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Sample records for ataxia telangiectasia patients

  1. Ataxia - telangiectasia

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

  2. Ataxia Telangiectasia

    Science.gov (United States)

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

  3. 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.

  4. 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.

  5. Anti-oxidative capacity in patients with ataxia telangiectasia

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    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

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

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    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.

  7. 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 ...

  8. 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.

  9. Genetics Home Reference: ataxia-telangiectasia

    Science.gov (United States)

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

  10. [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.

  11. 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.

  12. 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.

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

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    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.

  14. 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

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

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    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.

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

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    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.

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

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    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.

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

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    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.

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

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    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.

  20. 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...

  1. 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...

  2. 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.)

  3. 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

  4. 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

  5. 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.

  6. [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.

  7. 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-.

  8. 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

  9. 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).

  10. 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...

  11. Síndrome de Ataxia-Telangiectasia

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    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.

  12. 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).

  13. 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.

  14. 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.)

  15. 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

  16. 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

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

    Directory of Open Access Journals (Sweden)

    Vujić Dragana S.

    2013-01-01

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

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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/.

  3. 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

  4. Inmunodeficiencia con ataxia telangiectasia: presentación de 4 casos

    Directory of Open Access Journals (Sweden)

    Ma. Victoria Guntiñas Zamora

    2004-03-01

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

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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...

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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).

  15. 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.

  16. 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

  17. 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)

  18. 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.

  19. 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.

  20. 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...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-10-03

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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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...

  9. 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...

  10. 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.

  11. 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.

  12. 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

  13. 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...

  14. 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 ...

  15. 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 ...

  16. 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.

  17. 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).

  18. 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.

  19. 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...

  20. 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.

  1. 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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-09-01

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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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...

  14. 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

  15. 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

  16. 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)

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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....

  2. 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).

  3. 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.

  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. 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

  6. 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.

  7. 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...

  8. [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.

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Zhe-Wei Zhang

    2015-01-01

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

  11. 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.

  12. 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....

  13. 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

  14. 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.

  15. 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.

  16. Mutation study of Spanish patients with Hereditary Hemorrhagic Telangiectasia

    Directory of Open Access Journals (Sweden)

    Blanco Francisco J

    2008-08-01

    Full Text Available Abstract Background Hereditary Hemorrhagic Telangiectasia (HHT is an autosomal dominant and age-dependent vascular disorder characterised mainly by mutations in the Endoglin (ENG or activin receptor-like kinase-1 (ALK1, ACVRL1 genes. Methods Here, we have identified 22 ALK1 mutations and 15 ENG mutations, many of which had not previously been reported, in independent Spanish families afflicted with HHT. Results We identified mutations in thirty-seven unrelated families. A detailed analysis of clinical symptoms was recorded for each patient analyzed, with a higher significant presence of pulmonary arteriovenous malformations (PAVM in HHT1 patients over HHT2. Twenty-two mutations in ALK1 and fifteen in ENG genes were identified. Many of them, almost half, represented new mutations in ALK1 and in ENG. Missense mutations in ENG and ALK1 were localized in a tridimensional protein structure model. Conclusion Overall, ALK1 mutations (HHT2 were predominant over ENG mutations (HHT1 in our Spanish population, in agreement with previous data from our country and other Mediterranean countries (France, Italy, but different to Northern Europe or North America. There was a significant increase of PAVM associated with HHT1 over HHT2 in these families.

  17. 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.

  18. 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

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    M. Guzmán

    1994-12-01

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

  1. [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. 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...

  3. 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...

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Visual System Involvement in Patients with Friedreich's Ataxia

    Science.gov (United States)

    Fortuna, Filippo; Barboni, Piero; Liguori, Rocco; Valentino, Maria Lucia; Savini, Giacomo; Gellera, Cinzia; Mariotti, Caterina; Rizzo, Giovanni; Tonon, Caterina; Manners, David; Lodi, Raffaele; Sadun, Alfredo A.; Carelli, Valerio

    2009-01-01

    Optic neuropathy is common in mitochondrial disorders, but poorly characterized in Friedreich's ataxia (FRDA), a recessive condition caused by lack of the mitochondrial protein frataxin. We investigated 26 molecularly confirmed FRDA patients by studying both anterior and posterior sections of the visual pathway using a new, integrated approach.…

  9. 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.

  10. 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

  11. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, A D; Møller, T R; Brusgaard, K

    2005-01-01

    families. In 14 of the families we identified a disease-causing mutation. Thirty-nine patients (from 10 families) had HHT1 and 16 HHT patients from four families had HHT2. CONCLUSION: Amongst patients with HHT1 genotype the prevalence of PAVM was higher than amongst HHT patients with HHT2 genotype. HHT1......BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease, characterized by a wide variety of clinical manifestations, including epistaxis, gastrointestinal (GI) bleeding, pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. HHT is a genetically...... for PAVM and neurological evaluation. Blood tests were performed for analysis of disease-causing mutation, and clinical manifestations in the HHT subtypes were compared. The survival of the patients was studied in the follow-up period. RESULTS: Included in the study were 73 HHT patients representing 18...

  12. GAA repeat polymorphism in Turkish Friedreich's ataxia patients.

    Science.gov (United States)

    Yilmaz, M Bertan; Koç, A Filiz; Kasap, Halil; Güzel, A Irfan; Sarica, Yakup; Süleymanova, Dilara

    2006-05-01

    Friedreich's ataxia (FRDA), the most common subtype of early onset hereditary spinocerebellar ataxia (SCA), is an autosomal recessive neurodegenerative disorder caused by unstable GAA tri-nucleotide expansions in the first intron of FRDA gene located at 9q13-q21.1 position. Results of GAA repeat polymorphism in 80 Turkish SCA patients and 38 family members of 11 typical FRDA patients were reported. GAA triplet repeat size ranged from approximately 7 to 34 in normal alleles and from approximately 66 to 1300 in mutant alleles. Twenty six patients were homozygous for GAA expansion and size of expanded alleles differed from approximately 425 to 1300 repeats. Children 2 and 6 years old (showing no ataxia symptoms) of one family had homozygous GAA expansions reaching approximately 925 repeats. All 11 families studied had at least 1 afflicted child and 9 parents and 2 siblings were carrier (heterozygous) with mutant alleles ranging from 66 to 850 repeats. Family studies confirmed the meiotic instability and stronger effect of expansion in the smaller alleles on phenotype and a negative correlation between GAA repeat expansion size and onset-age of the disease.

  13. Pulmonary arteriovenous malformations and embolic complications in patients with hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Angriman, Federico; Ferreyro, Bruno L; Wainstein, Esteban J; Serra, Marcelo M

    2014-07-01

    Patients with hereditary hemorrhagic telangiectasia (HHT) and pulmonary arteriovenous malformation (PAVM) face higher risk of embolic complications. It is not clear whether poor outcomes are related to PAVM severity or pulmonary symptoms. Furthermore, there is currently no available data on HHT patients in Argentina. We conducted a cross sectional study in a teaching hospital in Buenos Aires, Argentina. We describe baseline characteristics of HHT and compare the prevalence of embolic complications in patients with significant PAVM compared to patients without significant PAVM. One hundred and eight consecutive patients were included. Significant PAVM was defined as: contrast echocardiography grade 2 or greater; bilateral PAVM or feeding artery bigger than 3mm; or previous PAVM treatment. Primary composite outcome was defined as: cerebrovascular accident, cerebral abscess or peripheral embolism. 20% of participants had embolic complications, the most frequent one was stroke. Embolic complications were associated with significant PAVM and respiratory symptoms. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

  14. Friedreich Ataxia and nephrotic syndrome: a series of two patients.

    Science.gov (United States)

    Shinnick, Julianna E; Isaacs, Charles J; Vivaldi, Sharon; Schadt, Kimberly; Lynch, David R

    2016-01-12

    Friedreich Ataxia (FRDA) is a neurodegenerative disorder characterized by gait and balance abnormalities, sensory loss, weakness, loss of reflexes, and ataxia. Previously, two cases of FRDA and Nephrotic Syndrome (NS) have been reported. Here we report two additional individuals with NS and FRDA, providing further evidence for a possible connection between the two diseases and focusing on the neuromuscular responsiveness of one individual to corticosteroid treatment, an effect not previously described in FRDA. We describe two patients with FRDA also presenting with NS. The first patient was diagnosed with FRDA at age 5 and NS at age 7 following the development of periorbital edema, abdominal swelling, problems with urination, and weight gain. The second patient was diagnosed with NS at age 2 after presenting with periorbital edema, lethargy, and abdominal swelling. He was diagnosed with FRDA at age 10. Nephrotic syndrome was confirmed by laboratory testing in both cases and both individuals were treated with corticosteroids. Nephrotic syndrome may occur in individuals with FRDA, but was not associated with myoclonic epilepsy in our patients as previously described. It is unlikely that this association is coincidental given the rarity of both conditions and the association of NS with mitochondrial disease in model systems, though coincidental coexistence is possible. One patient showed neurological improvement following steroid treatment. Although neurological improvement could be attributed to the treatment of NS, we also identified some degree of steroid responsiveness in a series of patients with FRDA but without NS.

  15. Investigation of recessive ataxia loci in patients with young age of onset.

    Science.gov (United States)

    Zühlke, C; Bernard, V; Gillessen-Kaesbach, G

    2007-08-01

    Autosomal recessive cerebellar ataxias are a phenotypically and genetically heterogeneous group of diseases. Major forms can be distinguished on the basis of clinical signs, age of onset, biochemical parameters or genotypes. To develop rational diagnostic strategies, phenotypic information, e.g., age of onset combined with population-specific disease frequencies could be highly favourable. We tested this hypothesis for single candidate loci and mutations in North European ataxia patients with juvenile and early adult onset. While we could prove that Friedreich ataxia (FRDA) is frequent in Germany, only few patients with ataxia-oculomotor apraxia type 1 (AOA1) and type 2 (AOA2) were diagnosed. The frequency of the mitochondrial recessive ataxia syndrome (MIRAS) and the infantile onset spinocerebellar ataxia (IOSCA) in this population remains unknown since no case with the common mutation of the corresponding gene was detected.

  16. Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia.

    Science.gov (United States)

    Hosman, A; Westermann, C J J; Snijder, R; Disch, F; Mummery, C L; Mager, J J

    2015-12-01

    Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue. We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide. Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop. Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered.

  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. Thalidomide for Epistaxis in Patients with Hereditary Hemorrhagic Telangiectasia: A Preliminary Study.

    Science.gov (United States)

    Fang, Jia; Chen, Xiaomeng; Zhu, Bijun; Ye, Haibo; Zhang, Weitian; Guan, Jian; Su, Kaiming

    2017-08-01

    To evaluate the effectiveness of thalidomide for epistaxis in hereditary hemorrhagic telangiectasia (HHT), 7 HHT patients with recurrent epistaxis were treated with thalidomide at an initial dose of 50 mg/d, gradually increasing to 100 mg/d if needed. The Epistaxis Severity Score (ESS) was used to evaluate the treatment effects. Patients reported that epistaxis improved 1 to 3 weeks after starting thalidomide. The mean ESS before treatment, at the end of treatment, and 3 months after stopping treatment was 5.03 ± 2.05, 0.90 ± 0.84 ( P = .003), and 1.98 ± 1.33 ( P = .006), respectively. Four patients reported mild to moderate side effects, including drowsiness, dizziness, constipation, nausea, and peripheral neuropathy. Two patients stopped the treatment because of adverse effects. Those results showed that thalidomide may be a treatment choice for recurrent epistaxis in HHT patients, although the side effects should be considered. Further study should focus on guidelines for dosing and course and investigate how to reduce the adverse effects.

  19. High Rates of Bleeding Complications among Hospitalized Patients with Hereditary Hemorrhagic Telangiectasia in the United States.

    Science.gov (United States)

    Brinjikji, Waleed; Wood, Christopher P; Lanzino, Giuseppe; Cloft, Harry J; Misra, Sanjay; Kallmes, David F; Kamath, Patrick; Pruthi, Rajiv K; Krowka, Michael J; Swanson, Karen L; Iyer, Vivek N

    2016-09-01

    There is sparse published literature on the causes and outcomes of hospitalization of patients with hereditary hemorrhagic telangiectasia (HHT). To evaluate rates of various complications, comorbidities, and in-hospital outcomes of patients with HHT using a large, multihospital inpatient database. We identified patients with HHT in the U.S. Nationwide Inpatient Sample between 2000 and 2012. Rates of hemorrhagic, neurological, hepatic, and cardiopulmonary complications among hospitalized patients with HHT were evaluated. We also studied procedure use rates for blood transfusion, endoscopy, and epistaxis treatment. Hospitalization outcomes, including in-hospital mortality, discharge status, charges, and length of stay, were evaluated. We identified 10,293 patients with HHT. The mean age of the HHT population was 60.7 years. Sixty percent of patients were female. More than 75% of HHT hospitalizations occurred in those older than 50 years of age. Patients with HHT had high rates of bleeding-related complications, including anemia (53.3%), epistaxis (16.2%), and gastrointestinal bleeding (10.8%). Overall, bleeding complications accounted for 62.7% of HHT-related complications. Thirty-eight percent of hospitalized patients with HHT received one or more transfusions of a blood product. Cardiopulmonary complications were present in 41.0% of the cases. Congestive heart failure was the second most common individual complication among patients with HHT, affecting 19.9% of patients. The in-hospital mortality rate was 1.9%. In this large, nationwide study, we found that nearly two-thirds of patients hospitalized with HHT experienced a bleeding-related complication. Nearly 40% of hospitalized patients with HHT required transfusion of blood products. Cardiopulmonary complications, including congestive heart failure, were the second most common complication. The high burden of bleeding-related complications points to a significant unmet clinical need for these patients.

  20. 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.

  1. Quantitative analysis of upper-limb ataxia in patients with spinocerebellar degeneration.

    Science.gov (United States)

    Ueda, Naohisa; Hakii, Yasuhito; Koyano, Shigeru; Higashiyama, Yuichi; Joki, Hideto; Baba, Yasuhisa; Suzuki, Yume; Kuroiwa, Yoshiyuki; Tanaka, Fumiaki

    2014-07-01

    Spinocerebellar degeneration (SCD) is a progressive neurodegenerative disorder in which cerebellar ataxia causes motor disability. There are no widely applicable methods for objective evaluation of ataxia in SCD. An objective system to evaluate ataxia is necessary for use in clinical trials of newly developed medication and rehabilitation. The aim of this study was to develop a simple method to quantify the degree of upper-limb ataxia. Forty-nine patients with SCD participated in this study. Patients were instructed to trace an Archimedean spiral template, and the gap between the template spiral and the drawn spiral (gap area; GA) was measured using Image J software. Ataxia was rated using the Scale for the Assessment and Rating of Ataxia (SARA) and cerebellar volume was evaluated in 37 patients using an axial cross-section of magnetic resonance images that were obtained within 6 months of clinical evaluation. Regression analysis was performed to assess the relation between GA and patient age, disease duration, SARA score, and cerebellar volume. GA was significantly related to total SARA score (r = 0.660, p ataxia, especially upper-limb ataxia, and can be widely adopted in various settings, including clinical trials.

  2. Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): A retrospective study of 46 patients

    Science.gov (United States)

    Fargeton, Anne-Emmanuelle; Simon, Anne-Claire; Duffau, Pierre; Harle, Jean-Robert; Lavigne, Christian; Carette, Marie-France; Bletry, Olivier; Leguy, Vanessa; Lerolle, Nathalie; Roux, Dominique; Lambert, Marc; Chinet, Thierry; Bonnet, Delphine; Dupuis-Girod, Sophie; Rivière, Sophie

    2017-01-01

    Background Bevacizumab, an anti-VEGF monoclonal antibody, has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT). Its utilization in this orphan disease has rapidly spread despite the lack of randomized trials and international guidelines. The objective of this study is to report the main clinical data (baseline characteristics, dose schedule, efficacy, adverse events and deaths) of HHT patients treated by intravenous bevacizumab in France. Methods Retrospective observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network. Results Forty-six patients (median age: 68 years) were treated between March 2009 and May 2015. Ten patients were treated for high output cardiac failure, 20 patients for severe hemorrhages and 16 for both indications. The standard protocol (6 infusions of 5mg/kg every 2 weeks) was initially used in 89% of the cases but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74% of the patients with a median effect’s duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each. One third of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients. Conclusion Intravenous bevacizumab seems to provide a clinical benefice in severe HHT patients. Precautions concerning wound healing and vascular pathologies must be respected. Prospective double blinded versus placebo trials are needed. PMID:29190827

  3. Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT: A retrospective study of 46 patients.

    Directory of Open Access Journals (Sweden)

    Alexandre Guilhem

    Full Text Available Bevacizumab, an anti-VEGF monoclonal antibody, has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT. Its utilization in this orphan disease has rapidly spread despite the lack of randomized trials and international guidelines. The objective of this study is to report the main clinical data (baseline characteristics, dose schedule, efficacy, adverse events and deaths of HHT patients treated by intravenous bevacizumab in France.Retrospective observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network.Forty-six patients (median age: 68 years were treated between March 2009 and May 2015. Ten patients were treated for high output cardiac failure, 20 patients for severe hemorrhages and 16 for both indications. The standard protocol (6 infusions of 5mg/kg every 2 weeks was initially used in 89% of the cases but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74% of the patients with a median effect's duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each. One third of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients.Intravenous bevacizumab seems to provide a clinical benefice in severe HHT patients. Precautions concerning wound healing and vascular pathologies must be respected. Prospective double blinded versus placebo trials are needed.

  4. Pulmonary arterial hypertension and portal hypertension in a patient with hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Pousada, Guillermo; Baloira, Adolfo; Valverde, Diana

    2015-03-15

    Pulmonary arterial hypertension (PAH) is a rare disease that could be inherited with an autosomal dominant pattern. Mutations in BMPR2 gene are described in over 70% of cases, although other genes are involved in lesser extend in PAH. Hereditary hemorrhagic telangiectasia (HHT) is another rare autosomal dominant disease. PAH is a rare complication of HHT that occurs in less than 1% of cases. Liver cirrhosis with portal hypertension is also associated with the presence of PAHs in 1-2% of cases. We present here a patient with HHT who developed PAH shortly after showing portal hypertension. Some genes (BMPR2, ACVRL1, ENG) seem to play an important role in PAH pathogenesis. We analyzed these genes, detecting mutations in BMPR2 gene (c.1021G>A (V341L), c.327G>A (p.Q109Q)), ACVRL1 (c.313+20C>A, c.1502+7A>G) and ENG (c.498G>A (Q166Q)). The patient also had 3 polymorphisms in the TRPC6 gene (c.1-361A>T, c.1-254C>G, c.1-218C>T). The study of these genes will help us to identify and track individuals susceptible for developing PAH associated with other diseases. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  5. 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.

  6. The effectiveness of allied health care in patients with ataxia: a systematic review.

    Science.gov (United States)

    Fonteyn, Ella M R; Keus, Samyra H J; Verstappen, Carla C P; Schöls, Ludger; de Groot, Imelda J M; van de Warrenburg, Bart P C

    2014-02-01

    Many patients with cerebellar ataxia have serious disabilities in daily life, while pharmacological treatment options are absent. Therefore, allied health care is considered to be important in the management of these patients. The goal of this review is to evaluate scientific evidence for allied health care in cerebellar ataxia, to identify effective treatment strategies, and to give recommendations for clinical practice and further research. A systematic search for clinical trials concerning allied health care in cerebellar ataxias was conducted using the electronic databases of PubMed, Medline, Embase, Cinahl and Pedro, and references lists of articles, in the time period from 1980 up to and including December 2011 in English and Dutch. We identified 14 trials, of which the four best studies were formally of moderate methodological quality. There was a wide variation in disease entities and interventions. The combined data indicate that physical therapy may lead to an improvement of ataxia symptoms and daily life functions in patients with degenerative cerebellar ataxia (level 2), and in other diseases causing cerebellar ataxia (level 3). When added to physical therapy, occupational therapy might improve global functional status, and occupational therapy alone may diminish symptoms of depression (level 3). There are insufficient data for speech and language therapy. Despite the widespread use of allied health care interventions in cerebellar ataxia, there is a lack of good quality studies that have evaluated such interventions. We found some support for the implementation of physical therapy and occupational therapy, but more research is needed to develop recommendations for clinical practice.

  7. Cerebellar theta burst stimulation in stroke patients with ataxia.

    Science.gov (United States)

    Bonnì, Sonia; Ponzo, Viviana; Caltagirone, Carlo; Koch, Giacomo

    2014-01-01

    Evidence for effective improvement of the symptoms of cerebellar stroke is still limited. Here, we investigated the effects of repetitive transcranial magnetic stimulation (rTMS) applied over the injured cerebellar hemisphere in six patients with posterior circulation stroke. We applied a two-week course of cerebellar intermittent theta burst stimulation (iTBS). Before and after the iTBS treatment, paired-pulse TMS methods were used to explore: i) the functional connectivity between the cerebellar hemisphere and the contralateral primary motor cortex (M1), by means of the cerebellar brain inhibition (CBI) protocol; and ii) the intracortical circuits in the contralateral M1, by means of the short intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF) protocols. Patients were also evaluated using the Modified International Cooperative Ataxia Rating Scale (MICARS). Cerebellar iTBS induced a decrease in CBI and an increase in ICF at an interstimulus interval of 15 msec. These neurophysiological changes were paralleled by a clinical improvement, shown by the MICARS posture and gait subscale scores. Cerebellar iTBS could be a promising tool to promote recovery of cerebellar stroke patients.

  8. Cerebellar ataxia and intrathecal baclofen therapy: Focus on patients´ experiences

    National Research Council Canada - National Science Library

    Shala Ghaderi Berntsson; Anne-Marie Landtblom; Gullvi Flensner

    2017-01-01

    ...) is the objective of the current study. A multicenter qualitative study with four patients included due to the rare combination of hereditary ataxia and ITB therapy was designed to elucidate participants...

  9. Patients with autosomal dominant spinocerebellar ataxia have more risk of falls, important balance impairment, and decreased ability to function

    Directory of Open Access Journals (Sweden)

    Carolina Yuri P. Aizawa

    2013-08-01

    Full Text Available OBJECTIVES: To assess balance and ability to function in patients with spinocerebellar ataxia. METHODS: A total of 44 patients with different spinocerebellar ataxia types 1, 2, 3, and 6 were evaluated using the Tinetti balance and gait assessment and the functional independence measure. The scale for the assessment and rating of ataxia and the international cooperative ataxia rating scale were used to evaluate disease severity. RESULTS: Most patients showed significant risk of falls. The balance scores were significantly different in spinocerebellar ataxia types. A significant positive correlation between balance and disease severity was found. CONCLUSION: Patients with spinocerebellar ataxia have important balance impairment and risk of falls that influence the ability to function such as self-care, transfers, and locomotion. Furthermore, the more severe ataxia is, the more compromised are postural balance, risk of falls, and ability to function.

  10. 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...

  11. Cognitive impairments in patients with spinocerebellar ataxia types 1, 2 and 3 are positively correlated to the clinical severity of ataxia symptoms.

    Science.gov (United States)

    Ma, Jianhua; Wu, Chuanjia; Lei, Jing; Zhang, Xiaoning

    2014-01-01

    This study is to assess cognitive function in patients with spinocerebellar ataxia types 1, 2 and 3 (SCA1, SCA2 and SCA3). We performed neuropsychological examinations on 8 SCA1 patients, 2 SCA2 patients, and 8 SCA3 patients, as well as 32 healthy subjects matching these patients in age, gender, nationality, and years of education. The neuropsychological examinations were focused on testing executive functions, visuo-spatial perception and verbal memory, attention, immediate and delayed recall, logical thinking function and orientation function. SCA1 patients had significantly impaired executive function, visuo-spatial perception, and attention compared to healthy subjects. Cognitive disorders such as immediate and delayed recall, executive function and verbal memory were observed in SCA2 and SCA3 patients, while attention and visuo-spatial function were not affected. The severity of motor impairment was determined using the international cooperative ataxia rating scale, the scores of which ranged from 11 to 78. The number of patients with mild ataxia, moderate ataxia and severe ataxia was 3, 11, and 3, respectively, with the most severe ataxia occurring on a patient with SCA1. The scores of activities of daily living scale ranged from 20 to 66. Our results showed that mild executive dysfunction occurred in patients with SCA1, SCA2 and SCA3, and verbal fluency and word memory dysfunctions were detected in patients with SCA2 and SCA3. In addition, we found that the decreased logical thinking function and orientation function were observed in patients with SCA1, SCA2 and SCA3. The cognitive status was correlated with the clinical severity of ataxia symptoms rather than age, age of onset, years of education and the duration of disease.

  12. Comparative multiplex dosage analysis in spinocerebellar ataxia type 2 patients.

    Science.gov (United States)

    Calì, F; Chiavetta, V; Ragalmuto, A; Vinci, M; Ruggeri, G; Schinocca, P; Romano, V

    2013-04-12

    We developed a new application of comparative multiplex dosage analysis (CMDA) for evaluation of the ataxin 2 gene. Expansions of the triplet CAG can cause spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease with an autosomal-dominant mode of inheritance. Molecular diagnosis of SCA2 is routinely based on the use of conventional PCR to detect the CAG expansion. However, PCR does not amplify an allele with an expansion of many triplets (>80), which is typically found in infantile and juvenile forms of SCA2, thus leading to false negatives. We propose the analysis of the ATXN2 gene by CMDA to complement existing methods currently used for the detection of large expansions of the CAG repeat. Using CMDA, the presence of any longer mutated allele in a heterozygous patient or fetus would be inferred due to dosage variation of the very frequent normal allele #22. CMDA can be completed in 1 day, at very low cost, and would be a useful tool for prenatal diagnosis and for diagnosis of presymptomatic forms of early-onset SCA2.

  13. 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.

  14. Functional recovery and rehabilitation of postural impairment and gait ataxia in patients with acute cerebellar stroke.

    Science.gov (United States)

    Bultmann, Uta; Pierscianek, Daniela; Gizewski, Elke R; Schoch, Beate; Fritsche, Nicole; Timmann, Dagmar; Maschke, Matthias; Frings, Markus

    2014-01-01

    Studies about recovery from cerebellar stroke are rare. The present study assessed motor deficits in the acute phase after isolated cerebellar stroke focusing on postural impairment and gait ataxia and outlines the role of lesion site on motor outcome, the course of recovery and the effect of treadmill training. 23 patients with acute and isolated cerebellar infarction participated. Deficits were quantified by ataxia scores and dynamic posturography in the acute phase and in a follow up after 2 weeks and 3 months. MRI data were obtained to correlate lesion site with motor performance. Half of the patients that gave informed consent and walked independently underwent a 2-week treadmill training with increasing velocity. In the acute phase patients showed a mild to severe ataxia with a worse performance in patients with infarction of the superior in comparison to the posterior inferior cerebellar artery. However, after 3 months differences between vascular territories were no longer significant. MRI data showed that patients with larger infarct volumes had a significantly more severe ataxia. In patients with ataxia of stance, gait and lower limbs lesions were more common in cerebellar lobules IV to VI. After 3 months a mild ataxia in lower limbs and gait, especially in gait speed persisted. Because postural impairment had fully recovered, remaining gait ataxia was likely related to incoordination of lower limbs. Treadmill training did not show significant effects. Future studies are needed to investigate whether intensive coordinative training is of benefit in patients with cerebellar stroke. Copyright © 2013. Published by Elsevier B.V.

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. Local Stability of the Trunk in Patients with Degenerative Cerebellar Ataxia During Walking.

