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Sample records for ataxia

  1. 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. PMID:23622331

  2. 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 ...

  3. 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, ...

  4. Diagnosis of Ataxia

    Science.gov (United States)

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

  5. 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

  6. Causes of Ataxia

    Science.gov (United States)

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

  7. Acute cerebellar ataxia

    Science.gov (United States)

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

  8. Friedreich's Ataxia Research Alliance

    Science.gov (United States)

    ... Adolescents Affected by Friedreich's Ataxia: A One-Year Longitudinal Study Pharmacological treatments for Friedreich ataxia FARA News ... FA What is FA Message for New Families Cardiac Primer Basics of Drug Development Participation in Clinical ...

  9. Autosomal recessive cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    Palau Francesc

    2006-11-01

    Full Text Available Abstract Autosomal recessive cerebellar ataxias (ARCA are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2–4/100,000, ataxia-telangiectasia (1–2.5/100,000 and early onset cerebellar ataxia with retained tendon reflexes (1/100,000. Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder, ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, α-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED, aprataxin in ataxia with oculomotor apraxia (AOA1, and senataxin in ataxia with oculomotor apraxia (AOA2. Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning, electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.

  10. Gene Testing for Hereditary Ataxia

    Science.gov (United States)

    FAQ NATIONAL ATAXIA FOUNDATION FREQUENTLY ASKED QUESTIONS ABOUT... Gene Testing for Hereditary Ataxia This fact sheet provides an overview of gene testing for ataxia. It also addresses commonly asked ...

  11. Friedreich's Ataxia (FA)

    Science.gov (United States)

    Facts About Friedreich’s Ataxia Updated December 2009 Michelle Moffitt Smith Michelle and James Smith at their wedding Dear Friends: W hen I was ... some tests, I found out I had Friedreich’s ataxia. My parents and I immediately learned all we ...

  12. Diet for Ataxia

    Science.gov (United States)

    ... discuss these guidelines with a physical therapist and nutritionist familiar with movement disorders. Ataxia is a complex ... fiber to your diet with your physician or nutritionist, ask them if you might also benefit by ...

  13. Brain pathology of spinocerebellar ataxias

    NARCIS (Netherlands)

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

    2012-01-01

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

  14. Genetics Home Reference: Friedreich ataxia

    Science.gov (United States)

    Skip to main content Your Guide to Understanding Genetic Conditions Enable Javascript for addthis links to activate. ... Conditions Genes Chromosomes & mtDNA Resources Help Me Understand Genetics Home Health Conditions Friedreich ataxia Friedreich ataxia Enable ...

  15. Genetics Home Reference: episodic ataxia

    Science.gov (United States)

    ... mapping for a large pedigree with episodic ataxia. Neurology. 2005 Jul 12;65(1):156-8. Citation ... RW. Clinical spectrum of episodic ataxia type 2. Neurology. 2004 Jan 13;62(1):17-22. Citation ...

  16. National Ataxia Foundation

    Science.gov (United States)

    ... 60th NAF Annual Ataxia Conference San Antonio, TX March 10-11, 2017 2017 AAC Announcment 2017 AAC Information Support MY Conference Campaign 2017 AAC Sponsor Packet 2017 AAC Exhibitor Packet 2016 AAC Presentations AAC Travel Grant Fund Adult Travel Grant Application Child Travel ...

  17. 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.

  18. Ataxia-telangiectasia

    OpenAIRE

    Nelson Pires Ferreira

    1983-01-01

    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.

  19. Genetics Home Reference: ataxia-telangiectasia

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions ataxia-telangiectasia ataxia-telangiectasia Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Ataxia-telangiectasia is a rare inherited disorder that affects ...

  20. Genetics Home Reference: ataxia with oculomotor apraxia

    Science.gov (United States)

    ... Genetics Home Health Conditions ataxia with oculomotor apraxia ataxia with oculomotor apraxia Enable Javascript to view the ... boxes. Download PDF Open All Close All Description Ataxia with oculomotor apraxia is a condition characterized by ...

  1. Neurophysiological evaluation in children with Friedreich's ataxia

    NARCIS (Netherlands)

    Sival, D A; du Marchie Sarvaas, G J; Brouwer, O F; Uges, D R; Verschuuren-Bemelmans, C C; Maurits, N M; Brunt, E R; van der Hoeven, J H

    2009-01-01

    INTRODUCTION: In children with Friedreich's ataxia (FRDA children), clinical ataxia outcomes are hardly substantiated by underlying neurophysiological parameters. In young FRDA children, some reports (based upon International Cooperative Ataxia Rating Scale scores (ICARS)) mention transient neurolog

  2. 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.

  3. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias

    OpenAIRE

    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

    2015-01-01

    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, Mi...

  4. Genetics of the dominant ataxias

    NARCIS (Netherlands)

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

    2011-01-01

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

  5. Ataxia-telangiectasia

    Directory of Open Access Journals (Sweden)

    Nelson Pires Ferreira

    1966-09-01

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

  6. [Heart involvement in Friedreich's ataxia].

    Science.gov (United States)

    Weidemann, F; Scholz, F; Florescu, C; Liu, D; Hu, K; Herrmann, S; Ertl, G; Störk, S

    2015-03-01

    Friedreich's ataxia is a rare hereditary disease and although the gene defect has already been identified as a deficiency of the mitochondrial protein frataxin, the pathophysiology is still unknown. Although a multisystem disorder organ involvement is predominantly neurological. Besides the characteristic features of spinocerebellar ataxia the heart is frequently also affected. Cardiac involvement typically manifests as hypertrophic cardiomyopathy, which can progress to heart failure and death. So far most research has focused on the neurological aspects and cardiac involvement in Friedreich's ataxia has not been systematically investigated. Thus, a better understanding of the progression of the cardiomyopathy, cardiac complications and long-term cardiac outcome is warranted. Although no specific treatment is available general cardiac therapeutic options for cardiomyopathy should be considered. The current review focuses on clinical and diagnostic features of cardiomyopathy and discusses potential therapeutic developments for Friedreich's ataxia. PMID:24848865

  7. Therapeutic Developments in Friedreich Ataxia

    OpenAIRE

    Robert B Wilson

    2012-01-01

    Friedreich ataxia is an inherited, severe, progressive neuro- and cardiodegenerative disorder for which there currently is no approved therapy. Friedreich ataxia is caused by the decreased expression and/or function of frataxin, a mitochondrial matrix protein that binds iron and is involved in the formation of iron-sulfur clusters. Decreased frataxin function leads to decreased iron-sulfur cluster formation, mitochondrial iron accumulation, cytosolic iron depletion, oxidative stress, and mito...

  8. Ataxia-telangiectasia: future prospects

    OpenAIRE

    Chaudhary MW; Al-Baradie RS

    2014-01-01

    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 si...

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

    NARCIS (Netherlands)

    E. Brusse (Esther)

    2011-01-01

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

  10. 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.

  11. Genetics Home Reference: spinocerebellar ataxia type 2

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions SCA2 spinocerebellar ataxia type 2 Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Spinocerebellar ataxia type 2 ( SCA2 ) is a condition characterized by ...

  12. Genetics Home Reference: spinocerebellar ataxia type 3

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions SCA3 spinocerebellar ataxia type 3 Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Spinocerebellar ataxia type 3 ( SCA3 ) is a condition characterized by ...

  13. Genetics Home Reference: spinocerebellar ataxia type 6

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions SCA6 spinocerebellar ataxia type 6 Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Spinocerebellar ataxia type 6 ( SCA6 ) is a condition characterized by ...

  14. Genetics Home Reference: spinocerebellar ataxia type 1

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions SCA1 spinocerebellar ataxia type 1 Enable Javascript to view the expand/ ... Download PDF Open All Close All Description Spinocerebellar ataxia type 1 ( SCA1 ) is a condition characterized by ...

  15. Spinocerebellar Ataxia Type 14 (SCA14)

    Science.gov (United States)

    ... SCA14) is one of those types of hereditary cerebellar ataxias. The involved gene, discovered in 2003, is located ... evaluation by a physician makes the diagnosis of cerebellar ataxia. A CT or MRI scan of the brain ...

  16. 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.

  17. Ataxia telangiectasia: learning from previous mistakes

    OpenAIRE

    Kumar, Naveen; Aggarwal, Puneet; Dev, Nishanth; Kumar, Gunjan

    2012-01-01

    Ataxia telangiectasia is an early onset neurodegenerative disorder. We report a case of childhood onset ataxia and ocular telangiectasia, presenting with pulmonary infection. The patient was diagnosed as ataxia telangiectasia. The patient succumbed to death owing to late diagnosis and sepsis.

  18. Clinical challenges in the ataxias

    Institute of Scientific and Technical Information of China (English)

    S.H. Subramony

    2011-01-01

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

  19. Clinical Features of Friedreich Ataxia

    OpenAIRE

    Delatycki, Martin B.; Corben, Louise A

    2012-01-01

    Friedreich ataxia, the most common hereditary ataxia, affects about 1:29 000 Caucasians. In about 98% of these individuals it is due to homozygosity for a GAA trinucleotide repeat expansion in intron 1 of FXN; in the other 2% it is due to compound heterozygosity for a GAA expansion and point mutation or deletion. The condition affects multiple sites in the central and peripheral nervous system as well as a number of other organ systems, resulting in multiple signs and symptoms. Onset of this ...

  20. Language Impairment in Cerebellar Ataxia

    NARCIS (Netherlands)

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

    2014-01-01

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

  1. 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…

  2. Hereditary Cerebellar Ataxias: A Korean Perspective

    Directory of Open Access Journals (Sweden)

    Ji Sun Kim

    2015-05-01

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

  3. Cerebellar ataxia as presenting feature of hypothyroidism.

    Science.gov (United States)

    Kotwal, Suman Kumar; Kotwal, Shalija; Gupta, Rohan; Singh, Jang Bhadur; Mahajan, Annil

    2016-04-01

    Symptoms and signs of the hypothyroidism vary in relation to the magnitude and acuteness of the thyroid hormone deficiency. The usual clinical features are constipation, fatigue, cold intolerance and weight gain. Rarely it can present with neurologic problems like reversible cerebellar ataxia, dementia, peripheral neuropathy, psychosis and coma. Hypothyroidism should be suspected in all cases of ataxia, as it is easily treatable. A 40 year-old male presented with the history facial puffiness, hoarseness of voice and gait-ataxia. Investigations revealed frank primary hypothyroidism. Anti-TPO antibody was positive. Thyroxine was started and patient improved completely within eight weeks. Hypothyroidism can present with ataxia as presenting feature. Hypothyroidism should be considered in all cases of cerebellar ataxia as it is a reversible cause of ataxia. PMID:26886095

  4. Friedreich Ataxia and Diabetes Mellitus: family study

    OpenAIRE

    Melo, M; Fagulha, A; Barros, L.; Guimarães, J; Carrilho, F; Carvalheiro, M

    2005-01-01

    Friedreich's ataxia (FA) is one of the genetic syndromes sometimes associated with diabetes and the most common hereditary ataxia. It is a autosomal recessive neurodegenerative disease, caused by a mutation in the FRDA gene, which originates decreased expression of frataxin, a mitochondrial protein involved in iron metabolism. The disorder is usually manifest in childhood and is characterised by ataxia, dysarthria, scoliosis and feet deformity. About two thirds of patients have hypertrophic c...

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  6. 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 Enable Javascript to view ... boxes. Download PDF Open All Close All Description Ataxia with vitamin E deficiency is a disorder that ...

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

    Science.gov (United States)

    ... anemia and ataxia X-linked sideroblastic anemia and ataxia Enable Javascript to view the expand/collapse boxes. ... Close All Description X-linked sideroblastic anemia and ataxia is a rare condition characterized by a blood ...

  8. Genetics Home Reference: dilated cardiomyopathy with ataxia syndrome

    Science.gov (United States)

    ... dilated cardiomyopathy with ataxia syndrome dilated cardiomyopathy with ataxia syndrome Enable Javascript to view the expand/collapse ... Open All Close All Description Dilated cardiomyopathy with ataxia (DCMA) syndrome is an inherited condition characterized by ...

  9. Gluten ataxia of sporadic and hereditary cerebellar ataxia in patients from mainland China

    Directory of Open Access Journals (Sweden)

    Wen-Juan Guan

    2013-01-01

    Full Text Available Background: Gluten sensitivity (GS is a spectrum of disorders with diverse manifestations. Recent evidence suggests that ataxia may be the only manifestation of GS and that it may be one of the causes of sporadic ataxia. Aim: To investigate the prevalence of gluten ataxia among patients with ataxia in China. Materials and Methods: Serum levels of anti-gliadin, anti-transglutaminase 2 (TG2, and anti-transglutaminase 6 (TG6 antibodies measured in 125 patients with ataxia (100 patients with sporadic ataxia and 25 patients with hereditary ataxia and 51 healthy controls by enzyme-linked immunosorbent assay (ELISA. Results: The serum concentrations of anti-gliadin, anti-TG2 IgG, IgA, and TG6-IgG antibodies were elevated in ataxia patients, but the increase was not statistically significant. However, TG6-IgA serum levels were significantly higher in sporadic ataxia as compared to those in healthy controls (P < 0.05. Conclusions: These results provide evidence that sporadic ataxia in a subgroup of patients may be due to gluten ataxia in mainland China. Measurement of serum anti-TG6 antibodies along with anti-TG2 and anti-gliadin antibodies may be useful for diagnosing gluten ataxia.

  10. Ataxias and Cerebellar or Spinocerebellar Degeneration

    Science.gov (United States)

    ... Conditions that can cause acquired ataxia include stroke, multiple sclerosis, tumors, alcoholism, peripheral neuropathy, metabolic disorders, and vitamin deficiencies. Is there any treatment? There is no ...

  11. Radiosensitivity in ataxia-telangiectasia

    International Nuclear Information System (INIS)

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

  12. Radiosensitivity in ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

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

    1998-12-31

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

  13. Spinocerebellar ataxia type 23 : a genetic update

    NARCIS (Netherlands)

    Verbeek, Dineke S.

    2009-01-01

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

  14. Antigliadin antibody in sporadic adult ataxia

    Directory of Open Access Journals (Sweden)

    Mahdi Aloosh

    2012-09-01

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

  15. Friedreich's ataxia presenting after cardiac transplantation

    OpenAIRE

    Leonard, H; Forsyth, R.

    2001-01-01

    A 4 year old boy underwent cardiac transplantation because of cardiomyopathy with ischaemia. Following transplantation he developed neurological signs of Friedreich's ataxia and the diagnosis was confirmed with genetic testing. Cardiomyopathy is a rare presentation of Friedreich's ataxia and to our knowledge this is the first reported transplant operation for the cardiomyopathy associated with this condition.



  16. [From gene to disease; ataxia telangiectasia

    NARCIS (Netherlands)

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

    2003-01-01

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

  17. 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 in...

  18. Ataxias agudas en la infancia

    Directory of Open Access Journals (Sweden)

    Yaline Betancourt Fursow

    2013-09-01

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

  19. Reviewing the genetic causes of spastic-ataxias

    NARCIS (Netherlands)

    Bot, S.T. de; Willemsen, M.A.A.P.; Vermeer, S.; Kremer, H.P.H.; Warrenburg, B.P.C. van de

    2012-01-01

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

  20. Dystonia as presenting manifestation of ataxia telangiectasia : a case report.

    OpenAIRE

    Goyal V; Behari M

    2002-01-01

    Ataxia telangiectasia is a genetically inherited multisystem disorder with predominant feature being telangiectasia and cerebellar ataxia. In this report, a family of three siblings suffering from ataxia telangiectasia is described. The proband presented with dystonia and dystonic myoclonus, both of which are rare presenting features of ataxia telangiectasia.

  1. 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.

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

    Science.gov (United States)

    Anheim, M; Tranchant, C

    2011-01-01

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

  3. Sporadic Ataxia and Multiple System Atrophy (MSA)

    Science.gov (United States)

    ... It is unclear why some people with sporadic ataxia progress to develop MSA whereas others do not. Many people with adult onset cerebellar degeneration may have the dominantly inherited form, which ...

  4. Cerebellar Involvement in Ataxia and Generalized Epilepsy

    NARCIS (Netherlands)

    L. Kros (Lieke)

    2015-01-01

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

  5. Writer's cramp in spinocerebellar ataxia Type 1

    Science.gov (United States)

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

    2016-01-01

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

  6. Writer's cramp in spinocerebellar ataxia Type 1

    Science.gov (United States)

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

    2016-01-01

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

  7. 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, unip...... 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....

  8. 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

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

    NARCIS (Netherlands)

    Smeets, C J L M; Verbeek, D S

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Marcus Vinicius Cristino de Albuquerque

    2015-01-01

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

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

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions NARP neuropathy, ataxia, and retinitis pigmentosa Enable Javascript to view the ... Download PDF Open All Close All Description Neuropathy, ataxia, and retinitis pigmentosa ( NARP ) is a condition that ...

  12. Genetics Home Reference: infantile-onset spinocerebellar ataxia

    Science.gov (United States)

    ... Genetics Home Health Conditions IOSCA infantile-onset spinocerebellar ataxia Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Infantile-onset spinocerebellar ataxia ( IOSCA ) is a progressive disorder that affects the ...

  13. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Genetics Home Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Enable Javascript to view the expand/ ... Open All Close All Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by ...

  14. Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)

    Science.gov (United States)

    ... Resources and Publications Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS): Overview Skip sharing on social media ... this: Page Content Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset condition (occurs ...

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

    LENUS (Irish Health Repository)

    Hanley, A

    2010-04-01

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

  16. Cerebral Abnormalities in Adults with Ataxia-Telangiectasia

    OpenAIRE

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

    2013-01-01

    Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment with cerebellar atrophy, ocular and cutaneous telangiectasia, immunodeficiency, heightened sensitivity to ionizing radiation and susceptibility to developing lymphoreticular malignancy. Supratentorial brain abnormalities have been reported only rarely. In this study, brain MRI was performed in 10 adults with ataxia-telangiecta...

  17. Spinocerebellar Ataxia Types 1, 2, 3 and 6 : the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

    NARCIS (Netherlands)

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

    2012-01-01

    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 qua

  18. Recent advances in hereditary spinocerebellar ataxias

    NARCIS (Netherlands)

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

    2005-01-01

    In recent years, molecular genetic research has unraveled a major part of the genetic background of autosomal dominant and recessive spinocerebellar ataxias. These advances have also allowed insight in (some of) the pathophysiologic pathways assumed to be involved in these diseases. For the clinicia

  19. 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, unip...

  20. Spinocerebellar ataxia-10 with paranoid schizophrenia

    Directory of Open Access Journals (Sweden)

    Bhavesh Trikamji

    2015-01-01

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

  1. Quantitative evaluation of gait ataxia by accelerometers.

    Science.gov (United States)

    Shirai, Shinichi; Yabe, Ichiro; Matsushima, Masaaki; Ito, Yoichi M; Yoneyama, Mitsuru; Sasaki, Hidenao

    2015-11-15

    An appropriate biomarker for spinocerebellar degeneration (SCD) has not been identified. Here, we performed gait analysis on patients with pure cerebellar type SCD and assessed whether the obtained data could be used as a neurophysiological biomarker for cerebellar ataxia. We analyzed 25 SCD patients, 25 patients with Parkinson's disease as a disease control, and 25 healthy control individuals. Acceleration signals during 6 min of walking and 1 min of standing were measured by two sets of triaxial accelerometers that were secured with a fixation vest to the middle of the lower and upper back of each subject. We extracted two gait parameters, the average and the coefficient of variation of motion trajectory amplitude, from each acceleration component. Then, each component was analyzed by correlation with the Scale for the Assessment and Rating of Ataxia (SARA) and the Berg Balance Scale (BBS). Compared with the gait control of healthy subjects and concerning correlation with severity and disease specificity, our results suggest that the average amplitude of medial-lateral (upper back) of straight gait is a physiological biomarker for cerebellar ataxia. Our results suggest that gait analysis is a quantitative and concise evaluation scale for the severity of cerebellar ataxia.

  2. Eye movements in ataxia-telangiectasia.

    Science.gov (United States)

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

    1978-11-01

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

  3. Identification of telomere dysfunction in Friedreich ataxia

    OpenAIRE

    Anjomani Virmouni, Sara; Al-Mahdawi, Sahar; Sandi, Chiranjeevi; Yasaei, Hemad; Giunti, Paola; Slijepcevic, Predrag; Mark A. Pook

    2015-01-01

    Background Friedreich ataxia (FRDA) is a progressive inherited neurodegenerative disorder caused by mutation of the FXN gene, resulting in decreased frataxin expression, mitochondrial dysfunction and oxidative stress. A recent study has identified shorter telomeres in FRDA patient leukocytes as a possible disease biomarker. Results Here we aimed to investigate both telomere structure and function in FRDA cells. Our results confirmed telomere shortening in FRDA patient leukocytes and identifie...

  4. Axonal inclusions in spinocerebellar ataxia type 3

    OpenAIRE

    Seidel, Kay; den Dunnen, Wilfred F. A.; Schultz, Christian; Paulson, Henry; Frank, Stefanie; de Vos, Rob A.; Brunt, Ewout R.; Deller, Thomas; Harm H Kampinga; Rüb, Udo

    2010-01-01

    Protein aggregation is a major pathological hallmark of many neurodegenerative disorders including polyglutamine diseases. Aggregation of the mutated form of the disease protein ataxin-3 into neuronal nuclear inclusions is well described in the polyglutamine disorder spinocerebellar ataxia type 3 (SCA3 or Machado–Joseph disease), although these inclusions are not thought to be directly pathogenic. Neuropil aggregates have not yet been described in SCA3. We performed a systematic immunohistoch...

  5. Uterine tumors in ataxia-telangiectasia.

    Science.gov (United States)

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

    1989-02-01

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

  6. Radiological imaging in ataxia telangiectasia: a review.

    Science.gov (United States)

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

    2014-08-01

    The human genetic disorder ataxia telangiectasia (A-T) is characterised by neurodegeneration, immunodeficiency, radiosensitivity, cell cycle checkpoint defects, genomic instability and cancer predisposition. Progressive cerebellar ataxia represents the most debilitating aspect of this disorder. At present, there is no therapy available to cure or prevent the progressive symptoms of A-T. While it is possible to alleviate some of the symptoms associated with immunodeficiency and deficient lung function, neither the predisposition to cancer nor the progressive neurodegeneration can be prevented. Significant effort has focused on improving our understanding of various clinical, genetic and immunological aspects of A-T; however, little attention has been directed towards identifying altered brain structure and function using MRI. To date, most imaging studies have reported radiological anomalies in A-T. This review outlines the clinical and biological features of A-T along with known radiological imaging anomalies. In addition, we briefly discuss the advent of high-resolution MRI in conjunction with diffusion-weighted imaging, which enables improved investigation of the microstructural tissue environment, giving insight into the loss in integrity of motor networks due to abnormal neurodevelopmental or progressive neurodegenerative processes. Such imaging approaches have yet to be applied in the study of A-T and could provide important new information regarding the relationship between mutation of the ataxia telangiectasia mutated (ATM) gene and the integrity of motor circuitry. PMID:24683014

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

    OpenAIRE

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

    2010-01-01

    Mitochondrial dysfunction and oxidative damage are at the origin of numerous neurodegenerative diseases like Friedreich ataxia and Alzheimer and Parkinson diseases. Friedreich ataxia (FRDA) is the most common hereditary ataxia, with one individual affected in 50,000. This disease is characterized by progressive degeneration of the central and peripheral nervous systems, cardiomyopathy, and increased incidence of diabetes mellitus. FRDA is caused by a dynamic mutation, a GAA trinucleotide repe...

  8. Genetics Home Reference: PRICKLE1-related progressive myoclonus epilepsy with ataxia

    Science.gov (United States)

    ... with ataxia PRICKLE1-related progressive myoclonus epilepsy with ataxia Enable Javascript to view the expand/collapse boxes. ... All Description PRICKLE1 -related progressive myoclonus epilepsy with ataxia is a rare inherited condition characterized by recurrent ...

  9. Reviewing the genetic causes of spastic-ataxias.

    Science.gov (United States)

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

    2012-10-01

    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 hereditary spastic paraplegia type 7 are examples of genetic diseases with such a prominent spastic-ataxic syndrome as the clinical hallmark. We review the various causes of spastic-ataxic syndromes with a focus on the genetic disorders, and provide a clinical framework, based on age at onset, mode of inheritance, and additional clinical features and neuroimaging signs, that could serve the diagnostic workup. PMID:23033504

  10. Acute cerebellar ataxia with human parvovirus B19 infection

    OpenAIRE

    Shimizu, Y; Ueno, T.; Komatsu, H.; Takada, H.; Nunoue, T.

    1999-01-01

    A 2 year old boy developed acute cerebellar ataxia in association with erythema infectiosum. During the disease, genomic DNA and antibodies against human parvovirus B19 were detected in serum but not in cerebrospinal fluid. Parvovirus B19 associated acute cerebellar ataxia might occur due to transient vascular reaction in the cerebellum during infection.



  11. Leukoencephalopathy after prophylactic radiation for leukaemia in ataxia telangiectasia.

    OpenAIRE

    Eyre, J A; Gardner-Medwin, D; Summerfield, G P

    1988-01-01

    Children with ataxia telangiectasia have a high probability of developing acute lymphoblastic leukaemia, and have increased sensitivity to chemotherapy and irradiation. We report a 51/2 year old boy who had undiagnosed ataxia telangiectasia when he presented with acute lymphoblastic leukaemia. He subsequently developed a chemoradiation induced leukoencephalopathy after conventional central nervous system prophylaxis.

