion to define their utility in Friedreich’s ataxia. PMID:23239403

  1. Gly118Asp is a SCA14 founder mutation in the Dutch ataxia population

    NARCIS (Netherlands)

    Verbeek, DS; van de Warrenburg, BPC; Hennekam, FAM; Dooijes, D; Ippel, PF; Verschuuren-Bemelmans, CC; Kremer, HPH; Sinke, RJ

    Missense mutations in the PRKCG gene have recently been identified in spinocerebellar ataxia 14 (SCA14) patients; these include the Gly118Asp mutation that we found in a large Dutch autosomal dominant cerebellar ataxia (ADCA) family. We subsequently screened the current Dutch ataxia cohort

  2. Three novel KCNA1 mutations in episodic ataxia type I families

    NARCIS (Netherlands)

    Scheffer, H; Brunt, ERP; Mol, GJJ; van der Vlies, P; Stulp, RP; Verlind, E; Mantel, G; Averyanov, YN; Hofstra, RMW; Buys, CHCM

    Hereditary paroxysmal ataxia, or episodic ataxia (EA), is a rare, genetically heterogeneous neurological disorder characterized by attacks of generalized ataxia. By direct sequence analysis, a different missense mutation of the potassium channel gene (KCNA1) has been identified in three families

  3. Early onset cerebellar ataxia with retained tendon reflexes : foot deformity in a first grade family member

    NARCIS (Netherlands)

    Schelhaas, HJ; Van der Hulst, M; Ippel, E; Prevo, RL; Hageman, G

    1999-01-01

    Early onset cerebellar ataxia with retained tendon reflexes (EOCA) is a clinical syndrome characterised by progressive cerebellar ataxia with an onset before the age of 25 years and a wide spectrum of associated features. It is distinguished from Friedreich's ataxia (FA) mainly by the preservation

  4. Spinocerebellar ataxia type 6: MRI of three Japanese patients

    Energy Technology Data Exchange (ETDEWEB)

    Satoh, J.I.; Tokumoto, H.; Yukitake, M.; Matsui, M.; Kuroda, Y. [Division of Neurology, Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849 (Japan); Matsuyama, Z.; Kawakami, H.; Nakamura, S. [Third Department of Internal Medicine, Hiroshima University School of Medicine Hiroshima (Japan)

    1998-04-01

    We describe the MRI findings in three Japanese patients with spinocerebellar ataxia type 6 (SCA6) in which a polymorphic CAG repeat was identified in the gene encoding the {alpha}{sub 1A} voltage-dependent P/Q-type Ca{sup 2+} channel subunit (CACNL1A4). All showed slowly progressive cerebellar ataxia and mild pyramidal signs. Neuroradiologically, they had moderate cerebellar atrophy, most prominently in the superior vermis, whereas the brain stem appeared to be spared. No abnormal signal intensity was identified. (orig.) With 3 figs., 1 tab., 23 refs.

  5. Fisioterapia, aprendizagem e treino: teorema para viver com ataxia

    OpenAIRE

    Fernandes, Beatriz

    2013-01-01

    Caracterização da ataxia, sintomas relacionados com as alterações de movimento, objectivos da fisioterapia, importância do movimento. A fisioterapia pode ajudar as pessoas com ataxia a realizar as actividades funcionais para além da execução através de compensação; a aprendizagem motora é possível; treino de tarefas funcionais; repetição dos exercícios; exercícios que desafiem as capacidades do indivíduo.

  6. Progressive impairment of cerebellar mGluR signalling and its therapeutic potential for cerebellar ataxia in spinocerebellar ataxia type 1 model mice.

    Science.gov (United States)

    Shuvaev, Anton N; Hosoi, Nobutake; Sato, Yamato; Yanagihara, Dai; Hirai, Hirokazu