    Science.gov (United States)

    Chini, Giorgia; Ranavolo, Alberto; Draicchio, Francesco; Casali, Carlo; Conte, Carmela; Martino, Giovanni; Leonardi, Luca; Padua, Luca; Coppola, Gianluca; Pierelli, Francesco; Serrao, Mariano

    2017-02-01

    This study aims to evaluate trunk local stability in a group of patients with degenerative primary cerebellar ataxia and to correlate it with spatio-temporal parameters, clinical variables, and history of falls. Sixteen patients affected by degenerative cerebellar ataxia and 16 gender- and age-matched healthy adults were studied by means of an inertial sensor to measure trunk kinematics and spatio-temporal parameters during over-ground walking. Trunk local dynamic stability was quantified by the maximum Lyapunov exponent with short data series of the acceleration data. According to this index, low values indicate more stable trunk dynamics, while high values denote less stable trunk dynamics. Disease severity was assessed by means of International Cooperative Ataxia Rating Scale (ICARS) according to which higher values correspond to more severe disease, while lower values correspond to less severe disease.Patients displayed a higher short-term maximum Lyapunov exponent than controls in all three spatial planes, which was correlated with the age, onset of the disease, and history of falls. Furthermore, the maximum Lyapunov exponent was negatively correlated with ICARS balance, ICARS posture, and ICARS total scores.These findings indicate that trunk local stability during gait is lower in patients with cerebellar degenerative ataxia than that in healthy controls and that this may increase the risk of falls. Local dynamic stability of the trunk seems to be an important aspect in patients with ataxia and could be a useful tool in the evaluation of rehabilitative and pharmacological treatment outcomes.

  20. Impact of Dual Task on Parkinson's Disease, Stroke and Ataxia Patients' Gait: A Comparative Analysis

    Directory of Open Access Journals (Sweden)

    Michelly Arjona Maciel

    2014-01-01

    Full Text Available Introduction: Performing dual task for neurological patients is complex and it can be influenced by the localization of the neurological lesion. Objective: Comparing the impact of dual task on gait in patients with Parkinson's disease, stroke and ataxia. Method: Subjects with Parkinson's disease (PD in initial phase, stroke and ataxia, with independent gait, were evaluated while doing simple gait, with cognitive, motor and cognitive-motor gait demand, assessing average speed and number of steps. Results: Ataxia and stroke patients, compared with PD, showed an increase in the number of steps and decrease the average speed on the march with cognitive demand. Subjects with PD performed better on tasks when compared to others. Conclusion: In this study the impact of dual task was lower in Parkinson's disease patients.

  1. 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...

  2. 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.

  3. Mesial temporal lobe epilepsy in a patient with spinocerebellar ataxia type 13 (SCA13).

    Science.gov (United States)

    Bürk, Katrin; Strzelczyk, Adam; Reif, Philipp S; Figueroa, Karla P; Pulst, Stefan M; Zühlke, Christine; Oertel, Wolfgang H; Hamer, Hajo M; Rosenow, Felix

    2013-04-01

    We report a female patient of German descent with a molecular diagnosis of SCA13 who presented with a history of cerebellar ataxia and epilepsy. The underlying mutation R420H had been shown to cause a dominant negative effect on the functional properties of the voltage-gated potassium channel KCNC3. Despite widespread KCNC3 expression in the central nervous system, the patient presented with a left mesiotemporal electroencephalogram focus and left hippocampal sclerosis. This is the first case, which reports an association between mesial temporal lobe epilepsy and spinocerebellar ataxia type 13. This demonstrates that epilepsy of structural-metabolic cause may be contingent upon genetically defined channelopathies.

  4. Diagnostic value of anti-GQ1b antibodies in a patient with relapsing dysarthria and ataxia

    NARCIS (Netherlands)

    M.L. Kuijf (Mark); L. Ruts (Liselotte); P.A. van Doorn (Pieter); P.J. Koudstaal (Peter Jan); B.C. Jacobs (Bart)

    2009-01-01

    textabstractSerum antibodies to the ganglioside GQ1b are associated with immune-mediated ophthalmoplegia and ataxia in patients with Miller-Fisher syndrome (MFS) and Guillain-Barré syndrome. A patient with two clinically similar episodes of progressive bulbar signs, ophthalmoplegia and ataxia is

  5. Spinocerebellar ataxia type 3: subphenotypes in a cohort of brazilian patients

    Directory of Open Access Journals (Sweden)

    Adriana Moro

    2014-09-01

    Full Text Available Spinocerebellar ataxia type 3 (SCA3 involves cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems with strong phenotypic heterogeneity, that lead us to classify the disorder into different clinical subtypes according to the predominantly affected motor systems. Method The series comprises 167 SCA3 patients belonging to 68 pedigrees, studied from 1989-2013. These patients were categorized into seven different subphenotypes. Results SCA3 cases were clustered according to the predominant clinical features. Three most common forms were subphenotype 2, characterized by ataxia and pyramidal symptom was observed in 67.5%, subphenotype 3 with ataxia and peripheral signs in 13.3%, and subphenotype 6 with pure cerebellar syndrome in 7.2%. Conclusion Our study was the first to systematically classify SCA3 into seven subphenotypes. This classification may be particularly useful for determination of a more specific and direct phenotype/genotype correlation in future studies.

  6. Amplatzer Vascular Plugs Versus Coils for Embolization of Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Tau, Noam, E-mail: taunoam@gmail.com; Atar, Eliyahu [Rabin Medical Center – Beilinson and HaSharon Campuses, Department of Diagnostic Imaging (Israel); Mei-Zahav, Meir [Schneider Children’s Medical Center of Israel, Department of Pulmonology and National HHT Center (Israel); Bachar, Gil N. [Rabin Medical Center – Beilinson and HaSharon Campuses, Department of Diagnostic Imaging (Israel); Dagan, Tamir; Birk, Einat; Bruckheimer, Elchanan [Schneider Children’s Medical Center of Israel, Institute of Pediatric Cardiology (Israel)

    2016-08-15

    PurposeCoil embolization of pulmonary arteriovenous malformations (PAVMs) has a high re-canalization/re-perfusion rate. Embolization with Amplatzer plugs has been previously described, but the long-term efficacy is not established. This study reports the experience of a referral medical center with the use of coils and Amplatzer plugs for treating PAVMs in patients with hereditary hemorrhagic telangiectasia.MethodsThe study was approved by the Institutional Review Board with waiver of informed consent. The cohort included all patients who underwent PAVM embolization in 2004–2014 for whom follow-up imaging scans were available. The medical files were retrospectively reviewed for background data, embolization method (coils, Amplatzer plugs, both), and complications. Re-canalization of treated PAVMs was assessed from intrapulmonary angiograms (following percutaneous procedures) or computed tomography angiograms. Fisher’s exact test and Pearson Chi-squared test or t test were used for statistical analysis, with significance at p < 0.05.Results16 patients met the study criteria. Imaging scans were available for 63 of the total 110 PAVMs treated in 41 procedures. Coils were used for embolization in 37 PAVMs, Amplatzer plugs in 21, and both in five. Median follow-up time was 7.7 years (range 1.4–18.9). Re-canalization was detected in seven vessels, all treated with coils; there were no cases of re-canalization in plug-occluded vessels (p = 0.0413).ConclusionThe use of Amplatzer plugs for the embolization of PAVMs in patients with hemorrhagic telangiectasia is associated with a significantly lower rate of re-canalization of feeding vessels than coils. Long-term prospective studies are required to confirm these findings.

  7. Neuropsychological Features of Patients with Spinocerebellar Ataxia (SCA) Types 1, 2, 3, and 6

    NARCIS (Netherlands)

    Klinke, I.A.; Minnerop, M.; Schmitz-Hubsch, T.; Hendriks, M.P.H.; Klockgether, T.; Wüllner, U.; Helmstaedter, C.

    2010-01-01

    A subtype-specific impairment of cognitive functions in spinocerebellar ataxia (SCA) patients is still debated. Thirty-two SCA patients (SCA1, 6; SC2, 3; SCA3, 15; SCA6, 8) and 14 matched healthy controls underwent neuropsychological evaluation testing attention, executive functions, episodic and

  8. The effectiveness of allied health care in patients with ataxia: a systematic review

    NARCIS (Netherlands)

    Fonteyn, E.M.R.; Keus, S.H.J.; Verstappen, C.C.P.; Schols, L.; Groot, I.J.M. de; Warrenburg, B.P.C. van de

    2014-01-01

    Many patients with cerebellar ataxia have serious disabilities in daily life, while pharmacological treatment options are absent. Therefore, allied health care is considered to be important in the management of these patients. The goal of this review is to evaluate scientific evidence for allied

  9. Magnetic resonance imaging findings in patients presenting with (sub)acute cerebellar ataxia

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, Tanja [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Neuroradiology, Hamburg (Germany); The Johns Hopkins Hospital School of Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Neuroradiology, Baltimore, MD (United States); Thomalla, Goetz [University Medical Center Hamburg-Eppendorf, Department of Neurology, Hamburg (Germany); Goebell, Einar [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Neuroradiology, Hamburg (Germany); Piotrowski, Anna [The Johns Hopkins University School of Medicine, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (United States); Yousem, David Mark [The Johns Hopkins Hospital School of Medicine, Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Neuroradiology, Baltimore, MD (United States)

    2015-02-17

    Acute or subacute cerebellar inflammation is mainly caused by postinfectious, toxic, neoplastic, vascular, or idiopathic processes and can result in cerebellar ataxia. Previous magnetic resonance (MR) studies in single patients who developed acute or subacute ataxia showed varying imaging features. Eighteen patients presenting with acute and subacute onset of ataxia were included in this study. Cases of chronic-progressive/hereditary and noncerebellar causes (ischemia, multiple sclerosis lesions, metastasis, bleedings) were excluded. MR imaging findings were then matched with the clinical history of the patient. An underlying etiology for ataxic symptoms were found in 14/18 patients (postinfectious/infectious, paraneoplastic, autoimmune, drug-induced). In two of five patients without MR imaging findings and three of eight patients with minimal imaging features (cerebellar atrophy, slight signal alterations, and small areas of restricted diffusion), adverse clinical outcomes were documented. Of the five patients with prominent MR findings (cerebellar swelling, contrast enhancement, or broad signal abnormalities), two were lost to follow-up and two showed long-term sequelae. No correlation was found between the presence of initial MRI findings in subacute or acute ataxia patients and their long-term clinical outcome. MR imaging was more flagrantly positive in cases due to encephalitis. (orig.)

  10. 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....

  11. Progressive interstitial renal fibrosis due to Chinese herbs in a patient with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome.

    Science.gov (United States)

    Nishimagi, E; Kawaguchi, Y; Terai, C; Kajiyama, H; Hara, M; Kamatani, N

    2001-10-01

    A 58-year-old woman with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome presented with slowly progressive renal dysfunction. She was normotensive with normal plasma renin activity and lacking symptoms of vasculitis. Mild proteinuria was of tubular origin, but serological tests and an absence of sicca symptoms excluded the possibility of Sjögren's syndrome. Light microscopic study of renal biopsy showed interstitial fibrosis with ectasia and degeneration of proximal tubule and lymphocyte infiltration. There were no remarkable changes in the glomeruli. Chromatographic analysis of the Chinese herbs regimen that she had been taking for several years demonstrated aristolochic acid. She was diagnosed as Chinese herbs nephropathy. Therapy with oral prednisolone was markedly effective in improving renal function and anemia. To our knowledge, this is the first report of Chinese herbs nephropathy complicating connective tissue disease. It is important to consider the possibility of Chinese herbs nephropathy when patients treated with Chinese herbs develop renal dysfunction.

  12. Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency.

    Science.gov (United States)

    El Euch-Fayache, Ghada; Bouhlal, Yosr; Amouri, Rim; Feki, Moncef; Hentati, Fayçal

    2014-02-01

    Ataxia with vitamin E deficiency is an autosomal recessive cerebellar ataxia caused by mutations in the α-tocopherol transfer protein coding gene localized on chromosome 8q, leading to lower levels of serum vitamin E. More than 91 patients diagnosed with ataxia with vitamin E deficiency have been reported worldwide. The majority of cases originated in the Mediterranean region, and the 744delA was the most common mutation among the 22 mutants previously described. We examined the clinical and molecular features of a large cohort of 132 Tunisian patients affected with ataxia with vitamin E deficiency. Of these patients, nerve conduction studies were performed on 45, and nerve biopsy was performed on 13. Serum vitamin E was dramatically reduced for 105 of the patients analysed. Molecular analysis revealed that 91.7% of the patients (n = 121) were homozygous for the 744delA mutation. Three other mutations were detected among the remaining patients (8.3%, n = 11) in the homozygous state. Two were previously reported (400C>T and 205-1G>T), and one was novel (553+1T>A). Age of onset was 13.2 ± 5.9 years, with extremes of 2 and 37 years. All described patients exhibited persistent progressive cerebellar ataxia with generally absent tendon reflexes. Deep sensory disturbances, pyramidal syndrome and skeletal deformities were frequent. Head tremor was present in 40% of the patients. Absence of neuropathy or mild peripheral neuropathy was noted in more than half of the cohort. This is the largest study of the genetic, clinical and peripheral neuropathic characteristics in patients with ataxia and vitamin E deficiency. The 744delA mutation represents the most common pathological mutation in Tunisia and worldwide, likely because of a Mediterranean founder effect. Our study led us to suggest that any patient displaying an autosomal recessive cerebellar ataxia phenotype with absent tendon reflexes and minor nerve abnormalities should first be screened for the 744delA mutation

  13. Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations.

    Science.gov (United States)

    Doi, Hiroshi; Koyano, Shigeru; Miyatake, Satoko; Nakajima, Shinji; Nakazawa, Yuka; Kunii, Misako; Tomita-Katsumoto, Atsuko; Oda, Kayoko; Yamaguchi, Yukie; Fukai, Ryoko; Ikeda, Shingo; Kato, Rumiko; Ogata, Katsuhisa; Kubota, Shun; Hayashi, Noriko; Takahashi, Keita; Tada, Mikiko; Tanaka, Kenichi; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Miyake, Noriko; Saitsu, Hirotomo; Ogi, Tomoo; Aihara, Michiko; Takeuchi, Hideyuki; Matsumoto, Naomichi; Tanaka, Fumiaki

    2018-02-05

    Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.

  14. Cerebellar transcranial direct current stimulation in patients with ataxia: A double-blind, randomized, sham-controlled study.

    Science.gov (United States)

    Benussi, Alberto; Koch, Giacomo; Cotelli, Maria; Padovani, Alessandro; Borroni, Barbara

    2015-10-01

    Numerous studies have highlighted the possibility of modulating the excitability of cerebellar circuits using transcranial direct current stimulation. The present study investigated whether a single session of cerebellar anodal transcranial direct current stimulation could improve symptoms in patients with ataxia. Nineteen patients with ataxia underwent a clinical and functional evaluation pre- and post-double-blind, randomized, sham, or anodal transcranial direct current stimulation. There was a significant interaction between treatment and time on the Scale for the Assessment and Rating of Ataxia, on the International Cooperative Ataxia Rating Scale, on the 9-Hole Peg Test, and on the 8-Meter Walking Time (P cerebellar transcranial direct current stimulation can transiently improve symptoms in patients with ataxia and might represent a promising tool for future rehabilitative approaches. © 2015 International Parkinson and Movement Disorder Society.

  15. Cerebellar peduncle injury in patients with ataxia following diffuse axonal injury.

    Science.gov (United States)

    Hong, Ji Heon; Kim, Oh Lyong; Kim, Seong Ho; Lee, Mi Young; Jang, Sung Ho

    2009-08-28

    No diffusion tensor imaging (DTI) study has yet investigated ataxia in diffuse axonal injury (DAI). In the current study, we used DTI to investigate cerebellar peduncle lesions of patients who showed severe ataxia following DAI. Six patients with severe ataxia following DAI and six age-and sex-matched control subjects were recruited. DTIs were acquired using a sensitivity-encoding head coil on a 1.5T system. Using DTI-Studio software, three cerebellar peduncles (superior cerebellar peduncle, SCP; middle cerebellar peduncle, MCP; inferior cerebellar peduncle, ICP) were evaluated. In each cerebellar peduncle, fractional anisotropy was estimated using the regions of interest method. We defined a lesion as a fractional anisotropy value two standard deviations below that of normal controls. All six patients had an average of 6.3 lesions (range 3-12). Twenty of 36 total cerebellar peduncles revealed more than one lesion (SCP: 8, ICP: 7, MCP: 5). In each of the 20 cerebellar peduncles, all the lesions displaying the lowest FA values relative to that of normal controls (11 peduncles; 55%) were located in the junction between brain stem and cerebellum and post-junctional area (nine peduncles; 45%). The junction and peri-junctional areas between the brain stem and cerebellum appear to be the most vulnerable area by DAI, with the order of incidence SCP, ICP, and MCP. Evaluation of the cerebellar peduncles using DTI can be helpful in patients with ataxia following DAI.

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

    Science.gov (United States)

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

    2017-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Chiara Sartor

    2013-07-01

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

  18. Cerebellar Ataxia.

    Science.gov (United States)

    Perlman

    2000-05-01

    There is nothing more discouraging than for a patient to be given a specific diagnosis, then to be told that there is nothing that can be done. Physicians are equally disheartened to see exponential progress being made in the understanding of the pathophysiology of a complex disorder but few direct benefits resulting for their patients. Over the past 5 years, molecular genetic research has completely revolutionized the way in which the progressive cerebellar ataxias are classified and diagnosed, but it has yet to produce effective gene-based, neuroprotective, or neurorestorative therapies. The treatment of cerebellar ataxia remains primarily a neurorehabilitation challenge, employing physical, occupational, speech, and swallowing therapy; adaptive equipment; driver safety training; and nutritional counseling. Modest additional gains are seen with the use of medications that can improve imbalance, incoordination, or dysarthria (amantadine, buspirone, acetazolamide); cerebellar tremor (clonazepam, propranolol); and cerebellar or central vestibular nystagmus (gabapentin, baclofen, clonazepam). Many of the progressive cerebellar syndromes have associated features involving other neurologic systems (eg, spasticity, dystonia or rigidity, resting or rubral tremor, chorea, motor unit weakness or fatigue, autonomic dysfunction, peripheral or posterior column sensory loss, neuropathic pain or cramping, double vision, vision and hearing loss, dementia, and bowel, bladder, and sexual dysfunction), which can impede the treatment of the ataxic symptoms or can worsen with the use of certain drugs. Treatment of the associated features themselves may in turn worsen the ataxia either directly (as side effects of medication) or indirectly (eg, relaxation of lower limb spasticity that was acting as a stabilizer for an ataxic gait). Secondary complications of progressive ataxia can include deconditioning or immobility, weight loss or gain, skin breakdown, recurrent pulmonary and

  19. Can Latent Class Analysis Be Used to Improve the Diagnostic Process in Pediatric Patients with Chronic Ataxia?

    Science.gov (United States)

    Klassen, Samantha; Dufault, Brenden; Salman, Michael S

    2017-04-01

    Chronic ataxia is a relatively common symptom in children. There are numerous causes of chronic ataxia, making it difficult to derive a diagnosis in a timely manner. We hypothesized that the efficiency of the diagnostic process can be improved with systematic analysis of clinical features in pediatric patients with chronic ataxia. Our aim was to improve the efficiency of the diagnostic process in pediatric patients with chronic ataxia. A cohort of 184 patients, aged 0-16 years with chronic ataxia who received medical care at Winnipeg Children's Hospital during 1991-2008, was ascertained retrospectively from several hospital databases. Clinical details were extracted from hospital charts. The data were compared among the more common diseases using univariate analysis to identify pertinent clinical features that could potentially improve the efficiency of the diagnostic process. Latent class analysis was then conducted to detect unique patterns of clinical features and to determine whether these patterns could be associated with chronic ataxia diagnoses. Two models each with three classes were chosen based on statistical criteria and clinical knowledge for best fit. Each class represented a specific pattern of presenting symptoms or other clinical features. The three classes corresponded to a plausible and shorter list of possible diagnoses. For example, developmental delay and hypotonia correlated best with Angelman syndrome. Specific patterns of presenting symptoms or other clinical features can potentially aid in the initial assessment and diagnosis of pediatric patients with chronic ataxia. This will likely improve the efficiency of the diagnostic process.

  20. Intravenous Bevacizumab Therapy in a Patient with Hereditary Hemorrhagic Telangiectasia, ENG E137K, Alcoholic Cirrhosis, and Portal Hypertension

    Directory of Open Access Journals (Sweden)

    Luigi F. Bertoli

    2017-05-01

    Full Text Available Intravenous bevacizumab decreased mucosal bleeding in some patients with hereditary hemorrhagic telangiectasia (HHT. We treated a 47-year-old male who had HHT, severe epistaxis, and gastrointestinal bleeding, alcoholic cirrhosis, and portal hypertension with intravenous bevacizumab 2.5 mg/kg every 2 weeks. We tabulated these measures weekly during weeks 1–33 (no bevacizumab; 34–57 (bevacizumab; and 58–97 (no bevacizumab: hemoglobin (Hb levels; platelet counts; units of transfused packed erythrocytes (PRBC units; and quantities of iron infused as iron dextran to support erythropoiesis. We performed univariate and multivariable analyses. We sequenced his ENG and ACVRL1 genes. Epistaxis and melena decreased markedly during bevacizumab treatment. He reported no adverse effects due to bevacizumab. Mean weekly Hb levels were significantly higher and mean weekly PRBC units and quantities of intravenous iron were significantly lower during bevacizumab treatment. We performed a multiple regression on weekly Hb levels using these independent variables: bevacizumab treatment (dichotomous; weekly platelet counts; weekly PRBC units; and weekly quantities of intravenous iron. There was 1 positive association: (bevacizumab treatment; p = 0.0046 and 1 negative association (PRBC units; p = 0.0004. This patient had the novel ENG mutation E137K (exon 4; c.409G→A. Intravenous bevacizumab treatment 2.5 mg/kg every 2 weeks for 24 weeks was well-tolerated by a patient with HHT due to ENG E137K and was associated with higher weekly Hb levels and fewer weekly PRBC units.

  1. [Anaesthesia for correction of scoliosis in pediatric patient with Friedreich's ataxia].

    Science.gov (United States)

    Agámez Medina, G L; Pantin, E J; Lorthé, J; Therrien, P J

    2015-01-01

    Friedreich ataxia (FA) is an inherited autosomal recessive disease characterized by a neurological degenerative process of the cerebellum, spinal cord, and peripheral nerves. FA is associated with ataxia, dysarthria, motor and sensory impairment, scoliosis, cardiomyopathy, and diabetes. There is a significant risk of perioperative major complications during the anesthetic management of these patients. We present the case of a fourteen-year-old patient with FA, who had a posterior spinal fusion and instrumentation underwent to total intravenous anesthesia. Copyright © 2013 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

  2. Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich's Ataxia.

    Science.gov (United States)

    Gramegna, Laura Ludovica; Tonon, Caterina; Manners, David Neil; Pini, Antonella; Rinaldi, Rita; Zanigni, Stefano; Bianchini, Claudio; Evangelisti, Stefania; Fortuna, Filippo; Carelli, Valerio; Testa, Claudia; Lodi, Raffaele

    2017-02-01

    Friedreich's ataxia (FRDA) is the commonest autosomal recessive ataxia, caused by GAA triplet expansion in the frataxin gene. Neuropathological studies in FRDA demonstrate that besides the primary neurodegeneration of the dorsal root ganglia, there is a progressive atrophy of the cerebellar dentate nucleus. Diffusion-weighted imaging (DWI) detected microstructural alterations in the cerebellum of FRDA patients. To investigate the biochemical basis of these alterations, we used both DWI and proton MR spectroscopy (1H-MRS) to study the same cerebellar volume of interest (VOI) including the dentate nucleus. DWI and 1H-MRS study of the left cerebellar hemisphere was performed in 28 genetically proven FRDA patients and 35 healthy controls. In FRDA mean diffusivity (MD) values were calculated for the same 1H-MRS VOI. Clinical severity was evaluated using the International Cooperative Ataxia Rating Scale (ICARS). FRDA patients showed a significant reduction of N-acetyl-aspartate (NAA), a neuroaxonal marker, and choline (Cho), a membrane marker, both expressed relatively to creatine (Cr), and increased MD values. In FRDA patients NAA/Cr negatively correlated with MD values (r = -0.396, p = 0.037) and with ICARS score (r = -0.669, p cerebellar NAA/Cr in FRDA suggests that neuroaxonal loss is related to the microstructural changes determining higher MD values. The correlation between NAA/Cr and the severity of disability suggests that this biochemical in vivo MR parameter might be a useful biomarker to evaluate therapeutic interventions.

  3. Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia.

    Science.gov (United States)

    Benussi, Alberto; Dell'Era, Valentina; Cotelli, Maria Sofia; Turla, Marinella; Casali, Carlo; Padovani, Alessandro; Borroni, Barbara

    Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. The present study investigated whether a two-weeks' treatment with cerebellar anodal tDCS could improve symptoms in patients with neurodegenerative cerebellar ataxia and could modulate cerebello-motor connectivity, at short and long term. We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia. Each patient underwent a clinical evaluation pre- and post-anodal tDCS or sham stimulation. A follow-up evaluation was performed at one and three months. Cerebello-motor connectivity was evaluated using transcranial magnetic stimulation (TMS) at baseline and at follow-up. Patients who underwent anodal tDCS showed a significant improvement in all performance scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale, 9-hole peg test, 8-m walking time) and in cerebellar brain inhibition compared to patients who underwent sham stimulation. A two-weeks' treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Absceso intramedular en paciente con enfermedad de Rendu-Osler-Weber Spinal abscess in a patient with hereditary hemorrhagic telangiectasia

    Directory of Open Access Journals (Sweden)

    Lorena V Maldonado

    2007-12-01

    Full Text Available La enfermedad de Rendu-Osler-Weber es una enfermedad autosómica dominante que se manifiesta por telangiectasias en piel y mucosas y malformaciones arteriovenosas en diversos órganos. El compromiso neurológico puede ocurrir por la presencia de malformaciones arterio-venosas cerebrales, hemorragia intracraneal, y más habitualmente por accidentes cerebrovasculares isquémicos y abscesos cerebrales secundarios a embolia paradojal, en pacientes con malformaciones arteriovenosas pulmonares. El absceso intramedular es una entidad rara, inusual como complicación de la enfermedad de Rendu-Osler-Weber. Presentamos el caso de una mujer de 56 años de edad, con antecedentes familiares de enfermedad de Rendu-Osler- Weber, que ingresó a Terapia Intensiva con cuadriplejia aguda e hipoxemia, en quien se diagnosticó fístulas arteriovenosas pulmonares y un absceso intramedular cervical.Rendu-Osler-Weber syndrome is an autosomal dominant disorder characterized by multiple skin and mucosal telangiectasis and multiorgan arteriovenous malformations. Neurological manifestations may occur because of cerebral arteriovenous malformations, intracranial hemorrhage, and most commonly by ischemic stroke and brain abscess secondary to paradoxical embolization in patients with pulmonary arteriovenous malformations. Intramedullary abscess is a rare, unusual condition, in Rendu-Osler-Weber syndrome. We report the case of a 56 years old woman, with a familial history of Rendu-Osler-Weber syndrome, admitted to intensive care with acute quadriplegia and hypoxemia. Our diagnosis was pulmonary arteriovenous malformations and intramedullary abscess.