  12. A case of spinocerebellar ataxia type 6 mimicking olivopontocerebellar atrophy

    Energy Technology Data Exchange (ETDEWEB)

    Nakagawa, N.; Katayama, T.; Makita, Y.; Kuroda, K.; Aizawa, H.; Kikuchi, K. [First Dept. of Internal Medicine, Asahikawa Medical Coll. (Japan)

    1999-07-01

    Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant, slowly progressive cerebellar ataxia without multisystem involvement. We report a 57-year-old woman with genetically confirmed SCA6 who showed clinical features of olivopontocerebellar atrophy. Conventional T2-weighted and FLAIR MRI demonstrated high signal in the middle cerebellar peduncles, in addition to mild atrophy of the pons and cerebellum. (orig.)

  13. Drug-induced cerebellar ataxia: a systematic review

    NARCIS (Netherlands)

    Gaalen, J. van; Kerstens, F.G.; Maas, R.P.P.W.M.; Harmark, L.; Warrenburg, B.P.C. van de

    2014-01-01

    BACKGROUND AND OBJECTIVES: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR). METHODS: We performed a systematic literature search in Pubmed (1966 to January 2014) and EMB

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  15. Longitudinal Cerebral Blood Flow Changes during Speech in Hereditary Ataxia

    Science.gov (United States)

    Sidtis, John J.; Strother, Stephen C.; Naoum, Ansam; Rottenberg, David A.; Gomez, Christopher

    2010-01-01

    The hereditary ataxias constitute a group of degenerative diseases that progress over years or decades. With principal pathology involving the cerebellum, dysarthria is an early feature of many of the ataxias. Positron emission tomography was used to study regional cerebral blood flow changes during speech production over a 21 month period in a…

  16. Dysarthria and Friedreich's Ataxia: What Can Intelligibility Assessment Tell Us?

    Science.gov (United States)

    Blaney, Bronagh; Hewlett, Nigel

    2007-01-01

    Background: Friedreich's ataxia is one of the most common hereditary disorders of the nervous system. Dysarthria is a pervasive symptom of Friedreich's ataxia, yet the clinical presentation of speech symptoms remains poorly understood, leaving clinicians without the evidence required to develop therapy interventions. Aims: The research reported…

  17. Friedreich's ataxia--a case of aberrant transcription termination?

    Science.gov (United States)

    Butler, Jill Sergesketter; Napierala, Marek

    2015-01-01

    Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia. We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia.

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

    NARCIS (Netherlands)

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

    2002-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Jin Zhang

    2013-01-01

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

  20. [Buspirone in the treatment of cerebellar ataxia].

    Science.gov (United States)

    Svetel, M; Vojvodić, N; Filipović, S R; Dragasević, N; Sternić, N; Kostić, V S

    1999-01-01

    Ataxia is defined as a disturbance which, quite independent of any motor weakness, alters direction and extent of voluntary movement and impairs the sustained voluntary of reflex muscle contraction necessary for maintaining postiue and equilibrium [1]. Since pathophysiological basis of cerebeller ataxia is still not completely clear, the current therapeutic attempts are mainly symptom-oriented [3]. One possible approach could be a modification of potentially involved neurotransmitter systems of the cerebellum, where particularly interesting is the serotonergic system. However, attempts with levorotatory form of tryptophan (5-HT precursors) proved to be ineffective [4, 5]. Since receptors in the cerebellum are mainly of 5-HTIA subtype, the use of specific agonists might be a more reasonable therapy [6]. The study initially involved 11 patients, but only 9 completed the protocol due to unfavorable side effects. Our open label prospective study lasted for 15 weeks. The patients were tested before the beginning of the treatment (initial visit), at 7th (first visit) and 11th week (second visit) of continuous therapy, and eventually at 15th week (final visit). The daily dose was 40 mg at the first and 60 mg at the second visit. We used the evaluation scale gurposed for cerebellar functions testing (speech, gait, coordination and ocular movements). Significant improvement of cerebellar ataxia in patients under buspiron therapy has been noted. We analyzed the results obtained from our 9 patients (4 females and 5 males), of which 6 patients suffered from cerebellar degeneration, one from multiple sclerosis, one from Ramsey-Hunt syndrome, and one from pontine myelinolysis. At the initial visit the patient score was 18.9 (SD = 7.3), subsequently, at the iirst visit the score was 15.4 (SD = 8), while the second visit yielded the score of 12.9 (SD = 8.2), and finally, after a two-weeks lasting wash-out period, it was 17.7 (SD = 7.1) (Table 1). It was found that patients

  1. Síndrome de Ataxia-Telangiectasia

    Directory of Open Access Journals (Sweden)

    Amauri Batista da Silva

    1971-06-01

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

  2. Friedreich`s ataxia in American families

    Energy Technology Data Exchange (ETDEWEB)

    D`Costa, A.; Maguire, B.A.; Sylvester, J.E. [Hahnemann Univ., Philadephia, PA (United States)] [and others

    1994-09-01

    Freidreich`s ataxia (FRDA) is a progressive neurodegenerative disorder presenting with dysarthia, loss of tendon reflexes, and ataxic gait. Both diabetes mellitus and cardiomyopathy are frequently found associated with the disease. The gene, FRDA, has been localized to 9q13-21. Recent reports of recombination events in individuals homozygous by descent have positioned the gene to a 450 KB region in the FRDA locus centromeric to the original markers. Candidate cDNA`s have been isolated from part of this region, and characterized, but not shown to be responsible for the disease. We have performed linkage analysis on 46 American families with markers in the FRDA region. A recombination has been detected in a family which has the phenotypic criteria for Friedreich`s; none of the three affected exhibit signs of cardiomyopathy which is a required diagnostic criteria. Since this recombination lies within the now excluded D9S5/D9S15 region, it is being tested for linkage to the {open_quotes}ataxia with selective vitamin E deficiency{close_quotes} (AVED) locus on chromosome 8q. Our lab has work in progress to subclone appropriate regions from YACs in order to identify expressed sequences and nucleotide variations (by SSCP) in the FRDA locus.

  3. 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.)

  4. Assessment of speech in early-onset ataxia : a pilot study

    NARCIS (Netherlands)

    Kuiper, Marieke J.; Brandsma, Rick; Lawerman, T.F.; Lunsing, Roelineke J.; Keegstra, Anne L.; Burger, Huibert; De Koning, Tom J.; Tijssen, Marina A. J.; Sival, Deborah A.

    2014-01-01

    AIM: The aim of the study was to determine whether paediatric ataxia speech subscores are reliably applicable for international early-onset ataxia (EOA) databases. If so, we reasoned that ataxia speech subscores should be associated with ataxia scores and involve high interobserver agreement, includ

  5. 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.

  6. Ataxia espinocerebelar tipo 6: relato de caso

    Directory of Open Access Journals (Sweden)

    Bianca Simone Zeigelboim

    2014-10-01

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

  7. Malignancies in pediatric patients with ataxia telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, R.C.; Berdon, W.E.; Ruzal-Shapiro, C. [Babies and Children`s Hospital of New York, Department of Radiology, NY (United States); Hall, E.J. [Center for Radiological Research, Columbia Univ., New York, NY (United States); Kornecki, A.; Daneman, A. [Hospital for Sick Children, Dept. of Diagnostic Imaging, Toronto, ON (Canada); Brunelle, F. [Groupe-Hospitalier, Necker-Enfants-Malades, Paris (France); Campbell, J.B. [Arnold Palmer Hospital for Children and Women, Dept. of Radiology, Orlando, FL (United States)

    1999-04-01

    Background. Patients with ataxia telangiectasia (AT), known to have an inherent increased susceptibility to the development of cancer, may present with malignancies that are unusual for the patient`s age, are often difficult to diagnose clinically and radiographically and respond poorly to conventional therapy. Materials and methods. We reviewed the clinical presentation and imaging studies of 12 AT patients who developed malignancies. Results. Eight of the twelve patients developed non-Hodgkin`s lymphoma (CNS, thorax, bone), two developed Hodgkin`s disease, and two were diagnosed with gastrointestinal mucinous adenocarcinoma. Conclusion. The lymphomas were commonly extra nodal, and infiltrative rather than mass-like. The recognition of the tumors was often delayed due to confusion with the known infectious complications in AT patients. (orig.) With 8 figs., 1 tab., 12 refs.

  8. Research progress of spinocerebellar ataxia type 1

    Directory of Open Access Journals (Sweden)

    Lin-wei ZHANG

    2014-05-01

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

  9. Complementation analysis of ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-01-01

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

  10. Neuropathology in classical and variant ataxia-telangiectasia.

    NARCIS (Netherlands)

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

    2012-01-01

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

  11. Genetics Home Reference: myoclonic epilepsy myopathy sensory ataxia

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions MEMSA myoclonic epilepsy myopathy sensory ataxia Enable Javascript to view the ... Accessibility FOIA Viewers & Players U.S. Department of Health & Human Services National Institutes of Health National Library of ...

  12. Acute cerebellar ataxia: A neurological manifestation in malaria

    Directory of Open Access Journals (Sweden)

    Peddametla Shravan Kumar

    2014-01-01

    Full Text Available Malaria is a vector-borne disease transmitted by the bite of an infected female anopheles mosquito presents with varied clinical manifestations. Neurological manifestations include headaches, confusion, convulsions, hemiplegia, ataxia, cerebral palsy, cortical blindness, and Guillain-Barre syndrome (GBS. We are presenting a case report of acute cerebellar ataxia in a 20-year-old male patient who presented with fever and positive for Plasmodium vivax and Plasmodium falciparum malaria antibodies.

  13. Deep Learning for Cerebellar Ataxia Classification and Functional Score Regression

    OpenAIRE

    Yang, Zhen; Zhong, Shenghua; Carass, Aaron; Ying, Sarah H.; Prince, Jerry L.

    2014-01-01

    Cerebellar ataxia is a progressive neuro-degenerative disease that has multiple genetic versions, each with a characteristic pattern of anatomical degeneration that yields distinctive motor and cognitive problems. Studying this pattern of degeneration can help with the diagnosis of disease subtypes, evaluation of disease stage, and treatment planning. In this work, we propose a learning framework using MR image data for discriminating a set of cerebellar ataxia types and predicting a disease ...

  14. Study on diagnosis and treatment of hereditary ataxia

    Directory of Open Access Journals (Sweden)

    TANG Bei-sha

    2012-06-01

    Full Text Available Hereditary ataxia (HA is a clinically and genetically heterogeneous group of neurodegenerative disorders with high mortality and morbidity. It is characterized by progressive cerebellar ataxia of gait and limbs variably associated with ophthalmoplegia, pigmentary retinopathy, pyramidal and extrapyramidal signs, dementia and peripheral neuropathy. The molecular diagnosis process is proposed based on molecular classification. So far, symptomatic treatment is the mainly approach, with the lack of effective therapeutic method.

  15. Friedreich's Ataxia as a Cause of Premature Coronary Artery Disease

    OpenAIRE

    Giugliano, Gregory R.; Sethi, Prabhdeep S.

    2007-01-01

    Friedreich's ataxia is the most common hereditary neurodegenerative disorder, and more than half of all patients show echocardiographic evidence of cardiomyopathy. Although angina has been reported in these patients, the role of coronary artery disease has previously been dismissed and is therefore underestimated. Premature obstructive coronary disease has rarely been angiographically demonstrated in patients with Friedreich's ataxia. We present an unusual case of a 35-year-old woman with Fri...

  16. 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.

  17. Ataxia, acute mountain sickness, and high altitude cerebral edema

    Institute of Scientific and Technical Information of China (English)

    Wu Tianyi; Ma Siqing; Bian Huiping; Zhang Minming

    2013-01-01

    Previous investigations suggest that ataxia is common and often one of the most reliable warning signs of high altitude cerebral edema(HACE).The aim of this study was to investigate the diagnostic role of ataxia in acute mountain sickness (AMS) and HACE among mountain rescuers on the quake areas,and in approaching the relation between AMS and HACE.After the earthquake on April 14,2010,approximately 24080 lowland rescuers were rapidly transported from sea level or lowlands to the mountainous rescue sites at 3750 ~ 4568 m,and extremely hardly worked for an emergency treatment after arrival.Assessments of acute altitude illness on the quake areas were using the Lake Louise Scoring System.73 % of the rescuers were found to be developed AMS.The incidence of high altitude pulmonary edema(HAPE) and HACE was 0.73 % and 0.26 %,respectively,on the second to third day at altitude.Ataxia sign was measured by simple tests of coordination including a modified Romberg test.The clinical features of 62 patients with HACE were analyzed.It was found that the most frequent,serious neurological symptoms and signs were altered mental status(50/62,80.6 %)and truncal ataxia (47/62,75.8 %).Mental status change was rated slightly higher than ataxia,but ataxia occurred earlier than mental status change and other symptoms.The earliest sign of ataxia was a vague unsteadiness of gait,which may be present alone in association with or without AMS.Advanced ataxia was correlated with the AMS scores,but mild ataxia did not correlate with AMS scores at altitudes of 3750~4568 m.Of them,14 patients were further examined by computerized tomographic scanning of the brain and cerebral magnetic resonance imagines were examined in another 15 cases.These imaging studies indicated that the presence of the cerebral edema was in 97 % of cases who were clinically diagnosed as HACE (28/29).Ataxia seems to be a reliable sign of advanced AMS or HACE,so does altered mental status.

  18. Sudden stopping in patients with cerebellar ataxia.

    Science.gov (United States)

    Serrao, Mariano; Conte, Carmela; Casali, Carlo; Ranavolo, Alberto; Mari, Silvia; Di Fabio, Roberto; Perrotta, Armando; Coppola, Gianluca; Padua, Luca; Monamì, Stefano; Sandrini, Giorgio; Pierelli, Francesco

    2013-10-01

    Stopping during walking, a dynamic motor task frequent in everyday life, is very challenging for ataxic patients, as it reduces their gait stability and increases the incidence of falls. This study was conducted to analyse the biomechanical characteristics of upper and lower body segments during abrupt stopping in ataxic patients in order to identify possible strategies used to counteract the instability in the sagittal and frontal plane. Twelve patients with primary degenerative cerebellar ataxia and 12 age- and sex-matched healthy subjects were studied. Time-distance parameters, dynamic stability of the centre of mass, upper body measures and lower joint kinematic and kinetic parameters were analysed. The results indicate that ataxic patients have a great difficulty in stopping abruptly during walking and adopt a multi-step stopping strategy, occasionally with feet parallel, to compensate for their inability to coordinate the upper body and to generate a well-coordinated lower limb joint flexor-extensor pattern and appropriate braking forces for progressively decelerating the progression of the body in the sagittal plane. A specific rehabilitation treatment designed to improve the ability of ataxic patients to transform unplanned stopping into planned stopping, to coordinate upper body and to execute an effective flexion-extension pattern of the hip and knee joints may be useful in these patients in order to improve their stopping performance and prevent falls.

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

    Science.gov (United States)

    Boder, E; Sedgwick, R P

    1970-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Walter Oleschko Arruda

    1997-09-01

    Full Text Available As heredoataxias constituem grupo complexo de doenças neurodegenerativas hereditárias, para o qual várias formas de classificação clínica e patológica foram propostas com sucesso variável. O desenvolvimento das técnicas de biologia molecular trouxe informações importantes que têm permitido caracterizar geneticamente as ataxias cerebelares hereditárias. O reconhecimento das doenças causadas por expansões de trinucleotídeos abre novo capítulo para a pesquisa sobre outros mecanismos de doenças, como na ataxia de Friedreich e nas várias formas de ataxia cerebelar autossômica dominante(SCAl a SCA7, das quais a doença de Machado-Joseph / SCA3 parece ser a mais comum no nosso meio. A deficiência familial de vitamina E (cromossomo 8q leva a quadro semelhante ao da ataxia de Friedreich (cromossomo 9p, mas responde à reposição oral de tocoferol. Formas familiais de ataxia periódica com (cromossomo 12p ou sem (cromossomo 19p mioquimia foram caracterizadas, a primeira resultado de mutações dos gens de canais de potássio. Os portadores do gen da ataxia-teleangiectasia (cromossomo 1 lq representam 1-3% da população e são suscetíveis aos efeitos oncogênicos da radiação iônica. Sem olvidar da importância da avaliação clínica neurológica, a avaliação genética laboratorial passa a ser valiosa ferramenta para o diagnóstico e aconselhamento genético, além do melhor entendimento da patogênese dessas doenças.The hereditary ataxias comprise a complex group of neurological disorders involving the cerebellum and its connections. Several classifications based on clinical and/or pathological data have been only partially successful. Recent progress in molecular genetics has identified the genic loci of hereditary ataxias and has allowed a more precise diagnosis of distinct genetic diseases. Trinucleotide repeat expansions has been recognized as a mechanism of disease in some autosomal dominant spinocerebellar ataxias (ADCA

  1. 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.

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

    NARCIS (Netherlands)

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

    2003-01-01

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

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

    Science.gov (United States)

    ... Genetics Home Health Conditions ARSACS autosomal recessive spastic ataxia of Charlevoix-Saguenay Enable Javascript to view the ... Open All Close All Description Autosomal recessive spastic ataxia of Charlevoix-Saguenay , more commonly known as ARSACS , ...

  4. Genetics Home Reference: fragile X-associated tremor/ataxia syndrome

    Science.gov (United States)

    ... Home Health Conditions FXTAS fragile X-associated tremor/ataxia syndrome Enable Javascript to view the expand/collapse ... All Close All Description Fragile X-associated tremor/ataxia syndrome ( FXTAS ) is characterized by problems with movement ...

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

    NARCIS (Netherlands)

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

    2008-01-01

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

  6. Is Friedreich ataxia an epigenetic disorder?

    Directory of Open Access Journals (Sweden)

    Kumari Daman

    2012-01-01

    Full Text Available Abstract Friedreich ataxia (FRDA is a debilitating and frequently fatal neurological disorder that is recessively inherited. It belongs to the group of genetic disorders known as the Repeat Expansion Diseases, in which pathology arises from the deleterious consequences of the inheritance of a tandem repeat array whose repeat number exceeds a critical threshold. In the case of FRDA, the repeat unit is the triplet GAA•TTC and the tandem array is located in the first intron of the frataxin (FXN gene. Pathology arises because expanded alleles make lower than normal levels of mature FXN mRNA and thus reduced levels of frataxin, the FXN gene product. The repeats form a variety of unusual DNA structures that have the potential to affect gene expression in a number of ways. For example, triplex formation in vitro and in bacteria leads to the formation of persistent RNA:DNA hybrids that block transcription. In addition, these repeats have been shown to affect splicing in model systems. More recently, it has been shown that the region flanking the repeats in the FXN gene is enriched for epigenetic marks characteristic of transcriptionally repressed regions of the genome. However, exactly how repeats in an intron cause the FXN mRNA deficit in FRDA has been the subject of much debate. Identifying the mechanism or mechanisms responsible for the FXN mRNA deficit in FRDA is important for the development of treatments for this currently incurable disorder. This review discusses evidence for and against different models for the repeat-mediated mRNA deficit.

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

    Directory of Open Access Journals (Sweden)

    Menon Ramshekhar

    2009-01-01

    Full Text Available We report an unusual case of sporadic adult onset cerebellar ataxia with hypogonadism. A 40-year-old unmarried man presented with progressive ataxia and dysarthria along with complaints of non-development of secondary sexual characteristics and erectile dysfunction. There were complaints of intermittent diarrhea. Clinical examination revealed a pan-cerebellar syndrome with features of hypoandrogenism. No eye movement abnormalities were evident. There were signs of malabsorption. Investigations confirmed the presence of auto-antibodies found in celiac disease, and a duodenal biopsy confirmed the same. Hypoandrogenism was postulated to be due to hypergonadotropic hypogonadism which has been mentioned in a few patients of celiac disease. However, the pattern seen in our patient was of a hypogonadotropic hypogonadism. This is probably secondary to an autoimmune hypophysitis seen in some patients in the absence of other clinical manifestations. Autoantibody testing should be a diagnostic necessity in any adult with a sporadic cerebellar ataxia.

  8. Scale for the assessment and rating of ataxia: development of a new clinical scale.

    NARCIS (Netherlands)

    Schmitz-Hubsch, T.; Montcel, S.T. du; Baliko, L.; Berciano, J.; Boesch, S.; Depondt, C.; Giunti, P.; Globas, C.; Infante, J.; Kang, J.S.; Kremer, H.P.H.; Mariotti, C.; Melegh, B.; Pandolfo, M.; Rakowicz, M.; Ribai, P.; Rola, R.; Schols, L.; Szymanski, S.; Warrenburg, B.P.C. van de; Durr, A.; Klockgether, T.; Fancellu, R.

    2006-01-01

    OBJECTIVE: To develop a reliable and valid clinical scale measuring the severity of ataxia. METHODS: The authors devised the Scale for the Assessment and Rating of Ataxia (SARA) and tested it in two trials of 167 and 119 patients with spinocerebellar ataxia. RESULTS: The mean time to administer SARA

  9. Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases

    NARCIS (Netherlands)

    Jezierska, Justyna; Stevanin, Giovanni; Watanabe, Hiroyuki; Fokkens, Michiel R.; Zagnoli, Fabien; Kok, Jerome; Goas, Jean-Yves; Bertrand, Pierre; Robin, Christophe; Brice, Alexis; Bakalkin, Georgy; Durr, Alexandra; Verbeek, Dineke S.

    2013-01-01

    We have recently identified missense mutations in prodynorphin (PDYN), the precursor to dynorphin opioid peptides, as the cause for spinocerebellar ataxia (SCA23) in Dutch ataxia cases. We report a screen of PDYN for mutations in 371 cerebellar ataxia cases, which had a positive family history; most

  10. Early onset cerebellar ataxia with retained tendon reflexes : foot deformity in a first grade family member

    NARCIS (Netherlands)

    Schelhaas, HJ; Van der Hulst, M; Ippel, E; Prevo, RL; Hageman, G

    1999-01-01

    Early onset cerebellar ataxia with retained tendon reflexes (EOCA) is a clinical syndrome characterised by progressive cerebellar ataxia with an onset before the age of 25 years and a wide spectrum of associated features. It is distinguished from Friedreich's ataxia (FA) mainly by the preservation o

  11. 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

    2005-01-01

    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 (approxim

  12. Cerebellar ataxia as the presenting manifestation of Lyme disease.

    Science.gov (United States)

    Arav-Boger, Ravit; Crawford, Thomas; Steere, Allen C; Halsey, Neal A

    2002-04-01

    A 7-year-old boy from suburban Baltimore who presented with cerebellar ataxia and headaches was found by magnetic resonance imaging to have multiple cerebellar enhancing lesions. He had no history of tick exposure. He was initially treated with steroids for presumptive postinfectious encephalitis. Lyme disease was diagnosed 10 weeks later after arthritis developed. Testing of the cerebrospinal fluid obtained at the time cerebellar ataxia was diagnosed revealed intrathecal antibody production to Borrelia burgdorferi. Treatment with intravenous antibiotics led to rapid resolution of persistent cerebellar findings.

  13. Episodic ataxia : a case report and review of literature.

    Directory of Open Access Journals (Sweden)

    Singhvi J

    2000-01-01

    Full Text Available This report describes the clinical features of a 29 year female presenting with a 3 years history of episodes of cerebellar ataxia, dysarthria and nystagmus lasting 3-5 days, recurring almost every month. Sleep disturbance and buzzing in ears were noted 3-4 days before each episode. No other precipitant factor was present. Family history was negative. She was diagnosed as a case of episodic ataxia type-2 and was successfully treated with acetazolamide, a carbonic anhydrase inhibitor. She was asymptomatic at 2 year followup.

  14. Bilateral maculopathy in a patient with ataxia telangiectasia.

    Science.gov (United States)

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

    2016-02-01

    We report a case of toxoplasmosis with bilateral maculopathy in a 7-year-old boy diagnosed with ataxia telangiectasia (AT) at age 6. AT manifests as ataxia, apraxia, telangiectasia, and dysarthria. Common ophthalmologic findings in AT include fine conjunctival telangiectasia. Patients also suffer from recurrent sinopulmonary infections; however, serious opportunistic infection is rarely diagnosed. At 8 years of age he developed disseminated Toxoplasma gondii (toxoplasmosis) infection and meningoencephalitis. This ophthalmologic finding and the subsequent toxoplasmosis meningoencephalitis have not been previously reported in AT. PMID:26917084

  15. 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.

  16. Deranged calcium signaling in Purkinje cells and pathogenesis in spinocerebellar ataxia 2 (SCA2) and other ataxias.

    Science.gov (United States)

    Kasumu, Adebimpe; Bezprozvanny, Ilya

    2012-09-01

    Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 30 autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by progressive ataxia and cerebellar atrophy. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, 17 different gene loci have so far been implicated as culprits in these SCAs. It is not currently understood how mutations in these 17 proteins lead to the cerebellar atrophy and ataxia. Several pathogenic mechanisms have been studied in SCAs but there is yet to be a promising target for successful treatment of SCAs. Emerging research suggests that a fundamental cellular signaling pathway is disrupted by a majority of these mutated genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. We propose that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic sympoms and eventually proceed to Purkinje cell death. Here, we discuss a calcium hypothesis of Purkinje cell neurodegeneration in SCAs by primarily focusing on an example of spinocerebellar ataxia 2 (SCA2). We will also present evidence linking deranged calcium signaling to the pathogenesis of other SCAs (SCA1, 3, 5, 6, 14, 15/16) that lead to significant Purkinje cell dysfunction and loss in patients.