    2017-01-01

    Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a gene defect, leading to movement disorder such as cerebellar ataxia. It remains largely unknown which functional defect contributes to the cerebellar ataxic phenotype in SCA1. In this study, we report progressive dysfunction of metabotropic glutamate receptor (mGluR) signalling, which leads to smaller slow synaptic responses, reduced dendritic Ca2+ signals and impaired synaptic plasticity at cerebellar synapses, in the early disease stage of SCA1 model mice. We also show that enhancement of mGluR signalling by a clinically available drug, baclofen, leads to improvement of motor performance in SCA1 mice. SCA1 is an incurable disease with no effective treatment, and our results may provide mechanistic grounds for targeting mGluRs and a novel drug therapy with baclofen to treat SCA1 patients in the future. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that presents with cerebellar ataxia and motor learning defects. Previous studies have indicated that the pathology of SCA1, as well as other ataxic diseases, is related to signalling pathways mediated by the metabotropic glutamate receptor type 1 (mGluR1), which is indispensable for proper motor coordination and learning. However, the functional contribution of mGluR signalling to SCA1 pathology is unclear. In the present study, we show that SCA1 model mice develop a functional impairment of mGluR signalling which mediates slow synaptic responses, dendritic Ca2+ signals, and short- and long-term synaptic plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in a progressive manner from the early disease stage (5 postnatal weeks) prior to PC death. Notably, impairment of mGluR-mediated dendritic Ca2+ signals linearly correlated with a reduction of PC capacitance (cell surface area) in disease progression. Enhancement of mGluR signalling by baclofen, a clinically available GABAB receptor

  7. Diagnostic and pathogenetic role of café-au-lait macules in nevoid basal cell carcinoma syndrome

    Directory of Open Access Journals (Sweden)

    Ponti Giovanni

    2012-10-01

    Full Text Available Abstract Café au lait spots (CALS are common dermatologic findings that can at the same time arise in a variety of pathologic conditions such as Neurofibromatosis type 1 (NF1, together with numerous hereditary syndromes for which they represent either diagnostic criteria or associated elements (McCune Albright, Silver-Russell, LEOPARD, Ataxia-Telangiectasia. A review of the literature also revealed two cases of association with NBCCS. We report here the case of a female proband with CALS associated to Nevoid Basal Cell Carcinoma Syndrome (NBCCS with known PTCH1 germline mutation (C.1348-2A>G who had been misdiagnosed with NF1 in her childhood because of 5 CALS and cutaneous nodules. The patient presented a giant cell tumor of the skin, palmar and calcaneal epidermoidal cystic nodules, odontogenic keratocystic tumors and deformity of the jaw profile. Her family history brought both her brother and father to our attention because of the presence of KCOTs diagnosed at early age: after genetic testing, the same PTCH1 germline mutation was identified in the three family members. Clinical criteria are used for discerning NF1 diagnosis (size, number and onset age, while there are no definite guidelines concerning CALS except for their presence. In our experience, we have noted an association of CALS with NBCCS; this seems interesting because we already know clinical criteria are a dynamic entity and can be modified by epidemiologic evidences.

  8. Analysis of hypermethylation and expression profiles of APC and ATM genes in patients with oral squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Rigi-Ladiz Mohammad

    2011-11-01

    Full Text Available Abstract Background Adenomatous polyposis coli (APC and Ataxia-telangiectasia-mutated (ATM gene products have an important role in cell cycle control and maintenance of genomic stability. Our aim was to analyze ATM and APC methylation and its relationship with oral squamous cell carcinoma (OSCC. Materials and methods Eighty-four OSCC tissues that have been fixed in paraffin along with 57 control oral samples have been used for analyzing promoter methylation of ATM and APC genes by Methylation Specific Polymerase Chain Reaction (MS-PCR. In addition, 10 cases of OSCC and the same of matched controls were examined for estimating expression of the above mentioned genes using Real-Time Reverse-Transcription PCR. Results Observed promoter methylations were 71.42% and 87.71% for the APC gene and 88.09% and 77.19% for the ATM gene in cases and controls, respectively. Analysis of these data showed that promoter methylation at APC was significantly different in cases compared to healthy controls (p = 0.01, but no difference was detected for the ATM gene. Furthermore, the mRNA expression levels did not differ statistically between cases and controls for both ATM (cases = 9, controls = 10 and APC (cases = 11, controls = 10 genes. Conclusions Our results, for the first time, provide methylation profiles of ATM and APC genes in a sample of patients with OSCC in a southeast Iranian population. The present data support related evidence of APC methylation effect on OSCC development.

  9. Diagnostic and pathogenetic role of café-au-lait macules in nevoid basal cell carcinoma syndrome.

    Science.gov (United States)

    Ponti, Giovanni; Tomasi, Aldo; Pastorino, Lorenza; Ruini, Cristel; Guarneri, Carmelo; Mandel, Victor Desmond; Seidenari, Stefania; Pellacani, Giovanni