  5. Different treatment modalities for choroidal neovascularization in two eyes of one patient with bilateral type 2A parafoveal telangiectasia

    Directory of Open Access Journals (Sweden)

    Vivek Dave

    2013-01-01

    Full Text Available A 60-year-old diabetic man presented with a history of decrease in vision in both eyes since 2 weeks. At presentation, best corrected visual acuity (BCVA in the right eye (RE was 20/30 and that in the left eye (LE was 20/80. The right fundus revealed a grayish reflex, yellowish crystalline deposits and retinal pigment epithelial hyperplasia at the macula. The left fundus showed subretinal fluid and temporal subretinal hemorrhage near a grayish reflex at the macula. A diagnosis in both eyes of idiopathic macular telangiectasia (IMT type 2A with RE stage 4 and LE stage 5, choroidal neovascularization (CNVM was made. The patient was treated with photodynamic therapy (PDT in LE. The visual acuity improved to 20/40 over the next 6 months. At a 4-year follow-up, he developed decreased vision in RE diagnosed as IMT with CNV and was treated with intravitreal ranibizumab. At 6-month follow-up post injection, the vision was 20/40p.

  6. Cerebellar Dysfunction and Ataxia in Patients with Epilepsy: Coincidence, Consequence, or Cause?

    Science.gov (United States)

    Marcián, Václav; Filip, Pavel; Bareš, Martin; Brázdil, Milan

    2016-01-01

    Basic epilepsy teachings assert that seizures arise from the cerebral cortex, glossing over infratentorial structures such as the cerebellum that are believed to modulate rather than generate seizures. Nonetheless, ataxia and other clinical findings in epileptic patients are slowly but inevitably drawing attention to this neural node. Tracing the evolution of this line of inquiry from the observed coincidence of cerebellar atrophy and cerebellar dysfunction (most apparently manifested as ataxia) in epilepsy to their close association, this review considers converging clinical, physiological, histological, and neuroimaging evidence that support incorporating the cerebellum into epilepsy pathology. We examine reports of still controversial cerebellar epilepsy, studies of cerebellar stimulation alleviating paroxysmal epileptic activity, studies and case reports of cerebellar lesions directly associated with seizures, and conditions in which ataxia is accompanied by epileptic seizures. Finally, the review substantiates the role of this complex brain structure in epilepsy whether by coincidence, as a consequence of deleterious cortical epileptic activity or antiepileptic drugs, or the very cause of the disease. PMID:27375960

  7. 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 ...

  8. Effects of different exercise modalities on ataxia in multiple sclerosis patients: a randomized controlled study.

    Science.gov (United States)

    Salcı, Yeliz; Fil, Ayla; Armutlu, Kadriye; Yildiz, F Gökçem; Kurne, Aslı; Aksoy, Songül; Nurlu, Gülay; Karabudak, Rana

    2017-12-01

    To investigate the effects of different exercise protocols on ataxia in patients with multiple sclerosis (MS). A total of 42 MS patients, 17 male and 25 female (Expanded Disability Status Scale (EDSS): 3-5), were enrolled in this randomized controlled study. The patients were divided into three groups: a balance training (BT) group, a lumbar stabilization (LS) group and a task-oriented training (TT) group. All groups received balance training; additionally, the LS group received lumbar stabilization exercises, and the TT group received task-oriented training. The Berg Balance Scale (BBS), International Cooperative Ataxia Rating Scale (ICARS), Functional Reach Test (FRT), 2-Minute Walk Test (2MWT), Sensory Organization Test (SOT), and measurement of Somatosensory Evoked Potentials (SSEPs) were performed before and at the end of the 18 training sessions. The BBS, ICARS, FRT, 2MWT, and composite balance score of the SOT were improved in all groups. The ICARS kinetic function sub-score and the left limb cortical onset amplitudes of SSEPs were increased significantly in both the TT and the LS groups. The ICARS total score, composite balance score, and 2MWT were different between groups (p  0.005). The 2MWT results were better for the LS group than the BT group, while the BT and the TT groups improved similarly. Balance training alone is not sufficient for rehabilitation of ataxic MS patients. A combination of lumbar stabilization exercises or task-oriented training increases the success of balance rehabilitation. Implications for rehabilitation Multiple sclerosis is a chronic inflammatory and autoimmune disease of central nervous system and ataxia is one of the most challenging symptoms of this disease. Different exercise modalities are commonly employed to control ataxic symptoms in MS patients. Lumbar stabilization exercises or task-oriented training should be considered as complementary approach to improve balance and coordination in ataxic multiple sclerosis

  9. Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia.

    Directory of Open Access Journals (Sweden)

    Ferdos Alaa El Din

    Full Text Available Hereditary Hemorrhagic Telangiectasia syndrome (HHT or Rendu-Osler-Weber (ROW syndrome is an autosomal dominant vascular disorder. Two most common forms of HHT, HHT1 and HHT2, have been linked to mutations in the endoglin (ENG and activin receptor-like kinase 1 (ACVRL1or ALK1 genes respectively. This work was designed to examine the pathogenicity of 23 nucleotide variations in ACVRL1 gene detected in more than 400 patients. Among them, 14 missense mutations and one intronic variant were novels, and 8 missense mutations were previously identified with questionable implication in HHT2. The functionality of missense mutations was analyzed in response to BMP9 (specific ligand of ALK1, the maturation of the protein products and their localization were analyzed by western blot and fluorescence microscopy. The splicing impairment of the intronic and of two missense mutations was examined by minigene assay. Functional analysis showed that 18 out of 22 missense mutations were defective. Splicing analysis revealed that one missense mutation (c.733A>G, p.Ile245Val affects the splicing of the harboring exon 6. Similarly, the intronic mutation outside the consensus splicing sites (c.1048+5G>A in intron 7 was seen pathogenic by splicing study. Both mutations induce a frame shift creating a premature stop codon likely resulting in mRNA degradation by NMD surveillance mechanism. Our results confirm the haploinsufficiency model proposed for HHT2. The affected allele of ACVRL1 induces mRNA degradation or the synthesis of a protein lacking the receptor activity. Furthermore, our data demonstrate that functional and splicing analyses together, represent two robust diagnostic tools to be used by geneticists confronted with novel or conflicted ACVRL1 mutations.

  10. Prevalence of hereditary hemorrhagic telangiectasia in patients operated for cerebral abscess

    DEFF Research Database (Denmark)

    Larsen, Lykke; Rostgaard Marker, Christian; Kjeldsen, Anette Drøhse

    2017-01-01

    previously described. A retrospective study was carried out of all patients treated surgically for CA between January 1995 and September 2014 at the Department of Neurosurgery, Odense University Hospital. The cases were then cross-referenced with the Danish HHT database. Eighty patients aged 5–79 years were...

  11. Two patients with spinocerebellar ataxia type 7 presenting with profound binocular visual loss yet minimal ophthalmoscopic findings

    Science.gov (United States)

    Thurtell, Matthew J.; Fraser, J. Alexander; Bala, Elisa; Tomsak, Robert L.; Biousse, Valérie; Leigh, R. John; Newman, Nancy J.

    2010-01-01

    We report two patients with genetically-confirmed spinocerebellar ataxia type 7 (SCA-7), who presented with progressive central visual loss and dyschromatopsia. Ocular funduscopic changes were subtle, with only mild retinal artery attenuation and subtle macular changes. Despite this, the electroretinogram (ERG) was abnormal in both patients. Both patients also had slowing of saccades and partially limited ductions, although neither reported diplopia. Although the older patient had cerebellar ataxia, the younger only had an unsteady tandem gait. This constellation of signs should indicate SCA-7 as a diagnostic possibility, and prompt further investigation with ERG and genetic studies. PMID:19726939

  12. Ataxia and tremor due to lesions involving cerebellar projection pathways: a DTI tractographic study in six patients.

    Science.gov (United States)

    Marek, M; Paus, S; Allert, N; Mädler, B; Klockgether, T; Urbach, H; Coenen, V A

    2015-01-01

    Focal lesions of brainstem, thalamus, and subcortical white matter may cause movement disorders that are clinically indistinguishable from cerebellar symptoms. It is suspected that ataxia in these cases is due to damage of efferent or afferent pathways of the cerebellum. However, the precise anatomical correlate often remains undefined. We used deterministic diffusion tensor magnetic resonance imaging (DTI) tractography to study the anatomical relationship between lesions causing ataxia and efferent cerebellar pathways. Study subjects were six male patients with focal lesions of different etiology (demyelination, hemorrhage, ischemia, neoplasm) outside the cerebellum. Five patients had cerebellar-like ataxia with prominent contralateral upper limb involvement. One patient with an almost midline mesencephalic lesion had a symmetrical ataxic syndrome. We used 3T MRI (Intera, Philips Medical Systems, Best, Netherlands) and DTI tractography (32 directions, StealthViz DTI, Medtronic Navigation, Louisville, USA) to delineate the dentato-rubro-thalamo-cortical tract (DRT). In all patients, tractography demonstrated focal lesions affecting the DRT in different locations. We conclude that in vivo mapping of cerebral pathways using DTI tractography in patients with focal extracerebellar brain lesions may provide direct evidence of circumscribed damage to the DRT, causing unilateral cerebellar-like ataxia. Also, a unilateral mesencephalic lesion at the level of the crossing of the DRT may cause bilateral ataxia.

  13. 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.

  14. Evaluation of acetazolamine response in patients with cerebellar ataxia using dynamic quantitative F-18-FDG PET

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Y. K.; Lee, D. S.; Lee, J. S.; Kim, M. H.; Lee, K. M.; Yeo, J. S.; Chung, J. K.; Lee, M. C. [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

    2001-07-01

    Cerebellar Ataxia (CA) usually shows dramatic response to acetazolamide treatment. But few cases of acetazolamide unresponse CA were reported recently. Using dynamic FDG PET, we tried to evaluate the metabolic abnormality and its drug response in CA. Quantitative F-18-FDG PET was performed prior and after treatment of acetazolamide (250 mg qid for 10 days) in two patient suspected episodic cerebellar ataxia. Using Model-based clustering method, the regional cerebral glucose metabolic rate (rCMRglu) was calculated. Two patients showed different treatment response to acetazolamide. In one patient who showed markedly reduced frequency of the ataxic attack after treatment. FDG PET showed that mean cerebellar glucose metabolism was increased after treatment ({delta}rCMRglu:9%). However, in the other who showed poor response to acetazolamide, FDG PET showed the more decrease metabolism in cerebellar metabolism after treatment ({delta}rCMRglu:-17%). The change of the cerebellar glucose metabolism on FDG PET reflected the symptomatic improvement after acetazolamide in these two CA patients. We could expected that FDG PET might be a very useful tool to quantitatively predict the treatment response in CA and other neurologic disorder.

  15. SCA1 patients may present as hereditary spastic paraplegia and must be included in spastic-ataxias group.

    Science.gov (United States)

    Pedroso, José Luiz; de Souza, Paulo Victor Sgobbi; Pinto, Wladimir Bocca Vieira de Rezende; Braga-Neto, Pedro; Albuquerque, Marcus Vinicius Cristino; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Barsottini, Orlando Graziani Povoas

    2015-10-01

    The combination of cerebellar ataxia and spasticity is common. However, autosomal dominant genetic diseases presenting with spastic-ataxia are a smaller group. Pyramidal signs have been frequently observed in several SCA subtypes, particularly in spinocerebellar ataxia type 1. We prospectively evaluated the pyramidal signs and spasticity in SCA1 patients, and correlated the data with genetic and clinical features. In this study, we observed that spasticity may be an early and presenting feature of SCA1, since 3 patients had pyramidal signs and spasticity as the first neurological sign. SCA1 patients with spasticity were significantly younger. SCA1 may rarely present with pure spastic paraplegia, resembling hereditary spastic paraplegia, before the appearance of cerebellar signs. This observation may confuse the neurologist when a genetic testing is requested for an autosomal dominant spastic paraplegia, directing research to hereditary spastic paraplegia group. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Massive Uterine Leiomyoma in a Patient with Friedreich's Ataxia: Is There a Possible Association?

    Directory of Open Access Journals (Sweden)

    Evangelos P. Misiakos

    2011-01-01

    Full Text Available A possible association between Friedreich's ataxia (FA and neoplastic development has been recognized. FA patients have low frataxin levels and insufficient response to oxidative stress. In these patients fibroblasts are characterized by a high rate of mutations. Herein, a case of a 39-year-old woman with FA tetraplegia, who was admitted in our department with intestinal obstruction due to a huge uterine tumor, is described. An abdominal CT revealed a huge intra-abdominal mass originating from the right cornu of the uterus. Tumor excision and adhesionlysis were performed. The histological examination of the tumor revealed a leiomyoma. FA patients seem to present with a variety of neoplasms uncommon for their young age. This is the first report of a leiomyoma originating from the genital system in a female patient with FA tetraplegia. Therefore it is important to identify neoplasms at an early stage in patients with FA and start immediate therapy.

  17. Temporal retinal nerve fiber loss in patients with spinocerebellar ataxia type 1.

    Directory of Open Access Journals (Sweden)

    Sarah Stricker

    Full Text Available BACKGROUND: Autosomal dominant spinocerebellar ataxia type 1 is an adult onset progressive disorder with well characterized neurodegeneration in the cerebellum and brainstem. Beyond brain atrophy, few data exist concerning retinal and optic nerve involvement. OBJECTIVE: To evaluate retinal changes in SCA1 patients compared to age and gender matched healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: Nine patients with SCA1 were prospectively recruited from the ataxia clinic and were compared to nine age and gender matched healthy controls. Both cohorts received assessment of visually evoked potentials and eye examination by optical coherence tomography to determine retinal nerve fiber layer thickness and total macular volume. While no differences were found in visually evoked potentials, SCA1 patients showed a significant reduction of mean retinal nerve fiber layer thickness (RNFLT compared to healthy controls (84±13 µm vs. 97±8 µm, p = 0.004. Temporal areas showed the most prominent RNFLT reduction with high statistical significances (temporal-inferior: p<0.001, temporal: p<0.001, temporal-superior: p = 0.005 whereas RNFLT in nasal areas was in the range of the control group. From six SCA1 patients an additional macular scan was obtained. The comparison to the corresponding healthy control showed a slight but not significant reduction in TMV (8.22±0.68 mm(3 vs. 8.61±0.41 mm(3, p = 0.15. CONCLUSION: In SCA1 patients, we found evidence for degeneration of retinal nerve fibers. The temporal focus of the observed retinal nerve fiber layer reduction suggests an involvement of the papillo-macular bundle which resembles pathology found in toxic or mitochondrial optic nerve disease such as Leber's hereditary optic neuropathy (LHON or dominant optic atrophy (DOA.

  18. Attention for action? Examining the link between attention and visuomotor control deficits in a patient with optic ataxia.

    Science.gov (United States)

    Striemer, Christopher; Locklin, Jason; Blangero, Annabelle; Rossetti, Yves; Pisella, Laure; Danckert, James

    2009-05-01

    The classic definition of 'pure' optic ataxia suggests that these patients' visuomotor impairments are independent of perceptual or attentional deficits. More recent work suggests that some patients with optic ataxia also have difficulty attending to targets in their ataxic field. Thus, an important question is whether these attentional deficits might be related to the well-known problems in visuomotor control evident in these patients. To investigate this question we had controls (N=5) and CF, a patient with optic ataxia in his left visual field, perform tasks that required them to detect or reach towards targets presented in either central vision, or at different target eccentricities in the periphery. As expected, CF was less accurate than controls when reaching to targets in his ataxic (left) visual field, and was much slower than controls to detect the presence of targets in his ataxic field. The reaction times to lift the hand in the pointing and the detecting conditions were correlated in the ataxic field of patient CF, suggesting a common attentional deficit in both tasks. Importantly, although CF was slower to detect targets in the ataxic field, and less accurate to reach towards those same targets, the two deficits did not follow the same pattern. Specifically, only reaching errors in the ataxic field were strongly modulated by target eccentricity. These results suggest that dorsal posterior parietal lesions result in attention and visuomotor control problems in optic ataxia that arise from damage to independent mechanisms.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Hereditary hemorrhagic telangiectasia (HHT), an inherited vascular disorder, is, in the majority of cases (85%), caused by mutations in one of three genes (ENG, ACVRL1, and SMAD4). In the remaining group of individuals with clinical HHT, mutations have not been identified, suggesting yet...... had a different vascular-anomaly syndrome, the suspicion that BMP9 mutations might cause HHT remained. To evaluate if germline mutations in BMP9 can be identified in HHT patients, we investigated the Danish and the French Lyon cohort of mutation-negative and clinically definite HHT patients. Exons...... and exon-intron boundaries of BMP9 were analyzed by bi-directional Sanger sequencing in 28 clinical HHT patients (from 28 different families) with no pathogenic mutations in ENG, ACVRL1 or SMAD4. No mutations of potential pathogenicity were identified in BMP9. This study does not suggest that BMP9...

  20. Atypical Friedreich ataxia in patients with FXN p.R165P point mutation or comorbid hemochromatosis

    DEFF Research Database (Denmark)

    Ygland, Emil; Taroni, Franco; Gellera, Cinzia

    2014-01-01

    BACKGROUND: Compound heterozygosity for a trinucleotide repeat expansion and a point mutation in the FXN gene is a rare cause of Friedreich ataxia (FRDA). METHODS: We identified three Swedish FRDA patients with an FXN p.R165P missense mutation and compared their clinical features with six...

  1. 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...

  2. 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...

  3. Two patients with spinocerebellar ataxia type 7 presenting with profound binocular visual loss yet minimal ophthalmoscopic findings

    OpenAIRE

    Thurtell, Matthew J.; Fraser, J. Alexander; Bala, Elisa; Tomsak, Robert L.; Biousse, Valérie; Leigh, R. John; Newman, Nancy J.

    2009-01-01

    We report two patients with genetically-confirmed spinocerebellar ataxia type 7 (SCA-7), who presented with progressive central visual loss and dyschromatopsia. Ocular funduscopic changes were subtle, with only mild retinal artery attenuation and subtle macular changes. Despite this, the electroretinogram (ERG) was abnormal in both patients. Both patients also had slowing of saccades and partially limited ductions, although neither reported diplopia. Although the older patient had cerebellar ...

  4. 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.

  5. 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.

  6. 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.

  7. Health-related quality of life in patients with spinocerebellar ataxia.

    Science.gov (United States)

    Sánchez-López, C R; Perestelo-Pérez, L; Escobar, A; López-Bastida, J; Serrano-Aguilar, P

    2017-04-01

    The progressive deterioration of patients with spinocerebellar ataxia (SCA) has a major impact on their health-related quality of life (HRQOL). This study evaluates HRQOL in a sample of patients diagnosed with SCA and aims to estimate the predictive ability of a set of sociodemographic variables for the different dimensions of the General Health Questionnaire. A total of 80 patients diagnosed with SCA were assessed using a sociodemographic questionnaire and the SF-36 General Health Questionnaire. The sociodemographic variables studied were sex, age, presence of a carer, employment status, and time elapsed from diagnosis of the disease. The 8 subscales of the SF-36 show positive and significant correlations to one another. Mean scores obtained on each SF-36 subscale differ between women and men, although this difference is significant only on the general health subscale, with men scoring higher than women. We found significant age differences on the vitality and social function subscales, with higher scores among younger patients (total variance of the questionnaire. The SF-36 is a valid and useful instrument for evaluating HRQOL in patients diagnosed with SCA. Presence of a carer seems to be a determinant of self-perceived quality of life in these patients. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia

    DEFF Research Database (Denmark)

    Brusgaard, K; Kjeldsen, A D; Poulsen, L

    2004-01-01

    Hereditary haemorrhagic telangiectasia (HHT) is a rare disorder with one per 6000-10,000 affected individuals in the general Caucasian population. HHT is genetically heterogeneous, involving at least two loci HHT1 mapping to chromosome 9q34.1 and HHT2 mapping to chromosome 12q31. The loci have been...... identified as endoglin (ENG) and activin receptor-like kinase 1 (ALK1). In order to gain knowledge of the genotype distribution and prevalence in the Danish population and to establish a reproducible and sensitive molecular genetic test method, we developed a denaturating gradient gel electrophoresis...... protocol for mutation scanning of the two loci. Twenty-five Danish HHT families were tested. A total of eight new as well as seven previously reported mutations were identified. A founder mutation was characterized present in seven families and possibly introduced around 350 years ago. In one individual...

  9. 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.

  10. 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. ...

  11. Polg mutation in a patient with recurrent major depression, cardiomyopathy and ataxia

    NARCIS (Netherlands)

    Verhoeven, W.M.A.; Egger, J.I.M.; Kremer, H.P.H.; Pont, B.J.H.B. de; Marcelis, C.L.M.

    2012-01-01

    Introduction Spinocerebellar ataxias represent a heterogeneous group of neurodegenerative disorders. Over the last decade, novel mitochondrial genetic diseases have been identified in which mutations in DNA polymerase γ (POLG) gene are involved. POLG1 is essential for mitochondrial (mt) DNA

  12. Walking Exercise in Water Improving Practical Ambulation in a Patient with Chronic Cerebellar Ataxia

    OpenAIRE

    池永, 康規; 豊田, 多喜子; 八幡, 徹太郎; 染矢, 富士子; 立野, 勝彦

    2002-01-01

    The specific effect of general dynamic water exercise in 41 year-old woman with chronic cerebellar ataxia induced by meningitis was observed. She was conservatively treated and took bed rest for two weeks, and she suffered from severe dynamic and static ataxia. And exercise under weight-bearing and bandage pressure and Frenkel exercise was applied for nine months. However her disability was not improved. And then she took a 30-minute walking practice in water twice weekly. After that training...

  13. 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.

  14. Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3.

    Science.gov (United States)

    Barca, E; Musumeci, O; Montagnese, F; Marino, S; Granata, F; Nunnari, D; Peverelli, L; DiMauro, S; Quinzii, C M; Toscano, A

    2016-08-01

    Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10 , while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. 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.

  16. 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...

  17. Social and Cultural Elements Associated with Neurocognitive Dysfunctions in Spinocerebellar Ataxia Type 2 Patients

    Science.gov (United States)

    Mercadillo, Roberto Emmanuele; Galvez, Víctor; Díaz, Rosalinda; Paredes, Lorena; Velázquez-Moctezuma, Javier; Hernandez-Castillo, Carlos R.; Fernandez-Ruiz, Juan

    2015-01-01

    Spinocerebellar Ataxia Type 2 (SCA2) is a rare genetic disorder producing cerebellar degeneration and affecting motor abilities. Neuroimaging studies also show neurodegeneration in subcortical and cortical regions related to emotional and social processes. From social neuroscience, it is suggested that motor and social abilities can be influenced by particular cultural dynamics so, culture is fundamental to understand the effect of brain-related alterations. Here, we present the first analysis about the cultural elements related to the SCA2 disorder in 15 patients previously evaluated with neuroimaging and psychometric instruments, and their nuclear relationships distributed in six geographical and cultural regions in Mexico. Ethnographic records and photographic and video archives about the quotidian participant’s routine were obtained from the patients, their relatives and their caregivers. The information was categorized and interpreted taking into consideration cultural issues and patients’ medical files. Our analyses suggest that most of the participants do not understand the nature of the disease and this misunderstanding favors magic and non-medical explanations. Patients’ testimonies suggest a decrease in pain perception as well as motor alterations that may be related to interoceptive dysfunctions. Relatives’ testimonies indicate patients’ lack of social and emotional interests that may be related to frontal, temporal, and cerebellar degeneration. In general, participants use their religious beliefs to deal with the disease and only a few of them trust the health system. Patients and their families are either openly rejected and ignored, tolerated or even helped by their community accordingly to different regional traits. We propose that ethnography can provide social representations to understand the patients’ alterations, to formulate neurobiological hypotheses, to develop neurocognitive interventions, and to improve the medical approach to

  18. Social and cultural elements associated with neurocognitive dysfunctions in Spinocerebellar Ataxia Type 2 patients

    Directory of Open Access Journals (Sweden)

    Roberto Emmanuele Mercadillo

    2015-06-01

    Full Text Available Spinocerebellar Ataxia Type 2 (SCA2 is a rare genetic disorder producing cerebellar degeneration and affecting motor abilities. Neuroimaging studies also show neurodegeneration in subcortical and cortical regions related to emotional and social processes. From social neuroscience it is suggested that motor and social abilities can be influenced by particular cultural dynamics so, culture is fundamental to understand the effect of brain related alterations. Here we present the first analysis about the cultural elements related to the SCA2 disorder in 15 patients previously evaluated with neuroimaging and psychometric instruments, and their nuclear relationships distributed in six geographical and cultural regions in Mexico. Ethnographic records and photographic and video archives about the quotidian participant’s routine were obtained from the patients, their relatives and their caregivers. The information was categorized and interpreted taking into consideration cultural issues and patients’ medical files. Our analyses suggest that most of the participants do not understand the nature of the disease and this misunderstanding favors magic and non-medical explanations. Patients’ testimonies suggest a decrease in pain perception as well as motor alterations that may be related to interoceptive dysfunctions. Relatives’ testimonies indicate patients’ lack of social and emotional interests that may be related to frontal, temporal and cerebellar degeneration. In general, participants use their religious beliefs to deal with the disease and only a few of them trust the health system. Patients and their families are either openly rejected and ignored, tolerated or even helped by their community accordingly to different regional traits. We propose that ethnography can provide social representations to understand the patients’ alterations, to formulate neurobiological hypotheses, to develop neurocognitive interventions, and to improve the

  19. Extensive White Matter Alterations and Its Correlations with Ataxia Severity in SCA 2 Patients

    Science.gov (United States)

    Hernandez-Castillo, Carlos R.; Galvez, Victor; Mercadillo, Roberto; Diaz, Rosalinda; Campos-Romo, Aurelio; Fernandez-Ruiz, Juan

    2015-01-01

    Background Previous studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo. Methods Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA) and mean diffusivity (MD). Significant diffusion differences were correlated with the patient's ataxia impairment. Results Our analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle. Conclusion Our findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2. PMID:26263162

  20. Extensive White Matter Alterations and Its Correlations with Ataxia Severity in SCA 2 Patients.

    Directory of Open Access Journals (Sweden)

    Carlos R Hernandez-Castillo

    Full Text Available Previous studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo.Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA and mean diffusivity (MD. Significant diffusion differences were correlated with the patient's ataxia impairment.Our analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle.Our findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2.

  1. 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

  2. Gene expression profiling of mitochondrial oxidative phosphorylation (OXPHOS complex I in Friedreich ataxia (FRDA patients.

    Directory of Open Access Journals (Sweden)

    Mohammad Hossein Salehi

    Full Text Available Friedreich ataxia (FRDA is the most frequent progressive autosomal recessive disorder associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes for the mitochondrial frataxin protein. The number of repeats correlates with disease severity, where impaired transcription of the FXN gene results in reduced expression of the frataxin protein. Gene expression studies provide insights into disease pathogenicity and identify potential biomarkers, an important goal of translational research in neurodegenerative diseases. Here, using real-time PCR (RT-PCR, the expression profiles of mitochondrial (mtDNA and nuclear DNA (nDNA genes that encode for the mitochondrial subunits of respiratory oxidative phosphorylation (OXPHOS complex I in the blood panels of 21 FRDA patients and 24 healthy controls were investigated. Here, the expression pattern of mtDNA-encoded complex I subunits was distinctly different from the expression pattern of nDNA-encoded complex I subunits, where significant (p<0.05 down-regulation of the mitochondrial ND2, ND4L, and ND6 complex I genes, compared to controls, were observed. In addition, the expression pattern of one nDNA-encoded gene, NDUFA1, was significantly (p<0.05 down-regulated compared to control. These findings suggest, for the first time, that the regulation of complex I subunit expression in FRDA is complex, rather than merely being a reflection of global co-regulation, and may provide important clues toward novel therapeutic strategies for FRDA and mitochondrial complex I deficiency.