  17. A practical approach to late-onset cerebellar ataxia: putting the disorder with lack of order into order.

    NARCIS (Netherlands)

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

    2012-01-01

    The clinical management of cerebellar ataxia is challenging, mainly because ataxia is a symptom of many neurological diseases. Many types of ataxia disorders are genetic and some are extremely rare. Here, the authors suggest a diagnostic approach to ataxia developed around a case of sporadic, late-o

  18. Republished: A practical approach to late-onset cerebellar ataxia: putting the disorder with lack of order into order.

    NARCIS (Netherlands)

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

    2012-01-01

    The clinical management of cerebellar ataxia is challenging, mainly because ataxia is a symptom of many neurological diseases. Many types of ataxia disorders are genetic and some are extremely rare. Here, the authors suggest a diagnostic approach to ataxia developed around a case of sporadic, late-o

  19. Neuropathology in classical and variant ataxia-telangiectasia

    NARCIS (Netherlands)

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

    2012-01-01

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

  20. 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.

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

    NARCIS (Netherlands)

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

    2015-01-01

    Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immu

  2. Deep Learning for Cerebellar Ataxia Classification and Functional Score Regression

    Science.gov (United States)

    Yang, Zhen; Zhong, Shenghua; Carass, Aaron; Ying, Sarah H.; Prince, Jerry L.

    2014-01-01

    Cerebellar ataxia is a progressive neuro-degenerative disease that has multiple genetic versions, each with a characteristic pattern of anatomical degeneration that yields distinctive motor and cognitive problems. Studying this pattern of degeneration can help with the diagnosis of disease subtypes, evaluation of disease stage, and treatment planning. In this work, we propose a learning framework using MR image data for discriminating a set of cerebellar ataxia types and predicting a disease related functional score. We address the difficulty in analyzing high-dimensional image data with limited training subjects by: 1) training weak classifiers/regressors on a set of image subdomains separately, and combining the weak classifier/regressor outputs to make the decision; 2) perturbing the image subdomain to increase the training samples; 3) using a deep learning technique called the stacked auto-encoder to develop highly representative feature vectors of the input data. Experiments show that our approach can reliably classify between one of four categories (healthy control and three types of ataxia), and predict the functional staging score for ataxia. PMID:25553339

  3. 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.…

  4. Voicing Status of Word Final Plosives in Friedreich's Ataxia Dysarthria

    Science.gov (United States)

    Blaney, B. E.; Hewlett, N.

    2007-01-01

    In a previous study, the authors identified final plosive voicing contrast as the highest single error source in dysarthria associated with Friedreich's Ataxia in a group of Irish English-speaking participants. This study aimed to determine the acoustic features underlying misperceptions of voicing status and implications for clinical management.…

  5. Speech Perception Ability in Individuals with Friedreich Ataxia

    Science.gov (United States)

    Rance, Gary; Fava, Rosanne; Baldock, Heath; Chong, April; Barker, Elizabeth; Corben, Louise; Delatycki

    2008-01-01

    The aim of this study was to investigate auditory pathway function and speech perception ability in individuals with Friedreich ataxia (FRDA). Ten subjects confirmed by genetic testing as being homozygous for a GAA expansion in intron 1 of the FXN gene were included. While each of the subjects demonstrated normal, or near normal sound detection, 3…

  6. Speech Characteristics Associated with Three Genotypes of Ataxia

    Science.gov (United States)

    Sidtis, John J.; Ahn, Ji Sook; Gomez, Christopher; Sidtis, Diana

    2011-01-01

    Purpose: Advances in neurobiology are providing new opportunities to investigate the neurological systems underlying motor speech control. This study explores the perceptual characteristics of the speech of three genotypes of spino-cerebellar ataxia (SCA) as manifest in four different speech tasks. Methods: Speech samples from 26 speakers with SCA…

  7. 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

  8. 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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    Aasef G Shaikh

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

  11. Cerebellar Ataxia and Glutamic Acid Decarboxylase Antibodies

    Science.gov (United States)

    Ariño, Helena; Gresa-Arribas, Nuria; Blanco, Yolanda; Martínez-Hernández, Eugenia; Sabater, Lidia; Petit-Pedrol, Mar; Rouco, Idoia; Bataller, Luis; Dalmau, Josep O.; Saiz, Albert; Graus, Francesc

    2016-01-01

    IMPORTANCE Current clinical and immunologic knowledge on cerebellar ataxia (CA) with glutamic acid decarboxylase 65 antibodies (GAD65-Abs) is based on case reports and small series with short-term follow-up data. OBJECTIVE To report the symptoms, additional antibodies, prognostic factors, and long-term outcomes in a cohort of patients with CA and GAD65-Abs. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study and laboratory investigations at a center for autoimmune neurologic disorders among 34 patients with CA and GAD65-Abs, including 25 with long-term follow-up data (median, 5.4 years; interquartile range, 3.1-10.3 years). MAIN OUTCOMES AND MEASURES Analysis of clinicoimmunologic features and predictors of response to immunotherapy. Immunochemistry on rat brain, cultured neurons, and human embryonic kidney cells expressing GAD65, GAD67, α1-subunit of the glycine receptor, and a repertoire of known cell surface autoantigens were used to identify additional antibodies. Twenty-eight patients with stiff person syndrome and GAD65-Abs served as controls. RESULTS The median age of patients was 58 years (range, 33-80 years); 28 of 34 patients (82%) were women. Nine patients (26%) reported episodes of brainstem and cerebellar dysfunction or persistent vertigo several months before developing CA. The clinical presentation was subacute during a period of weeks in 13 patients (38%). Nine patients (26%) had coexisting stiff person syndrome symptoms. Systemic organ-specific autoimmunities (type 1 diabetes mellitus and others) were present in 29 patients (85%). Twenty of 25 patients with long-term follow-up data received immunotherapy (intravenous immunoglobulin in 10 and corticosteroids and intravenous immunoglobulin or other immunosuppressors in 10), and 7 of them (35%) improved. Predictors of clinical response included subacute onset of CA (odds ratio [OR], 0.50; 95% CI, 0.25-0.99; P = .047) and prompt immunotherapy (OR, 0.98; 95% CI, 0.96-0.99; P = .01). Similar

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase...... 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...

  13. 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.

  14. [Hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada].

    Science.gov (United States)

    Dupré, N; Chrestian, N; Thiffault, I; Brais, B; Rouleau, G A; Bouchard, J-P

    2008-01-01

    It has been demonstrated, for many inherited diseases, that historical events have shaped the various regional gene pools of Eastern Canada. In so doing, it has given rise to the increased prevalence of some rare diseases due, to founder effects. The following neurogenetic disorders were first identified in patients from Eastern Canada: AOA-2, Arsacs, HSN-2, Arca-1, HMSN/ACC and Arsal. The population of Eastern Canada, we are convinced, will still allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies as well as contribute to the uncovering of their mutated genes. We have summarized our current knowledge of the various hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada. The study of the more common and homogenous features of these diseases has been largely completed.

  15. 遗传性共济失调%Hereditary ataxia

    Institute of Scientific and Technical Information of China (English)

    耿德勤; 刘春风

    2006-01-01

    @@ 共济失调是患者不能按一定的形式维持精细步态、完成精确动作的一种病理状态,任何累及小脑传入或传出途径的病变都可能导致共济失调,其中多数由遗传因素所致,故统称为遗传性共济失调(hereditary ataxia,HA).HA包括一组比较接近的变性疾病.病变部位主要在脊髓、小脑和脑干,故也称为脊髓-小脑-脑干疾病,或称为脊髓小脑共济失调( spinocerebellar ataxia, SCA) .

  16. Inherited Ataxias%遗传性共济失调

    Institute of Scientific and Technical Information of China (English)

    蒋雨平; 邬剑军

    2011-01-01

    Inherited ataxia consists of spinal cord, cerebellum and brainstem degeneration. It also involves the peripheral nerves, optic nerve, brain and other regions. Although the causes of inherited ataxia were unknown, genetic, biochemical, metabolic abnormalities or other endogenous factors caused specific cell degeneration. Thisarticledescribedtheclinicalclassificationofhereditaryataxiaandsomeinterestingproblems.%遗传性共济失调是一组以脊髓、小脑、脑干为主的变性病,有时也累及周围神经、视神经、大脑等区域,病因不明.可能与遗传、生化代谢异常或尚未明确的内源性因素造成细胞变性有关.本文对遗传性共济失调的临床症状、分型和研究进展予以介绍.

  17. 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 < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the 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 < 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P < 0.05). Cerebellum-localized gray matter changes are seen in young 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. PMID:25042086

  18. A case of Spinocerebellar Ataxia from ethnic tribe of Assam

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    Kayal Ashok

    2011-01-01

    Full Text Available Here we present the case of a 17-year-old girl belonging to an ethnic tribe (Bodo tribe of Assam, presenting with bilateral cerebellar signs and with history suggestive of an autosomal dominant pattern of inheritance, who was found to have spinocerebellar ataxia 7 on genetic testing. This case throws light on the probability of more such cases in the multi-ethnic society of the North-Eastern Indian states, which are not studied or reported till date.

  19. Clinical and genetic analysis of hereditary and sporadic ataxia in central Italy.

    Science.gov (United States)

    Cellini, E; Forleo, P; Nacmias, B; Tedde, A; Latorraca, S; Piacentini, S; Parnetti, L; Gallai, V; Sorbi, S

    We have clinically and genetically evaluated 24 affected patients belonging to 22 Italian Friedreich ataxia (FA) families, 52 patients from 32 kindreds with proven autosomal dominant cerebellar ataxia (ADCA), 9 patients belonging to 5 families with autosomal recessive hereditary ataxia (ARCA) and 103 sporadic cases, 89 of which affected by idiopathic late onset cerebellar ataxia (ILOCA). Genotype-phenotype correlation analyses in FA patients have evidenced an inverse relationship between GAA repeat expansion length and age of onset, disease duration, and presence of cardiomyopathy. Among autosomal dominant types, spinocerebellar ataxia 2 (SCA2) genotype has been found in 31% of our ADCA families, resulting the most frequent form of ataxia. Phenotypic analysis of the various SCA subtypes evidenced a marked heterogeneity of symptoms with a substantial overlap between different syndromes. PMID:11719273

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

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    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.

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

    Science.gov (United States)

    Boder, E

    1975-01-01

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

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

    OpenAIRE

    Fujioka Shinsuke; Sundal Christina; Wszolek Zbigniew K

    2013-01-01

    Abstract 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...

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

    Directory of Open Access Journals (Sweden)

    Luigi Nespoli

    2013-01-01

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

  4. Guidelines and quality measures for the diagnosis of optic ataxia

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    Svenja eBorchers

    2013-07-01

    Full Text Available Since the first description of a systematic mis-reaching by Bálint in 1909, a reasonable number of patients showing a similar phenomenology, later termed optic ataxia (OA, has been described. However, there is surprising inconsistency regarding the behavioral measures that are used to detect OA in experimental and clinical reports, if the respective measures are reported at all. A typical screening method, that was presumably used by most researchers and clinicians, reaching for a target object in the peripheral visual space, has never been evaluated. We developed a set of instructions and evaluation criteria for the scoring of a semi-standardized version of this reaching task. We tested 36 healthy participants, a group of 52 acute and chronic stroke patients, and 24 patients suffering from cerebellar ataxia. We found a high interrater reliability and a moderate test-retest reliability comparable to other clinical instruments in the stroke sample. The calculation of cut-off thresholds based on healthy control and cerebellar patient data showed an unexpected high number of false positives in these samples due to individual outliers that made a considerable number of errors in peripheral reaching. This study provides first empirical data from large control and patient groups for a screening procedure that seems to be widely used but rarely explicity reported and prepares the grounds for its use as a standard tool for the description of patients who are included in single case or group studies addressing optic ataxia similar to the use of neglect, extinction, or apraxia screening tools.

  5. Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene

    NARCIS (Netherlands)

    C. Sevin; S. Ferdinandusse; H.R. Waterham; R.J. Wanders; P. Aubourg

    2011-01-01

    ABSTRACT: OBJECTIVE: To expand the spectrum of genetic causes of autosomal recessive cerebellar ataxia (ARCA). Case report: Two brothers are described who developed progressive cerebellar ataxia at 3 1/2 and 18 years, respectively. After ruling out known common genetic causes of ARCA, analysis of bl

  6. EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood

    NARCIS (Netherlands)

    Warrenburg, B.P.C. van de; Gaalen, J. van; Boesch, S.; Burgunder, J.M.; Durr, A.; Giunti, P.; Klockgether, T.; Mariotti, C.; Pandolfo, M.; Riess, O.

    2014-01-01

    BACKGROUND AND OBJECTIVES: The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical

  7. Two sisters with mental retardation, cataract, ataxia, progressive hearing loss, and polyneuropathy.

    OpenAIRE

    Begeer, J H; Scholte, F A; van Essen, A J

    1991-01-01

    Two sisters are described with a disorder characterised by mental retardation, congenital cataract, progressive spinocerebellar ataxia, sensorineural deafness, and signs of peripheral neuropathy. Progressive hearing loss, ataxia, and polyneuropathy became evident in the third decade. The differential diagnosis of this syndrome is discussed including the syndromes described by Berman et al and Koletzko et al.

  8. Prepulse Inhibition in Patients with Fragile X-associated Tremor Ataxia Syndrome

    OpenAIRE

    Schneider, Andrea; Ballinger, Elizabeth; Chavez, Alyssa; Tassone, Flora; Randi J Hagerman; Hessl, David

    2010-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects carriers of the fragile X premutation, typically after age 50. Common symptoms include intention tremor, ataxia, neuropathy, autonomic dysfunction, cognitive decline, and dementia.

  9. 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 att

  10. A GENE FOR EPISODIC ATAXIA/MYOKYMIA MAPS TO CHROMOSOME 12P13

    NARCIS (Netherlands)

    LITT, M; KRAMER, P; BROWNE, D; GANCHER, S; BRUNT, ERP; ROOT, D; PHROMCHOTIKUL, T; DUBAY, CJ; NUTT, J

    1994-01-01

    Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. Families with autosomal dominant EA represent at least two distinct clinical syndromes. One clinical type of EA (MIM 160120) includes individua

  11. HEREDITARY MYOKYMIA AND PAROXYSMAL ATAXIA LINKED TO CHROMOSOME-12 IS RESPONSIVE TO ACETAZOLAMIDE

    NARCIS (Netherlands)

    LUBBERS, WJ; BRUNT, ERP; SCHEFFER, H; LITT, M; STULP, R; BROWNE, DL; VANWEERDEN, TW

    1995-01-01

    A sixth family with autosomal dominantly inherited myokymia and paroxysmal ataxia is described. The syndrome in this family is linked to the recently discovered locus for inherited myokymia and paroxysmal ataxia on the human chromosome 12p, and a missense mutation is shown in the KCNA1 gene. The att

  12. There May Be More to Reaching than Meets the Eye: Re-Thinking Optic Ataxia

    Science.gov (United States)

    Jackson, Stephen R.; Newport, Roger; Husain, Masud; Fowlie, Jane E.; O'Donoghue, Michael; Bajaj, Nin

    2009-01-01

    Optic ataxia (OA) is generally thought of as a disorder of visually guided reaching movements that cannot be explained by any simple deficit in visual or motor processing. In this paper we offer a new perspective on optic ataxia; we argue that the popular characterisation of this disorder is misleading and is unrepresentative of the pattern of…

  13. Ramsay Hunt Syndrome : Clinical Characterization of Progressive Myoclonus Ataxia Caused by GOSR2 Mutation

    NARCIS (Netherlands)

    van Egmond, Martje E.; Verschuuren - Bemelmans, Cornelia; Nibbeling, Esther A.; Elting, Jan Willem J.; Sival, Deborah A.; Brouwer, Oebele F.; de Vries, Jeroen J.; Kremer, Hubertus P.; Sinke, Richard J.; Tijssen, Marina A.; de Koning, Tom J.

    2014-01-01

    BACKGROUND: Ramsay Hunt syndrome (progressive myoclonus ataxia) is a descriptive diagnosis characterized by myoclonus, ataxia, and infrequent seizures. Often the etiology cannot be determined. Recently, a mutation in the GOSR2 gene (c.430G>T, p.Gly144Trp) was reported in 6 patients with childhood-on

  14. Disturbed calcium signaling in spinocerebellar ataxias and Alzheimer's disease.

    Science.gov (United States)

    Egorova, Polina; Popugaeva, Elena; Bezprozvanny, Ilya

    2015-04-01

    Neurodegenerative disorders, such as spinocerebellar ataxias (SCAs) and Alzheimer's disease (AD) represent a huge scientific and medical question, but the molecular mechanisms of these diseases are still not clear. There is increasing evidence that neuronal calcium signaling is abnormal in many neurodegenerative disorders. Abnormal neuronal calcium release from the endoplasmic reticulum may result in disturbances of cell homeostasis, synaptic dysfunction, and eventual cell death. Neuronal loss is observed in most cases of neurodegenerative diseases. Recent experimental evidence supporting the role of neuronal calcium signaling in the pathogenesis of SCAs and AD is discussed in this review.

  15. EPISODIC ATAXIA MYOKYMIA SYNDROME IS ASSOCIATED WITH POINT MUTATIONS IN THE HUMAN POTASSIUM CHANNEL GENE, KCNA1

    NARCIS (Netherlands)

    BROWNE, DL; GANCHER, ST; NUTT, JG; BRUNT, ERP; SMITH, EA; KRAMER, P; LITT, M

    1994-01-01

    Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks. Linkage studies in fou

  16. 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.

  17. Urinary Symptoms and Urodynamics Findings in Patients with Friedreich's Ataxia

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    Andre F. A. Musegante

    2013-12-01

    Full Text Available Purpose To assess the prevalence of LUTS, urinary tract and urodynamics changes in patients with Friedreich's Ataxia (FA, the most common form of hereditary ataxia. Materials and Methods This study evaluated 258 patients with genetically confirmed diagnoses of FA. Of the patients, 158 responded to a questionnaire which assessed their urinary symptoms. Patients with clinical changes underwent renal function examinations, ultrasound, and urodynamic studies (UDS. Results The sample analyzed showed that 82% of the patients complained of LUTS, although only 22% related the symptoms with quality of life impairment. Twenty eight (18% of them agreed to undergo urodynamic evaluation. Urgency was the most common symptom. The exam was normal in 4 (14% and detrusor underactivity was the most common finding. 14% (4 patients presented with dilatation of the upper urinary tract at ultrasound scans. None of them had creatinine alterations. Conclusions LUTS was found in a large percentage of patients with FA, but only a few related it to their quality of life impairment. Although creatinine levels was normal in this sample, some patients may show upper urinary tract abnormalities, with deserves close observation and proper care.

  18. Enfermedad cardiovascular en pacientes cubanos afectados por Ataxia de Friedreich.

    Directory of Open Access Journals (Sweden)

    Tania Cruz Mariño

    2010-01-01

    Full Text Available Al describir la ataxia de Friedreich, Nicholaus hizo referencia a la patología cardiaca. Esta enfermedad autosómica recesiva se debe a una mutación dinámica en el gen FRDA, codificándose deficientemente la proteína Frataxina, conduciendo a estrés oxidativo y muerte celular cardiaca. La presente investigación se desarrolló con el objetivo de describir las anomalías cardiovasculares presentes en los pacientes cubanos afectados por ataxia de Friedreich. A los individuos con diagnóstico molecular confirmatorio de la enfermedad se les realizó electrocardiograma y ecocardiograma, así como evaluación clínica mediante escalas validadas internacionalmente: ICARS y SARA. Los trastornos de repolarización ventricular difusos, los trastornos de conducción intraauricular, así como los trastornos de la función diastólica resultaron hallazgos frecuentes. El patrón restrictivo apreciado provee evidencia invivo de que la enfermedad conduce a disfunción diastólica del ventrículo izquierdo. La ocurrencia de un Infarto Agudo del Miocardio silente indica la importancia de identificar formas incipientes de afectación miocárdica.

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

    International Nuclear Information System (INIS)

    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.)

  20. 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).

  1. Altered lipid metabolism in a Drosophila model of Friedreich's ataxia.

    Science.gov (United States)

    Navarro, Juan A; Ohmann, Elisabeth; Sanchez, Diego; Botella, José A; Liebisch, Gerhard; Moltó, María D; Ganfornina, María D; Schmitz, Gerd; Schneuwly, Stephan

    2010-07-15

    Friedreich's ataxia (FRDA) is the most common form of autosomal recessive ataxia caused by a deficit in the mitochondrial protein frataxin. Although demyelination is a common symptom in FRDA patients, no multicellular model has yet been developed to study the involvement of glial cells in FRDA. Using the recently established RNAi lines for targeted suppression of frataxin in Drosophila, we were able to study the effects of general versus glial-specific frataxin downregulation. In particular, we wanted to study the interplay between lowered frataxin content, lipid accumulation and peroxidation and the consequences of these effects on the sensitivity to oxidative stress and fly fitness. Interestingly, ubiquitous frataxin reduction leads to an increase in fatty acids catalyzing an enhancement of lipid peroxidation levels, elevating the intracellular toxic potential. Specific loss of frataxin in glial cells triggers a similar phenotype which can be visualized by accumulating lipid droplets in glial cells. This phenotype is associated with a reduced lifespan, an increased sensitivity to oxidative insult, neurodegenerative effects and a serious impairment of locomotor activity. These symptoms fit very well with our observation of an increase in intracellular toxicity by lipid peroxides. Interestingly, co-expression of a Drosophila apolipoprotein D ortholog (glial lazarillo) has a strong protective effect in our frataxin models, mainly by controlling the level of lipid peroxidation. Our results clearly support a strong involvement of glial cells and lipid peroxidation in the generation of FRDA-like symptoms.

  2. 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.)

  3. Ataxia cerebelosa persistente despues de la administracion toxica de difenilhidantoina

    Directory of Open Access Journals (Sweden)

    Andrés M. Villa

    1994-12-01

    Full Text Available La intoxicacion cronica con difenilhidantoina (DFH es bien conocida como causa de ataxia irreversible en pacientes epilépticos debida a atrofia cerebelosa con perdida de células de Purkinje. No es asi con la intoxicación aguda, puesto que sus signos y síntomas son reversibles. Presentamos un paciente con convulsiones parciales complejas, secundarias a un quiste temporal, que habia sido tratado irregularmente con DFH durante dos años con dosis variables que oscilaban en los 100 mg/dia. Dada la refractariedad de su cuadro convulsivo en una entrevista previa a su ingreso se le indico un aumento brusco de la dosis del fármaco que alcanzo a los 400 mg/dia. Ello ocasiono un sindrome pancerebeloso severo que motivo su internación. Posteriormente a la suspension de la DFH y la exeresis del quiste temporal mejoro su cuadro convulsivo, aunque quedo con ataxia de miembros inferiores y asinergia de tronco, cuadro con el que fue dado de alta. Un año despues, el paciente se encontraba libre de convulsiones, pero su sindrome cerebeloso no se habia modificado. El estudio por imágenes no evidencio atrofia cerebelosa.

  4. 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

  5. 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.

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

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    Huang Lijia

    2012-09-01

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

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

    DEFF Research Database (Denmark)

    Winkelmann, Juliane; Lin, Ling; Schormair, Barbara;

    2012-01-01

    Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT.......GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding...

  8. Kidney infarction in Friedreich's ataxia with dilated cardiomyopathy.

    Science.gov (United States)

    Evangelopoulos, Dimitrios Stergios; Pirvu, Tatiana Nataly; Exadaktylos, Aristomenis; Kohl, Sandro

    2012-09-30

    A 37-year-old man with advanced Friedreich's ataxia was referred to our emergency department with acute exacerbated abdominal pain of unclear aetiology. Laboratory tests showed slightly increased inflammatory parameters, elevated troponin and B-type natriuretic peptide, as well as minimal proteinuria. Transthoracic echocardiography revealed a pre-existing dilated cardiomyopathy. Abdominal sonography showed no pathological alterations. Owing to persistent pain under analgesia, a contrast-enhanced CT-abdomen was performed, which revealed a non-homogeneous perfusion deficit of the right kidney, although neither abdominal vascular alteration, cardiac thrombus, deep vein thrombosis nor a patent foramen ovale could be detected. Taking all clinical and radiological results into consideration, the current incident was diagnosed as a thromboembolic kidney infarction. As a consequence, lifelong oral anticoagulation was initiated.