    2012-10-29

    Café au lait spots (CALS) are common dermatologic findings that can at the same time arise in a variety of pathologic conditions such as Neurofibromatosis type 1 (NF1), together with numerous hereditary syndromes for which they represent either diagnostic criteria or associated elements (McCune Albright, Silver-Russell, LEOPARD, Ataxia-Telangiectasia). A review of the literature also revealed two cases of association with NBCCS. We report here the case of a female proband with CALS associated to Nevoid Basal Cell Carcinoma Syndrome (NBCCS) with known PTCH1 germline mutation (C.1348-2A>G) who had been misdiagnosed with NF1 in her childhood because of 5 CALS and cutaneous nodules. The patient presented a giant cell tumor of the skin, palmar and calcaneal epidermoidal cystic nodules, odontogenic keratocystic tumors and deformity of the jaw profile. Her family history brought both her brother and father to our attention because of the presence of KCOTs diagnosed at early age: after genetic testing, the same PTCH1 germline mutation was identified in the three family members. Clinical criteria are used for discerning NF1 diagnosis (size, number and onset age), while there are no definite guidelines concerning CALS except for their presence. In our experience, we have noted an association of CALS with NBCCS; this seems interesting because we already know clinical criteria are a dynamic entity and can be modified by epidemiologic evidences.

  10. Hereditary hemorrhagic telangiectasia with bilateral pulmonary vascular malformations: A case report

    Directory of Open Access Journals (Sweden)

    Lončarević Olivera

    2016-01-01

    Full Text Available Introduction. Hereditary hemorrhagic telangiectasia (HHT also known as Osler-Weber-Rendu syndrome is an autosomal dominant disease that occurs due to vascular dysplasia associated with the disorder in the signaling pathway of transforming growth factor β (TGF-β. The clinical consequence is a disorder of blood vessels in multiple organ systems with the existence of telangiectasia which causes dilation of capillaries and veins, are present from birth and are localized on the skin and mucosa of the mouth, respiratory, gastrointestinal and urinary tract. They can make a rupture with consequent serious bleeding that can end up with fatal outcome. Since there is a disruption of blood vessels of more than one organic system, the diagnosis is very complex and requires a multidisciplinary approach. Case report. We reported a 40-year-old female patient with a long-time evolution of problems, who was diagnosed and treated at the Clinic for Lung Diseases of the Military Medical Academy in Belgrade, Serbia, because of bilaterally pulmonary arteriovenous malformations associated with HHT. Embolization was performed in two acts, followed with normalization of clinical, radiological and functional findings with the cessation of hemoptysis, effort intolerance with a significant improvement of the quality of life. Conclusion. HHT is a rare dominant inherited multisystem disease that requires multidisciplinary approach to diagnosis and treatment. Embolization is the method of choice in the treatment of arteriovenous malformations with minor adverse effects and very satisfying therapeutic effect.

  11. Ondine's curse with accompanying trigeminal and glossopharyngeal neuralgia secondary to medullary telangiectasia.

    Science.gov (United States)

    Kapnadak, Siddhartha G; Mikolaenko, Ivan; Enfield, Kyle; Gress, Daryl R; Nathan, Barnett R

    2010-06-01

    Central hypoventilation syndrome ("Ondine's Curse") is an infrequent disorder that can lead to serious acute or chronic health consequences. This syndrome, especially in adults, is rare, and even less frequent in the absence of clear pathogenic lesions on MRI. In addition, we are not aware of any previously reported cases with associated cranial nerve neuralgias. We describe a patient with baseline trigeminal and glossopharyngeal neuralgia, admitted with episodes of severe hypoventilatory failure of central origin, consistent with "Ondine's Curse". After evaluation, she was found to have a medullary capillary telangiectasia, thought to be the causative lesion, and which could explain her complete neurologic and hypoventilatory syndrome. The patient was treated with placement of a diaphragmatic pacing system, which has been effective thus far. This case illustrates the need for investigation of centrally mediated apnea, especially when co-occurring cranial nerve neuralgia is present and cardiopulmonary evaluation is negative. It provides an example of capillary telangiectasia as the causative lesion, one that to our knowledge has not been reported before. Placement of a diaphragmatic pacing system was warranted and became lifesaving as the patient was deemed to be severely incapacitated by chronic ventilatory insufficiency.

  12. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1.

    Science.gov (United States)

    Heimdal, K; Dalhus, B; Rødningen, O K; Kroken, M; Eiklid, K; Dheyauldeen, S; Røysland, T; Andersen, R; Kulseth, M A

    2016-02-01

    Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is an autosomal dominant inherited disease defined by the presence of epistaxis and mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in internal organs. In most families (~85%), HHT is caused by mutations in the ENG (HHT1) or the ACVRL1 (HHT2) genes. Here, we report the results of genetic testing of 113 Norwegian families with suspected or definite HHT. Variants in ENG and ACVRL1 were found in 105 families (42 ENG, 63 ACVRL1), including six novel variants of uncertain pathogenic significance. Mutation types were similar to previous reports with more missense variants in ACVRL1 and more nonsense, frameshift and splice-site mutations in ENG. Thirty-two variants were novel in this study. The preponderance of ACVRL1 mutations was due to founder mutations, specifically, c.830C>A (p.Thr277Lys), which was found in 24 families from the same geographical area of Norway. We discuss the importance of founder mutations and present a thorough evaluation of missense and splice-site variants. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. RNA gain-of-function in spinocerebellar ataxia type 8.