  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. Evidence of oxidative stress and mitochondrial dysfunction in spinocerebellar ataxia type 2 (SCA2) patient fibroblasts

    DEFF Research Database (Denmark)

    Cornelius, Nanna; Wardman, Jonathan H; Hargreaves, Iain P

    2017-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-2 gene. We show increased oxidative stress, abnormalities in the antioxidant system, changes in complexes involved in oxidative phosphorylation and changes in mitochondrial...

  5. 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...

  6. 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...

  7. A novel de novo exon 21 DNMT1 mutation causes cerebellar ataxia, deafness, and narcolepsy in a Brazilian patient.

    Science.gov (United States)

    Pedroso, José Luiz; Povoas Barsottini, Orlando Graziani; Lin, Ling; Melberg, Atle; Oliveira, Acary S B; Mignot, Emmanuel

    2013-08-01

    Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is caused by DNMT1 mutations. Diagnosing the syndrome can be difficult, as all clinical features may not be present at onset, HLA-DQB1*06:02 is often negative, and sporadic cases occur. We report on clinical and genetic findings in a 31-year-old woman with cerebellar ataxia, deafness, and narcolepsy, and discuss diagnostic challenges. Clinical and genetic investigation in a patient and family members. Ataxia clinic, São Paulo, Brazil. One patient and her family members. N/A. Narcolepsy was supported by polysomnographic and multiple sleep latency testing. HLA-DQB1*06:02 was positive. CSF hypocretin-1 was 191 pg/mL (normal values > 200 pg/mL). Mild brain atrophy was observed on MRI, with cerebellar involvement. The patient, her asymptomatic mother, and 3 siblings gave blood samples for genetic analysis. DNMT1 exons 20 and 21 were sequenced. Haplotyping of polymorphic markers surrounding the mutation was performed. The proband had a novel DNMT1 mutation in exon 21, p.Cys596Arg, c.1786T > C. All 4 parental haplotypes could be characterized in asymptomatic siblings without the mutation, indicating that the mutation is de novo in the patient. The Brazilian patient reported here further adds to the worldwide distribution of ADCA-DN. The mutation is novel, and illustrates a sporadic case with de novo mutation. We believe that many more cases with this syndrome are likely to be diagnosed in the near future, mandating knowledge of this condition and consideration of the diagnosis.

  8. 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

  9. KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.

    Science.gov (United States)

    Figueroa, Karla P; Minassian, Natali A; Stevanin, Giovanni; Waters, Michael; Garibyan, Vartan; Forlani, Sylvie; Strzelczyk, Adam; Bürk, Katrin; Brice, Alexis; Dürr, Alexandra; Papazian, Diane M; Pulst, Stefan M

    2010-02-01

    We recently identified KCNC3, encoding the Kv3.3 voltage-gated potassium channel, as the gene mutated in SCA13. One g.10684G>A (p.Arg420His) mutation caused late-onset ataxia resulting in a nonfunctional channel subunit with dominant-negative properties. A French early-onset pedigree with mild mental retardation segregated a g.10767T>C (p.Phe448Leu) mutation. This mutation changed the relative stability of the channel's open conformation. Coding exons were amplified and sequenced in 260 autosomal-dominant ataxia index cases of European descent. Functional analyses were performed using expression in Xenopus oocytes. The previously identified p.Arg420His mutation occurred in three families with late-onset ataxia. A novel mutation g.10693G>A (p.Arg423His) was identified in two families with early-onset. In one pedigree, a novel g.10522G>A (p.Arg366His) sequence variant was seen in one index case but did not segregate with affected status in the respective family. In a heterologous expression system, the p.Arg423His mutation exhibited dominant-negative properties. The p.Arg420His mutation, which results in a nonfunctional channel subunit, was recurrent and associated with late-onset progressive ataxia. In two families the p.Arg423His mutation was associated with early-onset slow-progressive ataxia. Despite a phenotype reminiscent of the p.Phe448Leu mutation, segregating in a large early-onset French pedigree, the p.Arg423His mutation resulted in a nonfunctional subunit with a strong dominant-negative effect. (c) 2009 Wiley-Liss, Inc.

  10. KCNC3: Phenotype, mutations, channel biophysics – a study of 260 familial ataxia patients

    Science.gov (United States)

    Figueroa, Karla P.; Minassian, Natali A.; Stevanin, Giovanni; Waters, Michael; Garibyan, Vartan; Forlani, Sylvie; Strzelczyk, Adam; Bűrk, Katrin; Brice, Alexis; Dűrr, Alexandra; Papazian, Diane M.; Pulst, Stefan-M

    2009-01-01

    We recently identified KCNC3, encoding the Kv3.3 voltage-gated potassium channel, as the gene mutated in SCA13. One g.10684G>A (p.Arg420His) mutation caused late-onset ataxia resulting in a non-functional channel subunit with dominant-negative properties. A French early-onset pedigree with mild mental retardation segregated a g.10767T>C (p.Phe448Leu) mutation. This mutation changed the relative stability of the channel’s open conformation. Coding exons were amplified and sequenced in 260 autosomal-dominant ataxia index cases of European descent. Functional analyses were performed using expression in Xenopus oocytes. The previously identified p.Arg420His mutation occurred in three families with late-onset ataxia. A novel mutation g.10693G>A (p.Arg423His) was identified in two families with early-onset. In one pedigree, a novel g.10522G>A (p.Arg366His) sequence variant was seen in one index case but did not segregate with affected status in the respective family. In a heterologous expression system, the p.Arg423His mutation exhibited dominant negative properties. The p.Arg420His mutation, results in a non-functional channel subunit was recurrent and associated with late-onset progressive ataxia. In two families the p.Arg423His mutation was associated with early-onset slow progressive ataxia. Despite a phenotype reminiscent of the p.Phe448Leu mutation, segregating in a large early-onset French pedigree, the p.Arg423His mutation resulted in a nonfunctional subunit with a strong dominant-negative effect. PMID:19953606

  11. [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.

  12. 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 ...

  13. Cerebellar TMS in treatment of a patient with cerebellar ataxia: evidence from clinical, biomechanics and neurophysiological assessments.

    Science.gov (United States)

    Farzan, Faranak; Wu, Yunfen; Manor, Brad; Anastasio, Elana M; Lough, Matthew; Novak, Vera; Greenstein, Patricia E; Pascual-Leone, Alvaro

    2013-10-01

    We describe a patient with a probable diagnosis of idiopathic late-onset cerebellar atrophy who shows improvement of limb coordination, speech, and gait following 21 days of transcranial magnetic stimulation (TMS) applied to scalp regions presumably corresponding to the cerebellum. This case study provides, for the first time, a quantitative assessment of gait improvement in response to TMS therapy in ataxia, as well as neurophysiological evidence in support of modification of cerebellar-cortical interaction that may underlie some of the improvements.

  14. Expansion of the Spinocerebellar ataxia type 10 (SCA10 repeat in a patient with Sioux Native American ancestry.

    Directory of Open Access Journals (Sweden)

    Khalaf Bushara

    Full Text Available Spinocerebellar ataxia type 10 (SCA10, an autosomal dominant cerebellar ataxia, is caused by the expansion of the non-coding ATTCT pentanucleotide repeat in the ATAXIN 10 gene. To date, all cases of SCA10 are restricted to patients with ancestral ties to Latin American countries. Here, we report on a SCA10 patient with Sioux Native American ancestry and no reported Hispanic or Latino heritage. Neurological exam findings revealed impaired gait with mild, age-consistent cerebellar atrophy and no evidence of epileptic seizures. The age at onset for this patient, at 83 years of age, is the latest documented for SCA10 patients and is suggestive of a reduced penetrance allele in his family. Southern blot analysis showed an SCA10 expanded allele of 1400 repeats. Established SNPs surrounding the SCA10 locus showed a disease haplotype consistent with the previously described "SCA10 haplotype". This case suggests that the SCA10 expansion represents an early mutation event that possibly occurred during the initial peopling of the Americas.

  15. 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.

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

    LENUS (Irish Health Repository)

    Brady, A P

    2012-01-31

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

  17. Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study.

    Science.gov (United States)

    Dupuis-Girod, Sophie; Chesnais, Anne-Laure; Ginon, Isabelle; Dumortier, Jérôme; Saurin, Jean-Christophe; Finet, Gérard; Decullier, Evelyne; Marion, Denis; Plauchu, Henri; Boillot, Olivier

    2010-03-01

    Hepatic involvement occurs in up to 74% of patients with hereditary hemorrhagic telangiectasia (HHT) and is characterized by a spectrum of arteriovenous malformations. Three different types of intrahepatic shunting may be present: hepatic artery to hepatic veins, hepatic artery to portal vein, and portal vein to hepatic vein. Hepatic involvement in HHT may lead to biliary ischemia, portal hypertension, or high-output cardiac failure (HOCF). Orthotopic liver transplantation (OLT) has been proposed as the only definitive curative treatment. The aim of this study was to evaluate the long-term outcome of patients with hepatic involvement due to HHT after OLT with respect to mortality, cardiac and hepatic status, epistaxis, and quality of life. Patients with HHT and severe hepatic vascular malformations who underwent OLT in the Lyon Liver Transplant Unit (LLTU) from 1993 to 2007 were followed at the LLTU and the French Reference Center for HHT. Quality of life was evaluated with the Short Form 36 questionnaire. There were 13 patients who fulfilled the entry criteria of the study (12 women and 1 man). The mean age at the time of OLT was 51.8 years (range = 33-65 years). Indications for OLT were cardiac failure (n = 9), biliary necrosis (n = 2), both cardiac failure and biliary necrosis (n = 1), and hemobilia (n = 1). The mean duration of follow-up was 109 months (range = 1-200 months). Twelve patients (92.3%) are still alive. For the 9 patients with HOCF, the mean cardiac index decreased from 5.4 L/minute/m(2) before OLT to 3.0 L/minute/m(2) after OLT. No severe hepatic complications were observed after OLT. Nine of the surviving patients (75%) experienced dramatic improvements in epistaxis and quality of life, including an ability to undertake more physical activity. In conclusion, OLT is an important therapeutic option for patients with HHT who have severe hepatic involvement. In the reported cohort, the mortality after OLT for this indication was low.

  18. 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.

  19. 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.

  20. Manuseio anestésico de paciente portador de telangiectasia hemorrágica hereditária (síndrome de Rendu-Osler-Weber: relato de caso Manoseo anestésico de paciente portador de telangiectasia hemorrágica hereditaria (síndrome de Rendu - Osler - Weber: relato de caso Anesthetic management of a patient with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome: case report

    Directory of Open Access Journals (Sweden)

    Alexandre Palmeira Goulart

    2009-02-01

    characterized by mucocutaneous and visceral vascular dysplasia associated with frequent episodes of epistaxis and gastrointestinal bleeding. The objective of this report was to describe the anesthesia of a patient with this syndrome. CASE REPORT: A 25 years old male patient underwent surgical correction of an orbital fracture. He had the triad of recurrent epistaxis, family history, and telangiectasia, and had been diagnosed with HHT. Pulmonary, brain, or gastrointestinal tract vascular malformations were not detected in the preoperative investigation. The patient underwent total venous anesthesia one hour after the administration of an antifibrinolytic drug. Bleeding was considered normal for this type of surgery, and hemodynamic instability or the need of perioperative blood transfusion was not detected. The patient was extubated in the operating room; he was transferred to the room after 60 minutes and discharged from the hospital after 24 hours. CONCLUSIONS: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder that leads to mucocutaneous and visceral vascular dysplasia. Perioperative blood loss can be greater than expected in patients with this syndrome. Since bleeding does not result from a defect in the coagulation cascade but from the surgical exposure of malformed vascular structures, perioperative conduct includes the use of antifibrinolytics, adequate homeostasis, and induced hypotension in the absence of contraindications. Pre-anesthetic evaluation should include the search for brain, lung, and gastrointestinal vascular malformation.

  1. Functional impairment in patients with myotonic dystrophy type 1 can be assessed by an ataxia rating scale (SARA).

    Science.gov (United States)

    DiPaolo, Giovanni; Jimenez-Moreno, Cecilia; Nikolenko, Nikoletta; Atalaia, Antonio; Monckton, Darren G; Guglieri, Michela; Lochmüller, Hanns

    2017-04-01

    Myotonic dystrophy type 1 (DM1) is not characterised by ataxia per se; however, DM1 and ataxia patients show similar disturbances in movement coordination often experiencing walking and balance difficulties, although caused by different underlying pathologies. This study aims to investigate the use of a scale previously described for the assessment and rating of ataxia (SARA) with the hypothesis that it could have utility in DM1 patients as a measure of disease severity and risk of falling. Data from 54 DM1 patients were pulled from the PHENO-DM1 natural history study for analysis. Mean SARA score in the DM1 population was 5.45 relative to the maximum score of eight. A flooring effect (score 0) was observed in mild cases within the sample. Inter-rater and test-retest reliability was high with intraclass coefficients (ICC) of 0.983 and 1.00, respectively. Internal consistency was acceptable as indicated by a Cronbach's alpha of 0.761. Component analysis revealed two principle components. SARA correlated with: (1) all measures of muscle function tested, including quantitative muscle testing of ankle dorsiflexion (r = -0.584*), the 6 min walk test (r = -0.739*), 10 m walk test (r = 0.741*), and the nine hole peg test (r = 0.602*) and (2) measures of disease severity/burden, such as MIRS (r = 0.718*), MDHI (r = 0.483*), and DM1-Activ (r = -0.749*) (*p < 0.001). The SARA score was predicted by an interaction between modal CTG repeat length and age at sampling (r = 0.678, p = 0.003). A score of eight or above predicted the use of a walking aid with a sensitivity of 100% and a specificity of 85.7%. We suggest that further research is warranted to ascertain whether SARA or components of SARA are useful outcome measures for clinical trials in DM1. As a tool, it can be used for gathering information about disease severity/burden and helping to identify patients in need of a walking aid, and can potentially be applied in both research and healthcare

  2. Identification and sizing of GAA trinucleotide repeat expansion, investigation for D-loop variations and mitochondrial deletions in Iranian patients with Friedreich's ataxia.

    Science.gov (United States)

    Houshmand, Massoud; Panahi, Mehdi Shafa Shariat; Nafisi, Shahriar; Soltanzadeh, Akbar; Alkandari, Fawziah M

    2006-04-01

    Friedreich's Ataxia (FA) is the commonest genetic cause of ataxia and is associated with the expansion of a GAA repeat in intron 1 of the frataxin gene. Iron accumulation in the mitochondria of patients with FA would result in hypersensitivity to oxidative stress. Mitochondrial DNA (mtDNA) could be considered a candidate modifier factor for FA disease, since mitochondrial oxidative stress is thought to be involved in the pathogenesis of this disease. We studied 25 Iranian patients (16 females and 9 males) from 12 unrelated families. DNA from each patient was extracted and frequency and length of (GAA)(n) repeat was analyzed using a long-range polymerase chain reaction (PCR) test. Also we investigated impact of GAA size on neurological findings, age of onset and disease development. In order to identify polymorphic sites and genetic background, the sequence of two hypervariable regions (HVR-I and HVR-II) of mtDNA was obtained from FA patients harbouring GAA trinucletide expansions. Alignment was made with the revised cambridge reference sequence (rCRS) and any differences recorded as single base substitution (SBS), insertions and deletions. Homozygous GAA expansion was found in 21 (84%) of all cases. In four cases (16%), no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, ataxia, scoliosis and pes cavus, cardiac abnormalities and some neurological findings occurred more frequently than in our patients without GAA expansion. Molecular analysis was imperative for diagnosis of Friedreich's ataxia, not only for typical cases, but also for atypical ones. Diagnosis bases only on clinical findings is limited, however, it aids in better screening for suspected cases that should be tested. Our results showed that the rate of D-loop variations was higher in FA patients than control (P<0.05). mtDNA deletions were present in 76% of our patients representing mtDNA damage, which may be due to iron accumulation in mitochondria.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. Identification of specific gait patterns in patients with cerebellar ataxia, spastic paraplegia, and Parkinson's disease: A non-hierarchical cluster analysis.

    Science.gov (United States)

    Serrao, Mariano; Chini, Giorgia; Bergantino, Matteo; Sarnari, Diego; Casali, Carlo; Conte, Carmela; Ranavolo, Alberto; Marcotulli, Christian; Rinaldi, Martina; Coppola, Gianluca; Bini, Fabiano; Pierelli, Francesco; Marinozzi, Franco

    2017-09-26

    Patients with degenerative neurological diseases such as cerebellar ataxia, spastic paraplegia, and Parkinson's disease often display progressive gait function decline that inexorably impacts their autonomy and quality of life. Therefore, considering the related social and economic costs, one of the most important areas of intervention in neurorehabilitation should be the treatment of gait abnormalities. This study aims to determine whether an entire dataset of gait parameters recorded in patients with degenerative neurological diseases can be clustered into homogeneous groups distinct from each other and from healthy subjects. Patients affected by three different types of primary degenerative neurological diseases were studied. These diseases were: i) cerebellar ataxia (28 patients), ii) hereditary spastic paraplegia (31 patients), and iii) Parkinson's disease (70 patients). Sixty-five gender-age-matched healthy subjects were enrolled as a control group. An optoelectronic motion analysis system was used to measure time-distance parameters and lower limb joint kinematics during gait in both patients and healthy controls. When clustering single parameters, step width and ankle joint range of motion (RoM) in the sagittal plane differentiated cerebellar ataxia group from the other groups. When clustering sets of two, three, or four parameters, several pairs, triples, and quadruples of clusters differentiated the cerebellar ataxia group from the other groups. Interestingly, the ankle joint RoM parameter was present in 100% of the clusters and the step width in approximately 50% of clusters. In addition, in almost all clusters, patients with cerebellar ataxia showed the lowest ankle joint RoM and the largest step width values compared to healthy controls, patients with hereditary spastic paraplegia, and Parkinson's disease subjects. This study identified several clusters reflecting specific gait patterns in patients with degenerative neurological diseases. In particular

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

    NARCIS (Netherlands)

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

    2002-01-01

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

  9. 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 ...

  10. 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.

  11. 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.

  12. Hereditary haemorrhagic Telangiectasia

    DEFF Research Database (Denmark)

    Kjeldsen, Anette Drøhse; Vase, P.; Green, Anders

    1999-01-01

    1974 in the County of Fyn, Denmark, were identified. In 1995–97 a follow-up study of mortality was performed of the initial patient sample, and a new point prevalence rate of HHT as of 1 January 1995 was calculated. All live patients and their families were invited to attend a detailed clinical...

  13. 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.

  14. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia.

    Directory of Open Access Journals (Sweden)

    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.

  15. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia.

    Science.gov (United States)

    Chen, Ying-Hao; Lee, Yi-Chung; Tsai, Yu-Shuen; Guo, Yuh-Cherng; Hsiao, Cheng-Tsung; Tsai, Pei-Chien; Huang, Jin-An; 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.

  16. 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.

  17. 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.

  18. Memory for Spatial Locations in a Patient with Near Space Neglect and Optic Ataxia: Involvement of the Occipitotemporal Stream

    Directory of Open Access Journals (Sweden)

    Sergio Chieffi

    2017-05-01

    Full Text Available Previous studies suggested that the occipitoparietal stream orients attention toward the near/lower space and is involved in immediate reaching, whereas the occipitotemporal stream orients attention toward the far/upper space and is involved in delayed reaching. In the present study, we investigated the role of the occipitotemporal stream in attention orienting and delayed reaching in a patient (GP with bilateral damage to the occipitoparietal areas and optic ataxia. GP and healthy controls took part in three experiments. In the experiment 1, the participants bisected lines oriented along radial, vertical, and horizontal axes. GP bisected radial lines farther, and vertical lines more above, than the controls, consistent with an attentional bias toward the far/upper space and near/lower space neglect. The experiment 2 consisted of two tasks: (1 an immediate reaching task, in which GP reached target locations under visual control and (2 a delayed visual reaching task, in which GP and controls were asked to reach remembered target locations visually presented. We measured constant and variable distance and direction errors. In immediate reaching task, GP accurately reached target locations. In delayed reaching task, GP overshot remembered target locations, whereas the controls undershot them. Furthermore, variable errors were greater in GP than in the controls. In the experiment 3, GP and controls performed a delayed proprioceptive reaching task. Constant reaching errors did not differ between GP and the controls. However, variable direction errors were greater in GP than in the controls. We suggest that the occipitoparietal damage, and the relatively intact occipitotemporal region, produced in GP an attentional orienting bias toward the far/upper space (experiment 1. In turns, the attentional bias selectively shifted toward the far space remembered visual (experiment 2, but not proprioceptive (experiment 3, target locations. As a whole, these

  19. 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

  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. 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.

  2. Friedreich's Ataxia

    Science.gov (United States)

    ... Barré Syndrome Information Page Headache Information Page Hemicrania Continua Information Page Hemifacial Spasm Information Page Hereditary Spastic ... the Spotlight Find NINDS Clinical Trials Patient & Caregiver Education Fact Sheets Hope Through Research Know Your Brain ...

  3. 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.

  4. 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 ...

  5. 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.

  6. [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.

  7. A Patient with Fragile X-Associated Tremor/Ataxia Syndrome Presenting with Executive Cognitive Deficits and Cerebral White Matter Lesions

    Directory of Open Access Journals (Sweden)

    Kensaku Kasuga

    2011-05-01

    Full Text Available Fragile X-associated tremor/ataxia syndrome (FXTAS is a late-onset neurodegenerative disorder that primarily affects males who are carriers of a premutation of a CGG expansion in the FMR1 gene. In Asian populations, FXTAS has rarely been reported. Here, we report the case of a Japanese FXTAS patient who showed predominant executive cognitive deficits as the main feature of his disease. In contrast, the patient exhibited only very mild symptoms of intention tremor and ataxia, which did not interfere with daily activities. A gene analysis revealed that the patient carried a premutation of a CGG expansion (111 CGG repeats in the FMR1 gene. The mRNA expression level of FMR1 in the patient was 1.5-fold higher than in controls. On brain MRI scans, fluid-attenuated inversion recovery images showed high-intensity lesions in the middle cerebellar peduncles and the cerebral white matter, with a frontal predominance. The present case extends previous notions regarding the cognitive impairment in FXTAS patients. Recognizing FXTAS patients with predominant cognitive impairment from various ethnic backgrounds would contribute to our understanding of the phenotypic variation of this disease.

  8. Gluten-related disorders: gluten ataxia.

    Science.gov (United States)

    Hadjivassiliou, Marios; Sanders, David D; Aeschlimann, Daniel P

    2015-01-01

    The term gluten-related disorders (GRD) refers to a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. They include both intestinal and extraintestinal manifestations. Gluten ataxia (GA) is one of the commonest neurological manifestations of GRD. It was originally defined as otherwise idiopathic sporadic ataxia in the presence of circulating antigliadin antibodies of IgA and/or IgG type. Newer more specific serological markers have been identified but are not as yet readily available. GA has a prevalence of 15% amongst all ataxias and 40% of all idiopathic sporadic ataxias. It usually presents with gait and lower limb ataxia. It is of insidious onset with a mean age at onset of 53 years. Up to 40% of patients have evidence of enteropathy on duodenal biopsy. Gastrointestinal symptoms are seldom prominent and are not a reliable indicator for the presence of enteropathy. Furthermore, the presence of enteropathy does not influence the response to a gluten-free diet. Most patients will stabilise or improve with strict adherence to gluten-free diet depending on the duration of the ataxia prior to the treatment. Up to 60% of patients with GA have evidence of cerebellar atrophy on MR imaging, but all patients have spectroscopic abnormalities primarily affecting the vermis. Recent evidence suggests that patients with newly diagnosed coeliac disease presenting to the gastroenterologists have abnormal MR spectroscopy at presentation associated with clinical evidence of subtle cerebellar dysfunction. The advantage of early diagnosis and treatment (mean age 42 years in patients presenting with gastrointestinal symptoms vs. 53 years in patients presenting with ataxia) may protect the first group from the development and/or progression of neurological dysfunction. © 2015 S. Karger AG, Basel.

  9. 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.

  10. Reduced cardiac {sup 123}I-metaiodobenzylguanidine uptake in patients with spinocerebellar ataxia type 2: a comparative study with Parkinson's disease

    Energy Technology Data Exchange (ETDEWEB)

    De Rosa, Anna; De Leva, Maria Fulvia; Maddaluno, Gennaro; Filla, Alessandro; De Michele, Giuseppe [University Federico II, Department of Neurosciences and Reproductive and Odontostomatologic Sciences, Naples (Italy); Pappata, Sabina; Pellegrino, Teresa [National Council of Research, Institute of Biostructure and Bioimaging, Naples (Italy); Fiumara, Giovanni [Institute of Diagnostic and Nuclear Development, SDN Foundation, Naples (Italy); Carotenuto, Raffaella; Cuocolo, Alberto [University Federico II, Department of Advanced Biomedical Sciences, Naples (Italy); Petretta, Mario [University Federico II, Department of Translational Medical Sciences, Naples (Italy)

    2013-12-15

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia, supranuclear ophthalmoplegia, and peripheral neuropathy. Autonomic nervous system dysfunction is often present. This study evaluated the cardiac sympathetic function in patients with SCA2 using {sup 123}I-metaiodobenzylguanidine (MIBG) in comparison with patients with Parkinson's disease (PD) and control subjects. Nine patients with SCA2, nine patients with PD, and nine control subjects underwent {sup 123}I-MIBG imaging studies from which early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates were calculated. Early (F = 12.3, p < 0.0001) and late (F = 16.8, p < 0.0001) H/M ratios were significantly different among groups. In controls, early and late H/M ratios (2.2 {+-} 0.12 and 2.1 {+-} 0.20) were significantly higher than in patients with SCA2 (1.9 {+-} 0.23 and 1.8 {+-} 0.20, both p < 0.05) and with patients with PD (1.7 {+-} 0.29 and 1.4 {+-} 0.35, both p < 0.001). There was also a significant difference in washout rates among groups (F = 11.7, p < 0.0001). In controls the washout rate (19.9 {+-} 9.6 %) was significantly lower (p < 0.005) than in patients with PD (51.0 {+-} 23.7 %), but not different from that in SCA2 patients (19.5 {+-} 9.4 %). In SCA2 patients, in a multivariable linear regression analysis only the Scale for the Assessment and Rating of Ataxia score was independently associated with early H/M ratio ({beta} = -0.12, p < 0.05). {sup 123}I-MIBG myocardial scintigraphy demonstrated an impairment of cardiac sympathetic function in patients with SCA2, which was less marked than in PD patients. These results suggest that {sup 123}I-MIBG cardiac imaging could become a useful tool for analysing the pathophysiology of SCA2. (orig.)

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  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. Ataxia with Vitamin E Deficiency in Norway

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    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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. Bioenergetics of the calf muscle in Friedreich ataxia patients measured by 31P-MRS before and after treatment with recombinant human erythropoietin.