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

    Science.gov (United States)

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

    2015-12-01

    Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document. PMID:26621971

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

    Directory of Open Access Journals (Sweden)

    Jayesh M. Bhatt

    2015-12-01

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

  11. Expanding the ataxia with oculomotor apraxia type 4 phenotype.

    Science.gov (United States)

    Paucar, Martin; Malmgren, Helena; Taylor, Malcolm; Reynolds, John J; Svenningsson, Per; Press, Rayomand; Nordgren, Ann

    2016-02-01

    Ataxia with oculomotor apraxia type 4 (AOA4) is an autosomal recessive (AR) disorder recently delineated in a Portuguese cohort and caused by mutations in the PNKP (polynucleotide kinase 3'-phosphatase) gene.(1) AOA4 is a progressive, complex movement disorder that includes hyperkinetic features, eye movement abnormalities, polyneuropathy, varying degrees of cognitive impairment, and obesity. PNKP mutations were initially discovered to be the cause of the severe nonprogressive syndrome microcephaly, early-onset intractable seizures, and developmental delay (MCSZ).(2) Here we describe a patient with compound heterozygous PNKP mutations presenting with an AOA4 phenotype. New features that we report include both mutations, presence of chorea, absence of oculomotor apraxia (OMA), and slow disease progression. PMID:27066586

  12. Vitamin B12 deficiency presenting as acute ataxia.

    Science.gov (United States)

    Crawford, John Ross; Say, Daphne

    2013-03-26

    A previously healthy 7-year-old Caucasian boy was hospitalised for evaluation of acute ataxia and failure to thrive, initially suspicious for an intracranial mass. Weight and body mass index were below the third percentile and he demonstrated loss of joint position and vibratory sense on examination. Laboratory studies revealed megaloblastic anaemia while an initial MRI of the brain showed no evidence of mass lesions or other abnormalities. A dietary history revealed the child subscribed to a restrictive vegan diet with little to no intake of animal products or other fortified foods. The child was diagnosed with presumed vitamin B12 deficiency and was treated with intramuscular B12 injections. Neurological symptoms resolved promptly within several days after starting therapy. This case underlines the importance of assessing nutritional status in the evaluation of neurological dysfunction in the pediatric patient.

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

    Science.gov (United States)

    Dar, M Saeed

    2015-08-01

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

  14. Ayurvedic approach in the management of spinocerebellar ataxia-2.

    Science.gov (United States)

    Singh, Sarvesh Kumar; Rajoria, Kshipra

    2016-01-01

    Spinocerebellar ataxia -2 is a progressive, degenerative genetic disease caused by an expanded (CAG) trinucleotide repetition on the chromosome 12 resulting in production of an abnormal protein called ataxin-2. There is no known effective management or cure in biomedicine for this genetic disease. In the present study a case of SCA2 that was treated with Ayurvedic intervention is reported. Ayurvedic treatments in this case were directed towards alleviating symptoms and to reduce severe disability due to progressive nature of disease. A 42 year old male patient was diagnosed for Vāta vyādhi (group of various neurological disorders) and was- treated with Śālisastika pinda svedana (sudation with bolus of medicated cooked rice) for 30 days-, Śirobasti (sudation of head with the help of a cap on head) with Aśvagandhā taila for 45 days and Balādi ksīra basti (enema with medicated milk) with Aśvagandhā taila anuvāsana (enema with oil) for 30 days in Karma basti krama (30 days regime of purification and oleation enema) along with a combination of Ayurvedic oral drugs which consisted of Brahadvātacintāmanirasa - 125 mg, Vasantāmaltī rasa- 125 mg, Daśamūla kvātha- 40 ml, Aśvagandhā cūrṇa (powder of Withania somnifera DUNAL)- 3g, Amrtā cūrṇa (powder of Tinospora cordifolia Willd.)- 500 mg, Muktāśukti pisti - 500 mg, Yogarāja Guggulu - 500 mg twice a day for 2 months. Patient's condition was assessed on the Scale for Assessment and Rating of Ataxia (SARA). Before treatment, mean SARA score was 35. This reduced to 15 after treatment. Good relief in dysarthria, fasciculation, heaviness in eye, blurred vision, axial tremor; constipation and quality of life were observed in this case. PMID:27143801

  15. Machado-Joseph disease is genetically different from Holguin dominant ataxia (SCA2)

    Energy Technology Data Exchange (ETDEWEB)

    Silveria, I.; Manaia, A. (Univ. Porto (Portugal) Hopital Necker-Enfants Malades, Paris (France)); Melki, J.; Burlet, P.; Rozet, J.M.; Munnich, A. (Hopital Necker-Enfants Malades, Paris (France)); Magarino, C.; Gispert, S. (Univ. Porto (Portugal) Centro Nacional Genetica Medica, Havana (Cuba)); Lunkes, A.; Auburger, G. (Univ. Hospital, Duesseldorf (Germany))

    1993-09-01

    Machado-Joseph disease (MJD) and Holguin ataxia (SCA2) are autosomal dominant multisystem degenerations with spinocerebellar involvement that are predominant among people of Portuguese-Azorean and of Cuban descent, respectively. Their clinical distinction may at times be difficult to make in individual patients, due to significant phenotypic overlapping (similar overall age-of-onset and duration of cerebellar ataxia, eye movement, and, often, other common problems). The recent mapping of SCA2 to chromosome 12q provided another candidate region for linkage studies of MJD. Original data on 10 families with Holguin ataxia show that the locus of phenylalanine hydroxylase (PAH) on chromosome 12q is linked to SCA2 at 4 cM and is thus far its closest marker. The exclusion of linkage 15 cM on each side of PAH in 16 families with MJD shows that these two forms of dominant ataxia are genetically distinct and at different chromosomal locations (nonallelic). 20 refs., 2 tabs.

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

    Science.gov (United States)

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

    2015-07-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  18. Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes.

    Science.gov (United States)

    Mehta, Nishaki; Chacko, Paul; Jin, James; Tran, Tam; Prior, Thomas W; He, Xin; Agarwal, Gunjan; Raman, Subha V

    2016-08-01

    Patients with Friedreich ataxia typically die of cardiomyopathy, marked by myocardial fibrosis and abnormal left ventricular (LV) geometry. We measured procollagen I carboxyterminal propeptide (PICP), a serum biomarker of collagen production, and characterized genotypes, phenotypes, and outcomes in these patients. Twenty-nine patients with Friedreich ataxia (mean age, 34.2 ± 2.2 yr) and 29 healthy subjects (mean age, 32.5 ± 1.1 yr) underwent serum PICP measurements. Patients underwent cardiac magnetic resonance imaging and outcome evaluations at baseline and 12 months. Baseline PICP values were significantly higher in the patients than in the control group (1,048 ± 77 vs 614 ± 23 ng/mL; P ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy. PMID:27547137

  19. 4-aminopyridine reverses ataxia and cerebellar firing deficiency in a mouse model of spinocerebellar ataxia type 6.

    Science.gov (United States)

    Jayabal, Sriram; Chang, Hui Ho Vanessa; Cullen, Kathleen E; Watt, Alanna J

    2016-01-01

    Spinocerebellar ataxia type 6 (SCA6) is a devastating midlife-onset autosomal dominant motor control disease with no known treatment. Using a hyper-expanded polyglutamine (84Q) knock-in mouse, we found that cerebellar Purkinje cell firing precision was degraded in heterozygous (SCA6(84Q/+)) mice at 19 months when motor deficits are observed. Similar alterations in firing precision and motor control were observed at disease onset at 7 months in homozygous (SCA6(84Q/84Q)) mice, as well as a reduction in firing rate. We further found that chronic administration of the FDA-approved drug 4-aminopyridine (4-AP), which targets potassium channels, alleviated motor coordination deficits and restored cerebellar Purkinje cell firing precision to wildtype (WT) levels in SCA6(84Q/84Q) mice both in acute slices and in vivo. These results provide a novel therapeutic approach for treating ataxic symptoms associated with SCA6. PMID:27381005

  20. Hereditary ataxias and paraplegias in Cantabria, Spain. An epidemiological and clinical study.

    Science.gov (United States)

    Polo, J M; Calleja, J; Combarros, O; Berciano, J

    1991-04-01

    A clinical, genetic and epidemiological study of hereditary ataxias and paraplegias was conducted within a defined area (Cantabria) in Northern Spain from 1974 to 1986. The series comprised 48 index cases and 65 affected relatives. On prevalence day, 103 patients were alive, giving a prevalence of 20.2 cases per 100,000. There were 24 patients (18 families) with Friedreich's ataxia (FA), 12 (6 families) with early onset cerebellar ataxia (EOCA) differing from FA, 6 (3 families) with dominantly transmitted late onset cerebellar ataxia (LOCA), 11 with 'idiopathic' LOCA, 49 (9 families) with 'pure' hereditary spastic paraplegia (HSP), and 1 patient with congenital cerebellar ataxia. The prevalence found here is comparable with the highest figures described in previous surveys. This may in part be due to the great number of secondary cases in our series. A high frequency of parental consanguinity occurred in FA patients, 'pseudodominant' inheritance being observed in 1 family. The clinical features were those of classical FA except for later onset and slower course in 1 family, and retained tendon reflexes in the lower limbs in 2 cases. Such data indicate the need for modification of the essential criteria for the disease. EOCA included 4 patients with normoreflexic ataxia and 1 patient with ataxia and luteinizing hormone-releasing hormone deficiency. In addition, there were 7 patients from 2 unrelated families with a homogeneous syndrome characterized by autosomal recessive inheritance, cerebellar ataxia, retinitis pigmentosa and sensory neuropathy. This syndrome is therefore a well defined nosological entity to be added to the list of autosomal recessive mendelian phenotypes. The clinical picture of patients with LOCA was either a 'pure' cerebellar or a 'cerebellar-plus' syndrome. Genetic subgroups of 'pure' HSP were autosomal dominant type I in 5 families and type II in 2, and autosomal recessive in 2 families. PMID:2043954

  1. Genetically Engineered Mouse Models of the Trinucleotide-Repeat Spinocerebellar Ataxias

    OpenAIRE

    Ingram, Melissa A.C.; Harry T Orr; Clark, H. Brent

    2011-01-01

    The spinocerebellar ataxias (SCA) are dominantly inherited disorders that primarily affect coordination of motor function but also frequently involve other brain functions. The models described in this review address mechanisms of trinucleotide-repeat expansions, particularly those relating to polyglutamine expression in the mutant proteins. Modeling chronic late-onset human ataxias in mice is difficult because of their short life-span. While this potential hindrance has been partially overco...

  2. Avances en el tratamiento de las ataxias crónicas

    Directory of Open Access Journals (Sweden)

    María Celeste Buompadre

    2013-09-01

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

  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. 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

  5. Frequency analysis of autosomal dominant spinocerebellar ataxias in mainland Chinese patients and clinical and molecular characterization of spinocerebellar ataxia type 6

    Institute of Scientific and Technical Information of China (English)

    JIANG Hong; TANG Bei-sha; XU Bo; ZHAO Guo-hua; SHEN Lu; TANG Jian-guang; LI Qing-hua; XIA Kun

    2005-01-01

    Background Dominantly inherited spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous group of neurodegenerative disorders. This study was to further assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, SCA8, SCA10, SCA12, SCA14, SCA17 and DRPLA (dentatorubro-pallidoluysian atrophy) in mainland Chinese, and to specifically characterize mainland Chinese patients with SCA6 in terms of clinical and molecular features.Methods Using a molecular approach, we investigated SCA in 120 mainland Chinese families with dominantly inherited ataxias and in 60 mainland Chinese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 13 patients from 4 families. Results SCA3/MJD was the most common type of autosomal dominant SCA in mainland Chinese, accounting for 83 patients from 59 families (49.2%), followed by SCA2[8(6.7%)], SCA1[7(5.8%)], SCA6[4(3.3%)], SCA7[1(0.8%)], SCA8(0%), SCA10(0%), SCA12(0%), SCA14(0%), SCA17(0%) and DRPLA(0%). The genes responsible for 41 (34.2%) of dominantly inherited SCA families remain to be determined. Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) was found to harbor SCA3 mutations while none was found to harbor SCA6 mutations. In the 4 families with SCA6, significant anticipation was found in the absence of genetic instability on transmission.Conclusion A geographic cluster of families with SCA6 subtype was initially identified in a mainland Chinese population.

  6. Reliability and validity of the Chinese version of the Scale for Assessment and Rating of Ataxia

    Institute of Scientific and Technical Information of China (English)

    TAN Song; NIU Hui-xia; ZHAO Lu; GAO Yuan; LU Jia-meng; SHI Chang-he; Chandra Avinash

    2013-01-01

    Background The Scale for the Assessment and Rating of Ataxia (SARA) was shown to be a reliable and valid measurement for patients with spinocerebellar ataxia (SCA).The Brazilian version and the Japanese version of SARAwere favorable for good reliability and validity.This study aimed to translate SARA into Chinese and test its reliability and validity in measurement of cerebellar ataxia.Methods SARA was translated into Chinese.A total 39 patients with degeneration cerebellar ataxia were evaluated independently by two neurologists with the Chinese version of SARA.Then the patients were evaluated by one of above neurologists with International Cooperative Ataxia Rating Scale (ICARS).The statistical analyses were performed using SPSS 17.0 for Windows.Results The Cronbach's alpha coefficient of the Chinese version of SARA was 0.78,which represents a good internal consistence.The correlation coefficient of the Chinese version of SARA scores between the two evaluators was 0.86,illustrating that the inter-rater reliability of Chinese version of SARA was good.The correlation coefficient between the Chinese version of SARA and ICARS was 0.91,illustrating that the criterion validity of Chinese version of SARA was not bad.Conclusions The Chinese version of SARA is reliable and effective for the assessment of degeneration cerebellar ataxia.Compared with ICARS,the evaluation of Chinese version of SARA is more objective,the assessment time is shortened,and the maneuverability is better.

  7. 100 CHILDREN WITH ACUTE ATAXIA; A SURVEY IN MOFID CHILDREN'S HOSPITAL

    Directory of Open Access Journals (Sweden)

    P. Karimzadeh

    2006-10-01

    Full Text Available Objective:The term "Ataxia" refers to disturbances of body posture and movementthat are normally controlled by the cerebellum, frontal lobes and theposterior columns of the spinal cord. The primary symptom and themost prominent feature of ataxia is abnormal gait which is characterizedby lurching and wide base walking.Ataxia was considered acute, if it had occurred within the two precedingweeks. Knowing how frightening acute-onset Ataxia is for the familyis not surprising that the condition prompts an immediate visit to thephysician.Material & Methods:In view of the lack of information in our country, on the etiology ofsudden-onset Ataxia, the authors enrolled 100 children with the chiefcomplaint of acute loss of equilibrium, who came to the attention ofthe Pediatric Neurology Department over a two year duration(Sept.2001-Sept 2003; they were admitted to the Mofid Childrens'Hospital and all necessary investigations were carried out.Results & Conclusion:The results revealed that Acute Cerebellar Ataxia was the most commoncause of the problem, the second most frequent being drug intoxication,which most commonly occurred in patients, 2-4years old. The remainingcausative factors in order of descending frequency consisted ofinfectious polyneuropathy, migraine, opsoclonus-myoclonus, braintumor, acute disseminated encephalomyelitis, multiple sclerosis, andepilepsy.

  8. Ataxia episódica não familiar possivelmente associada com o uso de nicotina: relato de caso Non-familial episodic ataxia possibly associated with the use of nicotine: case report

    Directory of Open Access Journals (Sweden)

    ANDERSON KUNTZ GRZESIUK

    2000-09-01

    Full Text Available O autor relata um caso clínico de ataxia episódica não familiar responsiva a acetazolamida, semelhante clinicamente a ataxia episódica tipo 2 (EA-2, no qual a nicotina pode representar ser um possível fator na gênese dos episódios atáxicos.The author reports a case of non-familial episodic ataxia responsive to acetazolamide, clinically similar to episodic ataxia type 2 (EA-2, in which nicotine is a possible factor in the origin of the ataxic episodes.

  9. Cytokines in Machado Joseph Disease/Spinocerebellar Ataxia 3.

    Science.gov (United States)

    da Silva Carvalho, Gerson; Saute, Jonas Alex Morales; Haas, Clarissa Branco; Torrez, Vitor Rocco; Brochier, Andressa Wigner; Souza, Gabriele Nunes; Furtado, Gabriel Vasata; Gheno, Tailise; Russo, Aline; Monte, Thais Lampert; Schumacher-Schuh, Artur; D'Avila, Rui; Donis, Karina Carvalho; Castilhos, Raphael Machado; Souza, Diogo Onofre; Saraiva-Pereira, Maria Luiza; Torman, Vanessa Leotti; Camey, Suzi; Portela, Luis Valmor; Jardim, Laura Bannach

    2016-08-01

    The aim of the present study is to describe the serum concentrations of a broad spectrum of cytokines in symptomatic and asymptomatic carriers of Machado Joseph disease (SCA3/MJD) CAG expansions. Molecularly confirmed carriers and controls were studied. Age at onset, disease duration, and clinical scales Scale for the Assessment and Rating of Ataxia (SARA), Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), SCA Functional Index (SCAFI), and Composite Cerebellar Functional Score (CCFS) were obtained from the symptomatic carriers. Serum was obtained from all individuals and a cytokine panel "consisted of" eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-a, MIP-b, regulated on activation, normal T cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-α was analyzed. In a subgroup of symptomatic carriers, the cytokine panel was repeated after 360 days. Cytokine distribution among groups was studied by discriminant analysis; changes in serum levels after 360 days were studied by generalized estimation equation. Sixty-six symptomatic carriers, 13 asymptomatic carriers, and 43 controls were studied. No differences in cytokine patterns were found between controls and carriers of the CAG expansions or between controls and symptomatic carriers only. In contrast, eotaxin concentrations were significantly higher in asymptomatic than in symptomatic carriers or in controls (p = 0.001, ANCOVA). Eotaxin did not correlate with age, disease duration, CAG expansion, NESSCA score, and SARA score. Among symptomatic carriers, eotaxin dropped after 360 days (p = 0.039, GEE). SCA3/MJD patients presented a benign pattern of

  10. 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.

  11. DNA triplex structures in neurodegenerative disorder, Friedreich's ataxia

    Indian Academy of Sciences (India)

    Moganty R Rajeswari

    2012-07-01

    It is now established that a small fraction of genomic DNA does adopt the non-canonical B-DNA structure or ‘unusual’ DNA structure. The unusual DNA structures like DNA-hairpin, cruciform, Z-DNA, triplex and tetraplex are represented as hotspots of chromosomal breaks, homologous recombination and gross chromosomal rearrangements since they are prone to the structural alterations. Friedreich’s ataxia (FRDA), the autosomal recessive degenerative disorder of nervous and muscles tissue, is caused by the massive expansion of (GAA) repeats that occur in the first intron of Frataxin gene X25 on chromosome 9q13-q21.1. The purine strand of the DNA in the expanded (GAA) repeat region folds back to form the (R∙R*Y) type of triplex, which further inhibits the frataxin gene expression, and this clearly suggests that the shape of DNA is the determining factor in the cellular function. FRDA is the only disease known so far to be associated with DNA triplex. Structural characterization of GAA-containing DNA triplexes using some simple biophysical methods like UV melting, UV absorption, circular dichroic spectroscopy and electrophoretic mobility shift assay are discussed. Further, the clinical aspects and genetic analysis of FRDA patients who carry (GAA) repeat expansions are presented. The potential of some small molecules that do not favour the DNA triplex formation as therapeutics for FRDA are also briefly discussed.

  12. Kv3.3 potassium channels and spinocerebellar ataxia.

    Science.gov (United States)

    Zhang, Yalan; Kaczmarek, Leonard K

    2016-08-15

    The voltage-dependent potassium channel subunit Kv3.3 is expressed at high levels in cerebellar Purkinje cells, in auditory brainstem nuclei and in many other neurons capable of firing at high rates. In the cerebellum, it helps to shape the very characteristic complex spike of Purkinje cells. Kv3.3 differs from other closely related channels in that human mutations in the gene encoding Kv3.3 (KCNC3) result in a unique neurodegenerative disease termed spinocerebellar ataxia type 13 (SCA13). This primarily affects the cerebellum, but also results in extracerebellar symptoms. Different mutations produce either early onset SCA13, associated with delayed motor and impaired cognitive skill acquisition, or late onset SCA13, which typically produces cerebellar degeneration in middle age. This review covers the localization and physiological function of Kv3.3 in the central nervous system and how the normal function of the channel is altered by the disease-causing mutations. It also describes experimental approaches that are being used to understand how Kv3.3 mutations are linked to neuronal survival, and to develop strategies for treatment. PMID:26442672

  13. Ataxia and deafness in a young male: An unusual aetiology

    Directory of Open Access Journals (Sweden)

    Prakash A

    2006-01-01

    Full Text Available We report here a case of 18 year old male with tremors of hands, deafness, tendency to fall while walking, drowsiness and double vision of total duration 1½ years. He had internuclear ophthalmoplegia, broken saccades, hypertonia and hyperreflexia of all four limbs, intention tremors, signs of gait and limb ataxia. Pupillary reactions and fundus examination were normal and signs of meningeal irritation or sensory neurological deficit were absent. MRI head and cervical spine with gadolinium enhancement revealed demyelination as evident from multiple oblong foci isointense on T1-weighted images and hyperintense on T2-weighted and fluid attenuated inversion recovery sequences in corpus callosum, sub-cortical white matter, right thalamus, pons and periaqueductal region of midbrain. Ill-defined linear hyperintense signals were observed in cervical spinal cord. No skeletal abnormality was noted in the skull or cervical spine. Oligoclonal bands were present in the cerebrospinal fluid. Brainstem auditory evoked potentials were abnormal, although visual evoked potentials were in normal range. A diagnosis of primary progressive multiple sclerosis (PPMS was made fulfilling the revised criteria as laid down. In view of its presentation, it is a unique case of PPMS from India.

  14. Radiation hypersensitivity and radioresistant DNA synthesis in ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Patients with the autosomal recessive genetic disease, ataxia-telangiectasia (A-T), are cancer-prone and hypersensitive to the killing effects of ionizing radiation. In an attempt to isolate the gene(s) responsible for the hypersensitivity of A-T cells, they were transfected with normal human DNA in cosmid vectors containing a rescuable marker (G-418 resistance), and revertants to normal sensitivity were isolated and characterized. The failure of radioresistant revertants to demonstrate a reversion of the phenotype, radioresistant DNA synthesis, shows that this feature is dependent on a gene separate from the one conferring resistance to cell killing. Cells from every A-T patient thus far examined demonstrate both hypersensitivity, in terms of radiation-induced cell killing, and radioresistant DNA synthesis. The results reported here, however, show that the former is not a result of the latter, as previously proposed. Moreover, the fact that these two characteristics can be uncoupled obscures the role(s) that either of them plays in the etiology of the disease, or in the development in its other features, including cancer-proneness

  15. 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.

  16. Spinocerebellar ataxia type 6 in eastern India: Some new observations

    Directory of Open Access Journals (Sweden)

    Kalyan B Bhattacharyya

    2016-01-01

    Full Text Available Introduction: Spinocerebellar ataxias (SCAs are hereditary, autosomal dominant progressive neurodegenerative disorders showing clinical and genetic heterogeneity. They are usually manifested clinically in the third to fifth decade of life although there is a wide variability in the age of onset. More than 36 different types of SCAs have been reported so far and about half of them are caused by pathological expansion of the trinucleotide, Cytosine Alanine Guanine (CAG repeat. The global prevalence of SCA is 0.3-2 per 100,000 population, SCA3 being the commonest variety worldwide, accounting for 20-50 per cent of all cases, though SCA 2 is generally considered as the commonest one in India. However, SCA6 has not been addressed adequately from India though it is common in the eastern Asian countries like, Japan, Korea and Thailand. Objective: The present study was undertaken to identify the prevalence of SCA6 in the city of Kolkata and the eastern part of India. Materials and Methods: 83 consecutive patients were recruited for the study of possible SCAs and their clinical features and genotype were investigated. Results: 6 of the 83 subjects turned out positive for SCA6, constituting therefore, 13.33% of the patient pool. Discussion: SCA6 is prevalent in the eastern part of India, though not as frequent as the other common varieties. Conclusions: Further community based studies are required in order to understand the magnitude of SCA6 in the eastern part, as well as in other regions of India.

  17. 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.

  18. False-positive head-impulse test in cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Olympia eKremmyda

    2012-11-01

    Full Text Available Abstract:The objective of this study was to compare the findings of the bedside head impulse test (HIT, passive head rotation gain, and caloric irrigation in patients with cerebellar ataxia (CA. In 16 patients with CA and bilaterally pathological bedside HIT, VOR gains were measured during HIT and passive head rotation by scleral search coil technique. Eight of the patients had pathologically reduced caloric responsiveness, while the other eight had normal caloric responses. Those with normal calorics showed a slightly reduced HIT gain (mean±SD: 0.73±0.15. In those with pathological calorics, gains 80ms and 100 ms after the HIT as well as the passive rotation VOR gains were significantly lower. The corrective saccade after head turn occurred earlier in patients with pathological calorics (111±62 ms after onset of the HIT than in those with normal calorics. (191±17 ms, p=0.0064 We indentified two groups of patients with CA: those with an isolated moderate HIT deficit only, probably due to floccular dysfunction, and those with combined HIT, passive rotation and caloric deficit, probably due to a peripheral vestibular deficit. From a clinical point of view, these results show that the bedside HIT alone can be false positive for establishing a diagnosis of a bilateral peripheral vestibular deficit in patients with CA.

  19. Molecular basis of ataxia telangiectasia and related diseases

    Institute of Scientific and Technical Information of China (English)

    Lindsay G BALL; Wei XIAO

    2005-01-01

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

  20. The history of spinocerebellar ataxia type 10 in Brazil: travels of a gene A história da ataxia espinocerebelar tipo 10 no Brasil: as viagens de um gene

    Directory of Open Access Journals (Sweden)

    Hélio A.G. Teive

    2007-12-01

    Full Text Available The authors report the history of spinocerebellar ataxia 10 (SCA10, since its first report in a large Portuguese-ancestry Family with autosomal dominant pure cerebellar ataxia, till the final identification of further families without Mexican ancestry. These families present a quite different phenotype from those SCA10 families described in Mexico.Os autores apresentam a história da descoberta da ataxia espinocerebelar tipo 10 (AEC10 no Brasil, desde o primeiro relato em uma família com ancestrais portugueses com ataxia cerebelar pura, autossômica dominante, até a identificação de famílias sem ancestrais mexicanos. Essas famílias apresentam um fenótipo de AEC10, com ataxia cerebelar "pura", distinta daquele descrito nas famílias no México.