    Directory of Open Access Journals (Sweden)

    Randy S Daughters

    2009-08-01

    Full Text Available Microsatellite expansions cause a number of dominantly-inherited neurological diseases. Expansions in coding-regions cause protein gain-of-function effects, while non-coding expansions produce toxic RNAs that alter RNA splicing activities of MBNL and CELF proteins. Bi-directional expression of the spinocerebellar ataxia type 8 (SCA8 CTG CAG expansion produces CUG expansion RNAs (CUG(exp from the ATXN8OS gene and a nearly pure polyglutamine expansion protein encoded by ATXN8 CAG(exp transcripts expressed in the opposite direction. Here, we present three lines of evidence that RNA gain-of-function plays a significant role in SCA8: 1 CUG(exp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons in the brain; 2 loss of Mbnl1 enhances motor deficits in SCA8 mice; 3 SCA8 CUG(exp transcripts trigger splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4. In vivo optical imaging studies in SCA8 mice confirm that Gabt4 upregulation is associated with the predicted loss of GABAergic inhibition within the granular cell layer. These data demonstrate that CUG(exp transcripts dysregulate MBNL/CELF regulated pathways in the brain and provide mechanistic insight into the CNS effects of other CUG(exp disorders. Moreover, our demonstration that relatively short CUG(exp transcripts cause RNA gain-of-function effects and the growing number of antisense transcripts recently reported in mammalian genomes suggest unrecognized toxic RNAs contribute to the pathophysiology of polyglutamine CAG CTG disorders.

  14. Multispectral imaging flow cytometry reveals distinct frequencies of γ-H2AX foci induction in DNA double strand break repair defective human cell lines.

    Science.gov (United States)

    Bourton, Emma C; Plowman, Piers N; Zahir, Sheba Adam; Senguloglu, Gonul Ulus; Serrai, Hiba; Bottley, Graham; Parris, Christopher N

    2012-02-01

    The measurement of γ-H2AX foci induction in cells provides a sensitive and reliable method for the quantitation of DNA damage responses in a variety of cell types. Accurate and rapid methods to conduct such observations are desirable. In this study, we have employed the novel technique of multispectral imaging flow cytometry to compare the induction and repair of γ-H2AX foci in three human cell types with different capacities for the repair of DNA double strand breaks (DSB). A repair normal fibroblast cell line MRC5-SV1, a DSB repair defective ataxia telangiectasia (AT5BIVA) cell line, and a DNA-PKcs deficient cell line XP14BRneo17 were exposed to 2 Gy gamma radiation from a (60)Cobalt source. Thirty minutes following exposure, we observed a dramatic induction of foci in the nuclei of these cells. After 24 hrs, there was a predictable reduction on the number of foci in the MRC5-SV1 cells, consistent with the repair of DNA DSB. In the AT5BIVA cells, persistence of the foci over a 24-hr period was due to the failure in the repair of DNA DSB. However, in the DNA-PKcs defective cells (XP14BRneo17), we observed an intermediate retention of foci in the nuclei indicative of partial repair of DNA DSB. In summary, the application of imaging flow cytometry has permitted an evaluation of foci in a large number of cells (20,000) for each cell line at each time point. This provides a novel method to determine differences in repair kinetics between different cell types. We propose that imaging flow cytometry provides an alternative platform for accurate automated high through-put analysis of foci induction in a variety of cell types. Copyright © 2011 International Society for Advancement of Cytometry.