    Directory of Open Access Journals (Sweden)

    Wolfgang Nachbauer

    Full Text Available Friedreich ataxia (FRDA is caused by a GAA repeat expansion in the FXN gene leading to reduced expression of the mitochondrial protein frataxin. Recombinant human erythropoietin (rhuEPO is suggested to increase frataxin levels, alter mitochondrial function and improve clinical scores in FRDA patients. Aim of the present pilot study was to investigate mitochondrial metabolism of skeletal muscle tissue in FRDA patients and examine effects of rhuEPO administration by phosphorus 31 magnetic resonance spectroscopy (31P MRS. Seven genetically confirmed FRDA patients underwent 31P MRS of the calf muscles using a rest-exercise-recovery protocol before and after receiving 3000 IU of rhuEPO for eight weeks. FRDA patients showed more rapid phosphocreatine (PCr depletion and increased accumulation of inorganic phosphate (Pi during incremental exercise as compared to controls. After maximal exhaustive exercise prolonged regeneration of PCR and slowed decline in Pi can be seen in FRDA. PCr regeneration as hallmark of mitochondrial ATP production revealed correlation to activity of complex II/III of the respiratory chain and to demographic values. PCr and Pi kinetics were not influenced by rhuEPO administration. Our results confirm mitochondrial dysfunction and exercise intolerance due to impaired oxidative phosphorylation in skeletal muscle tissue of FRDA patients. MRS did not show improved mitochondrial bioenergetics after eight weeks of rhuEPO exposition in skeletal muscle tissue of FRDA patients.EU Clinical Trials Register2008-000040-13.

  11. Avances en el tratamiento de las ataxias crónicas

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    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.

  12. 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.

  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. 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.

  15. Bone mineral density in patients with multiple sclerosis, hereditary ataxia or hereditary spastic paraplegia after at least 10 years of disease - a case control study.

    Science.gov (United States)

    Simonsen, Cecilia Smith; Celius, Elisabeth Gulowsen; Brunborg, Cathrine; Tallaksen, Chantal; Eriksen, Erik Fink; Holmøy, Trygve; Moen, Stine Marit

    2016-12-05

    Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA). We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years. In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (-2.5 < T- score < -1.0) or osteoporosis (T- score ≤ -2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers. Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases.

  16. 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.

  17. Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich's ataxia.

    Science.gov (United States)

    Stefanescu, Maria R; Dohnalek, Moritz; Maderwald, Stefan; Thürling, Markus; Minnerop, Martina; Beck, Andreas; Schlamann, Marc; Diedrichsen, Joern; Ladd, Mark E; Timmann, Dagmar

    2015-05-01

    Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich's ataxia to matched controls (P cerebellar

  18. Effect of Long-Term Climbing Training on Cerebellar Ataxia: A Case Series

    Directory of Open Access Journals (Sweden)

    Stephan Marianne Anke

    2011-01-01

    Full Text Available Background. Efficient therapy for both limb and gait ataxia is required. Climbing, a complex task for the whole motor system involving balance, body stabilization, and the simultaneous coordination of all 4 limbs, may have therapeutic potential. Objective. To investigate whether long-term climbing training improves motor function in patients with cerebellar ataxia. Methods. Four patients suffering from limb and gait ataxia underwent a 6-week climbing training. Its effect on ataxia was evaluated with validated clinical balance and manual dexterity tests and with a kinematic analysis of multijoint arm and leg pointing movements. Results. The patients increased their movement velocity and achieved a more symmetric movement speed profile in both arm and leg pointing movements. Furthermore, the 2 patients who suffered the most from gait ataxia improved their balance and 2 of the 4 patients improved manual dexterity. Conclusion. Climbing training has the potential to serve as a new rehabilitation method for patients with upper and lower limb ataxia.

  19. Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus.

    Directory of Open Access Journals (Sweden)

    Sahar Al-Mahdawi

    Full Text Available Friedreich ataxia (FRDA is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, which induces epigenetic changes and FXN gene silencing. Bisulfite sequencing studies have identified 5-methylcytosine (5 mC DNA methylation as one of the epigenetic changes that may be involved in this process. However, analysis of samples by bisulfite sequencing is a time-consuming procedure. In addition, it has recently been shown that 5-hydroxymethylcytosine (5 hmC is also present in mammalian DNA, and bisulfite sequencing cannot distinguish between 5 hmC and 5 mC.We have developed specific MethylScreen restriction enzyme digestion and qPCR-based protocols to more rapidly quantify DNA methylation at four CpG sites in the FXN upstream GAA region. Increased DNA methylation was confirmed at all four CpG sites in both FRDA cerebellum and heart tissues. We have also analysed the DNA methylation status in FRDA cerebellum and heart tissues using an approach that enables distinction between 5 hmC and 5 mC. Our analysis reveals that the majority of DNA methylation in both FRDA and unaffected tissues actually comprises 5 hmC rather than 5 mC. We have also identified decreased occupancy of the chromatin insulator protein CTCF (CCCTC-binding factor at the FXN 5' UTR region in the same FRDA cerebellum tissues.Increased DNA methylation at the FXN upstream GAA region, primarily 5 hmC rather than 5 mC, and decreased CTCF occupancy at the FXN 5' UTR are associated with FRDA disease-relevant human tissues. The role of such molecular mechanisms in FRDA pathogenesis has now to be determined.

  20. 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 ...

  1. 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.

  2. 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.

  3. 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

  4. Partial correction of sensitivity to oxidant stress in Friedreich ataxia patient fibroblasts by frataxin-encoding adeno-associated virus and lentivirus vectors.

    Science.gov (United States)

    Fleming, Jane; Spinoulas, Afroditi; Zheng, Maolin; Cunningham, Sharon C; Ginn, Samantha L; McQuilty, Robert C; Rowe, Peter B; Alexander, Ian E

    2005-08-01

    Peripheral nervous system (PNS) sensory neurons are directly involved in the pathophysiology of a number of debilitating inherited and acquired neurological conditions. The lack of effective treatments for many such conditions provides a strong rationale for exploring novel therapeutic approaches, including gene therapy. Friedreich ataxia (FRDA), a sensory neuropathy, is a progressive neurodegenerative disease associated with a loss of large sensory neurons from the dorsal root ganglia. Because a mouse model for this well-characterized disease has been generated, we elected to use FRDA as a model disease. In previous studies we achieved efficient and sustained delivery of a reporter gene to PNS sensory neurons, using recombinant adeno-associated viral (AAV) and lentiviral (LV) vectors. In the current study, AAV and LV vectors encoding the human frataxin cDNA were constructed and assessed for frataxin expression and function in primary FRDA patient fibroblast cell lines. FRDA fibroblasts have been shown to exhibit subtle biochemical changes, including increased mitochondrial iron and sensitivity to oxidant stress. Despite the inherent difficulty in working with primary cells, transduction of patient fibroblasts with either vector resulted in the expression of appropriately localized frataxin and partial reversal of phenotype.

  5. 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).

  6. 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...

  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. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

    Science.gov (United States)

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

    2016-04-01

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

  9. 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...

  10. 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

  11. 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 ...

  12. 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.

  13. 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...

  14. 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.

  15. 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

  16. DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients.

    Science.gov (United States)

    Castaldo, I; Pinelli, M; Monticelli, A; Acquaviva, F; Giacchetti, M; Filla, A; Sacchetti, S; Keller, S; Avvedimento, V E; Chiariotti, L; Cocozza, S

    2008-12-01

    The most frequent mutation of Friedreich ataxia (FRDA) is the abnormal expansion of a GAA repeat located within the first intron of FXN gene. It is known that the length of GAA is directly correlated with disease severity. The effect of mutation is a severe reduction of mRNA. Recently, a link among aberrant CpG methylation, chromatin organisation and GAA repeat was proposed. In this study, using pyrosequencing technology, we have performed a quantitative analysis of the methylation status of five CpG sites located within the region upstream of GAA repeat, in 67 FRDA patients. We confirm previous observation about differences in the methylation degree between FRDA individuals and controls. We showed a direct correlation between CpG methylation and triplet expansion size. Significant differences were found for each CpG tested (ANOVA p<0.001). These differences were largest for CpG1 and CpG2: 84.45% and 76.80%, respectively, in FRDA patients compared to 19.65% and 23.34% in the controls. Most importantly, we found a strong inverse correlation between CpG2 methylation degree and age of onset (Spearman's rho = -0.550, p<0.001). Because epigenetic changes may cause or contribute to gene silencing, our data may have relevance for the therapeutic approach to FRDA. Since the analysis can be performed in peripheral blood leucocytes (PBL), evaluation of the methylation status of specific CpG sites in FRDA patients could be a convenient biomarker.

  17. 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.

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    Genko Oyama

    2014-07-01

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

  20. Ataxia and Its Association with Hearing Impairment in Childhood Bacterial Meningitis.

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    Roine, Irmeli; Pelkonen, Tuula; Bernardino, Luis; Leite Cruzeiro, Manuel; Peltola, Heikki; Pitkäranta, Anne

    2015-08-01

    Ataxia, deemed usually a minor sequela, follows childhood bacterial meningitis (BM) in up to 18% of cases. Although mostly transient and benign, it can predict permanent hearing loss and vestibular dysfunction. We explored the clinical meaning of ataxia by following its course in a large number of BM patients and examining its relation with hearing loss. The presence, degree (no, mild, moderate and severe) and course (transient, prolonged and late) of ataxia in BM were registered prospectively by predefined criteria. These data were compared with several patient, disease, and outcome variables including hearing loss (none, moderate, severe and profound) on day 7 of treatment and at a follow-up visit 1 month after discharge. Ataxia was present in 243 of 361 (67%) patients on day 7, being slight in 21%, moderate in 38% and severe in 41%. Its course was transient in 41%, prolonged in 24% and late in 5%, whereas 30% of the patients did not present ataxia at any time. Ataxia associated most significantly not only with several measures of BM severity and suboptimal outcome (P ataxia correlated with the extent of hearing loss (rho, 0.37; P Ataxia is more frequent and lasts longer after BM than learned from previous studies. The presence and intensity of ataxia associate with hearing loss and its magnitude.

  1. Optimal management of hereditary hemorrhagic telangiectasia

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    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. The assessment and treatment of postural disorders in cerebellar ataxia: a systematic review.

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    Marquer, A; Barbieri, G; Pérennou, D

    2014-03-01

    Gait and balance disorders are often major causes of handicap in patients with cerebellar ataxia. Although it was thought that postural and balance disorders in cerebellar ataxia were not treatable, recent studies have demonstrated the beneficial effects of rehabilitation programs. This article is the first systematic review on the treatment of postural disorders in cerebellar ataxia. Nineteen articles were selected, of which three were randomized, controlled trials. Various aetiologies of cerebellar ataxia were studied: five studies assessed patients with multiple sclerosis, four assessed patients with degenerative ataxia, two assessed stroke patients and eight assessed patients with various aetiologies. Accurate assessment of postural disorders in cerebellar ataxia is very important in both clinical trials and clinical practice. The Scale for the Assessment and Rating of Ataxia (SARA) is a simple, validated measurement tool, for which 18 of the 40 points are related to postural disorders. This scale is useful for monitoring ataxic patients with postural disorders. There is now moderate level evidence that rehabilitation is efficient to improve postural capacities of patients with cerebellar ataxia - particularly in patients with degenerative ataxia or multiple sclerosis. Intensive rehabilitation programs with balance and coordination exercises are necessary. Although techniques such as virtual reality, biofeedback, treadmill exercises with supported bodyweight and torso weighting appear to be of value, their specific efficacy has to be further investigated. Drugs have only been studied in degenerative ataxia, and the level of evidence is low. There is now a need for large, randomized, controlled trials testing rehabilitation programs suited to postural and gait disorders of patients with cerebellar ataxia. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

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

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    Iscia Lopes-Cendesi

    1997-09-01

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

  4. Novel Diagnostic Paradigms for Friedreich Ataxia

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    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

  5. Distinct Neurochemical Profiles of Spinocerebellar Ataxias 1, 2, 6, and Cerebellar Multiple System Atrophy

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    Öz, Gülin; Iltis, Isabelle; Hutter, Diane; Thomas, William; Bushara, Khalaf O.; Gomez, Christopher M.

    2011-01-01

    Hereditary and sporadic neurodegenerative ataxias are movement disorders that affect the cerebellum. Robust and objective biomarkers are critical for treatment trials of ataxias. In addition, such biomarkers may help discriminate between ataxia subtypes because these diseases display substantial overlap in clinical presentation and conventional MRI. Profiles of 10–13 neurochemical concentrations obtained in vivo by high field proton magnetic resonance spectroscopy (1H MRS) can potentially provide ataxia-type specific biomarkers. We compared cerebellar and brainstem neurochemical profiles measured at 4 T from 26 patients with spinocerebellar ataxias (SCA1, N=9; SCA2, N=7; SCA6, N=5) or cerebellar multiple system atrophy (MSA-C, N=5) and 15 age-matched healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA) was used to assess disease severity. The patterns of neurochemical alterations relative to controls differed between ataxia types. Myo-inositol levels in the vermis, myo-inositol, total N-acetylaspartate, total creatine, glutamate, glutamine in the cerebellar hemispheres and myo-inositol, total N-acetylaspartate, glutamate in the pons were significantly different between patient groups (Bonferroni corrected pataxia types. Studies with higher numbers of patients and other ataxias are warranted to further investigate the clinical utility of neurochemical levels as measured by high-field MRS as ataxia biomarkers. PMID:20838948

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

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    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.

  7. 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...

  8. 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...

  9. 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...

  10. 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.

  11. 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.

  12. Colorectal choriocarcinoma in a patient with probable Lynch syndrome

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    Viktor Hendrik Koelzer

    2016-11-01

    Full Text Available Background: Personalized therapy of colorectal cancer (CRC is influenced by morphological, molecular and host-related factors. Here we report the comprehensive clinicopathological and molecular analysis of a pure extra-gestational colorectal choriocarcinoma in a patient with probable Lynch syndrome.Case presentation: A 61 year old female with history of gastric cancer at age 36 presented with a transmurally invasive tumor of the right hemicolon and liver metastasis. A right hemicolectomy was performed. Histopathological analysis showed a mixed trophoblastic and syncytiotrophoblastic differentiation, consistent with choriocarcinoma. Disease progression was rapid under oxaliplatin, capecitabine, irinotecan (XELOXIRI and bevacizumab. Molecular phenotyping identified loss of the mismatch-repair (MMR protein PMS2, microsatellite instability, a lack of MLH1 promoter methylation and lack of of BRAF mutation suggestive of Lynch-Syndrome. Targeted next generation sequencing revealed an Ataxia Telangiectasia Mutated (ATM p.P604S missense mutation. A bleomycin, etoposide and cisplatin (BEP treatment protocol targeting germ-cell neoplasia lead to disease remission and prolonged survival of 34 months.Conclusions: Comprehensive immunohistochemical and genetic testing is essential to identify uncommon cancers possibly related to Lynch syndrome. For rare tumors, personalized therapeutic approaches should take both molecular and morphological information into account.Key words: Colorectal cancer, choriocarcinoma, histopathology, prognostic factors, Lynch syndrome, microsatellite instability, ataxia telangiectasia mutated, molecular pathology, next generation sequencing, personalized medicine

  13. 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.

  14. Downregulated Ku70 and ATM associated to poor prognosis in colorectal cancer among Chinese patients

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    Lu YF

    2014-10-01

    Full Text Available Yuanfang Lu,1,2 Jingyan Gao,1,3 Yuanming Lu,1 1Department of Toxicology, School of Public Health, Guilin Medical University, Guangxi, People's Republic of China; 2Department of Clinical Research Center, Affiliated 2nd Hospital of Nanjing Medical University, Nanjing, People's Republic of China; 3Department of Human Anatomy and Histo-Embryology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China Background: Double-strand DNA breaks (DSBs are a key factor in carcinogenesis. The necessary repair of DSBs is pivotal in maintaining normal cell division. To address the relationship between altered expression of DSB repair of proteins Ku70 and ataxia-telangiectasia mutated (ATM in colorectal cancer (CRC, we examined the expression levels and patterns of Ku70 and ATM in CRC samples. Methods: Expression and coexpression of Ku70 and ATM were investigated by using real-time quantitative polymerase chain reaction assays and confirmed further with fluorescent immunohistochemistry in CRC and pericancerous samples from 112 Chinese patients. Results: Downexpression patterns for both Ku70 and ATM were found in the CRC samples and were significantly associated with advanced tumor node metastasis stage and decreased 5-year overall survival rate. Conclusion: Downregulated Ku70 and ATM were associated with poor disease-free survival. Loss of Ku70 and ATM expression might act as a biomarker to predict poor prognosis in patients with CRC. Keywords: DNA double-strand breaks, ataxia-telangiectasia mutated, Ku70, colorectal cancer

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

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    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

  16. Bilateral parietal lesions disrupt the beneficial effects of prism adaptation: evidence from a patient with optic ataxia.

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    Striemer, Christopher; Blangero, Annabelle; Rossetti, Yves; Boisson, Dominique; Rode, Gilles; Salemme, Romeo; Vighetto, Alain; Pisella, Laure; Danckert, James

    2008-05-01

    Prism adaptation (PA) alleviates some neglect symptoms, however, the mechanisms underlying these effects are unclear. One brain area that may be important in generating these beneficial effects is the superior parietal lobe (SPL), a region not typically damaged in neglect, and known to be important for attention, visuomotor control, and eye movements. We examined the effects of rightward PA on covert attention in CF, a patient with bilateral SPL lesions, compared to a group of controls (N = 26) who underwent sham adaptation. In contrast to previous work in neglect, there was no reduction in CF's leftward disengage deficit, or rightward attentional bias following PA. These results suggest that the SPL plays an important role in generating the beneficial after-effects of prisms on attention.

  17. An unusual cause of adult onset cerebellar ataxia with hypogonadism

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    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. 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.

  19. 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.

  20. Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2)

    NARCIS (Netherlands)

    Rueb, U.; Farrag, K.; Seidel, K.; Brunt, E. R.; Heinsen, H.; Buerk, K.; Melegh, B.; von Gall, C.; Auburger, G.; Bohl, J.; Korf, H. W.; Hoche, F.; den Dunnen, W.

    2013-01-01

    Aims: Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of

  1. 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.

  2. 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.

  3. 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...

  4. 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 ...

  5. 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 ...

  6. Genetics Home Reference: spinocerebellar ataxia type 3

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    ... 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 ...

  7. 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 ...

  8. 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.

  9. 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

  10. Idiopathic very late-onset cerebellar ataxia: a Brazilian case series.

    Science.gov (United States)

    Teive, Hélio A G; Moscovich, Mariana; Moro, Adriana; Farah, Marina; Arruda, Walter O; Munhoz, Renato P

    2015-11-01

    The authors present a Brazilian case series of eight patients with idiopathic very-late onset (mean 75.5 years old) cerebellar ataxia, featuring predominantly gait ataxia, associated with cerebellar atrophy. 26 adult patients with a diagnosis of idiopathic late onset cerebellar ataxia were analyzed in a Brazilian ataxia outpatient clinic and followed regularly over 20 years. Among them, 8 elderly patients were diagnosed as probable very late onset cerebellar ataxia. These patients were evaluated with neurological, ophthalmologic and Mini-Mental Status examinations, brain MRI, and EMG. 62.5% of patients were males, mean age was 81.9 years-old, and mean age of onset was 75.5 years. Gait cerebellar ataxia was observed in all patients, as well as, cerebellar atrophy on brain MRI. Mild cognitive impairment and visual loss, due to macular degeneration, were observed in 50% of cases. Chorea was concomitantly found in 3 patients. We believe that this condition is similar the one described by Marie-Foix-Alajouanine presenting with mild dysarthria, associated with gait ataxia, and some patients had cognitive dysfunction and chorea.

  11. 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...

  12. 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.

  13. 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.

  14. [Gluten Ataxia: Anti-Transglutaminase-6 Antibody as a New Biomarker].

    Science.gov (United States)

    Sato, Kenji; Nanri, Kazunori

    2017-08-01

    Gluten-related disorders (GRDs) are conditions that develop in response to the common trigger of gluten ingestion and manifest as a variety of clinical symptoms. GRDs have been considered rare in Asian countries, including Japan, because of lower consumption of wheat products than in Europe and the U.S.A. and differences in genetic background. Recently, however, GRDs, such as celiac disease and gluten ataxia, have been reported in Japan, albeit sporadically and their presence is now recognized in this country. Gluten ataxia is defined as an anti-gliadin antibody positive sporadic ataxia. Recently, it was reported that the presence of anti-transglutaminase-6 (TG6) antibody can be used to diagnose gluten ataxia. Herein, we will review evidence relating to gluten ataxia and report two cases of anti-TG6 antibody positive gluten ataxia. In patients with gluten ataxia, sensory disturbance is generally considered to be so mild that it contributes minimally to ataxia. However, our patients showed a positive Romberg sign. Deep sensory disturbance, in addition to cerebellar disturbance, may have been involved in the clinical symptoms of our cases.

  15. From dizziness to severe ataxia and dysarthria: New cases of anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia suggest a broad clinical spectrum.

    Science.gov (United States)

    Wallwitz, Ulrike; Brock, Sebastian; Schunck, Antje; Wildemann, Brigitte; Jarius, Sven; Hoffmann, Frank

    2017-08-15

    In 2010, a novel anti-neuronal autoantibody, termed anti-Ca, was described in a patient with subacute cerebellar ataxia, and Rho GTPase-activating protein 26 (ARHGAP26) was identified as the target antigen. Recently, three additional cases of anti-Ca-positive cerebellar ataxia have been published. In addition to ataxia, cognitive decline and depression have been observed in some patients. Here, we report two new cases of anti-Ca-associated autoimmune cerebellar ataxia. Patient 1 presented with dizziness and acute yet mild limb and gait ataxia. Symptoms stabilized with long-term oral corticosteroid therapy but transiently worsened when steroids were tapered. Interestingly, both initial occurrence and worsening of the patient's neurological symptoms after steroid withdrawal were accompanied by spontaneous cutaneous hematomas. Patient 2 initially presented with an increased startle response and myoclonic jerks, and subsequently developed severe limb and gait ataxia, dysarthria, oculomotor disturbances, head and voice tremor, dysphagia, cognitive symptoms and depression. Steroid treatment was started five years after disease onset. The symptoms then responded only poorly to corticosteroids. At most recent follow-up, 19 years after disease onset, the patient was wheelchair-bound. These cases extend the clinical spectrum associated with anti-ARHGAP26 autoimmunity and suggest that early treatment may be important in patients with this rare syndrome. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. 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.

  17. Friedreich Ataxia Clinical Outcome Measures: Natural History Evaluation in 410 Participants

    Science.gov (United States)

    Regner, Sean R.; Wilcox, Nicholas; Friedman, Lisa S.; Seyer, Lauren; Schadt, Kim; Brigatti, Karlla W.; Perlman, Susan; Delatycki, Martin; Wilmot, George R.; Gomez, Christopher M.; Bushara, Khalaf O.; Mathews, Katherine D.; Subramony, S.H.; Ashizawa, Tetsuo; Ravina, Bernard; Brocht, Alicia; Farmer, Jennifer M.; Lynch, David R.

    2013-01-01

    Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia, dysarthria, and areflexia. We report the progress of a large international non-interventional cohort (n = 410), tracking the natural history of disease progression using the neurological exam-based Friedreich Ataxia Rating Scale. We analyzed the rate of progression with cross-sectional analysis and longitudinal analysis over a 2-year period. The Friedreich Ataxia Rating Scale captured disease progression when used at 1 and 2 years following initial evaluation, with a lower ratio of standard deviation of change to mean change over 2 years of evaluation. However, modeling of disease progression identified substantial ceiling effects in the Friedreich Ataxia Rating Scale, suggesting this measure is most useful in patients before maximal deficit is approached. PMID:22752494

  18. 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

  19. 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…

  20. Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases.

    Science.gov (United States)

    Singh, Ankur; Faruq, Mohammed; Mukerji, Mitali; Dwivedi, Manish Kumar; Pruthi, Sumit; Kapoor, Seema

    2014-01-01

    Autosomal dominant cerebellar ataxia type I is a heterogeneous group of spinocerebellar ataxias with variable neurologic presentations, with age of onset varying from infancy to adulthood. Autosomal dominant cerebellar ataxia type I is composed mainly of 3 prevalent spinocerebellar ataxia types with different pathogenic loci, specifically spinocerebellar ataxia 1 (6p24-p23), spinocerebellar ataxia 2 (12q24.1), and spinocerebellar ataxia 3 (14q32.1). The shared pathogenic mutational event is the expansion of the CAG repeat that results in polyglutamine extended stretches in the encoded proteins. CAG repeat disorders generally show the phenomenon of anticipation, which is more often associated with paternal transmission. In this report, we describe a patient with infantile-onset spinocerebellar ataxia type 2 (~320 CAG repeat) who inherited the disease from his father (47 CAG repeats). We have summarized the clinical, neuroimaging, electroencephalographic (EEG), and molecular data of previous cases and attempt to highlight the most consistent findings. Our intent is to help treating clinicians to suspect this disorder and to offer timely genetic counseling for a currently potentially untreatable disorder.

  1. 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.

  2. Friedreich's Ataxia: a review from a cardiology perspective.

    LENUS (Irish Health Repository)

    Bourke, T

    2011-12-01

    Neuromuscular disorders are not among the common causes of cardiomyopathy in the general population; however, cardiomyopathy is known to occur in several neuromuscular disorders including Friedreich\\'s Ataxia (FA). In patients with neuromuscular disorders, concomitant cardiac involvement contributes significantly to morbidity and mortality and often leads to premature death.

  3. [A case of chronic active Epstein-Barr virus infection associated with recurrent cerebellar ataxia and skin eruptions].

    Science.gov (United States)

    Araki, Katsuya; Okuno, Tatsusada; Honorat, Josephe Archie; Kinoshita, Makoto; Takahashi, Masanori P; Mizuki, Masao; Kitagawa, Kazuo; Mochizuki, Hideki

    2013-01-01

    A 62-year-old woman presented with subacute cerebellar ataxia, lymph node swelling and skin eruption. Laboratory tests revealed elevated titers of anti-VCA-IgG antibody and anti-EADR-IgG antibody, with Epstein-Barr virus (EBV) DNA detected from the blood and CSF by PCR. Since these data were highlighted with the diagnosis of chronic active EBV infection (CAEBV) and her ataxia improved concomitantly with the remission of other infectious mononucleosis-like symptoms, we supposed her ataxia is associated with CAEBV. Five years later, at the age of 67, her ataxia relapsed concurrently with skin eruptions, whereas MRI demonstrated progression of cerebellar atrophy. After high-dose intravenous methylprednisolone treatment, the clinical symptoms resolved. Initial infection of EBV in childhood often causes autoimmune acute cerebellitis but cerebellar ataxia has rarely been described in CAEBV. Furthermore, immunohistochemical analysis revealed a reactivity of the patient's serum and CSF on rat cerebellum, suggesting an autoimmune pathomechanism for the ataxia.

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

    OpenAIRE

    Salman, Michael S.; Chodirker, Bernard N.

    2015-01-01

    Chronic ataxia is a challenging problem in paediatric neurology. It is caused by a multitude of disorders that at least initially have similar or non-specific phenotype. Some of these disorders have associated neuro-ophthalmological signs (N-OS). The aims of this study are to describe the N-OS and their frequencies in general and by disease aetiology in paediatric patients with chronic ataxia. The authors identified 184 patients under age 17 years with chronic ataxia (>2 months duration or re...

  5. Deep Brain Stimulation for the Treatment of Tremor and Ataxia Associated with Abetalipoproteinemia

    Directory of Open Access Journals (Sweden)

    Antonios Mammis

    2012-07-01

    Full Text Available Background: Abetalipoproteinemia is a rare disorder of fat absorption, characterized by vitamin deficiency, acanthocytosis, and neurologic symptoms including ataxia and tremor.Case Report: A 41-year-old male with abetalipoproteinemia is presented. He underwent staged bilateral thalamic deep brain stimulation (DBS for the treatment of his tremors. After DBS, the patient achieved significant improvements in his tremors, ataxia, and quality of life.Discussion: Thalamic DBS proved to be both safe and efficacious in the management of ataxia and tremors in a patient with abetalipoproteinemia. This is the first report of DBS in abetalipoproteinemia in the literature. 