  1. Friedreich's ataxia reveals a mechanism for coordinate regulation of oxidative metabolism via feedback inhibition of the SIRT3 deacetylase

    OpenAIRE

    Wagner, Gregory R.; Pride, P. Melanie; Babbey, Clifford M.; Payne, R. Mark

    2012-01-01

    Friedreich's ataxia (FRDA) is the most common inherited human ataxia and is caused by a deficiency in the mitochondrial protein frataxin. Clinically, patients suffer from progressive spinocerebellar degeneration, diabetes and a fatal cardiomyopathy, associated with mitochondrial respiratory chain defects. Recent findings have shown that lysine acetylation regulates mitochondrial function and intermediary metabolism. However, little is known about lysine acetylation in the setting of pathologi...

  2. Cerebellar Cognitive Affective Syndrome and Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay : A Report of Two Male Sibs

    NARCIS (Netherlands)

    Verhoeven, Willem M. A.; Egger, Jos I. M.; Ahmed, Amir I. M.; Kremer, Berry P. H.; Vermeer, Sascha; van de Warrenburg, Bart P. C.

    2012-01-01

    Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder caused by mutations in the SACS gene (13q12) encoding the protein sacsin. It is characterized by early-onset cerebellar ataxia, lower limb spasticity, sensorimotor axonal polyneuropath

  3. The dynamic regulation of cortical excitability is altered in episodic ataxia type 2

    DEFF Research Database (Denmark)

    Helmich, Rick C; Siebner, Hartwig R; Giffin, Nicola;

    2010-01-01

    cerebral excitability after facilitatory events. We tested this hypothesis in patients with episodic ataxia type 2 (n = 6), patients with familial hemiplegic migraine (n = 7) and healthy controls (n = 13). All subjects received a high-frequency burst (10 pulses at 20 Hz) of transcranial magnetic...... during the 1 s period following the transcranial magnetic stimulation burst, patients with episodic ataxia type 2 had increased intracortical facilitation 1000 ms after the burst. Intracortical inhibition was unaltered between groups. Patients with familial hemiplegic migraine were not significantly......Episodic ataxia type 2 and familial hemiplegic migraine are two rare hereditary disorders that are linked to dysfunctional ion channels and are characterized clinically by paroxysmal neurological symptoms. Impaired regulation of cerebral excitability is thought to play a role in the occurrence...

  4. Location of the 9257 and ataxia mutations on mouse chromosome 18.

    Science.gov (United States)

    Griffith, A J; Radice, G L; Burgess, D L; Kohrman, D C; Hansen, G M; Justice, M J; Johnson, K R; Davisson, M T; Meisler, M H

    1996-06-01

    The location of three mutations on proximal Chromosome (Chr) 18 was determined by analysis of the offspring of several backcrosses. The results demonstrate that ataxia and the insertional mutation TgN9257Mm are separated by less than 1 cM and are located approximately 3 cM from the centromere, while the balding locus is 7 cM more distal. Previous data demonstrated that the twirler locus also maps within 1 cM of ataxia. The corrected locations will contribute to identification of appropriate candidate genes for these mutations. Two polymorphic microsatellite markers for proximal Chr 18 are described, D18Umi1 and D18Umi2. The Lama3 locus encoding the alpha 3 subunit of nicein was mapped distal to ataxia and did not recombine with Tg9257. PMID:8662222

  5. An elderly man with progressive ataxia and palatal tremor presenting with dizziness and oculopalatal tremor.

    Science.gov (United States)

    Tsukahara, Yuka; Suzuki, Keisuke; Kokubun, Norito; Nakamura, Toshiki; Takekawa, Hidehiro; Hirata, Koichi

    2016-08-31

    A 74-year-old man was referred to our department for dizziness and progressive unsteady gait over 6 years. His family history was unremarkable. Neurological examination showed dysarthria, saccadic eye movement, palatal tremor (1.7 Hz)-synchronous with rotational ocular movement, and truncal ataxia. T2-weighted magnetic resonance imaging (MRI) of the brain revealed hyperintense and hypertrophic bilateral inferior olivary nuclei at the medulla and mild cerebellar atrophy. On the basis of neurological findings of oculopalatal tremor and cerebellar ataxia with brain MRI findings, the diagnosis of progressive ataxia and palatal tremor (PAPT) was made. PAPT should be included in differential diagnosis of dizziness observed in elderly individuals. PMID:27477579

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    Corinna Lappe-Siefke

    2009-09-01

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

  8. 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.

  9. The interrelationship between disease severity, dynamic stability, and falls in cerebellar ataxia.

    Science.gov (United States)

    Schniepp, Roman; Schlick, Cornelia; Pradhan, Cauchy; Dieterich, Marianne; Brandt, Thomas; Jahn, Klaus; Wuehr, Max

    2016-07-01

    Cerebellar ataxia (CA) results in discoordination of body movements (ataxia), a gait disorder, and falls. All three aspects appear to be obviously interrelated; however, experimental evidence is sparse. This study systematically correlated the clinical rating of the severity of ataxia with dynamic stability measures and the fall frequency in patients with CA. Clinical severity of CA in patients with sporadic (n = 34) and hereditary (n = 24) forms was assessed with the Scale for the Assessment and Rating of Ataxia (SARA). Gait performance was examined during slow, preferred, and maximally fast walking speeds. Spatiotemporal variability parameters in the fore-aft and medio-lateral directions were analyzed. The fall frequency was assessed using a standardized interview about fall events within the last 6 months. Fore-aft gait variability showed significant speed-dependent characteristics with highest magnitudes during slow and fast walking. The SARA score correlated positively with fore-aft gait variability, most prominently during fast walking. The fall frequency was significantly associated to fore-aft gait variability during slow walking. Severity of ataxia, dynamic stability, and the occurrence of falls were interrelated in a speed-dependent manner: (a) Severity of ataxia symptoms was closely related to instability during fast walking. (b) Fall frequency was associated with instability during slow walking. These findings suggest the presence of a speed-dependent, twofold cerebellar locomotor control. Assessment of gait performance during non-preferred, slow and fast walking speeds provides novel insights into the pathophysiology of cerebellar locomotor control and may become a useful approach in the clinical evaluation of patients with CA. PMID:27159995

  10. Population-based study of acquired cerebellar ataxia in Al-Kharga district, New Valley, Egypt

    OpenAIRE

    Farghaly WMA; El-Tallawy HN; Shehata GA; Rageh TA; Abdel Hakeem N; Abo-Elfetoh NM

    2011-01-01

    Wafaa MA Farghaly1, Hamdy N El-Tallawy1, Ghaydaa A Shehata1, Tarek A Rageh1, Nabil Abdel Hakeem2, Noha M Abo-Elfetoh11Department of Neurology and Psychiatry, Assiut University, Assiut, Egypt; 2Al Azhar University, Assiut Branch, EgyptBackground: The aim of this research was to determine the prevalence and etiology of acquired ataxia in Al-Kharga district, New Valley, Egypt.Methods: A population-based study of acquired ataxia was conducted in a defined geographical region with a total populati...

  11. Childhood Ataxia with Cerebral Hypomyelination (CACH syndrome: A study of three siblings

    Directory of Open Access Journals (Sweden)

    Vaidya Sachin

    2004-07-01

    Full Text Available We report a family of three siblings with Childhood Ataxia with Cerebral Hypomyelination. All the siblings presented with early onset cerebellar ataxia beginning around five years of age with mild mental retardation. MRI showed diffuse white matter signal changes in all three patients with cerebellar atrophy while the spectroscopy was abnormal only in the eldest who was the most severely affected. The cases are reported for their rarity as well as for an opportunity of observing this uncommon disease in its stages of evolution in three siblings.

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

    Directory of Open Access Journals (Sweden)

    Mohammad Mehdi HEIDARI*

    2014-01-01

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

  13. Pelagra endógena e ataxia cerebelar sem aminoacidúria: doença de Hartnup? Endogenous pellagra and cerebellar ataxia without aminoaciduria: Hartnup disease?

    OpenAIRE

    Júlio César Possati Resende; Leonardo Rodrigues de Oliveira; Luciano Carvalho Dias; Lívia das Graças Vieito L. Teodoro; Luciano Borges Santiago

    2006-01-01

    Menino, 7 anos, com história de convulsão, hiperpigmentação cutânea em áreas de exposição solar e episódios recorrentes de ataxia cerebelar. Estabelecido diagnóstico clínico de doença de Hartnup, foi tratado com nicotinamida, com melhora. Análises não confirmaram aminoacidúria ou outras alterações metabólicas. Na doença de Hartnup ocorre defeito no transporte renal e intestinal de aminoácidos neutros, reduzindo triptofano disponível para produção de niacina. Cursa com ataxia cerebelar intermi...

  14. Pelagra endógena e ataxia cerebelar sem aminoacidúria: doença de Hartnup? Endogenous pellagra and cerebellar ataxia without aminoaciduria: Hartnup disease?

    Directory of Open Access Journals (Sweden)

    Júlio César Possati Resende

    2006-10-01

    Full Text Available Menino, 7 anos, com história de convulsão, hiperpigmentação cutânea em áreas de exposição solar e episódios recorrentes de ataxia cerebelar. Estabelecido diagnóstico clínico de doença de Hartnup, foi tratado com nicotinamida, com melhora. Análises não confirmaram aminoacidúria ou outras alterações metabólicas. Na doença de Hartnup ocorre defeito no transporte renal e intestinal de aminoácidos neutros, reduzindo triptofano disponível para produção de niacina. Cursa com ataxia cerebelar intermitente, erupções cutâneas pelagróides e distúrbios mentais. Aminoacidúria em cromatografia urinária confirma diagnóstico, porém são descritos casos compatíveis com doença de Hartnup sem aminoacidúria.A seven-year-old boy with history of convulsion, cutaneous hyperpigmentation in sun-exposed areas and recurrent episodes of cerebellar ataxia is presented. Once established the clinical diagnosis of Hartnup disease, treatment with nicotinamide was started, with improvement. Laboratorial results did not confirm aminoaciduria nor other identified metabolic changes. In Hartnup disease, defective renal and intestinal transport of neutral amino acids occurrs, resulting in reduction of tryptophan to produce to nicotinamide. Symptomatic cases present with intermittent episodes of cerebellar ataxia, pellagra-like skin rash and mental disturbances. Urinary chromatographic amino acid pattern confirms diagnosis; however, cases compatible with Hartnup disease, but without aminoaciduria, have been reported.

  15. Progressive ataxia associated with ocular apraxia type 1 (AOA1 with a presence of a novel mutation on the aprataxin gene

    Directory of Open Access Journals (Sweden)

    Abdul Qayyum Rana

    2013-01-01

    Full Text Available Ataxia, although rare, can be a symptom of many debilitating movement disorders. Hereditary ataxias are one subset of this condition and manifest when there is a genetic abnormality involved. Ataxia oculomotor apraxia type 1 (AOA1, an autosomal recessive ataxia, results from a mutation on the aprataxin gene (APTX. We characterized a novel homozygous deletion mutation (IVS4-12delT on the APTX gene in a 14-year-old male born to consanguineous parents. This case report emphasizes the importance of investigating and increasing awareness of novel genetic mutations in order to help diagnose and further classify hereditary ataxias.

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

    DEFF Research Database (Denmark)

    Hansen, Susanne K; Stummann, Tina C; Borland, Helena;

    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...

  17. Overexpression of cystathionine γ-lyase suppresses detrimental effects of spinocerebellar ataxia type 3

    NARCIS (Netherlands)

    Snijder, Pauline M; Baratashvili, Madina; Grzeschik, Nicola A; Leuvenink, Henri G D; Kuijpers, Lucas; Huitema, Sippie; Schaap, Onno; Giepmans, Ben N G; Kuipers, Jeroen; Miljkovic, Jan Lj; Mitrovic, Aleksandra; Bos, Eelke M; Szabó, Csaba; Kampinga, Harm H; Dijkers, Pascale F; Den Dunnen, Wilfred F A; Filipovic, Milos R; van Goor, Harry; Sibon, Ody C M

    2015-01-01

    Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ATXN3 gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. Th

  18. Overexpression of Cystathionine gamma-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

    NARCIS (Netherlands)

    Snijder, Pauline M.; Baratashvili, Madina; Grzeschik, Nicola A.; Leuvenink, Henri G. D.; Kuijpers, Lucas; Huitema, Sippie; Schaap, Onno; Giepmans, Ben N. G.; Kuipers, Jeroen; Miljkovic, Jan Lj; Mitrovic, Aleksandra; Bos, Eelke M.; Szabo, Csaba; Kampinga, Harm H.; Dijkers, Pascale F.; den Dunnen, Wilfred F. A.; Filipovic, Milos R.; Goor, van Harry; Sibon, Ody C. M.

    2015-01-01

    Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative

  19. Clinical, psychological, and genetic characteristics of spinocerebellar ataxia type 19 (SCA19).

    NARCIS (Netherlands)

    Schelhaas, H.J.; Warrenburg, B.P.C. van de

    2005-01-01

    The SCA19 locus on chromosome 1p21-q21 was identified in a Dutch family in 2002. Affected individuals displayed a lateonset slowly progressive mild cerebellar ataxia, hyporeflexia, and signs of frontal lobe dysfunction. A postural head tremor and myoclonic movements were observed occasionally. Befor

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-02-17

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

  1. Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia

    OpenAIRE

    Miura, Yumako; Devaux, Jérôme J.; Fukami, Yuki; Manso, Constance; Belghazi, Maya; Wong, Anna Hiu Yi; Yuki, Nobuhiro

    2015-01-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is clinically heterogeneous and shows varying responses to immunotherapy. In a cohort of 533 Japanese patients with CIDP, Miura et al. identify 13 patients with IgG4 antibodies against the axonal adhesion molecule, contactin-1. Antibodies are associated with subacute onset, sensory ataxia and good response to corticosteroids.

  2. Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

    NARCIS (Netherlands)

    Ferdinandusse, S.; Zomer, A.W.M.; Komen, J.C.; van den Brink, C.; Thanos, M.; Hamers, F.P.T.; Wanders, R.J.A.T.; van der Saag, P.T.; Poll-The, B.T.; Brites, P.

    2008-01-01

    Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigm

  3. Oculomotor abnormalities in myoclonic tremor : a comparison with spinocerebellar ataxia type 6

    NARCIS (Netherlands)

    Bour, L. J.; van Rootselaar, A. F.; Koelman, J. H. T. M.; Tijssen, M. A. J.

    2008-01-01

    In the present study, eye movements are recorded in two patient groups with an autosomal dominantly inherited cerebellar disorder, i.e. spinocerebellar ataxia type 6 (SCA6) and familial cortical myoclonic tremor with epilepsy (FCMTE). In SCA6 and FCMTE patients striking similarities with the extensi

  4. Fatigue in spinocerebellar ataxia: Patient self-assessment of an early and disabling symptom

    NARCIS (Netherlands)

    E. Brusse (Esther); M.G.J. Brusse-Keizer (Marjolein G.J.); H.J. Duivenvoorden (Hugo); J.C. van Swieten (John)

    2011-01-01

    textabstractObjective: To identify the prevalence and severity of fatigue and predicting factors for severe fatigue in autosomal dominant spinocerebellar ataxia (SCA). Methods: We studied a cross-section of 123 patients with SCA. Six functional scales were used in a self-assessment: the Fatigue Seve

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

    Directory of Open Access Journals (Sweden)

    Ishani Sahama

    2015-01-01

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

  6. Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting

    NARCIS (Netherlands)

    Verbeek, D. S.; Knight, M. A.; Harmison, G. G.; Fischbeck, K. H.; Howell, B. W.

    2005-01-01

    The protein kinase C gamma (PKCgamma) gene is mutated in spinocerebellar ataxia type 14 (SCA14). In this study, we investigated the effects of two SCA14 missense mutations, G118D and C150F, on PKCgamma function. We found that these mutations increase the intrinsic activity of PKCgamma. Direct visual

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

    Science.gov (United States)

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

    2016-02-01

    Patients with mutations in the polymerase gamma gene (POLG) may present with progressive ataxia and in such situations neuroimaging findings may suggest the diagnosis. Herein we report a patient with a POLG gene W748S homozygous mutation and characteristic lesions in the thalamus, cerebellum and inferior olivary nucleus seen on magnetic resonance imaging. PMID:26755490

  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 hea

  9. Physiotherapy in degenerative cerebellar ataxias: utilisation, patient satisfaction, and professional expertise

    NARCIS (Netherlands)

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

    2013-01-01

    Physiotherapy plays an important role in the management of patients with degenerative cerebellar ataxias. However, our insight in the quantity and quality of physiotherapy prescription in this group of patients is incomplete. The purposes of this study were to investigate the utilization of physioth

  10. Landmark based shape analysis for cerebellar ataxia classification and cerebellar atrophy pattern visualization

    Science.gov (United States)

    Yang, Zhen; Abulnaga, S. Mazdak; Carass, Aaron; Kansal, Kalyani; Jedynak, Bruno M.; Onyike, Chiadi; Ying, Sarah H.; Prince, Jerry L.

    2016-03-01

    Cerebellar dysfunction can lead to a wide range of movement disorders. Studying the cerebellar atrophy pattern associated with different cerebellar disease types can potentially help in diagnosis, prognosis, and treatment planning. In this paper, we present a landmark based shape analysis pipeline to classify healthy control and different ataxia types and to visualize the characteristic cerebellar atrophy patterns associated with different types. A highly informative feature representation of the cerebellar structure is constructed by extracting dense homologous landmarks on the boundary surfaces of cerebellar sub-structures. A diagnosis group classifier based on this representation is built using partial least square dimension reduction and regularized linear discriminant analysis. The characteristic atrophy pattern for an ataxia type is visualized by sampling along the discriminant direction between healthy controls and the ataxia type. Experimental results show that the proposed method can successfully classify healthy controls and different ataxia types. The visualized cerebellar atrophy patterns were consistent with the regional volume decreases observed in previous studies, but the proposed method provides intuitive and detailed understanding about changes of overall size and shape of the cerebellum, as well as that of individual lobules.

  11. 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…

  12. Elevated mutant dynorphin A causes Purkinje cell loss and motor dysfunction in spinocerebellar ataxia type 23

    NARCIS (Netherlands)

    Smeets, Cleo J. L. M.; Jezierska, Justyna; Watanabe, Hiroyuki; Duarri Pique, Anna; Fokkens, Michiel R.; Meijer, Michel; Zhou, Qin; Yakovleva, Tania; Boddeke, Erik; den Dunnen, Wilfred; van Deursen, Jan; Bakalkin, Georgy; Kampinga, Harm H.; van de Sluis, Bart; Verbeek, Dineke S.

    2015-01-01

    Spinocerebellar ataxia type 23 is caused by mutations in PDYN, which encodes the opioid neuropeptide precursor protein, prodynorphin. Prodynorphin is processed into the opioid peptides, a-neoendorphin, and dynorphins A and B, that normally exhibit opioid-receptor mediated actions in pain signalling

  13. The fragile X-associated tremor ataxia syndrome (FXTAS) in Indonesia

    NARCIS (Netherlands)

    Winarni, T.I.; Mundhofir, F.E.P.; Ediati, A.; Belladona, M.; Nillesen, W.M.; Yntema, H.G.; Hamel, B.C.J.; Faradz, S.M.H.; Hagerman, R.J.

    2013-01-01

    Fragile X-associated disorders caused by the premutation of the FMR1 gene, includes the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS affects more than 40% of premutation males over the age of 50 and 75% over the age of 80. FMR1 molecular analysis was done using PCR and confirmed by Sou

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

    NARCIS (Netherlands)

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

    2002-01-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  16. The humanδ2 glutamate receptor gene is not mutated in patients with spinocerebellar ataxia

    Institute of Scientific and Technical Information of China (English)

    Jinxiang Huang; Aiyu Lin; Haiyan Dong; Chaodong Wang

    2014-01-01

    The human glutamate receptor delta 2 gene (GRID2) shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion (IVS5-121_-118 GAGT) and two single nucleotide polymor-phisms (c.1251G>T and IVS14-63C>G) were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.

  17. Decreased Functional Brain Activation in Friedreich Ataxia Using the Simon Effect Task

    Science.gov (United States)

    Georgiou-Karistianis, N.; Akhlaghi, H.; Corben, L. A.; Delatycki, M. B.; Storey, E.; Bradshaw, J. L.; Egan, G. F.

    2012-01-01

    The present study applied the Simon effect task to examine the pattern of functional brain reorganization in individuals with Friedreich ataxia (FRDA), using functional magnetic resonance imaging (fMRI). Thirteen individuals with FRDA and 14 age and sex matched controls participated, and were required to respond to either congruent or incongruent…

  18. The Training and Support Programme for Parents of Children with Ataxia: Parents' Perspectives

    Science.gov (United States)

    Powell, L. A.; Barlow, J. H.

    2007-01-01

    The aim of the study was to assess the Training and Support Programme (TSP) among parents of children with ataxia. Twenty-seven parents and their children completed the TSP. Data were collected by home record sheets and observation sheets completed by parents and therapists, respectively, and telephone interviews with 10 parents. Benefits reported…

  19. Acute cerebellar ataxia in a child with transient pontine lesions demonstrated by MRI

    NARCIS (Netherlands)

    Groen, R.J.M.; Begeer, J H; Wilmink, J T; le Coultre, R

    1991-01-01

    A case of acute cerebellar ataxia with discrete signs of pyramidal and tegmental involvement is reported, several days after recovery from an upper respiratory infection of unknown etiology. Magnetic resonance imaging showed transient pontine lesions, disappearing in the convalescence phase. Laborat

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

    International Nuclear Information System (INIS)

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

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

    Directory of Open Access Journals (Sweden)

    Fujioka Shinsuke

    2011-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Fujioka Shinsuke

    2013-01-01

    Full Text Available Abstract 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.

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

    Directory of Open Access Journals (Sweden)

    Sarah L. Nickerson

    2015-10-01

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

  4. Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia

    NARCIS (Netherlands)

    Schelhaas, H J; Ippel, P F; Hageman, G; Sinke, R J; van der Laan, E N; Beemer, F A

    2001-01-01

    The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders characterised by progressive cerebellar dysfunction in combination with a variety of other associative features. Since 1993 ADCAs have been increasingly characterised in terms of their genetic

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

    Directory of Open Access Journals (Sweden)

    Leonardo Pires Capelli

    2010-10-01

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

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

    DEFF Research Database (Denmark)

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

    2004-01-01

    Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria, unip...... 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...

  7. X-linked congenital ataxia: a new locus maps to Xq25-q27.1.

    Science.gov (United States)

    Zanni, Ginevra; Bertini, Enrico; Bellcross, Cecelia; Nedelec, Brigitte; Froyen, Guy; Neuhäuser, Gerhard; Opitz, John M; Chelly, Jamel

    2008-03-01

    We report clinical and molecular studies on a large American family of Norwegian descent with X-linked nonprogressive congenital ataxia (XCA) in six affected males over three generations. Neuroimaging showed global cerebellar hypoplasia without evidence of supratentorial anomalies. Linkage analysis resulted in a maximum LOD score Z = 3.44 for marker DXS1192 at Theta = 0.0 with flanking markers DXS1047 and DXS1227 defining a region of 12 cM in Xq25-q27.1. The clinical and neuroradiological findings in the present family are very similar to those described in two reported X-linked families [Illarioshkin et al., 1996; Bertini et al., 2000]; however, the newly identified locus does not overlap with the one defined previously, indicating that there are at least two genes responsible for this rare form of X-linked congenital cerebellar ataxia with normal intelligence.

  8. Late onset autosomal dominant cerebellar ataxia a family description and linkage analysis with the hla system

    Directory of Open Access Journals (Sweden)

    Walter O. Arruda

    1991-09-01

    Full Text Available A family suffering an autosomal dominant form of late onset hereditary cerebellar ataxia is described. Eight affected family members were personally studied, and data from another four were obtained through anamnesis. The mean age of onset was 37.1±5.4 years (27-47 years. The clinical picture consisted basically of a pure ataxic cerebellar syndrome. CT-scan disclosed diffuse cerebellar atrophy with relative sparing of the brainstem (and no involvement of supratentorial structures. Neurophysiological studies (nerve conduction, VEP and BAEP were normal. Twenty-six individuals were typed for HLA histocompatibility antigens. Lod scores were calculated with the computer program LINKMAP. Close linkage of the ataxia gene with the HLA system in this family could be excluded - 0==0,02, z=(-2,17 - and the overall analysis of the lod scores suggest another chromossomal location than chromosome 6.