  15. A genome-wide analysis of gene-caffeine consumption interaction on basal cell carcinoma.

    Science.gov (United States)

    Li, Xin; Cornelis, Marilyn C; Liang, Liming; Song, Fengju; De Vivo, Immaculata; Giovannucci, Edward; Tang, Jean Y; Han, Jiali

    2016-12-01

    Animal models have suggested that oral or topical administration of caffeine could inhibit ultraviolet-induced carcinogenesis via the ataxia telangiectasia and rad3 (ATR)-related apoptosis. Previous epidemiological studies have demonstrated that increased caffeine consumption is associated with reduced risk of basal cell carcinoma (BCC). To identify common genetic markers that may modify this association, we tested gene-caffeine intake interaction on BCC risk in a genome-wide analysis. We included 3383 BCC cases and 8528 controls of European ancestry from the Nurses' Health Study and Health Professionals Follow-up Study. Single nucleotide polymorphism (SNP) rs142310826 near the NEIL3 gene showed a genome-wide significant interaction with caffeine consumption (P = 1.78 × 10-8 for interaction) on BCC risk. There was no gender difference for this interaction (P = 0.64 for heterogeneity). NEIL3, a gene belonging to the base excision DNA repair pathway, encodes a DNA glycosylase that recognizes and removes lesions produced by oxidative stress. In addition, we identified several loci with P value for interaction caffeine consumption-related SNPs reported by previous genome-wide association studies and risk of BCC, both individually and jointly, but found no significant association. In sum, we identified a DNA repair gene that could be involved in caffeine-mediated skin tumor inhibition. Further studies are warranted to confirm these findings. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Republished: A practical approach to late-onset cerebellar ataxia: putting the disorder with lack of order into order.

    NARCIS (Netherlands)

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

    2012-01-01

    The clinical management of cerebellar ataxia is challenging, mainly because ataxia is a symptom of many neurological diseases. Many types of ataxia disorders are genetic and some are extremely rare. Here, the authors suggest a diagnostic approach to ataxia developed around a case of sporadic,

  17. A practical approach to late-onset cerebellar ataxia: putting the disorder with lack of order into order.

    NARCIS (Netherlands)

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

    2012-01-01

    The clinical management of cerebellar ataxia is challenging, mainly because ataxia is a symptom of many neurological diseases. Many types of ataxia disorders are genetic and some are extremely rare. Here, the authors suggest a diagnostic approach to ataxia developed around a case of sporadic,

  18. 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.

  19. Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

    Science.gov (United States)

    2017-09-28

    -epilepsy-intellectual Disability Syndrome Due to TUD Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome Due to KIAA0226 Deficiency; Autosomal Recessive Cerebellar Ataxia-epilepsy-intellectual Disability Syndrome; Autosomal Recessive Cerebellar Ataxia With Late-onset Spasticity; Autosomal Recessive Cerebellar Ataxia Due to STUB1 Deficiency; Autosomal Recessive Cerebellar Ataxia Due to a DNA Repair Defect; Autosomal Recessive Cerebellar Ataxia - Saccadic Intrusion; Autosomal Recessive Cerebellar Ataxia - Psychomotor Retardation; Autosomal Recessive Cerebellar Ataxia - Blindness - Deafness; Autosomal Recessive Cerebellar Ataxia; Autosomal Dominant Spinocerebellar Ataxia Due to a Polyglutamine Anomaly; Autosomal Dominant Spinocerebellar Ataxia Due to a Point Mutation; Autosomal Dominant Spinocerebellar Ataxia Due to a Channelopathy; Autosomal Dominant Spastic Ataxia Type 1; Autosomal Dominant Spastic Ataxia; Autosomal Dominant Optic Atrophy; Ataxia-telangiectasia Variant; Ataxia-telangiectasia; Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy; Autosomal Dominant Cerebellar Ataxia Type 4; Autosomal Dominant Cerebellar Ataxia Type 3; Autosomal Dominant Cerebellar Ataxia Type 2; Autosomal Dominant Cerebellar Ataxia Type 1; Autosomal Dominant Cerebellar Ataxia; Ataxia-telangiectasia-like Disorder; Ataxia-intellectual Disability-oculomotor Apraxia-cerebellar Cysts Syndrome; Ataxia-deafness-intellectual Disability Syndrome; Ataxia With Vitamin E Deficiency; Ataxia With Dementia; Ataxia Neuropathy Spectrum; Ataxia - Tapetoretinal Degeneration; Ataxia - Photosensitivity - Short Stature; Ataxia - Pancytopenia; Ataxia - Oculomotor Apraxia Type 1; Ataxia - Hypogonadism - Choroidal Dystrophy; Ataxia - Other; Ataxia - Genetic Diagnosis - Unknown; Acquired Ataxia; Adult-onset Autosomal Recessive Cerebellar Ataxia; Alcohol Related Ataxia; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type II; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine

  20. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

    Science.gov (United States)

    ... onset, and diagnostic criteria of the two conditions. Fragile X Syndrome (FXS) FXS is present (though often not diagnosed) ... long face (more common as children get older). Fragile X-associated Tremor Ataxia Syndrome (FXTAS) FXTAS develops in adulthood—usually after age ...