  6. 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.

  7. 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.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-06-26

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

  10. 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.

  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. Childhood Ataxia: Clinical Features, Pathogenesis, Key Unanswered Questions, and Future Directions

    Science.gov (United States)

    Ashley, Claire N.; Hoang, Kelly D.; Lynch, David R.; Perlman, Susan L.; Maria, Bernard L.

    2013-01-01

    Childhood ataxia is characterized by impaired balance and coordination primarily due to cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies. PMID:22859693

  13. Predicting and correcting ataxia using a model of cerebellar function.

    Science.gov (United States)

    Bhanpuri, Nasir H; Okamura, Allison M; Bastian, Amy J

    2014-07-01

    Cerebellar damage results in uncoordinated, variable and dysmetric movements known as ataxia. Here we show that we can reliably model single-joint reaching trajectories of patients (n = 10), reproduce patient-like deficits in the behaviour of controls (n = 11), and apply patient-specific compensations that improve reaching accuracy (P cerebellar damage causes a mismatch between the brain's modelled dynamics and the actual body dynamics, resulting in ataxia. We used both behavioural and computational approaches to demonstrate that specific cerebellar patient deficits result from biased internal models. Our results strongly support the idea that an intact cerebellum is critical for maintaining accurate internal models of dynamics. Importantly, we demonstrate how subject-specific compensation can improve movement in cerebellar patients, who are notoriously unresponsive to treatment. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases

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    Albano Lilian M. J.

    2001-01-01

    Full Text Available INTRODUCTION: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a early age of onset (< 20 or 25 years, b autosomal recessive inheritance, c progressive ataxia of limbs and gait, and d absence of lower limb tendon reflexes. METHODS: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia - 19 typical and 6 atypical - using a long-range PCR test. RESULTS: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68% - all typical cases. In 8 patients (32% (6 atypical and 2 typical, no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions. DISCUSSION: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion.

  15. Experience of the Irish National Centre for hereditary haemorrhagic telangiectasia 2003-2008.

    LENUS (Irish Health Repository)

    Ni Bhuachalla, C F

    2012-01-31

    Hereditary haemorrhagic telangiectasia (HHT) is a group of autosomal dominant disorders of vascular structure. The Irish National Centre for HHT at the Mercy University Hospital, Cork, Ireland was founded in 2003. From 2003 to 2008, screening of 164 patients with contrast echocardiography, thoracic computerised tomography (CT) and cerebral magnetic resonance imaging (MRI) has identified 88 patients with definite HHT, 72 (82%) of whom had epistaxis, 70 (80%) had telangiectasia and 81 (92%) had a first-degree relative with HHT. We sought to describe the manifestations of HHT in an Irish population and to determine differences between internationally reported data. The HHT patient database was analysed to describe demographics, clinical manifestations and interventional procedures performed in all referred patients. Contrast echocardiography and\\/or CT were performed in 86 patients with definite HHT, identifying 27 patients (31%) with pulmonary arteriovenous malformations (pAVMs). Nineteen patients with single or multiple pAVMs had 28 embolisation procedures performed, with 1-6 pAVMs embolised per procedure. Cerebral MRI was performed in 78 (89%) patients and 2 (2.3%) had cerebral arteriovenous malformations (cAVMs). HHT prevalence is thought to be 1 in 2500-8000, suggesting that there are many undiagnosed cases in Irish patients. Internationally published data suggest a prevalence of 15-35% for pAVMs and 10-23% for cAVMs in patients with HHT. While the prevalence of pAVMs in our group is consistent with these data, the prevalence of cAVMs is considerably lower, suggesting that Irish patients with HHT may differ genotypically and phenotypically from those in other countries.

  16. Successful treatment of cerebellar ataxia and tremor in multiple sclerosis with topiramate: a case report.

    Science.gov (United States)

    Schroeder, Alexandra; Linker, Ralf A; Lukas, Carsten; Kraus, Peter H; Gold, Ralf

    2010-01-01

    We describe the clinical efficacy of topiramate for treatment of cerebellar dysfunction in a 33-year-old female patient with relapsing remitting multiple sclerosis. The patient presented severe ataxia and tremor precluding many activities of daily life. Topiramate was administered as a monotherapy and slowly tapered in to 150 mg daily without negative side effects. Treatment was well tolerated and led to a marked and lasting improvement of tremor as well as ataxia during an observation period of 2 years. Upon transient withdrawal of topiramate, ataxia and tremor worsened but were again improved after re-dosing of the drug. Multiple sclerosis immunotherapy was not changed in this period. In conclusion, topiramate may be a new therapeutic option to treat cerebellar tremor and ataxia in patients with multiple sclerosis.

  17. 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 ...

  18. 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 ...

  19. The Diagnostic Accuracy of Truncal Ataxia and HINTS as Cardinal Signs for Acute Vestibular Syndrome

    Directory of Open Access Journals (Sweden)

    Sergio Carmona

    2016-08-01

    Full Text Available The head impulse, nystagmus type, test of skew (HINTS protocol set a new paradigm to differentiate peripheral vestibular disease from stroke in patients with acute vestibular syndrome (AVS. The relationship between degree of truncal ataxia and stroke has not been systematically studied in patients with AVS. We studied a group of 114 patients who were admitted to a General Hospital due to AVS, 72 of them with vestibular neuritis (based on positive head impulse, abnormal caloric tests and negative MRI, and the rest with Stroke: 32 in the PICA territory (positive HINTS findings, positive MRI and 10 in the AICA territory (variable findings and grade 3 Ataxia, positive MRI. Truncal ataxia was measured by independent observers as grade 1, mild to moderate imbalance with walking independently; grade 2, severe imbalance with standing, but cannot walk without support; and grade 3, falling at upright posture.When we applied the HINTS protocol to our sample, we obtained 100% sensitivity and 94.4% specificity, similar to previously published findings. Only those patients with stroke presented with grade 3 ataxia. Of those with grade 2 ataxia (n = 38, 11 had cerebellar stroke and 28 had vestibular neuritis, not related to the patient's age. Grade 2-3 ataxia was 92.9% sensitive and 61.1% specific to detect AICA/PICA stroke in patients with AVS, with 100% sensitivity to detect AICA stroke. In turn, two signs (nystagmus of central origin and grade 2-3 Ataxia had 100% sensitivity and 61.1% specificity. Ataxia is less sensitive than HINTS but much easier to evaluate.

  20. Huntington’s disease masquerading as spinocerebellar ataxia

    OpenAIRE

    Rodríguez-Quiroga, Sergio Alejandro; Gonzalez-Morón, Dolores; Garretto, Nelida; Kauffman, Marcelo Andres

    2013-01-01

    Huntington’s disease (HD) is a neurodegenerative disorder of the central nervous system characterised by the presence of choreic abnormal movements, behavioural or psychiatric disturbances and dementia. Noteworthy, despite atypical motor symptoms other than chorea have been reported as initial presentation in some patients, a very few number of HD patients, presenting at onset mostly cerebellar dysfunction masquerading dominant spinocerebellar ataxias (SCA), were occasionally reported. We rep...

  1. 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.

  2. 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.

  3. The Diagnostic Accuracy of Truncal Ataxia and HINTS as Cardinal Signs for Acute Vestibular Syndrome

    Science.gov (United States)

    Carmona, Sergio; Martínez, Carlos; Zalazar, Guillermo; Moro, Marcela; Batuecas-Caletrio, Angel; Luis, Leonel; Gordon, Carlos

    2016-01-01

    The head impulse, nystagmus type, test of skew (HINTS) protocol set a new paradigm to differentiate peripheral vestibular disease from stroke in patients with acute vestibular syndrome (AVS). The relationship between degree of truncal ataxia and stroke has not been systematically studied in patients with AVS. We studied a group of 114 patients who were admitted to a General Hospital due to AVS, 72 of them with vestibular neuritis (based on positive head impulse, abnormal caloric tests, and negative MRI) and the rest with stroke: 32 in the posterior inferior cerebellar artery (PICA) territory (positive HINTS findings, positive MRI) and 10 in the anterior inferior cerebellar artery (AICA) territory (variable findings and grade 3 ataxia, positive MRI). Truncal ataxia was measured by independent observers as grade 1, mild to moderate imbalance with walking independently; grade 2, severe imbalance with standing, but cannot walk without support; and grade 3, falling at upright posture. When we applied the HINTS protocol to our sample, we obtained 100% sensitivity and 94.4% specificity, similar to previously published findings. Only those patients with stroke presented with grade 3 ataxia. Of those with grade 2 ataxia (n = 38), 11 had cerebellar stroke and 28 had vestibular neuritis, not related to the patient’s age. Grade 2–3 ataxia was 92.9% sensitive and 61.1% specific to detect AICA/PICA stroke in patients with AVS, with 100% sensitivity to detect AICA stroke. In turn, two signs (nystagmus of central origin and grade 2–3 Ataxia) had 100% sensitivity and 61.1% specificity. Ataxia is less sensitive than HINTS but much easier to evaluate. PMID:27551274

  4. Intravenous immunoglobulin and rituximab for cerebellar ataxia with glutamic acid decarboxylase autoantibodies.

    Science.gov (United States)

    Planche, Vincent; Marques, Ana; Ulla, Miguel; Ruivard, Marc; Durif, Franck

    2014-06-01

    Cerebellar ataxia associated with glutamic acid decarboxylase autoantibodies (GAD-ab) is a rare and usually slow progressive disease with moderate to severe gait and limb ataxia, dysarthria, and nystagmus. The treatment for this condition is still being discussed. We report the cases of three patients with GAD-ab cerebellar ataxia treated successively with intravenous immunoglobulin (IVIg) and rituximab. Symptoms improved in one case after rituximab therapy and were stabilized in another after a combined therapy of IVIg and rituximab. The third patient continued to worsen despite these treatments. We conclude that IVIg and rituximab therapy could improve or stabilize GAD-ab cerebellar ataxia. Early treatment, the lack of cerebellar atrophy on magnetic resonance imaging, and a subacute onset of the symptoms could be decisive prognostic factors.

  5. 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

  6. Successful treatment of facial telangiectasias using a micropulse 1,064-nm neodymium-doped yttrium aluminum garnet laser.

    Science.gov (United States)

    Rose, Amy E; Goldberg, David J

    2013-07-01

    To evaluate the safety and efficacy of a microsecond 1,064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser for the treatment of facial telangiectasias. Subjects ages 35-70 with Fitzpatrick skin types I to III and facial telangiectasias underwent two treatments with a micropulse (0.65 ms) 1,064-nm Nd:YAG laser. Treatments were spaced 30 days apart, with a final evaluation 60 days after the second treatment. Evaluation included digital photography and an assessment of the degree of improvement on a scale from 1 to 5 by the subject and a nontreating investigator. Twenty subjects (18 women, two men) with Fitzpatrick skin type II and III completed the study. The nontreating investigator rated the objective clinical response as total clearance (100% clear) in 10% (n = 2) of subjects, significant clearance (≥50% clear) in 75% (n = 15), and some clearance (0-49% clear) in 15% (n = 3). None of the subjects was rated as having no clearance or worsening. In terms of subjective clearance reported by subjects, 80% (n = 16) reported significant clearance, with the remainder reporting some clearance. No adverse events were reported. The micropulse 1,064-nm Nd:YAG successfully treated facial telangiectasias with a high degree of patient satisfaction, minimal discomfort, and no adverse events. © 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2014-10-28

    low dose of the intervention), in heterogenous groups of degenerative cerebellar ataxias. Three compounds were studied in two trials each: a levorotatory form of 5-hydroxytryptophan (L-5HT), idebenone and thyrotropin-releasing hormone tartrate (TRH-T); each of the other compounds (riluzole, varenicline, buspirone, betamethasone, coenzyme Q10 with vitamin E, α-tocopheryl quinone and erythropoietin) were studied in one trial. The 14th trial, involving a mixed group of participants with spinocerebellar ataxia, compared the effectiveness of nonspecific physiotherapy and occupational therapy within an inpatient hospital setting to no treatment. No studies utilised traditional speech therapies. We defined the primary outcome measure in this review as the percentage change (improvement) in overall speech production immediately following completion of the intervention or later, measured by any validated speech assessment tool. None of the trials included speech as a primary outcome or examined speech using any validated speech assessment tool. Eleven studies reported speech outcomes derived from a subscale embedded within disease rating scales. The remaining three studies used alternative assessments to measure speech, including mean time to produce a standard sentence, a subjective rating of speech on a 14-point analogue scale, patient-reported assessment of the impact of dysarthria on activities of daily living and acoustic measures of syllable length. One study measured speech both subjectively as part of a disease rating scale and with further measures of speech timing. Three studies utilised the Short Form-36 Health Survey (SF-36) and one used the Child Health Questionnaire as measures of general quality of life. A further study utilised the Functional Independence Measure to assess functional health.Five studies reported statistically significant improvement on an overall disease rating scale in which a speech subscale was included. Only three of those studies provided

  8. Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed Espectro clínico da ataxia cerebelar de início precoce com reflexos mantidos: uma ataxia autossômica recessiva para não ser esquecida

    Directory of Open Access Journals (Sweden)

    José Luiz Pedroso

    2013-06-01

    Full Text Available Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedreich ataxia, and also to perform a clinical spectrum study of this syndrome. In this data, 12 patients from different families met all clinical features for early onset cerebellar ataxia with retained tendon reflexes. Dysarthria and cerebellar atrophy were the most common features in our sample. It is uncertain, however, whether early onset cerebellar ataxia with retained tendon reflexes is a homogeneous disease or a group of phenotypically similar syndromes represented by different genetic entities. Further molecular studies are required to provide definitive answers to the questions that remain regarding early onset cerebellar ataxia with retained tendon reflexes.As ataxias cerebelares autossômicas recessivas são um grupo heterogêneo de doenças neurológicas. Em 1981, foi descrita uma entidade neurológica incluindo ataxia cerebelar progressiva de início precoce, disartria, liberação piramidal e manutenção ou aumento dos reflexos tendíneos nos membros superiores e inferiores. Essa síndrome é conhecida como ataxia cerebelar de início precoce com reflexos mantidos. Neste artigo, o objetivo foi chamar a atenção para o diagnóstico de ataxia cerebelar de início precoce com reflexos mantidos como a segunda causa mais comum de ataxia cerebelar autossômica recessiva, após a ataxia de Friedreich, e também realizar um estudo do espectro cl

  9. Progressive dysarthria and ataxia

    Directory of Open Access Journals (Sweden)

    Lynsey McAlpine

    2015-02-01

    Full Text Available ‘Guillain-Barre syndrome’ (GBS is a broad term used to describe a collection of clinical syndromes which manifest as acute immune-mediated demyelinating diseases or more rarely axonal diseases of the peripheral nervous system. The most commonly recognised form is ‘acute inflammatory demyelinating polyradiculoneuropathy’ (AIDP, which classically presents as a proximal and distal weakness with diminished reflexes, often involving the cranial nerves and muscles of respiration [1]. It is a neurological emergency as these patients are at risk of developing respiratory failure; one third will require admission to the Intensive Care Unit (ICU for ventilatory support, and mortality rates of 3-10% have been reported

  10. Genes and genetic testing in hereditary ataxias.

    Science.gov (United States)

    Sandford, Erin; Burmeister, Margit

    2014-07-22

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

  11. Ataxias agudas en la infancia

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    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.

  12. 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

  13. Hereditary ataxia and spastic paraplegia in Portugal: a population-based prevalence study.

    Science.gov (United States)

    Coutinho, Paula; Ruano, Luis; Loureiro, José L; Cruz, Vitor T; Barros, José; Tuna, Assunção; Barbot, Clara; Guimarães, João; Alonso, Isabel; Silveira, Isabel; Sequeiros, Jorge; Marques Neves, José; Serrano, Pedro; Silva, M Carolina

    2013-06-01

    Epidemiological data on hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are scarce. To present the prevalence and distribution of HCA and HSP in Portugal. Population-based, nationwide, systematic survey, from January 1, 1994, through April 15, 2004, in Portugal. Multiple sources of information were used (review of clinical files, active collaboration of neurologists and geneticists, and investigation of affected families), but the main source was active collaboration of general practitioners. Patients were examined by the same team of neurologists, using homogeneous inclusion criteria. The clinical data were registered, and all families were genetically tested. Overall, 1336 patients from a population of 10,322 million were diagnosed as having HCA or HSP, a prevalence of 12.9 per 100,000 population. Hereditary cerebellar ataxia was more prevalent (prevalence, 8.9 per 100,000 population; 5.6 for dominant and 3.3 for recessive ataxias) than HSP (prevalence, 4.1 per 100,000 population; 2.4 for dominant and 1.6 for recessive). Machado-Joseph disease (spinocerebellar ataxia type 3) (prevalence, 3.1 per 100,000 population), Friedreich ataxia (prevalence, 1.0 per 100,000 population), and ataxia with oculomotor apraxia (prevalence, 0.4 per 100,000 population) were the most frequent HCAs. Spastic paraplegia types 4 (prevalence, 0.91 per 100,000 population), 3 (prevalence, 0.14 per 100,000 population), and 11 (prevalence, 0.26 per 100,000 population) were the most prevalent HSPs. This population-based survey covered all the Portuguese territory and mobilized most general practitioners and health centers. To our best knowledge, this survey was the largest ever performed for HCA and HSP. Prevalence of autosomal dominant ataxias was high, particularly for Machado-Joseph disease (spinocerebellar ataxia type 3). The genetic cause has not been identified in 39.7% of the patients studied.

  14. X-ray sensitivity of fifty-three human diploid fibroblast cell strains from patients with characterized genetic disorders

    Energy Technology Data Exchange (ETDEWEB)

    Weichselbaum, R.R.; Nove, J.; Little, J.B.

    1980-03-01

    The in vitro response of 53 human diploid fibroblast strains to x-irradiation was studied using a clonogenic survival assay. The strains, derived from patients with a variety of characterized clinical conditions, most with a genetic component, ranged in Do (a measure of the slope of the survival curve) from 43 to 168 rads. The mean Do's of six strains from normal individuals was 140 to 152 rads, with an overall range, based on the extremes of their standard errors, of 128 to 164 rads. Three-quarters of the strains studied fell within this range. Strains identified as sensitive came from patients with ataxia telangiectasia, progeria, the two genetic forms of retinoblastoma, and partial trisomy of chromosome 13. No marked radiosensitivity was found among strains derived from patients with a number of other conditions associated with a predisposition to malignancy.

  15. Nephritis and cerebellar ataxia: rare presenting features of enteric fever.

    Directory of Open Access Journals (Sweden)

    Parmar R

    2000-07-01

    Full Text Available Enteric fever is a common infectious disease of the tropical world, about 80% of these cases occur in Asian countries. Enteric fever presenting with isolated cerebellar ataxia or nephritis is rare. We report three cases of enteric fever that presented with these complications. Isolated cerebellar ataxia usually occurs in the second week, whereas in our cases it presented within first four days of fever. The common complications of enteric fever related to the urinary tract are cystitis, pyelitis, and pyelonephritis. Glomerulonephritis is uncommon. Most patients with enteric glomerulonephritis present with acute renal failure, hypertensive encephalopathy, or nephritic syndrome. In comparison, our case had milder manifestations. All three patients were treated with parenteral ceftriaxone and showed a prompt recovery.

  16. Cognitive Functions in Ataxia with Oculomotor Apraxia Type 2

    OpenAIRE

    Klivényi, Peter; Nemeth, Dezso; Sefcsik, Tamas; Janacsek, Karolina; Hoffmann, Ildiko; Haden, Gabor Peter; Londe, Zsuzsa; Vecsei, Laszlo

    2012-01-01

    Background: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by cerebellar atrophy, peripheral neuropathy, oculomotor apraxia, and elevated serum alpha-fetoprotein (AFP) levels. The disease is caused by a recessive mutation in the senataxin gene. Since it is a very rare cerebellar disorder, no detailed examination of cognitive functions in AOA2 has been published to date. The aim of the present study was to investigate the neuropsychological profile of a 54-year-old patient with ...

  17. Cognitive Functions in Ataxia with Oculomotor Apraxia Type 2

    OpenAIRE

    Péter eKlivényi; Dezso eNemeth; Tamás eSefcsik; Karolina eJanacsek; Ildiko eHoffmann; Gábor Péter Háden; Zsuzsa eLonde; László eVécsei

    2012-01-01

    Background: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by cerebellar atrophy, peripheral neuropathy, oculomotor apraxia, and elevated serum alpha-fetoprotein levels. The disease is caused by a recessive mutation in the senataxin gene. Since it is a very rare cerebellar disorder, no detailed examination of cognitive functions in AOA2 has been published to date. The aim of the present study was to investigate the neuropsychological profile of a 54-year-old patient with AOA2. ...

  18. 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...

  19. 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

  20. Woman presenting with chronic iron deficiency anemia associated with hereditary hemorrhagic telangiectasia: a case report

    Directory of Open Access Journals (Sweden)

    Stross P

    2013-11-01

    Full Text Available Paul StrossDepartment of Haematology, St Richard's Hospital, Chichester, United KingdomBackground: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder associated with frequent nose bleeds that can be troublesome and difficult to contain. A further manifestation is telangiectasia, which may develop in the upper and lower gastrointestinal tract. The associated blood loss can be chronic, resulting in iron deficiency anemia which, when severe, has historically been treated by blood transfusions. Further pulmonary, neurologic, and hepatic complications may appear in later life, and are well documented. Administering blood transfusions requires provision, storage, and serological testing to select suitable units. Recognition of the inherent potential risks of donated blood, the expense, and the concerns regarding blood supply, has resulted in a national policy for conservation and appropriate use of blood. For an individual patient, there may be development of alloantibodies which complicates future cross-matching for transfusions.Case report: SG is a 66-year-old Caucasian woman who first presented to our hematology department in 2003, having just moved to the area. She had suffered with nose bleeds since her teenage years and presented with a low hemoglobin level and symptoms of iron deficiency anemia. Medical and nonmedical interventions failed to arrest the blood loss, which had not been massive or associated with hypovolemic shock. Pursuant to conserving blood supplies, and based on experience of patients with other causes of iron deficiency anemia, a regimen of high-dose iron supplementation was adopted. The aim was to sustain iron stores as a substrate for erythropoiesis and thereby achieve adequate hemoglobin levels whilst minimizing the need for blood transfusion.Discussion: This approach has maintained the patient's hemoglobin levels at 6.4–11.6 g/dL over a period of 9 years. Until the time of writing in 2011, the

  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. Efficacy of Intravitreal Bevacizumab in Treatment of Proliferative Type 2 Idiopathic Juxtafoveal Telangiectasia

    Directory of Open Access Journals (Sweden)

    Ökkeş Baz

    2017-06-01

    Full Text Available Objectives: To evaluate the effectiveness of intravitreal bevacizumab (IVB in patients with subretinal neovascularization secondary to type 2 juxtafoveal telangiectasia. Materials and Methods: Ten eyes of 10 patients were included in this retrospective study. All cases were treated with IVB (1.25 mg bevacizumab. Visual acuity and slit-lamp anterior and posterior segment examinations were performed at each visit. Central macular thickness (CMT and intraretinal/subretinal fluid were evaluated via spectral domain optical coherence tomography (OCT. Loss of a line in visual acuity chart and presence of fluid on OCT were defined as criteria for repeated treatment. Results: The mean age of patients was 66.0±7.0 years (56-75. The mean follow-up time was 54.7±16.0 month (24-72. The mean BCVA was 0.62±0.35 (0.00-1.00 logMAR at baseline and 0.54±0.35 (0.00-1.00 logMAR at final exam (p=0.03. The mean CMT was 251±25.4 µm at baseline and 239±39.3 µm at final exam (p=0.01. Patients received an average of 1.7±1.0 IVB injections during follow-up. At baseline, all cases had intraretinal/subretinal fluid. There was no fluid at final examination of all cases. Conclusion: IVB treatment may be effective in the treatment of subretinal neovascularization secondary to type 2 juxtafoveal telangiectasia.

  3. Hereditary hemorrhagic telangiectasia and pregnancy: potential adverse events and pregnancy outcomes

    Directory of Open Access Journals (Sweden)

    Bari O

    2017-05-01

    Full Text Available Omar Bari,1 Philip R Cohen2 1School of Medicine, University of California San Diego, La Jolla, CA, USA; 2Department of Dermatology, University of California San Diego, La Jolla, CA, USA Abstract: Hereditary hemorrhagic telangiectasia (HHT is an autosomal dominant condition with a prevalence of ~1 in 5,000 individuals. The pathophysiology of this condition centers on the lack of capillary beds between arterioles and venules, leading to direct contact between these vessels. This results in telangiectases on characteristic locations such as the face, fingers, mouth, and nasal mucosa. Visceral arteriovenous malformations (AVMs are also observed in many patients, and these are most commonly seen in the brain, gastrointestinal tract, and lungs. Liver AVMs are present in many patients with HHT, though these individuals are usually asymptomatic; however, liver AVMs may lead to serious complications, such as high output cardiac failure. Diagnosis of HHT hinges upon fulfilling three out of four criteria: family history of the condition, mucocutaneous telangiectases, spontaneous and recurrent episodes of epistaxis, and visceral AVMs. Management is guided by international consensus guidelines and targets patients’ specific AVMs. Prognosis is good, though severe complications including hemorrhage and paradoxical emboli are possible. Novel therapeutics are being explored in clinical trials; bevacizumab and pazopanib inhibit angiogenesis, while thalidomide bolsters blood vessel maturation. Pregnancy in patients with HHT is considered high risk. While the majority of pregnancies proceed normally, severe complications have been reported in some women with HHT; these include heart failure, intracranial hemorrhage, pulmonary hemorrhage, and stroke. Such complications occur most often in the second and third trimesters when maternal changes such as peripheral vasodilation and increased cardiac output are at their maximum. Awareness of the diagnosis of HHT has

  4. Does a basic deficit in force control underlie cerebellar ataxia?

    Science.gov (United States)

    Charles, Steven K; Okamura, Allison M; Bastian, Amy J

    2013-02-01

    Because damage to the cerebellum results in characteristic movement incoordination known as "ataxia," it has been hypothesized that it is involved in estimation of limb dynamics that occur during movement. However, cerebellar function may extend beyond movement to force control in general, with or without movement. Here we tested whether the cerebellum is involved in controlling force separate from estimating limb dynamics and whether ataxia could result from a deficit in force control. We studied patients with cerebellar ataxia controlling their arm force isometrically; in this condition arm dynamics are absent and there is no need for (or effect from an impairment in) estimations of limb dynamics. Subjects were required to control their force magnitude, direction, or both. Cerebellar patients were able to match force magnitude or direction similarly to control subjects. Furthermore, when controlling force magnitude, they intuitively chose directions (not specified) that required minimal effort at the joint level--this ability was also similar to control subjects. In contrast, cerebellar patients performed significantly worse than control subjects when asked to match both force magnitude and direction. This was surprising, since they did not exhibit significant impairment in doing either in isolation. These results show that cerebellum-dependent computations are not limited to estimations of body dynamics needed for active movement. Deficits occur even in isometric conditions, but apparently only when multiple degrees of freedom must be controlled simultaneously. Thus a fundamental cerebellar operation may be combining/coordinating degrees of freedom across many kinds of movements and behaviors.