  9. Ataxia and Hypogonadotropic Hypogonadism with Intrafamilial Variability Caused by RNF216 Mutation.

    Science.gov (United States)

    Alqwaifly, Mohammed; Bohlega, Saeed

    2016-06-15

    Gordon Holmes syndrome (GHS) is a distinct phenotype of autosomal recessive cerebellar ataxia, characterized by ataxia, dementia, reproductive defects and hypogonadism; it has been recently found to be associated with RNF216 mutation. We performed whole-exome sequencing and filtered the resulting novel variants by the coordinates of the shared autozygome. We identified a novel splicing variant in RNF216 that is likely to abolish the canonical splice site at the junction of exon/intron 13 (NM_207111.3:c.2061G>A). We herein report two patients with GHS caused by a novel RNF216 mutation as the first follow up report on RNF216-related GHS, and show interfamilial variability of phenotype supporting the previously reported RNF216-related cases. PMID:27441066

  10. A case of midbrain infarction with acute bilateral cerebellar ataxia visualized by diffusion tensor imaging.

    Science.gov (United States)

    Maya, Yuka; Kawabori, Masahito; Oura, Daisuke; Niiya, Yoshimasa; Iwasaki, Motoyuki; Mabuchi, Shoji

    2016-08-31

    An 85-year-old woman with hypertension was admitted with a sudden onset of gait disturbance and dysarthria. On admission, the patient showed severe bilateral cerebellar ataxia with moderate right medial longitudinal fasciculus (MLF) syndrome. Magnetic resonance (MR) imaging showed an acute infarction in the lower and medial part of midbrain. Diffusion tensor imaging (DTI) started from both cerebellar peduncles revealed that the lesion of the acute infarction matched the decussation of superior cerebellar peduncle where crossing of tract was seen and a part of its tract was interrupted at the site. Interruption of the cerebellum red nuclear path at the medial part of midbrain was considered to be the reason for bilateral cerebellar ataxia and visualization of cerebellum red nuclear path by DTI can give better understanding of the neurological symptom. PMID:27477572

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1995-06-19

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

  12. The contribution of the cerebellum to cognition in Spinocerebellar Ataxia Type 6

    OpenAIRE

    Cooper, Freya E.; Manon Grube; Elsegood, Kelly J.; Welch, John L.; Kelly, Thomas P.; Chinnery, Patrick F; Griffiths, Timothy D

    2010-01-01

    This study sought evidence for a specific cerebellar contribution to cognition by characterising the cognitive phenotype of Spinocerebellar Ataxia Type 6 (SCA-6); an autosomal dominant genetic disease which causes a highly specific late-onset cerebellar degeneration. A comprehensive neuropsychological assessment was administered to 27 patients with genetically confirmed SCA-6. General intellectual ability, memory and executive function were examined using internationally standardised tests (W...

  13. Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families.

    OpenAIRE

    Welshimer, K; Swift, M

    1982-01-01

    Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes. To test this hypothesis, medical records, death certificates, and questionnaires from 27 A-T families, 25 FA families, and 31 XP families were reviewed. Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retarda...

  14. Autosomal dominant ataxia: Genetic evidence for locus heterogeneity from a cuban founder-effect population

    OpenAIRE

    Auburger, Georg; Diaz, Guillermo Orozco; Capote, Raul Ferreira; Sanchez, Suzana Gispert; Perez, Marta Paradoa; del Cueto, Marianela Estrada; Meneses, Mirna Garcia; Farrall, Martin; Williamson, Robert; Chamberlain, Susan; Baute, Luis Heredero

    1990-01-01

    The locus for autosomal dominant ataxia with a diagnosis of olivo-ponto-cerebellar atrophy at autopsy has been previously assigned to chromosome 6p. However, evidence for two alternative locations has been reported. We have recently described a large potential founder-effect population of such patients in the Holguin province of Cuba. With an estimated 1,000 patients available for analysis, this extensive cluster of families provides a unique opportunity for the definitive localization of the...

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

    Directory of Open Access Journals (Sweden)

    Özge Pınar Akarsu

    2012-01-01

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

  16. KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function

    OpenAIRE

    Reichold, Markus; Zdebik, Anselm A.; Lieberer, Evelyn; Rapedius, Markus; Schmidt, Katharina; Bandulik, Sascha; Sterner, Christina; Tegtmeier, Ines; Penton, David; Baukrowitz, Thomas; Hulton, Sally-Anne; Witzgall, Ralph; Ben-Zeev, Bruria; Howie, Alexander J.; Kleta, Robert

    2010-01-01

    Mutations of the KCNJ10 (Kir4.1) K+ channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome. We investigated the localization of KCNJ10 and the homologous KCNJ16 in kidney and the functional consequences of KCNJ10 mutations found in our patients with EAST syndrome. Kcnj10 and Kcnj16 were found in the basolateral membrane of mouse distal convoluted tubules, connecting tubules, and cortical collecting ducts. In the hu...

  17. Cluster Analysis of Finger-to-nose Test for Spinocerebellar Ataxia Assessment

    OpenAIRE

    Velázquez Mariño, Michel; Atencia, Miguel; García Bermúdez, Rodolfo; Pupo-Ricardo, Daniel; Becerra García, Roberto; Velázquez Pérez, Luis; Sandoval, Francisco

    2015-01-01

    El test Finger-to-nose test (FNT) es una evaluación neurológica para estudiar la coordinación. Se presenta una metodología de análisis de datos de FNT, que permite evaluar la evolución del estado de enfermos de Ataxia Espinocerebral de tipo 2 (SCA2), mediante técnicas de aprendizaje computacional.

  18. Familial cerebellar ataxia and hypogonadotropic hypogonadism: evidence for hypothalamic LHRH deficiency.

    Science.gov (United States)

    Berciano, J; Amado, J A; Freijanes, J; Rebollo, M; Vaquero, A

    1982-01-01

    A family with familial cerebellar ataxia and hypogonadotropic hypogonadism is described. The condition was inherited as an autosomal recessive defect. CT scan in one case revealed cerebellar and brain stem atrophy. Endocrinological tests showed abnormalities only in two patients who were clinically affected. In both cases raised gonadotropic levels were found after repetitive stimulation with luteining hormone-releasing hormone which suggests that the hypogonadism was due to a primary hypothalamic disturbance. Images PMID:6813427

  19. Rehabilitation for Ataxia Following Chemotherapy for Burkitt Lymphoma Involving the Rectum

    OpenAIRE

    Kim, Hyoung Seop; Jung, Chul Oh; Jeon, Ha Ra; Sung, Lee Ho

    2012-01-01

    Burkitt lymphoma is a type of B-cell lymphoma that occurs mostly in children, and rarely in adults. The sporadic type is known to occur mostly at the ileum and cecum. Cytarabine, which is used for central nervous system prophylaxis during chemotherapy for Burkitt lymphoma, has known neurotoxicity, and its side effects include motor ataxia due to cerebellar injury, ataxic dysarthria, dysfunction of ocular movement, confusion, somnolence and lethargy. This case report is about a patient diagnos...

  20. Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models

    OpenAIRE

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

    2014-01-01

    Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pat...

  1. Ataxia telangiectasia mutated (Atm) is not required for telomerase-mediated elongation of short telomeres

    OpenAIRE

    Feldser, David; Strong, Margaret A.; Greider, Carol W

    2006-01-01

    Telomerase-mediated telomere addition counteracts telomere shortening due to incomplete DNA replication. Short telomeres are the preferred substrate for telomere addition by telomerase; however, the mechanism by which telomerase recognizes short telomeres is unclear. In yeast, the Ataxia telangiectasia mutated (Atm) homolog, Tel1, is necessary for normal telomere length regulation likely by altering telomere structure, allowing telomerase recruitment to short telomeres. To examine the role of...

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

    Directory of Open Access Journals (Sweden)

    Yogesh K Chutake

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

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

    OpenAIRE

    Fatma Deniz Aygün; Serdar Nepesov; Haluk Çokuğraş; Yıldız Camcıoğlu

    2015-01-01

    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 i...

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

    OpenAIRE

    Özge Pınar Akarsu; Cemile Üçgül Atılgan; Dilek Güven

    2012-01-01

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

  5. Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome.

    Science.gov (United States)

    O'Keefe, Joan A; Robertson-Dick, Erin E; Hall, Deborah A; Berry-Kravis, Elizabeth

    2016-08-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a "premutation" (PM) size CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Cerebellar gait ataxia is the primary feature in some FXTAS patients causing progressive disability. However, no studies have quantitatively characterized gait and mobility deficits in FXTAS. We performed quantitative gait and mobility analysis in seven FMR1 PM carriers with FXTAS and ataxia, six PM carriers without FXTAS, and 18 age-matched controls. We studied four independent gait domains, trunk range of motion (ROM), and movement transitions using an instrumented Timed Up and Go (i-TUG). We correlated these outcome measures with FMR1 molecular variables and clinical severity scales. PM carriers with FXTAS were globally impaired in every gait performance domain except trunk ROM compared to controls. These included total i-TUG duration, stride velocity, gait cycle time, cadence, double-limb support and swing phase times, turn duration, step time before turn, and turn-to-sit duration, and increased gait variability on several measures. Carriers without FXTAS did not differ from controls on any parameters, but double-limb support time was close to significance. Balance and disability scales correlated with multiple gait and movement transition parameters, while the FXTAS Rating Scale did not. This is the first study to quantitatively examine gait and movement transitions in FXTAS patients. Gait characteristics were consistent with those from previous cohorts with cerebellar ataxia. Sensitive measures like the i-TUG may help determine efficacy of interventions, characterize disease progression, and provide early markers of disease in FXTAS. PMID:26298472

  6. RNA-mediated neurodegeneration in fragile X-associated tremor/ataxia syndrome

    OpenAIRE

    Li, Yujing; Jin, Peng

    2012-01-01

    Carriers of fragile X syndrome (FXS) have FMR1 alleles, called premutations, with a number of 5’-untranslated CGG repeats somewhere between patients, who have over 200 repeats, and normal individuals, with fewer than 60 repeats. Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder, has been recognized in older male fragile X premutation carriers, and FXTAS is uncoupled from the neurodevelopmental disorder, FXS. Several lines of evidence have led to the ...

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

    Directory of Open Access Journals (Sweden)

    Horn Sigrun

    2010-03-01

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

  8. Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects

    OpenAIRE

    Bertrand Perroud; Paymaan Jafar-Nejad; Wikoff, William R.; Gatchel, Jennifer R.; Lu Wang; Barupal, Dinesh K.; Juan Crespo-Barreto; Oliver Fiehn; Zoghbi, Huda Y.; Rima Kaddurah-Daouk

    2013-01-01

    We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1(154Q/+)). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+) mice, with and without lithium treatment, were performed using gas chromatogra...

  9. Myocardial ischemia in the absence of epicardial coronary artery disease in Friedreich's ataxia

    OpenAIRE

    Dickerson Jennifer A; Raman Subha V; Al-Dahhak Roula

    2008-01-01

    Abstract We present the first in vivo detection of microvascular abnormality in a patient with Friedreich's ataxia (FA) without epicardial coronary artery disease using cardiac magnetic resonance (CMR). The patient had exertional chest pain and dyspnea prompting referral for cardiac evaluation. These symptoms were reproduced during intravenous adenosine infusion, and simultaneous first-pass perfusion imaging showed a significant subendocardial defect; both symptoms and perfusion deficit were ...

  10. Friedreich ataxia in Acadian families from eastern Canada: Clinical diversity with conserved haplotypes

    Energy Technology Data Exchange (ETDEWEB)

    Richter, A.; Poirier, J.; Mercier, J. [Hopital Sainte-Justine, Montreal (Canada)] [and others

    1996-09-06

    The gene for Friedreich ataxia (FRDA), an autosomal-recessive neurodegenerative disease, remains elusive. The current candidate region of about 150 kb lies between loci FR2 and F8101 near the D9S15/D9S5 linkage group at 9q13-21.1. Linkage homogeneity between classical FRDA and a milder, slowly progressive Acadian variant (FRDA-Acad) has been demonstrated. An extended D9S15-D9S5 haplotype (C6) predominates in FRDA-Acad chromosomes from Louisiana. We studied 10 Acadian families from New Brunswick, Canada. In eight families, affected individuals conformed to the clinical description of FRDA-Acad; in one, 2 sibs presented with spastic ataxia (SPA-Acad). In the last family, 2 sibs had FRDA-Acad, and one had SPA-Acad. We found that SPA-Acad is linked to the FRDA gene region. The C6 haplotype and a second major haplotype (137) were identified. The same ataxia-linked haplotypes segregated with both FRDA-Acad and SPA-Acad in two unrelated families. The parental origins of these haplotypes were different. Our observation of different phenotypes associated with the same combination of haplotypes may point to the influence of the parent of origin on gene expression, indicate the effect of modifier genes, or reflect the presence of different mutations on the same haplotype. Our findings underline the need to investigate families with autosomal-recessive ataxias for linkage to the FRDA region, despite lack of key diagnostic manifestations such as cardiomyopathy or absent deep-tendon reflexes. 28 refs., 4 figs., 3 tabs.

  11. Post-Plasmodium vivax malaria cerebellar ataxia and optic neuritis: A new form of delayed cerebellar ataxia or cerebellar variant of acute disseminated encephalomyelitis?

    Directory of Open Access Journals (Sweden)

    Gaurav M Kasundra

    2015-01-01

    Full Text Available Acute disseminated encephalomyelitis (ADEM is commonly seen after viral and bacterial infections, immunization, and Plasmodium falciparum (PF malaria. Plasmodium vivax (PV rarely causes ADEM. We report a 14-year-old female patient who presented with acute onset bilateral cerebellar ataxia and optic neuritis, 2 weeks after recovery from PV. Magnetic resonance imaging showed bilateral cerebellar hyperintensities suggestive of ADEM. No specific viral etiology was found on cerebrospinal fluid examination. Patient responded well to treatment without any sequelae. Thus, PV too is an important cause of ADEM along with PF. Two of the previously reported cases had co-infection with falciparum malaria. The only other two reported cases, as also this patient, are from Asia. A geographical or racial predisposition needs to be evaluated. Also, a possibility of post-PV delayed cerebellar ataxia, which is classically described post-PF infection, may be considered as it may be clinically, radiologically, and prognostically indistinguishable from a milder presentation of ADEM.

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

    Science.gov (United States)

    Paradisi, Irene; Ikonomu, Vassiliki; Arias, Sergio

    2016-03-01

    Dominantly inherited ataxias (spinocerebellar ataxias, SCAs) are a genetically heterogeneous group of neurologic diseases characterized by progressive cerebellar and spinal tract degeneration with ataxia and other signs, common to all known subtypes. Several types are relatively frequent worldwide, but in several countries, one specific SCA may show a higher prevalence owing to founder phenomena. In Venezuela, genetic epidemiological features of SCAs have been assessed during the last 30 years; mutations in ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), ATXN8 (SCA8), ATXN10 (SCA10), TBP (SCA17) and ATN1 (dentatorubral pallidoluysian atrophy, DRPLA) loci were searched among 115 independent families. SCA7 was the most frequent subtype (26.6%), followed by SCA3 (25.0%), SCA2 (21.9%), SCA1 (17.2%), SCA10 (4.7%) and DRPLA (3.1%); in 43% of the families, the subtype remained unidentified. SCA7 mutations displayed strong geographic aggregation in two independent founder foci, and SCA1 showed a very remote founder effect for a subset of families. SCA10 families were scattered across the country, but all had an identical in-phase haplotype carried also by Mexican, Brazilian and Sioux patients, supporting a very old common Amerindian origin. Prevalence for dominant SCAs in Venezuela was estimated as 1:25 000 nuclear families, provenances of which are either Caucasoid, African or Amerindian. PMID:26538302

  13. Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia

    Directory of Open Access Journals (Sweden)

    Yun Tae Hwang

    2016-09-01

    Full Text Available Mosaicism for FMR1 premutation (PM: 55–199 CGG/full mutation (FM: >200 CGG alleles or the presence of unmethylated FM (UFM have been associated with a less severe fragile X syndrome (FXS phenotype and fragile X associated tremor/ataxia syndrome (FXTAS—a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB, which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen.

  14. Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia

    Science.gov (United States)

    Hwang, Yun Tae; Dudding, Tracy; Aliaga, Solange Mabel; Arpone, Marta; Francis, David; Li, Xin; Slater, Howard Robert; Rogers, Carolyn; Bretherton, Lesley; du Sart, Desirée; Heard, Robert; Godler, David Eugeny

    2016-01-01

    Mosaicism for FMR1 premutation (PM: 55–199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)—a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen. PMID:27657133

  15. Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report.

    Science.gov (United States)

    Tamás, Gertrúd; Kovács, Norbert; Varga, Noémi Ágnes; Barsi, Péter; Erőss, Loránd; Molnár, Mária Judit; Balás, István

    2016-01-01

    We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved.

  16. POINT MUTATIONS ON MITOCHONDRIAL DNA IN IRANIAN PATIENTS WITH FRIEDREICH’S ATAXIA

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    S. Etemad Ahari

    2008-11-01

    Full Text Available ObjectiveMitochondrial DNA (mtDNA is considered a candidate modifier factor for neuro-degenerative disorders. The most common type of ataxia is Friedreich's ataxia (FA. The aim of this study was to investigate different parts of mtDNA in 20 Iranian FA patients and 80 age-matched controls by polymerase chain reaction (PCR and automated DNA sequencing methods to find any probable point mutations involved in the pathogenesis of FA.Materials and MethodsWe identified 13 nucleotide substitutions including A3505G, T3335C, G3421A, G8251A, A8563G, A8563G, G8584A, T8614C, T8598C, C8684T, A8701G, G8994A and A9024G.ResultsTwelve of 13 nucleotide substitutions had already been reported as polymorphism. One of the nucleotide substitutions (A9024G had not been reported before. The A9024G nucleotide substitution does not change its amino acid. The controls were also investigated for this polymorphism which was found in two of them (2.5%.ConclusionNone of the mutations found in this study can affect the clinical manifestations of FA. This survey also provides evidence that the mtDNA A9024G allele is a new nonpathogenic polymorphism. We suggest follow-up studies for this polymorphism in different populations.Keywords:Mitochondrial DNA, Friedreich's Ataxia

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

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    Cláudio M. Gomes

    2013-01-01

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

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

    Science.gov (United States)

    Paradisi, Irene; Ikonomu, Vassiliki; Arias, Sergio

    2016-03-01

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

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

    International Nuclear Information System (INIS)

    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

  20. The Pointing Errors in Optic Ataxia Reveal the Role of "Peripheral Magnification" of the PPC.

    Science.gov (United States)

    Vindras, Philippe; Blangero, Annabelle; Ota, Hisaaki; Reilly, Karen T; Rossetti, Yves; Pisella, Laure

    2016-01-01

    Interaction with visual objects in the environment requires an accurate correspondence between visual space and its internal representation within the brain. Many clinical conditions involve some impairment in visuo-motor control and the errors created by the lesion of a specific brain region are neither random nor uninformative. Modern approaches to studying the neuropsychology of action require powerful data-driven analyses and error modeling in order to understand the function of the lesioned areas. In the present paper we carried out mixed-effect analyses of the pointing errors of seven optic ataxia patients and seven control subjects. We found that a small parameter set is sufficient to explain the pointing errors produced by unilateral optic ataxia patients. In particular, the extremely stereotypical errors made when pointing toward the contralesional visual field can be fitted by mathematical models similar to those used to model central magnification in cortical or sub-cortical structure(s). Our interpretation is that visual areas that contain this footprint of central magnification guide pointing movements when the posterior parietal cortex (PPC) is damaged and that the functional role of the PPC is to actively compensate for the under-representation of peripheral vision that accompanies central magnification. Optic ataxia misreaching reveals what would be hand movement accuracy and precision if the human motor system did not include elaborated corrective processes for reaching and grasping to non-foveated targets. PMID:27507938

  1. Friedreich ataxia is not only a GAA repeats expansion disorder: implications for molecular testing and counselling.

    Science.gov (United States)

    Hoffman-Zacharska, Dorota; Mazurczak, Tomasz; Zajkowski, Tomasz; Tataj, Renata; Górka-Skoczylas, Paulina; Połatyńska, Katarzyna; Kępczyński, Łukasz; Stasiołek, Mariusz; Bal, Jerzy

    2016-08-01

    Friedreich ataxia (FRDA) is the most common hereditary ataxia. It is an autosomal recessive disorder caused by mutations of the FXN gene, mainly the biallelic expansion of the (GAA)n repeats in its first intron. Heterozygous expansion/point mutations or deletions are rare; no patients with two point mutations or a point mutation/deletion have been described, suggesting that loss of the FXN gene product, frataxin, is lethal. This is why routine FRDA molecular diagnostics is focused on (GAA)n expansion analysis. Additional tests are considered only in cases of heterozygous expansion carriers and an atypical clinical picture. Analyses of the parent's carrier status, together with diagnostic tests, are performed in rare cases, and, because of that, we may underestimate the frequency of deletions. Even though FXN deletions are characterised as 'exquisitely rare,' we were able to identify one case (2.4 %) of a (GAA)n expansion/exonic deletion in a group of 41 probands. This was a patient with very early onset of disease with rapid progression of gait instability and hypertrophic cardiomyopathy. We compared the patient's clinical data to expansion/deletion carriers available in the literature and suggest that, in clinical practice, the FXN deletion test should be taken into account in patients with early-onset, rapid progressive ataxia and severe scoliosis. PMID:26906906

  2. 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.

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

    Science.gov (United States)

    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

  4. Progression of brain atrophy in spinocerebellar ataxia type 2: a longitudinal tensor-based morphometry study.

    Directory of Open Access Journals (Sweden)

    Mario Mascalchi

    Full Text Available Spinocerebellar ataxia type 2 (SCA2 is the second most frequent autosomal dominant inherited ataxia worldwide. We investigated the capability of magnetic resonance imaging (MRI to track in vivo progression of brain atrophy in SCA2 by examining twice 10 SCA2 patients (mean interval 3.6 years and 16 age- and gender-matched healthy controls (mean interval 3.3 years on the same 1.5 T MRI scanner. We used T1-weighted images and tensor-based morphometry (TBM to investigate volume changes and the Inherited Ataxia Clinical Rating Scale to assess the clinical deficit. With respect to controls, SCA2 patients showed significant higher atrophy rates in the midbrain, including substantia nigra, basis pontis, middle cerebellar peduncles and posterior medulla corresponding to the gracilis and cuneatus tracts and nuclei, cerebellar white matter (WM and cortical gray matter (GM in the inferior portions of the cerebellar hemisphers. No differences in WM or GM volume loss were observed in the supratentorial compartment. TBM findings did not correlate with modifications of the neurological deficit. In conclusion, MRI volumetry using TBM is capable of demonstrating the progression of pontocerebellar atrophy in SCA2, supporting a possible role of MRI as biomarker in future trials.

  5. Deep brain stimulation or thalamotomy in fragile X-associated tremor/ataxia syndrome? Case report.

    Science.gov (United States)

    Tamás, Gertrúd; Kovács, Norbert; Varga, Noémi Ágnes; Barsi, Péter; Erőss, Loránd; Molnár, Mária Judit; Balás, István

    2016-01-01

    We present the case of a 66-year-old man who has been treated for essential tremor since the age of 58. He developed mild cerebellar gait ataxia seven years after tremor onset. Moderate, global brain atrophy was identified on MRI scans. At the age of 68, only temporary tremor relief could be achieved by bilateral deep brain stimulation of the ventral intermedius nucleus of the thalamus. Bilateral stimulation of the subthalamic nucleus also resulted only in transient improvement. In the meantime, progressive gait ataxia and tetraataxia developed accompanied by other cerebellar symptoms, such as nystagmus and scanning speech. These correlated with progressive development of bilateral symmetric hyperintensity of the middle cerebellar peduncles on T2 weighted MRI scans. Genetic testing revealed premutation of the FMR1 gene, establishing the diagnosis of fragile X-associated tremor/ataxia syndrome. Although this is a rare disorder, it should be taken into consideration during preoperative evaluation of essential tremor. Postural tremor ceased two years later after thalamotomy on the left side, while kinetic tremor of the right hand also improved. PMID:27375149

  6. 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 (< 0.8), and oligoclonal bands were present. PCR of the CSF was negative for HIV, JC virus, other HHVs, and mycosis. Previous reports presented HIV-infected patients with concurrent autoimmune diseases such as systemic lupus erythematosus, anti-phospholipid syndrome, autoimmune thrombocytopenia, vasculitis, polymyositis and dermatomyositis, sarcoidosis, Graves' disease, and hepatic diseases. These might have been present in patients with a CD4 T lymphocyte count of more than 200 cells/ml. On the other hand, paraneoplastic syndrome, gluten 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

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    Jijun eWan

    2011-09-01

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

  9. Occupational therapy in spinocerebellar ataxia type 3: an open-label trial

    Directory of Open Access Journals (Sweden)

    R.C.R. Silva

    2010-06-01

    Full Text Available Occupational therapy (OT is a profession concerned with promoting health and well-being through occupation, by enabling handicapped people to participate in the activities of everyday life. OT is part of the clinical rehabilitation of progressive genetic neurodegenerative diseases such as spinocerebellar ataxias; however, its effects have never been determined in these diseases. Our aim was to investigate the effect of OT on both physical disabilities and depressive symptoms of spinocerebellar ataxia type 3 (SCA3 patients. Genomically diagnosed SCA3 patients older than 18 years were invited to participate in the study. Disability, as evaluated by functional independence measurement and Barthel incapacitation score, Hamilton Rating Scale for Depression, and World Health Organization Quality of Life questionnaire (WHOQOL-BREF, was determined at baseline and after 3 and 6 months of treatment. Twenty-six patients agreed to participate in the study. All were treated because OT prevents blinding of a control group. Fifteen sessions of rehabilitative OT were applied over a period of 6 months. Difficult access to food, clothing, personal hygiene, and leisure were some of the main disabilities focused by these patients. After this treatment, disability scores and quality of life were stable, and the Hamilton scores for depression improved. Since no medication was started up to 6 months before or during OT, this improvement was related to our intervention. No association was found between these endpoints and a CAG tract of the MJD1 gene (CAGn, age, age of onset, or neurological scores at baseline (Spearman test. Although the possibly temporary stabilization of the downhill disabilities as an effect of OT remains to be established, its clear effect on depressive symptoms confirms the recommendation of OT to any patient with SCA3 or spinocerebellar ataxia.

  10. Treatment of fragile X-associated tremor ataxia syndrome (FXTAS and related neurological problems

    Directory of Open Access Journals (Sweden)

    Randi J Hagerman

    2008-06-01

    Full Text Available Randi J Hagerman1,2, Deborah A Hall3, Sarah Coffey1,2, Maureen Leehey3, James Bourgeois4, John Gould5, Lin Zhang6, Andreea Seritan4, Elizabeth Berry-Kravis7–9, John Olichney6, Joshua W Miller10, Amy L Fong11, Randall Carpenter12, Cathy Bodine13, Louise W Gane1,2, Edgar Rainin1, Hillary Hagerman1, Paul J Hagerman141M.I.N.D. Institute, 2Department of Pediatrics, 4Department of Psychiatry & Behavioral Sciences, 5Department of Urology, 6Department of Neurology, 10Department of Pathology and Laboratory Medicine, 14Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, USA; 3Department of Neurology, University of Colorado, Denver, CO, USA; 7Department of Pediatrics, Neurology, and Biochemistry, 8Department of Neurological Sciences, 9Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA; 11Physical Edge, Inc., Davis, CA, USA; 12Seaside Therapeutics, Cambridge, MA, USA; 13Department of Physical Medicine and Rehabilitation, University of Colorado Health Sciences Center, Denver, CO, USAAbstract: Fragile X-associated tremor/ataxia syndrome (FXTAS is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats of the fragile X (FMR1 gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently

  11. Walk on Floor Eyes Closed Test as a Measure of Postflight Ataxia

    Science.gov (United States)

    Reschke, M. F.; Fisher, E. A.; Kofman, I. S.; Cerisano, J. M.; Harm, D.L.; Peters, B. T.; Bloomberg, J. J.

    2010-01-01

    INTRODUCTION: Astronauts returning from space flight universally exhibit impaired posture and locomotion. Measurement of this impairment is an evolving process. The walk on the floor line test with the eyes closed (WOFEC) provides a unique procedure for quantifying postflight ataxia. Data from a modified WOFEC were obtained as part of an ongoing NASA interdisciplinary pre- and postflight study (Functional Task Test, FTT) designed to evaluate astronaut postflight functional performance. METHODS: Seven astronauts (5 short duration with flights of 12-16 days; 2 long duration crewmembers with flights of 6 months) were tested twice before flight, on landing day (short duration only), and 1, 6, and 30 days after flight. The WOFEC consisted of walking for 10 steps (repeated twice) with the feet heel to toe in tandem, arms folded across the chest and the eyes closed. The performance metric (scored by three examiners from video) was the percentage of correct steps completed over the three trials. A step was not counted as correct if the crewmember sidestepped, opened their eyes, or paused for more than three seconds between steps. RESULTS/ CONCLUSIONS: There was a significant decrease in percentage of correct steps on landing day (short duration crew) and on first day following landing (long duration) with partial recovery the following day, and full recovery beginning on day sixth after flight. Both short and long duration fliers appeared to be unaware of foot position relative to their bodies or the floor. Postflight, deviation from a straight path was common, and the test for two crewmembers elicited motion sickness symptoms. These data clearly demonstrate the sensorimotor challenges facing crewmembers after returning from spaceflight. The WOFEC test has value providing the investigator or crew surgeon with a simple method to quantify vestibular ataxia, as well as providing instant feedback of postural ataxia without the use of complex test equipment.

  12. Clinical Characteristics, Radiological Features and Gene Mutation in 10 Chinese Families with Spinocerebellar Ataxias

    Institute of Scientific and Technical Information of China (English)

    Jian-Wen Chen; Li Zhao; Feng Zhang; Lan Li; Yu-Hang Gu; Jing-Yuan Zhou; Hui Zhang

    2015-01-01

    Background:Spinocerebellar ataxias (SCAs) are a group ofneurodegenerative disorders that primarily cause the degeneration in the cerebellum,spinal cord,and brainstem.We study the clinical characteristics,radiological features and gene mutation in Chinese families with SCAs.Methods:In this study,we investigated 10 SCAs Chinese families with SCA1,SCA3/Machado-Joseph disease (MJD),SCA7,SCAB.There were 27 people who were genetically diagnosed as SCA,of which 21 people showed clinical symptoms,and 6 people had no clinical phenotype that we called them presymptomatic patients.In addition,3 people with cerebellar ataxia and cataracts were diagnosed according to the Harding diagnostic criteria but failed to be recognized as SCAs on genetic testing.Clinical characteristic analyses of each type of SCAs and radiological examinations were performed.Results:We found that SCA3/MJD was the most common subtype in Han population in China,and the ratio of the pontine tegmentum and the posterior fossa area was negatively correlated with the number of cytosine-adenine-guanine (CAG) repeats;the disease duration was positively correlated with the International Cooperative Ataxia Rating Scale score;and the CAG repeats number of abnormal alleles was negatively correlated with the age of onset.Conclusions:Collectively our study is a systematic research on SCAs in China,which may help for the clinical diagnosis and prenatal screening of this disease,and it may also aid toward better understanding of this disease.

  13. Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice

    NARCIS (Netherlands)

    Hunsaker, M.R.; Greco, C.M.; Spath, M.A.; Smits, A.P.T.; Navarro, C.S.; Tassone, F.; Kros, J.M.; Severijnen, L.A.; Berry-Kravis, E.M.; Berman, R.F.; Hagerman, P.J.; Willemsen, R.; Hagerman, R.J.; Hukema, R.K.

    2011-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. T

  14. 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

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

    NARCIS (Netherlands)

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

    2004-01-01

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

  16. The spinocerebellar ataxia 2 locus is located within a 3-cm interval on chromosome 12q23-24.1

    Energy Technology Data Exchange (ETDEWEB)

    Allotey, R.; Twells, R.; Cemal, C. [Imperial College, London (United Kingdom)] [and others

    1995-07-01

    The autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders characterized by a predominantly cerebellar syndrome of onset with gait ataxia, dysarthria, dysmetria, and dysdiadochokinesia. Pathologically, the disorders are characterized by premature neuronal loss in the cerebellar cortex and the inferior olivary and pontine nuclei, with degeneration of the spinal cord. We have previously assigned the spinocerebellar ataxia 2 locus to chromosome 12q23-24.1, within a 31-cM interval flanked by the loci D12S58 and PLA2. Linkage to SCA2 has been demonstrated in pedigrees from Europe, Japan, and North America, the latter serving to refine the candidate region to a 16-cM interval. We report here genetic analysis undertaken between SCA2 and nine microsatellite loci known to span 8 cM within this interval. 12 refs., 2 figs., 1 tab.

  17. Childhood encephalomyopathy with cytochrome c oxidase deficiency, ataxia, muscle wasting, and mental impairment.

    Science.gov (United States)

    Angelini, C; Bresolin, N; Pegolo, G; Bet, L; Rinaldo, P; Trevisan, C; Vergani, L

    1986-08-01

    The son of third cousins was normal until age 2 when he had difficulty walking. At age 8 there was limb weakness, ataxia, loss of tendon reflexes, dislalia, and he was mildly retarded. During fasting, urinary organic acid excretion was abnormally high. Cytochrome c oxidase activity in muscle was 7% of the normal mean. The enzyme in platelets was 16% of controls with a decreased cytochrome aa3 peak. These data suggest an autosomal recessive transmission of this variant of cytochrome c oxidase deficiency.

  18. Niveles de evolución de los trastornos de la marcha en pacientes con ataxia

    OpenAIRE

    Ponce, María Julia

    2014-01-01

    Objetivo: Determinar el nivel de evolución de de los trastornos de la marcha en pacientes con ataxia que realizan tratamiento kinésico en la ciudad de Mar del Plata. Material y métodos: Estudio descriptivo, no experimental, transversal de corte retrospectivo, mediante un muestreo no probabilístico accidental. Se seleccionó a 20 pacientes de 18 a 80 años, de ambos sexos, que concurren a rehabilitación en distintos centros kinésicos, en la ciudad de Mar del Plata, durante el año 2014. La rec...

  19. Human quadrupedalism is not an epiphenomenon caused by neurodevelopmental malformation and ataxia

    Science.gov (United States)

    Karaca, Sibel; Tan, Meliha; Tan, Uner

    2012-01-01

    Two cases with quadrupedal locomotion (QL) were presented. In both cases, cognitive and psychiatric functions were normal and, no neurological deficits were observed, except for a sequel paralysis of left leg in Case 2. It was suggested that human QL (1) should not be considered as an epiphenomenon caused by neurodevelopmental malformation and ataxia, but (2) may be considered as a re-emergence of the ancestral diagonal QL, and (3) it may spontaneously emerge in humans with entirely normal brains, by taking advantage of neural networks such as central pattern generators that have been preserved for about 400 million years. PMID:23112791

  20. Barr humbug: acute cerebellar ataxia due to Epstein-Barr virus.

    Science.gov (United States)

    Davies, Benjamin; Machin, Nicholas; Lavin, Timothy; Ul Haq, Mian Ayaz

    2016-01-01

    Epstein-Barr virus (EBV) infection is associated with neurological sequellae, but rarely there is acute cerebellar ataxia (ACA) in an adult. We present a novel case of a 26-year-old man, who presented with ACA. He had normal MRI and CSF analysis. Serum testing confirmed active EBV. A course of oral prednisolone 1 mg/kg for 4 weeks, with a subsequent taper was started. He made a full recovery within 3 weeks of presentation. PMID:27558189

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

    Science.gov (United States)

    Aygün, Fatma Deniz; Nepesov, Serdar; Çokuğraş, Haluk; Camcıoğlu, Yıldız

    2015-01-01

    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. PMID:26693373

  2. Human quadrupedalism is not an epiphenomenon caused by neurodevelopmental malformation and ataxia

    Directory of Open Access Journals (Sweden)

    Sibel eKaraca

    2012-10-01

    Full Text Available Two cases of individuals with quadrupedal locomotion (QL were presented. In both cases the brains and cognitive functions were normal and no neurological deficits were seen, except for a paralyzed leg in case 2. It was suggested that human QL (i should not be considered as an epiphenomenon caused by neurodevelopmental malformation and ataxia, but (ii may be considered as a re-emergence of the ancestral diagonal QL, and (iii it may spontaneously emerge in humans with entirely normal brains, by taking advantage of neural networks such as central pattern generators that have been preserved for about 400 million years.

  3. Brain Metabolic Changes of Cervical Dystonia with Spinocerebellar Ataxia Type 1 after Botulinum Toxin Therapy.

    Science.gov (United States)

    Kikuchi, Akio; Takeda, Atsushi; Sugeno, Naoto; Miura, Emiko; Kato, Kazuhiro; Hasegawa, Takafumi; Baba, Toru; Konno, Masatoshi; Oshima, Ryuji; Watanuki, Shoichi; Hiraoka, Kotaro; Tashiro, Manabu; Aoki, Masashi

    2016-01-01

    We occasionally observe long-term remission of cervical dystonia after several botulinum toxin treatments. However, botulinum toxin transiently acts on neuromuscular junctions. We herein report that a cervical dystonia patient with spinocerebellar ataxia type 1 could have long-term remission as a result of the depression of hypermetabolism in the bilateral putamen and primary sensorimotor cortex after botulinum toxin therapy. We suggest that botulinum toxin impacts the central nervous system, causing prolonged improvement through the normalization of basal ganglia circuits in addition to its effects at neuromuscular junctions. PMID:27432104

  4. Functional and Gait Assessment in Children and Adolescents Affected by Friedreich's Ataxia: A One-Year Longitudinal Study.

    Science.gov (United States)

    Vasco, Gessica; Gazzellini, Simone; Petrarca, Maurizio; Lispi, Maria Luisa; Pisano, Alessandra; Zazza, Marco; Della Bella, Gessica; Castelli, Enrico; Bertini, Enrico

    2016-01-01

    Friedreich's ataxia is the most common autosomal recessive form of neurodegenerative ataxia. We present a longitudinal study on the gait pattern of children and adolescents affected by Friedreich's ataxia using Gait Analysis and the Scale for the Assessment and Rating of Ataxia (SARA). We assessed the spectrum of changes over 12 months of the gait characteristics and the relationship between clinical and instrumental evaluations. We enrolled 11 genetically confirmed patients affected by Friedreich's ataxia in this study together with 13 normally developing age-matched subjects. Eight patients completed a 12-month follow-up under the same protocol. By comparing the gait parameters of Friedreich's ataxia with the control group, we found significant differences for some relevant indexes. In particular, the increased knee and ankle extension in stance revealed a peculiar biomechanical pattern, which correlated reliably with SARA Total, Gait and Sitting scores. The knee pattern showed its consistency also at the follow-up: Knee extension increased from 6.8±3.5° to -0.5±3.7° and was significantly correlated with the SARA total score. This feature anticipated the loss of the locomotor function in two patients. In conclusion, our findings demonstrate that the selective and segmental analysis of kinetic/kinematic features of ataxic gait, in particular the behavior of the knee, provides sensitive measures to detect specific longitudinal and functional alterations, more than the SARA scale, which however has proved to be a reliable and practical assessment tool. Functional outcomes measures integrated by instrumental evaluation increase their sensitivity, reliability and suitability for the follow-up of the disease progression and for the application in clinical trials and in rehabilitative programs. PMID:27598307

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

    Directory of Open Access Journals (Sweden)

    Hammond Sue

    2009-03-01

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

  6. Ataxia enzoótica en ciervo rojo (Cervus elaphus en Argentina Enzootic ataxia in red deer (Cervus elaphus in Argentina

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    J P Soler

    2007-01-01

    Full Text Available Se describe un caso de ataxia enzoótica (AE en ciervos rojos en cautiverio ocurrido en Argentina. La AE es una patología de los ciervos que causa parálisis lenta y progresiva de las extremidades posteriores y ha sido asociada a la deficiencia de cobre. Su presentación suele ser a partir de los 9 meses de edad. El problema afectó a dos ciervas rojas con debilidad de los miembros posteriores. Se realizó necropsia a una hembra preñada. Se tomaron muestras de órganos en formol al 10%, de suero y sangre entera. Al feto también se le realizó necropsia y se le tomó una muestra de hígado. A partir de muestras de pasto se determinaron los niveles de Cu, Fe, Zn, Mo y SO4. En el agua se analizaron los valores de sales totales, SO4, Ca, Mg, Na y Cl. La prevalencia de esta enfermedad en el establecimiento fue del 0,14%. Los valores de Cu hepático hallados en la hembra y su feto fueron 14,6 ppm y 337 ppm MS, respectivamente. El nivel de Cu en sangre de la cierva fue de 0,5 μg/ml y el hematocrito de 46%. En mιdula espinal se encontró degeneración mielínica generalizada con pérdida de la vaina de mielina, siendo de mayor severidad en las regiones dorsales de la médula. Se observó también vacuolización de la sustancia blanca sin respuesta inflamatoria. Los niveles hepáticos de Cu en la hembra necropsiada se encontraban por debajo del valor considerado como límite, pero a pesar de esto la cupremia se hallaba dentro del rango de referencia siendo ésta una característica comúnmente observada en los casos de deficiencia de Cu. Los valores de Cu hepático fetal también estaban por debajo del rango considerado como normal. A pesar de que los parámetros medidos en pasto y agua al momento del problema estaban dentro de valores de referencia, es probable que los ciervos hayan estado expuestos previamente a bajos valores de Cu dietario durante un tiempo prolongado, lo cual pudo verse agravado por la gran demanda de Cu que ejerce el

  7. Primary Sjogren’s Syndrome Presented with Sensory Ataxia Associated with Bilateral Hearing Loss and Dementia

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    Madjdinasab Nastaran

    2009-10-01

    Full Text Available Primary Sjorgen syndrome is one of the commonest autoimmune diseases with characteristic of involvement of lachrymal and salivary glands, but other organ involvements as peripheral and central nervous system are also possible. The reported case is a 23 year old lady presented with progressive sensory ataxia and weakness of four limbs, bilateral sensory hearing loss and cognitive impairment with minimental score equal to 15/30 since one year prior to admission with associated bilateral central corneal opacity, dry mouth and dry eyes. Electro physiologic studies showed sensory motor axonal polyneuropathy . A biopsy of sural nerve and salivary glands of lower lip showed lymphocytic infiltration. Serologic evidence showed positive Anti Ro (SS-B, negative HCV and HIV antibody, thereafter the diagnosis was confirmed and according to this diagnosis she received high dose of intravenous methyl prednisolon then both hearing loss and cognitive impairment improved partially (minimental score 21/30 . At last, she underwent plasmapheresis and her sensory ataxia improved greatly.

  8. TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich's Ataxia.

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    Pablo Calap-Quintana

    Full Text Available Friedreich's ataxia (FRDA, the most common inherited ataxia in the Caucasian population, is a multisystemic disease caused by a significant decrease in the frataxin level. To identify genes capable of modifying the severity of the symptoms of frataxin depletion, we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1 signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. Furthermore, rapamycin reduced the altered levels of malondialdehyde + 4-hydroxyalkenals and total glutathione of the model flies. The rapamycin-mediated protection against oxidative stress is due in part to an increase in the transcription of antioxidant genes mediated by cap-n-collar (Drosophila ortholog of Nrf2. Our results suggest that autophagy is indeed necessary for the protective effect of rapamycin in hyperoxia. Rapamycin increased the survival and aconitase activity of model flies subjected to high oxidative insult, and this improvement was abolished by the autophagy inhibitor 3-methyladenine. These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment.

  9. Health-related quality of life in sporadic adult-onset ataxia.

    Science.gov (United States)

    Abele, Michael; Klockgether, Thomas

    2007-02-15

    Despite progressive disability in sporadic adult-onset ataxia (SAOA), little is known about patients' assessment of their ataxic disorder and its impact on health-related quality of life (Hr-QoL). This study investigated Hr-QoL by means of the following self-administered scales: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Beck Depression Inventory (BDI), and the Medical Outcome Study Short Form (SF-36). Twenty-two unselected ataxia patients were included. Sleep-related complaints were found in 9 (41%) of 22 and symptoms of depression in 6 (38%) of 16 patients. Compared to a large german control group, SAOA patients had lower scores in all SF-36 dimensions except for bodily pain. The greatest impairment was found in the domain physical functioning, followed by the domains social functioning and role limitations (emotional problems). There was a significant negative correlation of all nonmotor SF-36 dimensions with the BDI score. Walking aid dependency was significantly correlated with poorer health status perception in several motor and nonmotor domains. In addition, impaired sleep quality was correlated with an impaired general health perception and with bodily pain. The study demonstrates a great impact of SAOA on Hr-QoL. Adequate treatment of depression, motor disability, and impaired sleep quality is essential to improve Hr-QoL in ataxic patients. PMID:17149704

  10. Rehabilitation for a Patient with Hemiplegia, Ataxia, and Cognitive Dysfunction Caused by Pontine Hemorrhage

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    Tetsuya Tsunoda

    2015-10-01

    Full Text Available Patients with pontine hemorrhage usually experience severe disturbances of consciousness, pupillary abnormalities, quadriparesis, and respiratory failure. However, little is known regarding cognitive dysfunction in patients with pontine hemorrhage. We report the case of a rehabilitation patient presenting with hemiplegia, ataxia, and cognitive dysfunction caused by a pontine hemorrhage. A 55-year-old, right-handed male suffered sudden onset of vertigo, dysarthria, and hemiplegia on the right side. He was diagnosed with brain stem hemorrhage, and conservative treatment was administered. The vertigo improved, but dysarthria, ataxia, hemiplegia, and gait disorder persisted. He was disoriented with respect to time and place and showed a poor attention span, impaired executive function, and reduced volition. A computed tomography revealed hematomas across the pons on both sides, but no lesions were obvious in the cerebellum and cerebrum. Single-photon emission tomography showed decreased perfusion in the brain stem, bilateral basal ganglia, and frontal and parietal lobes in the left hemisphere. The patient received exercise therapy and cognitive rehabilitation, and home modifications were performed to allow him to continue living at home under the supervision of his family. His symptoms improved, along with enhanced regional cerebral blood flow to the frontal and temporal lobes. These findings suggest that the pontine hemorrhage caused diaschisis resulting in secondary reduction of activity in the cerebral hemisphere and the occurrence of cortical symptoms. Therefore, rehabilitation is necessary, along with active instructions for the family members of patients with severe neurological deficits.

  11. Ataxia with loss of Purkinje cells in a mouse model for Refsum disease.

    Science.gov (United States)

    Ferdinandusse, Sacha; Zomer, Anna W M; Komen, Jasper C; van den Brink, Christina E; Thanos, Melissa; Hamers, Frank P T; Wanders, Ronald J A; van der Saag, Paul T; Poll-The, Bwee Tien; Brites, Pedro

    2008-11-18

    Refsum disease is caused by a deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal alpha-oxidation system, resulting in the accumulation of the branched-chain fatty acid phytanic acid. The main clinical symptoms are polyneuropathy, cerebellar ataxia, and retinitis pigmentosa. To study the pathogenesis of Refsum disease, we generated and characterized a Phyh knockout mouse. We studied the pathological effects of phytanic acid accumulation in Phyh(-/-) mice fed a diet supplemented with phytol, the precursor of phytanic acid. Phytanic acid accumulation caused a reduction in body weight, hepatic steatosis, and testicular atrophy with loss of spermatogonia. Phenotype assessment using the SHIRPA protocol and subsequent automated gait analysis using the CatWalk system revealed unsteady gait with strongly reduced paw print area for both fore- and hindpaws and reduced base of support for the hindpaws. Histochemical analyses in the CNS showed astrocytosis and up-regulation of calcium-binding proteins. In addition, a loss of Purkinje cells in the cerebellum was observed. No demyelination was present in the CNS. Motor nerve conduction velocity measurements revealed a peripheral neuropathy. Our results show that, in the mouse, high phytanic acid levels cause a peripheral neuropathy and ataxia with loss of Purkinje cells. These findings provide important insights in the pathophysiology of Refsum disease.

  12. Hereditary cerebellar ataxia progressively impairs force adaptation during goal-directed arm movements.

    Science.gov (United States)

    Maschke, Matthias; Gomez, Christopher M; Ebner, Timothy J; Konczak, Jürgen

    2004-01-01

    We investigated how humans with hereditary cerebellar degeneration [spinocerebellar ataxia (SCA) type 6 and 8, n = 9] and age- and sex-matched healthy controls (n = 9) adapted goal-directed arm movements to an unknown external force field. We tested whether learning could be generalized to untrained regions in the workspace, an aspect central to the idea of an internal model, and if any learning could be retained. After removal of the force field, SCA patients showed little or no learning-related aftereffects indicating that repeated force-field exposure never led to successful force compensation. In contrast, healthy control subjects quickly adapted their movements to the new force field. The difference in force adaptation was significant for movements to targets that required both the shoulder and elbow joint (P < 0.001). Moreover, the generalization of learned movements to targets outside the learned workspace was prevented by the cerebellar degeneration (P < 0.01). Retention of force adaptation was significantly lower in SCA patients (P = 0.003). The severity of ataxia in SCA patients correlated negatively with the extent of learning (r = -0.84, P = 0.004). Our findings imply that progressive loss of cerebellar function gradually impairs force adaptation. The failure to generalize learning suggests that cerebellar degeneration prevents the formation of an internal representation of the limb dynamics. PMID:13679403

  13. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Motor Dysfunction Modeled in Mice.

    Science.gov (United States)

    Foote, Molly; Arque, Gloria; Berman, Robert F; Santos, Mónica

    2016-10-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some carriers of the fragile X premutation (PM). In PM carriers, there is a moderate expansion of a CGG trinucleotide sequence (55-200 repeats) in the fragile X gene (FMR1) leading to increased FMR1 mRNA and small to moderate decreases in the fragile X mental retardation protein (FMRP) expression. The key symptoms of FXTAS include cerebellar gait ataxia, kinetic tremor, sensorimotor deficits, neuropsychiatric changes, and dementia. While the specific trigger(s) that causes PM carriers to progress to FXTAS pathogenesis remains elusive, the use of animal models has shed light on the underlying neurobiology of the altered pathways involved in disease development. In this review, we examine the current use of mouse models to study PM and FXTAS, focusing on recent advances in the field. Specifically, we will discuss the construct, face, and predictive validities of these PM mouse models, the insights into the underlying disease mechanisms, and potential treatments.