  5. Cerebellar ataxia in progressive supranuclear palsy: An autopsy study of PSP-C.

    Science.gov (United States)

    Koga, Shunsuke; Josephs, Keith A; Ogaki, Kotaro; Labbé, Catherine; Uitti, Ryan J; Graff-Radford, Neill; van Gerpen, Jay A; Cheshire, William P; Aoki, Naoya; Rademakers, Rosa; Wszolek, Zbigniew K; Ross, Owen A; Dickson, Dennis W

    2016-05-01

    Cerebellar ataxia is an exclusion criterion for the clinical diagnosis of progressive supranuclear palsy, but a variant with predominant cerebellar ataxia has been reported. The aims of this study were to estimate the frequency of progressive supranuclear palsy with predominant cerebellar ataxia in an autopsy series from the United States and to compare clinical, pathologic, and genetic differences between progressive supranuclear palsy with and without predominant cerebellar ataxia. We selected 100 consecutive patients with pathologically confirmed progressive supranuclear palsy who had been evaluated at the Mayo Clinic (referred to as the Mayo Clinic patient series) from our brain bank database (N = 1085). We next enriched in cases likely to have cerebellar ataxia by searching the remaining 985 cases for (1) an antemortem diagnosis of multiple system atrophy or (2) neuropathologic evidence of prominent degeneration of the cerebellum or cerebellar afferent nuclei. Subsequently, clinical, pathologic, and genetic features were compared between the two groups. One patient in the Mayo Clinic patient series (1%) met criteria for progressive supranuclear palsy with predominant cerebellar ataxia and had both cerebellar and mild midbrain atrophy on MRI. Four patients were identified with the targeted search. Four of the five patients were clinically misdiagnosed as multiple system atrophy. The severity of tau-related pathology and cerebellar degeneration were not different between the two groups. No differences were detected in tau genotypes. Although our data cannot provide definitive information about how to make an accurate clinical diagnosis, they should serve to raise awareness of progressive supranuclear palsy with predominant cerebellar ataxia in the differential diagnosis of multiple system atrophy. © 2016 Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  6. Surgical treatment of gastrointestinal hereditary hemorrhagic telangiectasia.

    Science.gov (United States)

    Yen, Min-Hsuan; Chen, Chiung-Nien

    2016-04-01

    A 48-year-old man with a history of gastrointestinal bleeding from Osler-Weber-Rendu disease presented with recurrent hematemesis and tarry stool. He received repeated endoscopic therapy, but profound component therapy was still needed. Because repeated gastrointestinal bleeding was caused by same bleeder, tattoo-assisted laparoscopic gastric wedge resection was carried out. The pathology showed vascular abnormalities that involved gastric mucosal and submucosal layers. After surgery, the blood transfusion for the patient is not seen. Osler-Weber-Rendu is a hereditary disease characterized by vascular abnormalities of the nose, skin, lung, brain, and gastrointestinal tract. Management of gastrointestinal bleeding requires medical treatment first, and there are rare reports of surgical treatment. Our pathology findings showed a transmucosal vessel lesion, which had poor response to endoscopic treatment. Surgical intervention may be considered in the patient with gastrointestinal bleeding refractory to endoscopic therapy.

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

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Lihua [Department of Radiation Oncology, The First Hospital of Jilin University, Changchun (China); Cui, Jingkun [Department of Internal Medicine, Nanling School District Hospital of Jilin University, Changchun (China); Tang, Fengjiao; Cong, Xiaofeng [Cancer Center, The First Hospital of Jilin University, Changchun (China); Han, Fujun, E-mail: fujun_han@aliyun.com [Cancer Center, The First Hospital of Jilin University, Changchun (China)

    2015-04-01

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

  8. Spinocerebellar ataxia type 7: Report of an Indian family

    Directory of Open Access Journals (Sweden)

    Gurusidheshwar M Wali

    2013-01-01

    Full Text Available Spinocerebellar ataxia type 7 (SCA7 is a form of autosomal dominant cerebellar ataxia which is associated with pigmentary retinal degeneration. It is known for its world-wide rarity except in the Scandinavian countries. It is very rarely reported from India and the neighbouring Asian countries . The present report describes the neurogenetic findings of a family of SCA7, from the northern part of Karnataka in South India. It documents the wide intrafamilial phenotypic variability, which could be correlated with the CAG repeat counts and phenomenon of anticipation. Genotype phenotype correlation highlighted certain disparities in comparison with the previous studies. The report highlights the need for multiethnic population studies and the role of genetic counseling and prenatal testing in SCA7 patients.

  9. A Case of Cerebellar Ataxia Associated with HIV Infection.

    Science.gov (United States)

    Anand, Kuljeet Singh; Wadhwa, Ankur; Garg, Jyoti

    2014-01-01

    Cerebellar complications of HIV infection primarily manifested in ataxia, usually arise as the result of cerebellar lesions due to opportunistic infections, vasculitis or neoplastic processes. A 28 year old female known to have HIV infection for last four years, presented to our hospital with progressive unsteadiness in walking, slurring of speech and intention tremors for the last two months. There was no family history of similar complaints, and she was on Anti retroviral treatment for last one and a half years. The results of examination were notable for severe dysarthria, slow saccades, a conspicuous dysmetria and dysdiadokokinesia. She had no cognitive, sensory or motor deficits. MRI revealed diffuse cerebellar atrophy. Extensive laboratory work up failed to disclose a cause for subacute ataxia. Isolated cerebellar degeneration in an HIV patient is rare and should prompt a diagnostic work up. © The Author(s) 2014.

  10. [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.

  11. 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.

  12. Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation.

    Science.gov (United States)

    Graves, Tracey D; Cha, Yoon-Hee; Hahn, Angelika F; Barohn, Richard; Salajegheh, Mohammed K; Griggs, Robert C; Bundy, Brian N; Jen, Joanna C; Baloh, Robert W; Hanna, Michael G

    2014-04-01

    Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15-65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0-40) was an average of 3.15 for all participants (range 0-14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean=50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1 phenocopies

  13. Episodic ataxia type 1: clinical characterization, quality of life and genotype–phenotype correlation

    Science.gov (United States)

    Graves, Tracey D.; Cha, Yoon-Hee; Hahn, Angelika F.; Barohn, Richard; Salajegheh, Mohammed K.; Griggs, Robert C.; Bundy, Brian N.; Jen, Joanna C.; Baloh, Robert W.

    2014-01-01

    Episodic ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15–65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0–40) was an average of 3.15 for all participants (range 0–14), but was only 2 in those with isolated episodic ataxia compared with 7.7 in those with progressive cerebellar ataxia in addition to episodic ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean = 50) were below normal with mental health being the lowest (41.3) in those with mutation positive episodic ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic ataxia type 1

  14. Telangiectasia hemorrágica hereditária: resposta hematológica após terapêutica com talidomida

    Directory of Open Access Journals (Sweden)

    Eduardo Ribeiro

    2013-03-01

    Full Text Available A telangiectasia hemorrágica hereditária (THH é uma doença autossómica dominante, que se distingue em dois tipos, devidos a mutações em genes diferentes. É caracterizada por telangiectasias mucocutâneas e viscerais, envolvendo vários órgãos com malformações vasculares. O sintoma comum é a anemia. O diagnóstico clínico é baseado na presença de pelo menos três das quatro principais características clínicas: epistáxis, telangiectasias cutâneas ou mucosas, envolvimento visceral e história familiar. Dependendo das manifestações da doença e da sua gravidade, existem várias formas de tratamento que variam desde terapêutica local, a cirurgia, ou terapêutica farmacológica. Apresentamos o caso de um paciente com THH e anemia por deficiência de ferro grave, dependente de transfusões de sangue frequentes, que teve uma melhoria dramática após terapêutica com a talidomida, sem ocorrência de efeitos colaterais. Hereditary hemorrhagic telangiectasia (HHT is an autosomal dominant disease and is distinguished into two types, which are due to mutations in different genes. It is characterized by mucocutaneous and visceral telangiectasia and involves several organs with vascular malformations. The common symptom is anemia. The clinical diagnosis is based on the presence of at least three of four main clinical features: epistaxis, cutaneous or mucosal telangiectases, visceral involvement and a family history. Depending on disease manifestation and it severity, there are several forms of therapy ranging from local therapy, surgery ou drug therapy. Here we describe a dramatic improvement of a patient with HHT and severe iron deficiency anemia, requiring frequent blood transfusion, successfully treated with thalidomide, without side effects.

  15. Gastrointestinal Manifestations of Hereditary Hemorrhagic Telangiectasia (HHT): A Systematic Review of the Literature.

    Science.gov (United States)

    Jackson, Samuel B; Villano, Nicholas P; Benhammou, Jihane N; Lewis, Michael; Pisegna, Joseph R; Padua, David

    2017-10-01

    Hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis.

  16. 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).

  17. Fragile X-associated tremor/ataxia syndrome: An under-recognised cause of tremor and ataxia.

    Science.gov (United States)

    Kalus, Sarah; King, John; Lui, Elaine; Gaillard, Frank

    2016-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X "premutation", defined as 55-200 CGG repeats in the 5'-untranslated region of the FMR1 gene. The FMR1 premutation occurs in 1/800 males and 1/250 females, with FXTAS affecting 40-45% of male and 8-16% of female premutation carriers over the age of 50. FXTAS typically presents with kinetic tremor and cerebellar ataxia. FXTAS has a classical imaging profile which, in concert with clinical manifestations and genetic testing, participates vitally in its diagnosis. The revised FXTAS diagnostic criteria include two major radiological features. The "MCP sign", referring to T2 hyperintensity in the middle cerebellar peduncle, has long been considered the radiological hallmark of FXTAS. Recently included as a major radiological criterion in the diagnosis of FXTAS is T2 hyperintensity in the splenium of the corpus callosum. Other imaging features of FXTAS include T2 hyperintensities in the pons, insula and periventricular white matter as well as generalised brain and cerebellar atrophy. FXTAS is an under-recognised and misdiagnosed entity. In patients with unexplained tremor, ataxia and cognitive decline, the presence of middle cerebellar peduncle and/or corpus callosum splenium hyperintensity should raise suspicion of FXTAS. Diagnosis of FXTAS has important implications not only for the patient but also, through genetic counselling and testing, for future generations. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. 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...

  19. 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 ...

  20. 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

  1. 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.

  2. 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.

  3. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video‐oculographic diagnosis

    National Research Council Canada - National Science Library

    Szmulewicz, David J; Waterston, John A; MacDougall, Hamish G; Mossman, Stuart; Chancellor, Andrew M; McLean, Catriona A; Merchant, Saumil; Patrikios, Peter; Halmagyi, G. Michael; Storey, Elsdon

    2011-01-01

    ... “cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome” (CANVAS). All patients had brain MRI and 22/27 had evidence of cerebellar atrophy involving anterior and dorsal vermis, as well as the hemispheric crus...

  4. 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.

  5. 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

  6. Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

    Science.gov (United States)

    Reich, Martin M; Brumberg, Joachim; Pozzi, Nicolò G; Marotta, Giorgio; Roothans, Jonas; Åström, Mattias; Musacchio, Thomas; Lopiano, Leonardo; Lanotte, Michele; Lehrke, Ralph; Buck, Andreas K; Volkmann, Jens; Isaias, Ioannis U

    2016-11-01

    Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar

  7. Cerebellar vermis defect, oligophrenia, congenital ataxia, and hepatic fibrocirrhosis without coloboma and renal abnormalities: report of three cases.

    Science.gov (United States)

    Coppola, G; Vajro, P; De Virgiliis, S; Ciccimarra, E; Boccone, L; Pascotto, A

    2002-08-01

    We describe 3 children (2 siblings aged 10 and 3 years, and 1 sporadic case aged 13 years) with cerebellar vermis defect associated with oligophrenia, congenital ataxia, and hepatic fibrocirrhosis. Differently from what is reported in COACH syndrome, coloboma and renal involvement were absent. Since in one patient hepatic involvement was subclinical and early therapy seemed to prevent disease progression, the presence of liver disease should be carefully investigated in any patient with ataxia and midline cerebellar defects.

  8. A double-blind, randomized study comparing pure chromated glycerin with chromated glycerin with 1% lidocaine and epinephrine for sclerotherapy of telangiectasias and reticular veins.

    Science.gov (United States)

    Kern, Philippe; Ramelet, Albert-Adrien; Wutschert, Robert; Mazzolai, Lucia

    2011-11-01

    Chromated glycerin (CG) is an effective, although painful, sclerosing agent for telangiectasias and reticular leg veins treatment. To determine pain level and relative efficacy of pure or one-third lidocaine-epinephrine 1% mixed chromated glycerin in a prospective randomized double-blind trial. Patients presenting with telangiectasias and reticular leg veins on the lateral aspect of the thigh (C(1A) or (S) E(P) A(S) P(N1) ) were randomized to receive pure CG or CG mixed with one-third lidocaine-epinephrine 1% (CGX) treatment. Lower limb photographs were taken before and after treatment and analyzed by blinded expert reviewers for efficacy assessment (visual vein disappearance). Patients' pain and satisfaction were assessed using visual analogue scales. Data from 102 of 110 randomized patients could be evaluated. Patient pain scores were significantly higher when pure CG was used than with CGX (p<.001). Patient satisfaction with treatment outcome was similar in the two groups. Objective visual assessment of vessel disappearance revealed no significant difference between the two agents (p=.07). Addition of lidocaine-epinephrine 1% to CG, in a ratio of one-third, significantly reduces sclerotherapy pain without affecting efficacy when treating telangiectasias and reticular leg veins. © 2011 by the American Society for Dermatologic Surgery, Inc.

  9. Mapping of Spinocerebellar Ataxia 13 to Chromosome 19q13.3-q13.4 in a Family with Autosomal Dominant Cerebellar Ataxia and Mental Retardation

    Science.gov (United States)

    Herman-Bert, Alexandra; Stevanin, Giovanni; Netter, Jean-Claude; Rascol, Olivier; Brassat, David; Calvas, Patrick; Camuzat, Agnès; Yuan, Qiu-ping; Schalling, Martin; Dürr, Alexandra; Brice, Alexis

    2000-01-01

    We examined a large French family with autosomal dominant cerebellar ataxia (ADCA) that was excluded from all previously identified spinocerebellar ataxia genes and loci. The patients—seven women and a 4-year-old boy—exhibited slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate mental retardation (IQ 62–76), and mild developmental delays in motor acquisition. Nystagmus and pyramidal signs were also observed in some cases. This unique association of clinical features clearly distinguishes this new entity from other previously described ADCA. Cerebral magnetic-resonance imaging showed moderate cerebellar and pontine atrophy in two patients. We performed a genomewide search and found significant evidence for linkage to chromosome 19q13.3-q13.4, in an ∼8-cM interval between markers D19S219 and D19S553. PMID:10820125

  10. 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

  11. 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

  12. Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia.

    Science.gov (United States)

    Travaglini, Lorena; Nardella, Marta; Bellacchio, Emanuele; D'Amico, Adele; Capuano, Alessandro; Frusciante, Roberto; Di Capua, Matteo; Cusmai, Raffaella; Barresi, Sabina; Morlino, Silvia; Fernández-Fernández, José M; Trivisano, Marina; Specchio, Nicola; Valeriani, Massimiliano; Vigevano, Federico; Bertini, Enrico; Zanni, Ginevra

    2017-05-01

    Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA). We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy. De novo missense mutations of CACNA1A were found in four patients (4/48, ∼8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases. Our results expand the clinical and mutational spectrum of CACNA1A-related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  13. 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.

  14. Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.

    Science.gov (United States)

    Heimer, G; Eyal, E; Zhu, X; Ruzzo, E K; Marek-Yagel, D; Sagiv, Doron; Anikster, Y; Reznik-Wolf, H; Pras, E; Oz Levi, D; Lancet, D; Ben-Zeev, B; Nissenkorn, A

    2017-09-15

    AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  15. Clinical Responses to Rituximab in a Case of Neuroblastoma with Refractory Opsoclonus Myoclonus Ataxia Syndrome

    Directory of Open Access Journals (Sweden)

    Samin Alavi

    2012-01-01

    Full Text Available Opsoclonus myoclonus ataxia syndrome (OMS is a rare neurologic syndrome. In a high proportion of children, it is associated with neuroblastoma. The etiology of this condition is thought to be immune mediated. In children, immunotherapy with conventional treatments such as corticosteroids, intravenous immunoglobulin, adrenocorticotropic hormone, and even antiepileptic drugs has been tried. Recently rituximab has been used safely for refractory OMS in children with neuroblastoma. Our patient was a 3.5-year-old girl referred for ataxia and dancing eye movements starting since 1.5 years ago. She was diagnosed with neuroblastoma on imaging studies on admission. The OMS was refractory to surgical resection, chemotherapy, corticosteroids, and intravenous immunoglobulin. Patient received rituximab simultaneously with chemotherapy. The total severity score decreased by 61.1% after rituximab. Patient's ataxia markedly improved that she was able to walk independently after 6 months. Our case confirmed the clinical efficacy and safety of rituximab in a refractory case of OMS.

  16. Intense pulsed light vs. long-pulsed dye laser treatment of telangiectasia after radiotherapy for breast cancer: a randomized split-lesion trial of two different treatments

    DEFF Research Database (Denmark)

    Nymann, P.; Hedelund, L.; Hædersdal, Merete

    2009-01-01

    ); the interventions were randomly assigned to left/right or upper/lower halves. Primary end-points were reduction in telangiectasia, patient satisfaction and preferred treatment. Secondary end-points were pain and adverse effects. Efficacy was registered by blinded photographic evaluations 3 months after the final......Background Chronic radiodermatitis is a common sequela of treatment for breast cancer and potentially a psychologically distressing factor for the affected women. Objectives To evaluate the efficacy and adverse effects of treatments with a long-pulsed dye laser (LPDL) vs. intense pulsed light (IPL...... treatment. Results Eleven patients completed the study. Telangiectasia cleared with both treatments but the efficacy of LPDL was superior. Blinded photographic evaluations showed median vessel clearances of 90% (LPDL) and 50% (IPL) (P = 0.01). LPDL treatments were associated with lower pain scores than IPL...

  17. Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts.

    Science.gov (United States)

    Synofzik, Matthis; Schüle, Rebecca; Schulze, Martin; Gburek-Augustat, Janina; Schweizer, Roland; Schirmacher, Anja; Krägeloh-Mann, Ingeborg; Gonzalez, Michael; Young, Peter; Züchner, Stephan; Schöls, Ludger; Bauer, Peter

    2014-04-17

    Mutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts. 300 subjects with degenerative ataxia (n = 167) or spastic paraplegia (n = 133) were screened for STUB1 variants by whole-exome-sequencing (n = 204) or shotgun-fragment-library-sequencing (n = 96). To control for the specificity of STUB1 variants, we screened an additional 1707 exomes from 891 index families with other neurological diseases. We identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1, including 3 mutations in its tetratricopeptide-repeat domain. All patients showed evidence of pyramidal tract damage. Cognitive impairment was present only in one and hypogonadism in none of them. Ataxia did not start before age 48 years in one subject. No recessive STUB1 variants were identified in families with other neurological diseases, demonstrating that STUB1 variants are not simply rare polymorphisms ubiquitous in neurodegenerative disease. STUB1-disease occurs also in Caucasian ataxia populations (1.8%). Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain. Moreover, they further delineate the phenotypic core features of STUB1-ataxia. Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity, thus adding STUB1-ataxia to the differential diagnosis of "spastic ataxias". However, STUB1 is rare in subjects with predominant spastic paraplegia (0/133). In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive

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

    NARCIS (Netherlands)

    Smets, K.; Duarri, A.; Deconinck, T.; Ceulemans, B.; Warrenburg, B.P.C. van de; Zuchner, S.; Gonzalez, M.A.; Schule, R.; Synofzik, M.; Aa, N. van der; Jonghe, P. De; Verbeek, D.S.; Baets, J.

    2015-01-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  20. 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 ...

  1. Epidemiology of Cerebellar Ataxia on the Etiological Basis: A Cross Sectional Study

    Directory of Open Access Journals (Sweden)

    Simindokht Hosseini Seyede

    2009-12-01

    Full Text Available Cerebellar ataxias are a heterogenous group of disorders, clinically and etiologically, that result in considerable health burden. Finding out about the various etiologies, and their relative prevalences in the population suffering from cerebellar ataxia helps the clinician to perform a better management, in treatment process. This is a cross sectional study designed to estimate the relative prevalence of each etiologic factor. One-hundred and thirty-five patients ,in the range of 6 to 73 years from march 1993 to march1999, were classified in different groups on the basis of etiological findings. Relative prevalence of each of the etiological factors , common accompanying disorders besides ataxia in the patients,CT and MRI changes,and CSF alterations are studied and recorded. A widely spread age group, and the extended number of the cases under study, are the advantages of the current study over the previously reported case series. Among the etiologic groups, multiple sclerosis, cerebrovascular accidents and hereditary cerebellar ataxia, were the most common etiologic factors associated with cerebellar ataxia respectively.

  2. A gene for nystagmus-associated episodic ataxia maps to chromosome 19p

    Energy Technology Data Exchange (ETDEWEB)

    Kramer, P.L.; Root, D.; Gancher, S. [and others

    1994-09-01

    Episodic ataxia (EA) is a rare, autosomal dominant disorder, characterized by attacks of generalized ataxia and relatively normal neurological function between attacks. Onset occurs in childhood or adolescence and persists through adulthood. Penetrance is nearly complete. EA is clinically heterogeneous, including at least two distinct entities: (1) episodes of ataxia and dysarthria lasting hours to days, generally with interictal nystagmus (MIM 108500); (2) episodes of ataxia and dysarthria lasting only minutes, with interictal myokymia (MMM 160120). The EA/nystagmus patients sometimes develop persistent ataxia and cerebellar atrophy. Previously we reported linkage in four EA/myokymia families to a K{sup +} channel gene on chromosome 12p. We excluded this region in a large family with EA/nystagmus. We now report evidence for linkage to chromosome 19p in this and in one other EA/nystagmus family, based on eight microsatellite markers which span approximately 30 cM. The region is flanked distally by D19S209 and proximally by D19S226. All six markers within this region gave positive evidence for linkage; the highest total two-point lod scores occurred wtih D19S221 (3.98 at theta = 0.10) and D19S413 (3.37 at theta = 0.05). Interestingly, Joutel et al. (1993) mapped a gene for familial hemiplegic migraine (FHM) to the region around D19S221. Some individuals in these families have ataxia, cerebellar atrophy and interictal nystagmus, but no episodic ataxia. These results demonstrate that the clinical heterogeneity in EA reflects underlying genetic hetreogeneity. In addition, they suggest that EA/nystagmus and some FHM may represent different mutations in the same gene locus on chromosome 19p.

  3. Unilateral Oculomotor Nerve Palsy Following Campylobacter Infection: A Mild Form of Miller Fisher Syndrome without Ataxia.

    Science.gov (United States)

    Ueno, Tatsuya; Kon, Tomoya; Kurihara, Ai-Ichiro; Tomiyama, Masahiko

    2017-11-01

    Unilateral oculomotor nerve palsy can result from various neurological disorders. We herein report the case of a 68-year-old man with complete unilateral oculomotor nerve palsy following campylobacter infection. Based on the antecedent infection and the patient's decreased tendon reflexes, incomplete Miller Fisher syndrome (MFS) without ataxia was suspected. His serum tested positive for anti-GQ1b antibodies. He recovered over a period of 87 days without immunotherapy. We conclude that incomplete MFS following campylobacter infection can cause unilateral oculomotor nerve palsy without ataxia. Mild MFS should be considered in patients presenting with unilateral isolated ophthalmoplegia and decreased tendon reflexes.

  4. Paroxysmal dysarthria-ataxia in remitting-relapsing Bickerstaff's-like encephalitis.

    Science.gov (United States)

    Piffer, Silvio; Turri, Giulia; Acler, Michele; Richelli, Silvia; Cerini, Roberto; Fiaschi, Antonio; Monaco, Salvatore; Bonetti, Bruno

    2014-06-15

    Paroxysmal dysarthria-ataxia is a rare neurological condition due to ephaptic transmission, generally appearing in multiple sclerosis patients characterized by stereotyped attacks of slurred speech usually accompanied by ataxia, appearing many times a day. Here we describe a patient with an unusual remitting-relapsing form of Bickerstaff's-like brainstem encephalitis who manifested PDA after a relapse with the involvement of a peculiar region below the red nuclei and benefited from lamotrigine. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Orthodeoxia without Platypnea in Hereditary Hemorrhagic Telangiectasia in the Presence of a Cerebral Abscess and Multiple Pulmonary Arteriovenous Malformations: Unusual Complications and Transcatheter Endovascular Treatment

    Directory of Open Access Journals (Sweden)

    Carlos Salazar

    2017-01-01

    Full Text Available Hereditary hemorrhagic telangiectasia is a rare autosomal-dominant condition affecting visceral blood vessel development. Cerebral and most commonly pulmonary arteriovenous malformations are found in the majority of symptomatic patients. The most common complications include embolic strokes and cerebral abscesses, which have been attributed to abnormal vessel communications. Platypnea orthodeoxia is a rare condition that presents dyspnea and oxygen desaturation when adopting an upright position and is relieved on decubitus. The association between hereditary hemorrhagic telangiectasia, pulmonary arteriovenous malformations, and platypnea orthodeoxia has been described in medical literature; however, orthodeoxia as a single entity without platypnea has not been described yet, especially associated with complications of this hereditary condition. We present the case of a 38-year-old male with persistent headaches, in whom a cerebral lesion was detected. Orthostatic tachycardia and severe orthodeoxia without platypnea were evidenced during physical examination. The patient was subsequently diagnosed with hereditary hemorrhagic telangiectasia and underwent cerebral abscess drainage as well as transcatheter endovascular closure of multiple pulmonary arteriovenous malformations. For this reason, the concept of platypnea orthodeoxia syndrome needs further revision. Patients presenting refractory hypoxemia should warn physicians to initially evaluate their oxygen saturation measurements during standing and decubitus position, even though platypnea may not be present.

  6. Telangiectasia hemorrágica hereditária: ácido tranexâmico no tratamento de úlcera plantar Hereditary hemorrhagic telangiectasia: tranexamic acid for plantar ulcer

    Directory of Open Access Journals (Sweden)

    Gabriella Corrêa de Albuquerque

    2005-12-01

    Full Text Available Relato de um caso de úlcera plantar por fístula arteriovenosa em paciente portador de telangiectasia hemorrágica hereditária ou doença de Rendu-Osler-Weber tratado com ácido tranexâmico. Este fármaco é utilizado para tratamento de epistaxe, referindo-se o principal achado deste artigo ao uso eficaz desse medicamento na terapia de úlceras plantares hemorrágicas. São descritos os aspectos fisiopatológicos e clínicos da doença e as propriedades antifibrinolíticas do ácido tranexâmico. Este foi bem tolerado e apresentou evidências de eficácia na utilização para controle do sangramento e cicatrização da úlcera.Case report of one patient with Hereditary Hemorrhagic Telangiectasia, also known as Rendu-Osler-Weber syndrome, treated with Tranexamic Acid for arteriovenous plantar ulcer. This drug has proved effective in controlling epistaxis, but the main point of this report is to expose the success use of this medication in the therapy of skin bleeding ulcer. The pathophysiologic and clinical features of the disease are reviewed and also the pharmacological aspects of the antifibrinolytic drugs. This drug was well tolerated by the patient and show evidence of good activity in the bleeding and healed the ulcer.

  7. Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation.

    Science.gov (United States)

    Dard, Rodolphe; Mignot, Cyril; Durr, Alexandra; Lesca, Gaetan; Sanlaville, Damien; Roze, Emmanuel; Mochel, Fanny

    2015-12-01

    ATP1A3, the gene encoding the α3-subunit of the Na(+) /K(+) -ATPase pump, has been involved in four clinical neurological entities: (1) alternating hemiplegia of childhood (AHC); (2) rapid-onset dystonia parkinsonism (RDP); (3) CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) syndrome; and (4) early infantile epileptic encephalopathy. Here, we report on a 34-year-old female presenting with a new ATP1A3-related entity involving a relapsing encephalopathy characterized by recurrent episodes of cerebellar ataxia and altered consciousness during febrile illnesses. The term RECA is suggested - relapsing encephalopathy with cerebellar ataxia. The phenotype of this patient, resembling mitochondrial oxidative phosphorylation defects, emphasizes the possible role of brain energy deficiency in patients with ATP1A3 mutations. Rather than multiple overlapping syndromes, ATP1A3-related disorders might be seen as a phenotypic continuum. © 2015 Mac Keith Press.

  8. 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 ...

  9. 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 ...

  10. Cerebellar Ataxia with Bilateral Vestibulopathy: Description of a Syndrome and Its Characteristic Clinical Sign

    Science.gov (United States)

    Migliaccio, Americo A.; Halmagyi, G. Michael; McGarvie, Leigh A.; Cremer, Phillip D.

    2004-01-01

    We report four patients with the syndrome of cerebellar ataxia with bilateral vestibulopathy (CABV) and, using search coil oculography, we validate its characteristic clinical sign, namely impairment of the visually enhanced vestibulo-ocular reflex (VVOR) or doll's head reflex. In our four patients, CABV began in the sixth decade of life; they are…

  11. 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

  12. 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....

  13. Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design.

    Science.gov (United States)

    Friedman, Lisa S; Farmer, Jennifer M; Perlman, Susan; Wilmot, George; Gomez, Christopher M; Bushara, Khalaf O; Mathews, Katherine D; Subramony, S H; Ashizawa, Tetsuo; Balcer, Laura J; Wilson, Robert B; Lynch, David R

    2010-03-15

    Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia of all four limbs, dysarthria, and arreflexia. A variety of measures are currently used to quantify disease progression, including the Friedreich Ataxia Rating Scale, examiner-rated functional disability scales, self-reported activities of daily living and performance measures such as the timed 25-foot walk, 9-hole pegboard test, PATA speech test, and low-contrast letter acuity vision charts. This study examines the rate of disease progression over one and two years in a cohort of 236 Friedreich ataxia patients using these scales and performance measure composites. The Friedreich Ataxia Rating Scale and performance-measure composites captured disease progression, with a greater sensitivity to change over 2 years than over 1 year. The measures differed in their sensitivity to change and in possible bias. These results help to establish norms for progression in FRDA that can be useful in measuring the long-term success of therapeutic agents and defining sample-size calculations for double-blind clinical trials.

  14. Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations.

    Science.gov (United States)

    Pfeffer, Gerald; Blakely, Emma L; Alston, Charlotte L; Hassani, Adam; Boggild, Mike; Horvath, Rita; Samuels, David C; Taylor, Robert W; Chinnery, Patrick F

    2012-09-01

    Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ∼50% cases. Mutations in the mitochondrially encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and, occasionally, have onset later in childhood. The authors report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indistinguishable from other spinocerebellar ataxia patients. Genetic screening study of the MTATP6 gene in 64 pedigrees with unexplained ataxia, and case series of two families who had MTATP6 mutations. Three pedigrees had mutations in MTATP6, two of which have not been reported previously and are detailed in this report. These families had the m.9185T>C and m.9035T>C mutations, respectively, which have not previously been associated with adult-onset cerebellar syndromes. Other investigations including muscle biopsy and respiratory chain enzyme activity were non-specific or normal. MTATP6 sequencing should be considered in the workup of undiagnosed ataxia, even if other investigations do not suggest a mitochondrial DNA disorder.

  15. Clinical and genetic characteristics of sporadic adult-onset degenerative ataxia.

    Science.gov (United States)

    Giordano, Ilaria; Harmuth, Florian; Jacobi, Heike; Paap, Brigitte; Vielhaber, Stefan; Machts, Judith; Schöls, Ludger; Synofzik, Matthis; Sturm, Marc; Tallaksen, Chantal; Wedding, Iselin M; Boesch, Sylvia; Eigentler, Andreas; van de Warrenburg, Bart; van Gaalen, Judith; Kamm, Christoph; Dudesek, Ales; Kang, Jun-Suk; Timmann, Dagmar; Silvestri, Gabriella; Masciullo, Marcella; Klopstock, Thomas; Neuhofer, Christiane; Ganos, Christos; Filla, Alessandro; Bauer, Peter; Tezenas du Montcel, Sophie; Klockgether, Thomas

    2017-09-05

    To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations. The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing. The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p 10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made. Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort. NCT02701036. © 2017 American Academy of Neurology.

  16. 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.

  17. Liver involvement in hereditary hemorrhagic telangiectasia: can breath test unmask impaired hepatic first-pass effect?

    Science.gov (United States)

    Candelli, Marcello; Pompili, Maurizio; Suppressa, Patrizia; Lenato, Gennaro M; Bosco, Giulia; Rapaccini, Gian Ludovico; Gasbarrini, Antonio; Scardapane, Arnaldo; Sabbà, Carlo

    2012-08-01

    Hepatic arteriovenous malformations (HAVMs) in hereditary hemorrhagic telangiectasia (HHT) have long been considered to have scarce clinical significance in most cases. Nevertheless, data are lacking regarding the influence of HAVMs on the liver first-pass effect on drugs in HHT patients. To gain insight into the effect of HAVMs on hepatic drug clearance by means of two specific (13)C-labeled probes, namely the (13)C-methacetin and (13)C-aminopyrine, 46 HHT patients and 44-matched healthy controls were enrolled. The liver first-pass effect was studied by the (13)C-based breath test using methacetin and aminopyrine. The methacetin breath test showed statistically significant reduced metabolism rates (p test values are significantly lower than those found in normal subjects, probably due to the effect of hepatic shunts. A reduced perfusion and an impaired hepatic metabolism might affect hepatic drug clearance in HHT. Therefore, an appropriate dosage adjustments should be considered when high-hepatic-metabolism drugs are administered to HHT patients.

  18. Intravitreal ranibizumab and laser photocoagulation in the management of idiopathic juxtafoveolar retinal telangiectasia type 1: a case report.

    Science.gov (United States)

    Ciarnella, Angela; Verrilli, Sara; Fenicia, Vito; Mannino, Cristina; Cutini, Alessandro; Perdicchi, Andrea; Recupero, Santi Maria

    2012-09-01

    Idiopathic juxtafoveolar retinal telangiectasia (IJRT) type 1 represents an uncommon cause of congenital unilateral visual loss and it typically affects males. Decrease in visual acuity is caused by serous and lipid exudation into the fovea with cystoid macular edema. In some cases, spontaneous resolution may be observed, but when there is a progressive loss of visual acuity, laser photocoagulation is often necessary. This treatment is not always successful and therapy for this condition is still controversial. A 57-year-old man referred a 2-month history of blurred and distorted vision in the right eye. Best-corrected visual acuity was 20/50 in the right eye and 20/20 in the left eye. Fundus examination showed temporal macular edema, confirmed by optical coherence tomography. Fluorescein angiography showed a localized area of hyperfluorescence probably due to telangiectasia type 1 located below the inferior temporal area of the fovea. A combined therapy of intravitreal ranibizumab injection and laser photocoagulation was performed. Visual acuity improved from 20/50 to 20/32 and the therapy was well tolerated by the patient. After 3 years of follow-up, both visual acuity and fundus examination were stable. This case suggests that the combined use of ranibizumab and laser photocoagulation may be considered an effective treatment for JRT type 1, leading to an improvement in both visual acuity and macular edema. We believe that intravitreal ranibizumab injection associated with laser photocoagulation should be considered as treatment for IJRT type 1.

  19. 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

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

    Science.gov (United States)

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

    2017-06-28

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

  1. 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

  2. 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.

  3. 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.

  4. 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...

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

    Science.gov (United States)

    Ramocki, Melissa B; Chapieski, Lynn; McDonald, Ryan O; Fernandez, Fabio; Malphrus, Amy D

    2008-09-01

    Spinocerebellar ataxia type 2 typically presents in adulthood with progressive ataxia, dysarthria, tremor, and slow saccadic eye movements. Childhood-onset spinocerebellar ataxia type 2 is rare, and only the infantile-onset form has been well characterized clinically. This article describes a girl who met all developmental milestones until age 3(1/2) years, when she experienced cognitive regression that preceded motor regression by 6 months. A diagnosis of spinocerebellar ataxia type 2 was delayed until she presented to the emergency department at age 7 years. This report documents the results of her neuropsychologic evaluation at both time points. This case broadens the spectrum of spinocerebellar ataxia type 2 presentation in childhood, highlights the importance of considering a spinocerebellar ataxia in a child who presents with cognitive regression only, and extends currently available clinical information to help clinicians discuss the prognosis in childhood spinocerebellar ataxia type 2.

  6. 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

  7. 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...

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

    Science.gov (United States)

    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.

  9. Spinocerebellar Ataxia Type 7: Clinical Course, Phenotype-Genotype Correlations, and Neuropathology

    Science.gov (United States)

    Horton, Laura C.; Frosch, Matthew P.; Vangel, Mark G.; Weigel-DiFranco, Carol; Berson, Eliot L.; Schmahmann, Jeremy D.

    2012-01-01

    INTRODUCTION Spinocerebellar ataxia type 7 is a neurodegenerative polyglutamine disease characterized by ataxia and retinal degeneration. The longitudinal course is unknown, and relationships between repeat expansion, clinical manifestations, and neuropathology remain uncertain. METHODS We followed 16 affected individuals of a 61-member kindred over 27 years with electroretinograms, neurological examinations including the Brief Ataxia Rating Scale, neuroimaging in 5, and autopsy in 4 cases. RESULTS We identified 4 stages of the illness. Stage 0; gene positive but phenotypically silent. Stage 1; no symptoms, but hyperreflexia and/or abnormal electroretinograms. Stage 2; symptoms and signs progress modestly. Stage 3; rapid clinical progression. CAG repeat length correlated inversely with age of onset of visual or motor signs (r=-0.74, p=0.002). Stage 3 rate of progression did not differ between cases (p=0.18). Electroretinograms correlated with Brief Ataxia Rating Scale score and were a biomarker of disease onset and progression. All symptomatic patients developed gait ataxia, extremity dysmetria, dysarthria, dysrhythmia, and oculomotor abnormalities. Funduscopy revealed pale optic discs and pigmentary disturbances. Visual acuity declined to blindness in those with longer CAG expansions. Hyperreflexia was present from Stage 1 onwards. Restless legs syndrome and sensory impairment were common. Neuropathological hallmarks were neuronal loss in cerebellar cortex, deep cerebellar nuclei, inferior olive, and anterior horns of the spinal cord, and axonal loss in spinocerebellar tracts, dorsal nerve roots and posterior columns. Retinal pathology included photoreceptor degeneration and disruption of retinal pigment epithelium. DISCUSSION Spinocerebellar ataxia type 7 evolves through 4 clinical stages; neuropathological findings underlie the clinical presentation; electroretinograms are a potential biomarker of disease progression. PMID:22915085

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

    Directory of Open Access Journals (Sweden)

    Bassam R Ali

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

  11. Novel mutations in typical and atypical genetic loci through exome sequencing in autosomal recessive cerebellar ataxia families.

    Science.gov (United States)

    Faruq, M; Narang, A; Kumari, R; Pandey, R; Garg, A; Behari, M; Dash, D; Srivastava, A K; Mukerji, M

    2014-10-01

    Nearly a thousand mutations mapping to 60 different loci have been identified in cerebellar ataxias. However, almost 50% of the cases remain genetically uncharacterized and there is a difference in prevalence as well as in the phenotypic spectrum of ataxia among various geographical regions. This poses a challenge for setting up a genetic panel for screening ataxia. In our ataxic cohort of 1014 families, 61% are genetically uncharacterized (UC). We investigated the potential of whole exome sequencing in conjunction with homozygosity mapping (HM) to delineate the genetic defects in three uncharacterized families with recessive inheritance each manifesting some unusual phenotype: (i) infantile onset ataxia with hearing loss (IOAH), (ii) Juvenile onset cerebellar ataxia with seizures (JCS) and (iii) Friedreich ataxia-like (FA-like). We identified a novel missense mutation in c10orf2 in the family with IOAH, compound heterozygous mutations in CLN6 in the family with JCS and a homozygous frame-shift mutation in SACS in the FA-like patient. Phenotypes observed in our families were concordant with reported phenotypes of known mutations in the same genes thus obviating the need for functional validation. Our study revealed novel variations in three genes, c10orf2, CLN6, and SACS, that have so far not been reported in India. This study also demonstrates the utility of whole exome screening in clinics for early diagnosis. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

    Science.gov (United States)

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

    2014-01-07

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

  13. Clinical and molecular studies in five Brazilian cases of Friedreich ataxia Avaliação clínica e molecular de cinco pacientes brasileiros com ataxia de Friedreich

    Directory of Open Access Journals (Sweden)

    IDA V.D. SCHWARTZ

    1999-03-01

    Full Text Available Friedreich ataxia (FRDA, the most common autosomal recessive ataxia, is caused in 94% of cases by homozygous expansions of an unstable GAA repeat localised in intron 1 of the X25 gene. We have investigated this mutation in five Brazilian patients: four with typical FRDA findings and one patient with atypical manifestations, who was considered to have some other form of cerebellar ataxia with retained reflexes. The GAA expansion was detected in all these patients. The confirmation of FRDA diagnosis in the atypical case may be pointing out, as in other reports, that clinical spectrum of Friedreich's ataxia is broader than previously recognised and includes cases with intact tendon reflexes.A ataxia de Friedreich (FRDA é a mais frequente das ataxias com herança autossômica recessiva. Em 94 % dos casos, é causada por uma expansão homozigota instável da repetição de trinucleotídeos GAA, localizada no primeiro íntron do gene X25. Esta mutação foi investigada em cinco pacientes brasileiros: quatro com quadro clínico típico de FRDA e um paciente com manifestações atípicas, cujo diagnóstico prévio era o de alguma outra forma de ataxia cerebelar com preservação de reflexos. A investigação foi positiva nos cinco casos. A confirmação do diagnóstico de FRDA no paciente com quadro atípico, assim como em outros casos semelhantes já relatados na literatura, sugere que o espectro de manifestações clínicas da FRDA seja mais amplo do que o classicamente reconhecido, incluindo casos com preservação de reflexos.

  14. 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

  15. Genetic heterogeneity in hereditary hemorrhagic telangiectasia: Possible correlation with clinical phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Papenberg, K.A.; Lennon, F.; Helmbold, E.A. [and others

    1994-09-01

    Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant generalized vascular dysplasia characterized by recurrent hemorrhage. Our initial linkage studies found an HHT gene to be localized to 9q3 in two large kindreds. In the present study, we have examined an additional five unrelated HHT families. The multipoint linkage analysis in this region resulted in a peak multipoint lod score of 13.03. Two additional proximal crossovers in affected individuals in one of these families have now further defined the candidate region on 9q3. In addition, significant evidence for heterogeneity of HHT found. The multipoint analysis supported the two-point studies with the odds of 3,000,000: 1 showing linkage and heterogeneity over linkage and homogeneity. Four of the seven families gave a posterior probability of > 99% of being of the linked type, while three families are unlinked to this region of 9q. The multipoint lod score using only the linked families is 21.70. Finally, a possible correlation in clinical phenotype between the 9q3-linked families and unlinked families is described. Although six of the seven families clearly meet the clinical criteria for HHT diagnosis, a significant absence of PAVMs is seen in all 9q3-unlinked families. This genetic heterogeneity and possible correlation to a clinical phenotype may have a significant impact on the clinical management and treatment of HHT patients.

  16. Dementia in Fragile X-associated Tremor/Ataxia Syndrome

    Directory of Open Access Journals (Sweden)

    Ricardo Nitrini

    Full Text Available Abstract Fragile X-associated tremor/ataxia syndrome (FXTAS is a cause of movement disorders and cognitive decline which has probably been underdiagnosed, especially if its prevalence proves similar to those of progressive supranuclear palsy and amyotrophic lateral sclerosis. We report a case of a 74-year-old man who presented with action tremor, gait ataxia and forgetfulness. There was a family history of tremor and dementia, and one of the patient's grandsons was mentally deficient. Neuropsychological evaluation disclosed a frontal network syndrome. MRI showed hyperintensity of both middle cerebellar peduncles, a major diagnostic hallmark of FXTAS. Genetic testing revealed premutation of the FMR1 gene with an expanded (CGG90 repeat. The diagnosis of FXTAS is important for genetic counseling because the daughters of the affected individuals are at high risk of having offspring with fragile X syndrome. Tremors and cognitive decline should raise the diagnostic hypothesis of FXTAS, which MRI may subsequently reinforce, while the detection of the FMR1 premutation can confirm the condition.

  17. 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.

  18. '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

  19. ‘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

  20. A randomized pilot study of stochastic vibration therapy in spinocerebellar ataxia.

    Science.gov (United States)

    Kaut, O; Jacobi, H; Coch, C; Prochnicki, A; Minnerop, M; Klockgether, T; Wüllner, U

    2014-04-01

    Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and rehabilitation. We examined the effect of stochastic WBV on ataxia in spinocerebellar ataxia types 1, 2, 3, and 6 (SCA 1, 2, 3 and 6) in a single-center double-blind sham-controlled study. Stochastic WBV was applied on four sequent days, each treatment consisting of five stimulus trains of 60-s duration at a frequency of 6.5 Hz and 60-s resting time between stimuli (n = 17). Patients allocated to the sham group received the same treatment with 1 Hz (n = 15). All patients were rated at baseline and after the last treatment using clinical scores (SARA, SCAFI, and INAS). After treatment, we found significant improvements of gait, posture, and speed of speech in the verum group while limb kinetics and ataxia of speech did not respond. Stochastic WBV might act on proprioceptive mechanisms and could also stimulate non-cerebellar/compensatory mechanisms. But at present, the involved cellular mechanism and the presumed neuronal loops cannot be deciphered. Thus, future work is needed to understand the mechanisms of whole body vibration. Finally, the use of stochastic WBV could provide a supplementation to treat ataxia in SCA and can be combined with physiotherapeutical motor training.

  1. Long-term outcome of deep brain stimulation in fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Weiss, Daniel; Mielke, Carina; Wächter, Tobias; Bender, Benjamin; Liscic, Rajka M; Scholten, Marlieke; Naros, Georgios; Plewnia, Christian; Gharabaghi, Alireza; Krüger, Rejko

    2015-03-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) presents as complex movement disorder including tremor and cerebellar ataxia. The efficacy and safety of deep brain stimulation of the nucleus ventralis intermedius of the thalamus in atypical tremor syndromes like FXTAS remains to be determined. Here, we report the long-term outcome of three male genetically confirmed FXTAS patients treated with bilateral neurostimulation of the nucleus ventralis intermedius for up to four years. All patients demonstrated sustained improvement of both tremor and ataxia - the latter included improvement of intention tremor and axial tremor. Kinematic gait analyses further demonstrated a regularization of the gait cycle. Initial improvements of hand functional disability were not sustained and reached the preoperative level of impairment within one to two years from surgery. Our data on patients with a genetic cause of tremor show favorable outcome and may contribute to improved patient stratification for neurostimulation therapy in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. 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

  3. 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...

  4. 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.

  5. 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.

  6. Effect of gluten-free diet on cerebellar MR spectroscopy in gluten ataxia.

    Science.gov (United States)

    Hadjivassiliou, Marios; Grünewald, Richard A; Sanders, David S; Shanmugarajah, Priya; Hoggard, Nigel

    2017-08-15

    To evaluate the effect of gluten free diet (GFD) on magnetic resonance spectroscopy (MRS) of the cerebellum in patients with gluten ataxia (GA). Patients with GA, defined as sporadic ataxia with positive antigliadin antibodies in the absence of an alternative cause, routinely undergo MRS at baseline and after the introduction of GFD as part of their clinical care. We present our experience of the effect of GFD on MRS of the cerebellum. A total of 117 consecutive patients with GA were included in this report. Sixty-three were on strict GFD with elimination of antigliadin antibodies, 35 were on GFD but were still positive for antigliadin antibodies, and 19 patients opted not to go on GFD. The N -acetylaspartate (NAA)/creatine (Cr) area ratio from the cerebellar vermis increased in 62 out of 63 (98%) patients on strict GFD, in 9 of 35 (26%) patients on GFD but positive antibodies, and in only 1 of 19 (5%) patients not on GFD. The NAA/Cr ratio decreased in all 14 ataxia control patients (cerebellar variant of multisystem atrophy). There were no differences in the MRS results between those patients who had and those who did not have enteropathy (celiac disease) within each group. The demonstration of increased NAA/Cr ratio on repeat scanning following strict GFD strengthens previous findings of clinical improvement of the ataxia in patients with GA. The presence of enteropathy is not a prerequisite for such improvement; therefore patients with positive serology and negative duodenal biopsy should still be treated with strict GFD. © 2017 American Academy of Neurology.

  7. Cerebral capillary telangiectasias: a meta-analysis and review of the literature.

    Science.gov (United States)

    Gross, Bradley A; Puri, Ajit S; Popp, A John; Du, Rose

    2013-04-01

    As a result of their presumed benign natural history, cerebral capillary telangiectasias (CCTs) are infrequently addressed in the neurosurgical literature. We performed a comprehensive review of CCTs via the PubMed database to synthesize overall epidemiological, radiographic, natural history, and treatment results. Across ten series with 203 patients, mean age was 47, and 45 % were male [95 % confidence interval (CI), 0.30-0.65]. Notably, 78 % of CCTs were in the pons (95 % CI, 0.58-1.0). Six percent of CCTs were symptomatic. Across five radiographic series, all lesions enhanced after gadolinium, and all were hypointense on gradient echo sequences. Thirty-three percent were hypointense on T1-weighted pre-contrast imaging (95 % CI, 0.2-0.51), 49 % were hyperintense on T2-weighted imaging (95 % CI, 0.31-0.72), and 74 % were hypointense on diffusion-weighted imaging (95 % CI, 0.5-1.0). Notably, 37 % were associated with a prominent draining vein (95 % CI, 0.21-0.6), and 11 % with a developmental venous anomaly (95 % CI, 0.04-0.25). Across four observational studies with 47 patients, there was no observed change in lesion morphology or hemorrhage in 65.7 patient-years of follow-up. Although the vast majority of CCTs are managed conservatively, we found ten cases of patients treated with surgical excision. We confirm that CCTs are a benevolent entity with a predilection for the pons. They have distinctive radiographic features including their lack of mass effect, consistent enhancement on T1-weighted sequences and hypointensity on gradient echo sequences, and common isointensity on pre-contrast T1-weighted and T2-weighted images. Management for these lesions has been nonoperative in almost all cases.

  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. Friedreich's Ataxia: a review from a cardiology perspective.

    Science.gov (United States)

    Bourke, T; Keane, D

    2011-12-01

    Neuromuscular disorders are not among the common causes of cardiomyopathy in the general population; however, cardiomyopathy is known to occur in several neuromuscular disorders including Friedreich's Ataxia (FA). In patients with neuromuscular disorders, concomitant cardiac involvement contributes significantly to morbidity and mortality and often leads to premature death. An extensive literature search of Medline and Pubmed was conducted to include all published reports on cardiac involvement in FA. Secondary articles were identified from key paper reference listings. Hypertrophic cardiomyopathy is a cardinal feature of FA; therefore all FA patients should be screened for cardiomyopathy. A cardiac examination, ECG and ECHO are advised at diagnosis, and also on the development of any cardiac symptoms. Treatment is determined by the presence of symptoms, the presence of left ventricular outflow gradient and the sudden death risk. Institution of aggressive medical therapy early in the course of the disease may help improve quality of life and provide survival benefit.

  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. 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

  12. A home balance exercise program improves walking in people with cerebellar ataxia.

    Science.gov (United States)

    Keller, Jennifer L; Bastian, Amy J

    2014-10-01

    Physical therapy intervention is the primary treatment for gait ataxia and imbalance in individuals with cerebellar damage. Our aim was to determine if a home balance exercise program is feasible for improving locomotor and balance abilities in these individuals. A total of 14 patients with cerebellar ataxia participated in a 6-week individualized home-based balance exercise program and attended 5 testing sessions (2 pretraining, 1 midtraining, 1 posttraining, and 1 one-month follow-up visit). Pretraining, posttraining, and follow-up testing included a neurological assessment, clinical gait and balance tests, and laboratory assessments of balance and walking. Participants kept logs of the frequency and level of balance challenge during their training. Walking speed improved across visits, as did stride length, percentage double-limb support time, Timed Up and Go (TUG), and Dynamic Gait Index. Post hoc comparisons in these measures revealed that significant rehabilitative improvements occurred over the 6-week training period, and all but TUG gains were retained 1 month later. There were no changes across the other measures for the group. Regression analysis indicated that improvements in walking speed were affected by the level of balance challenge but not by age, ataxia severity, proprioception, or duration of exercise. Improvement in locomotor performance in people with cerebellar ataxia was observable after a 6-week home balance exercise program. The exercise program must be designed to provide a significant challenge to the person's balance. © The Author(s) 2014.

  13. 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.

  14. Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.

    Science.gov (United States)

    Minnerop, Martina; Kurzwelly, Delia; Wagner, Holger; Soehn, Anne S; Reichbauer, Jennifer; Tao, Feifei; Rattay, Tim W; Peitz, Michael; Rehbach, Kristina; Giorgetti, Alejandro; Pyle, Angela; Thiele, Holger; Altmüller, Janine; Timmann, Dagmar; Karaca, Ilker; Lennarz, Martina; Baets, Jonathan; Hengel, Holger; Synofzik, Matthis; Atasu, Burcu; Feely, Shawna; Kennerson, Marina; Stendel, Claudia; Lindig, Tobias; Gonzalez, Michael A; Stirnberg, Rüdiger; Sturm, Marc; Roeske, Sandra; Jung, Johanna; Bauer, Peter; Lohmann, Ebba; Herms, Stefan; Heilmann-Heimbach, Stefanie; Nicholson, Garth; Mahanjah, Muhammad; Sharkia, Rajech; Carloni, Paolo; Brüstle, Oliver; Klopstock, Thomas; Mathews, Katherine D; Shy, Michael E; de Jonghe, Peter; Chinnery, Patrick F; Horvath, Rita; Kohlhase, Jürgen; Schmitt, Ina; Wolf, Michael; Greschus, Susanne; Amunts, Katrin; Maier, Wolfgang; Schöls, Ludger; Nürnberg, Peter; Zuchner, Stephan; Klockgether, Thomas; Ramirez, Alfredo; Schüle, Rebecca

    2017-06-01

    Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal

  15. Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics

    Science.gov (United States)

    2013-01-01

    Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments. PMID:23331413

  16. Mutations in the IRBIT domain of ITPR1 are a frequent cause of autosomal dominant nonprogressive congenital ataxia.

    Science.gov (United States)

    Barresi, S; Niceta, M; Alfieri, P; Brankovic, V; Piccini, G; Bruselles, A; Barone, M R; Cusmai, R; Tartaglia, M; Bertini, E; Zanni, G

    2017-01-01

    Congenital ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole-exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KC