  14. Double Disassociation of Anosognosia for Alexia and Simultanagnosia but Quantitative Awareness of Optic Ataxia.

    Science.gov (United States)

    Williams, Reed C; Patira, Riddhi; Altschuler, Eric L

    2016-03-01

    A 66-yr-old man with a history of atrial fibrillation and a pacemaker developed sudden onset confusion, disorientation, and visual disturbance without motor weakness. Clinically, significant deficits were found in reading (alexia) and simultaneous multiobject perception (simultanagnosia), both of which the patient denied limitation in, and in vision-right hemianopsia-which he readily acknowledged. Visual acuity in the left visual field was normal. The patient also demonstrated a symptom of optic ataxia-a lack of coordination between visual inputs and hand movements-a deficit he also acknowledged. Work-up with computed topography revealed a left posterior cerebral artery infarct affecting the occipital lobe and extending to involve the parietal lobe and the splenium of the corpus callosum. The authors describe and discuss this fascinating case-the first case to their knowledge of a double disassociation of anosognosia for alexia and simultanagnosia but full, indeed quantitative, awareness of hemianopsia and optic ataxia. This case may be informative on the mechanism of anosognosia in general and supports intentional feed-forward and exemplar reafference models. With regard to the rehabilitation process, appreciation that a patient has anosognosia for various deficits is crucial in recovery and health maintenance. PMID:26368835

  15. Recent Advancements in Targeted Delivery of Therapeutic Molecules in Neurodegenerative Disease - Spinocerebellar Ataxia - Opportunities and Challenges

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    Satya Prakash

    2008-01-01

    Full Text Available Drug discovery and its methodologies have been very effective in terms of treating cancers and immunological disorders but have not been able to stop genetic diseases as most of the drugs target at the protein level. They merely mitigate the symptoms of the disease. Spinocerebellar ataxia is a neurological genetic disorder that is caused by the formation of an abnormal protein. There have been several reports on ataxic drug development but actual clinical treatment is yet to be achieved. Oligonucleotide therapy called sequence specific siRNA mediated gene silencing has evolved with promising results. This approach emphasizes on suppressing the expression of the diseased gene at mRNA level. However, there is a limitation in delivery of siRNA to the target site. Several methods have been developed over the last decade to enhance the target specific delivery of DNA, siRNA, protein and small drug molecules for therapeutic purpose with less or no side effects. This review discusses the latest upcoming technologies in the field that focus on a number of nonviral nanocarriers for targeted delivery. In this review, we explore the promise and potential of novel therapeutics with interest on ataxia therapy.

  16. POINT MUTATIONS ON MITOCHONDRIAL DNA IN IRANIAN PATIENTS WITH FRIEDREICH’S ATAXIA

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    S. Etemad Ahari

    2007-11-01

    Full Text Available ObjectiveMitochondrial DNA (mtDNA is considered a candidate modifier factor for neuro-degenerative disorders. The most common type of ataxia is Friedreich’s ataxia (FA. The aim of this study was to investigate different parts of mtDNA in 20 Iranian FA patients and 80 age-matched controls by polymerase chain reaction (PCR and automated DNA sequencing methods to find any probable point mutations involved in the pathogenesis of FA. Materials and MethodsWe identified 13 nucleotide substitutions including A3505G, T3335C, G3421A, G8251A, A8563G, A8563G, G8584A, T8614C, T8598C, C8684T, A8701G, G8994A and A9024G. ResultsTwelve of 13 nucleotide substitutions had already been reported as polymorphism. One of the nucleotide substitutions (A9024G had not been reported before. The A9024G nucleotide substitution does not change its amino acid. The controls were also investigated for this polymorphism which was found in two of them (2.5%. ConclusionNone of the mutations found in this study can affect the clinical manifestations of FA. This survey also provides evidence that the mtDNA A9024G allele is a new nonpathogenic polymorphism. We suggest follow-up studies for this polymorphism in different populations.

  17. Advancements in the pathophysiology of Friedreich's Ataxia and new prospects for treatments.

    Science.gov (United States)

    Babady, Ngolela E; Carelle, Nadege; Wells, Robert D; Rouault, Tracey A; Hirano, Michio; Lynch, David R; Delatycki, Martin B; Wilson, Robert B; Isaya, Grazia; Puccio, Hélène

    2007-01-01

    On November 9-12, 2006, the Friedreich's Ataxia Research Alliance (FARA) and the National Institutes of Health (NIH) hosted the Third International Friedreich's Ataxia (FRDA) Scientific Conference at the NIH in Bethesda, Maryland, highlighting the exciting research leading now to a variety of clinical trials that show promise of effective treatments for this devastating disorder. Nearly 150 leading FRDA scientists from around the world discussed their new insights and findings. The presence of six pharmaceutical and biotechnology companies underscored the importance of the public-private partnership that has grown in the past years. Some of these companies are already involved in advancing promising drug compounds into clinical trials, while others are eager to help take newer discoveries through drug development and into subsequent clinical trials. National Institute of Neurological Disorders and Stroke (NINDS) Director Dr. Story Landis noted in her opening remarks for the conference that there was a "palpable sense of energy, excitement, and enthusiasm" over the scientific progress made since the FRDA gene was discovered over 10 years ago.

  18. White matter changes in patients with Friedreich ataxia after treatment with erythropoietin

    Science.gov (United States)

    Egger, Karl; Clemm von Hohenberg, Christian; Schocke, Michael F; Guttmann, Charles RG; Wassermann, Demian; Wigand, Marlene C; Nachbauer, Wolfgang; Kremser, Christian; Sturm, Brigitte; Scheiber-Mojdehkar, Barbara; Kubicki, Marek; Shenton, Martha E; Boesch, Sylvia

    2013-01-01

    Background and Purpose Erythropoietin (EPO) has received growing attention because of its neuro-regenerative properties. Preclinical and clinical evidence supports its therapeutic potential in brain conditions like stroke, multiple sclerosis and schizophrenia. Also in Friedreich ataxia, clinical improvement after EPO therapy was shown. The aim of the present study was to assess possible therapy-associated brain white-matter changes in these patients. Methods Nine patients with Friedreich ataxia underwent Diffusion Tensor Imaging (DTI) before and after EPO treatment. Tract-based spatial statistics (TBSS) was used for longitudinal comparison. Results We detected widespread longitudinal increase in fractional anisotropy (FA) and axial diffusivity (D||) in cerebral hemispheres bilaterally (p<0.05, corrected), while no changes were observed within the cerebellum, medulla oblongata and pons. Conclusions To the best of our knowledge, this is the first DTI study to investigate the effects of erythropoietin in a neurodegenerative disease. Anatomically, the diffusivity changes appear disease-unspecific, and their biological underpinnings deserve further study. PMID:24015771

  19. Motor Training in Degenerative Spinocerebellar Disease: Ataxia-Specific Improvements by Intensive Physiotherapy and Exergames

    Science.gov (United States)

    2014-01-01

    The cerebellum is essentially involved in movement control and plays a critical role in motor learning. It has remained controversial whether patients with degenerative cerebellar disease benefit from high-intensity coordinative training. Moreover, it remains unclear by which training methods and mechanisms these patients might improve their motor performance. Here, we review evidence from different high-intensity training studies in patients with degenerative spinocerebellar disease. These studies demonstrate that high-intensity coordinative training might lead to a significant benefit in patients with degenerative ataxia. This training might be based either on physiotherapy or on whole-body controlled videogames (“exergames”). The benefit shown in these studies is equal to regaining one or more years of natural disease progression. In addition, first case studies indicate that even subjects with advanced neurodegeneration might benefit from such training programs. For both types of training, the observed clinical improvements are paralleled by recoveries in ataxia-specific dysfunctions (e.g., multijoint coordination and dynamic stability). Importantly, for both types of training, the retention of the effects seems to depend on the frequency and continuity of training. Based on these studies, we here present preliminary recommendations for clinical practice, and articulate open questions that might guide future studies on neurorehabilitation in degenerative spinocerebellar disease. PMID:24877117

  20. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Motor Dysfunction Modeled in Mice.

    Science.gov (United States)

    Foote, Molly; Arque, Gloria; Berman, Robert F; Santos, Mónica

    2016-10-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects some carriers of the fragile X premutation (PM). In PM carriers, there is a moderate expansion of a CGG trinucleotide sequence (55-200 repeats) in the fragile X gene (FMR1) leading to increased FMR1 mRNA and small to moderate decreases in the fragile X mental retardation protein (FMRP) expression. The key symptoms of FXTAS include cerebellar gait ataxia, kinetic tremor, sensorimotor deficits, neuropsychiatric changes, and dementia. While the specific trigger(s) that causes PM carriers to progress to FXTAS pathogenesis remains elusive, the use of animal models has shed light on the underlying neurobiology of the altered pathways involved in disease development. In this review, we examine the current use of mouse models to study PM and FXTAS, focusing on recent advances in the field. Specifically, we will discuss the construct, face, and predictive validities of these PM mouse models, the insights into the underlying disease mechanisms, and potential treatments. PMID:27255703

  1. Clinical and genetic study of a Chinese family with spinocerebellar ataxia type 7

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    Han Yan

    2010-01-01

    Full Text Available Spinocerebellar ataxia 7 (SCA7 is a rare disease, and only few SCA7 families have been reported, especially from East Asia. Clinical features of a genetically confirmed SCA7 Chinese family were evaluated. The onset of the disease varied from 4 years to 48 years, and the initial presenting feature was cerebellar ataxia or visual impairment, or both. There were abnormal findings on fundus photography, electroretinogram, flash visual evoked potential and oscillatory potentials. Abnormal mitochondria were also found in skeletal muscle or liver biopsies. The number of cytosine adenine guanine (CAG repeats ranged from 50 to 97, and the length of CAG repeat was inversely correlated with the age of onset (r=-0.867, P=0.025. Conclusion: The clinical manifestations and SCA7 gene of SCA7 patients were homogeneous in this study. Larger CAG repeats had not only resulted in earlier onset, but also related to the rapid progression and severity of the disease. Abnormal mitochondria may be a common finding in biopsy studies of various organs in SCA7 patients.

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

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    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.

  3. Motor Training in Degenerative Spinocerebellar Disease: Ataxia-Specific Improvements by Intensive Physiotherapy and Exergames

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    Matthis Synofzik

    2014-01-01

    Full Text Available The cerebellum is essentially involved in movement control and plays a critical role in motor learning. It has remained controversial whether patients with degenerative cerebellar disease benefit from high-intensity coordinative training. Moreover, it remains unclear by which training methods and mechanisms these patients might improve their motor performance. Here, we review evidence from different high-intensity training studies in patients with degenerative spinocerebellar disease. These studies demonstrate that high-intensity coordinative training might lead to a significant benefit in patients with degenerative ataxia. This training might be based either on physiotherapy or on whole-body controlled videogames (“exergames”. The benefit shown in these studies is equal to regaining one or more years of natural disease progression. In addition, first case studies indicate that even subjects with advanced neurodegeneration might benefit from such training programs. For both types of training, the observed clinical improvements are paralleled by recoveries in ataxia-specific dysfunctions (e.g., multijoint coordination and dynamic stability. Importantly, for both types of training, the retention of the effects seems to depend on the frequency and continuity of training. Based on these studies, we here present preliminary recommendations for clinical practice, and articulate open questions that might guide future studies on neurorehabilitation in degenerative spinocerebellar disease.

  4. Motor training in degenerative spinocerebellar disease: ataxia-specific improvements by intensive physiotherapy and exergames.

    Science.gov (United States)

    Synofzik, Matthis; Ilg, Winfried

    2014-01-01

    The cerebellum is essentially involved in movement control and plays a critical role in motor learning. It has remained controversial whether patients with degenerative cerebellar disease benefit from high-intensity coordinative training. Moreover, it remains unclear by which training methods and mechanisms these patients might improve their motor performance. Here, we review evidence from different high-intensity training studies in patients with degenerative spinocerebellar disease. These studies demonstrate that high-intensity coordinative training might lead to a significant benefit in patients with degenerative ataxia. This training might be based either on physiotherapy or on whole-body controlled videogames ("exergames"). The benefit shown in these studies is equal to regaining one or more years of natural disease progression. In addition, first case studies indicate that even subjects with advanced neurodegeneration might benefit from such training programs. For both types of training, the observed clinical improvements are paralleled by recoveries in ataxia-specific dysfunctions (e.g., multijoint coordination and dynamic stability). Importantly, for both types of training, the retention of the effects seems to depend on the frequency and continuity of training. Based on these studies, we here present preliminary recommendations for clinical practice, and articulate open questions that might guide future studies on neurorehabilitation in degenerative spinocerebellar disease. PMID:24877117

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

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    Vahid Ezzatizadeh

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

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

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    Mohammad Mehdi Heidari

    2011-05-01

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

  7. Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity.

    Science.gov (United States)

    Stefely, Jonathan A; Licitra, Floriana; Laredj, Leila; Reidenbach, Andrew G; Kemmerer, Zachary A; Grangeray, Anais; Jaeg-Ehret, Tiphaine; Minogue, Catherine E; Ulbrich, Arne; Hutchins, Paul D; Wilkerson, Emily M; Ruan, Zheng; Aydin, Deniz; Hebert, Alexander S; Guo, Xiao; Freiberger, Elyse C; Reutenauer, Laurence; Jochem, Adam; Chergova, Maya; Johnson, Isabel E; Lohman, Danielle C; Rush, Matthew J P; Kwiecien, Nicholas W; Singh, Pankaj K; Schlagowski, Anna I; Floyd, Brendan J; Forsman, Ulrika; Sindelar, Pavel J; Westphall, Michael S; Pierrel, Fabien; Zoll, Joffrey; Dal Peraro, Matteo; Kannan, Natarajan; Bingman, Craig A; Coon, Joshua J; Isope, Philippe; Puccio, Hélène; Pagliarini, David J

    2016-08-18

    The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease. PMID:27499294

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

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    Maryam Rahimi Balaei

    2016-01-01

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

  9. 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.

  10. Ancestral origin of the ATTCT repeat expansion in spinocerebellar ataxia type 10 (SCA10.

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    Teresa Almeida

    Full Text Available Spinocerebellar ataxia type 10 (SCA10 is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia and seizures. The disease is caused by a large ATTCT repeat expansion in the ATXN10 gene. The first families reported with SCA10 were of Mexican origin, but the disease was soon after described in Brazilian families of mixed Portuguese and Amerindian ancestry. The origin of the SCA10 expansion and a possible founder effect that would account for its geographical distribution have been the source of speculation over the last years. To unravel the mutational origin and spread of the SCA10 expansion, we performed an extensive haplotype study, using closely linked STR markers and intragenic SNPs, in families from Brazil and Mexico. Our results showed (1 a shared disease haplotype for all Brazilian and one of the Mexican families, and (2 closely-related haplotypes for the additional SCA10 Mexican families; (3 little or null genetic distance in small normal alleles of different repeat sizes, from the same SNP lineage, indicating that they are being originated by a single step mechanism; and (4 a shared haplotype for pure and interrupted expanded alleles, pointing to a gene conversion model for its generation. In conclusion, we show evidence for an ancestral common origin for SCA10 in Latin America, which might have arisen in an ancestral Amerindian population and later have been spread into the mixed populations of Mexico and Brazil.

  11. Ataxia with Parkinsonism and dystonia after intentional inhalation of liquefied petroleum gas

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    Godani M

    2015-05-01

    Full Text Available Massimiliano Godani,1 Francesca Canavese,1 Sonia Migliorini,2 Massimo Del Sette1 1Neurology Unit, 2Department of Neuroradiology, Sant’Andrea Hospital, La Spezia, Italy Abstract: The practice of inhaling liquefied petroleum gas (LPG to commit suicide is uncommon and almost exclusively a prerogative of the prison population. Numerous cases of sudden deaths caused by intentional propane and/or butane inhalation have been described, but these cases survived and a description of the consequences is very rare. We describe a prisoner who survived after voluntary inhalation of LPG, and who developed ataxia, Parkinsonism, and dystonia. Brain MRI showed bilateral hyperintensity in the basal ganglia and in the cerebellar hemispheres. The clinical evolution and the MRI abnormalities are similar to those described in cases of poisoning by CO where the mechanism of brain injury is related to histotoxic hypoxia. We believe that LPG, considered until now a mixture of gas with low neurotoxic power, may have caused direct toxic damage to the brain, mediated by a mechanism of hypoxia, such as in CO intoxication. Keywords: ataxia, Parkinsonism, dystonia, liquefied petroleum gas

  12. 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.

  13. Fragile X-associated tremor/ataxia syndrome - features, mechanisms and management.

    Science.gov (United States)

    Hagerman, Randi J; Hagerman, Paul

    2016-07-01

    Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene that consists of 55-200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150-300 females, and 1 in 400-850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers. PMID:27340021

  14. Ataxia espinocerebelosa 7: Investigación clínica y genética en una familia argentina Spinocerebellar ataxia 7: Clinical and genetic investigation in an Argentine family

    Directory of Open Access Journals (Sweden)

    Juan I. Rojas

    2007-04-01

    Full Text Available Las ataxias espino cerebelosas (AEC, constituyen un grupo de trastornos hereditarios neurodegenerativos de herencia autosómica dominante. Se caracterizan principalmente por la presencia clínica de ataxia cerebelosa asociada a oftalmoplejía, disartria, signos piramidales o extrapiramidales y pérdida de la sensibilidad profunda. La AEC 7 pertenece al grupo de las ataxias espinocerebelosas en la cual el trastorno es consecuencia de la expansión del triplete CAG localizado en el cromosoma 3 p12-p21. La característica clínica de dicha ataxia es la pérdida de la agudeza visual y posterior ceguera. Presentamos tres individuos de una familia con ataxia cerebelosa, pérdida de la agudeza visual y otros signos neurológicos. El diagnóstico fue confirmado por medio del análisis genético en el cual se observó la anormalidad característica de la AEC 7. Este es el primer caso de AEC 7 en Argentina confirmado por estudio genético. En la revisión de la literatura (hasta enero 2006 se hallaron sólo dos familias notificadas en América Latina. El objetivo del trabajo es el de enfocar la atención en el diagnóstico de esta enfermedad degenerativa en pacientes que se presentan con ataxia cerebelosa progresiva asociada con disminución de la agudeza visual e historia familiar positiva.Spino cerebellar ataxia (SCA are a complex group of hereditary neurodegenerative disturbances of autosomal dominant pattern. They are largely characterized by the clinical presence of cerebellar ataxia related to ophtalmoplegia, dysarthria, pyramidal and extra-pyramidal signs and loss of deep sensitivity. SCA 7 belongs to the SCA group in which the disturbance is a result of the expansion of CAG triplet repetition located in the 3p12-p21 chromosome. The characteristic clinical feature of SCA7 is the loss of visual acuity and blindness. We present here three cases of ataxia, from the same family, with loss of visual acuity and other neurological disorders. The diagnosis

  15. 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...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

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    Yubin Wang

    2016-06-01

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

  18. Defects in the CAPN1 gene result in alterations in cerebellar development and in cerebellar ataxia in mice and humans

    Science.gov (United States)

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

    2016-01-01

    SUMMARY A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous CAPN1 null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knock-out (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1 mediated cleavage of PH domain and Leucine rich repeat Protein Phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis, and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans. PMID:27320912

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

    Science.gov (United States)

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

    2014-01-01

    PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher–Neuhäuser syndrome. Boucher–Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher–Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher–Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient’s genomic DNA from coding exons 26–29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher–Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases. PMID:25267340

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

    Science.gov (United States)

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

    2014-12-01

    PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases. PMID:25267340

  1. Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23

    NARCIS (Netherlands)

    Watanabe, Hiroyuki; Mizoguchi, Hirokazu; Verbeek, Dineke S.; Kuzmin, Alexander; Nyberg, Fred; Krishtal, Oleg; Sakurada, Shinobu; Bakalkin, Georgy

    2012-01-01

    We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu(5), Arg(6), and Arg(9) to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1-17) (Dyn A), a peptide with both

  2. Kinematic Analysis of Lingual Movements during Consonant Productions in Dysarthric Speakers with Friedreich's Ataxia: A Case-by-Case Analysis

    Science.gov (United States)

    Folker, Joanne E.; Murdoch, Bruce E.; Cahill, Louise M.; Delatycki, Martin B.; Corben, Louise A.; Vogel, Adam P.

    2011-01-01

    Articulatory kinematics were investigated using electromagnetic articulography (EMA) in four dysarthric speakers with Friedreich's ataxia (FRDA). Specifically, tongue-tip and tongue-back movements were recorded by the AG-200 EMA system during production of the consonants t and k as produced within a sentence utterance and during a rapid syllable…

  3. Ataxia Telangiectasia

    Science.gov (United States)

    ... the first decade of life. Telangiectasias (tiny, red "spider" veins), which appear in the corners of the ... States? An estimated 1 percent of the U.S. population, or about 2.5 million people, may be ...

  4. Ataxia - telangiectasia

    Science.gov (United States)

    Couples with a family history of this condition who are considering pregnancy may consider genetic counseling. Parents of a child with this disorder may have a slight increased risk for cancer. They ...

  5. 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.

  6. Clinical and genetic study of spinocerebellar ataxia type 7 in East Asian population

    Institute of Scientific and Technical Information of China (English)

    HAN Yan; YU Long; ZHENG Hui-min; GUAN Yang-tai

    2010-01-01

    Background Spinocerebellar ataxia type 7 (SCA7) is known as an autosomal dominant cerebellar ataxia; patients with genetically confirmed diagnoses of SCA7 have increased rapidly in recent years.However, SCA7 is a rare subtype of SCA, and most data available about SCA7 are those of white people.The aim of the present study was to systematically review the prevalence and clinical and genetic aspects of SCA7 patients in East Asian population.Methods A search for publications on SCA7 was performed by using the "PubMed" database with the published language limited in English.Publications mainly focusing on the prevalence of SCA7 in patients with SCA and the clinical and genetic features of SCA7 patients were fully reviewed and analyzed.Results The prevalence of SCA7 in SCA patients ranged from 0 to 7.7%, which was similar to those reported previously.The clinical manifestations were typically present at the 30's of its victims (median, 29 years; interquartile range (IQR),19.5-36.5 years), and the symptoms appeared 15 years ((15.17±4.22) years) earlier on average in the offspring than in the parents.Gait ataxia and visual impairment were both found in all patients of whom the clinical features were described.Mutant SCA7 alleles contained 40-100 CAG repeats, with a median of 47 repeats (IQR, 44.5-50.0); and the offspring had 13 more repeats on average compared with their parents (12.62±19.03).A strong negative correlation was found between CAG repeat size and the onset age of patients (r=-0.739, P=0.000).In addition, no significant difference was found in CAG repeat sizes between patients with visual impairment as the initial symptom and those with gait disturbance as their initial symptom (P=0.476).Conclusions The prevalence of SCA7 in SCA patients, the age at onset and CAG repeats of SCA7 patients in East Asia are consistent with those of white people.However, larger population study is needed to assess the correlation between the CAG repeat size and initial symptoms

  7. Walk on Floor Eyes Closed Test: A Unique Test of Spaceflight Induced Ataxia

    Science.gov (United States)

    Reschke, M. F.; Fisher, E. A.; Kofman, I. S.; Cerisano, J. M.; Harm, D. L.; Bloomberg, J. J.

    2011-01-01

    Measurement and quantification of posture and locomotion following spaceflight is an evolving process. Based on the data obtained from the current investigation we believe that the walk on the floor line test with the eyes closed (WOFEC) provides a unique procedure for quantifying postflight ataxia. As a part of an ongoing investigation designed to look at functional changes in astronauts returning from spaceflight seven astronauts (5 short duration with flights of 12-16 days; 2 long duration crewmembers with flights of 6 months) were tested twice before flight, on landing day (short duration only), and 1, 6, and 30 days after flight. The WOFEC consisted of walking for 10 steps (repeated twice) with the feet heel to toe in tandem, arms folded across the chest and the eyes closed. The performance metric (scored by three examiners from video) was the percentage of correct steps completed over the three trials. A step was not counted as correct if the crewmember side-stepped, opened their eyes, or paused for more than three seconds between steps. The data reveled a significant decrease in percentage of correct steps on landing day (short duration crew) and on the first day following landing (long duration) with partial recovery the following day, and full recovery beginning on day sixth after flight. Both short and long duration fliers appeared to be unaware of foot position relative to their bodies or the floor. Postflight, deviation from a straight path was common, and seemed to be determined by the angle of foot placement relative to their body. While deviation from a straight line could be either left or right, primary deviations were observed to occur to the right. Furthermore, the test for two crewmembers elicited motion sickness symptoms. These data clearly demonstrate the sensorimotor challenges facing crewmembers after returning from spaceflight. The WOFEC test has value providing the investigator or crew surgeon with a simple method to quantify vestibular

  8. Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families.

    Science.gov (United States)

    Welshimer, K; Swift, M

    1982-09-01

    Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes. To test this hypothesis, medical records, death certificates, and questionnaires from 27 A-T families, 25 FA families, and 31 XP families were reviewed. Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retardation, a significant excess compared to the FA and A-T families (3/1,439). There were four microcephalic XP blood relatives and none in the FA or A-T families. In the A-T families, idiopathic scoliosis and vertebral anomalies were in excess, while genitourinary and distal limb malformations were found in the FA families. A-T, FA, or XP heterozygotes may constitute an important proportion of individuals at risk for specific malformations or developmental abnormalities. PMID:7124732

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

    Directory of Open Access Journals (Sweden)

    Fatma Deniz Aygün

    2015-01-01

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

  10. Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia

    DEFF Research Database (Denmark)

    Minocherhomji, Sheroy; Hansen, Claus; Kim, Hyung-Goo;

    2014-01-01

    Genome instability, epigenetic remodelling and structural chromosomal rearrangements are hallmarks of cancer. However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood....... To understand the genetic-epigenetic interplay at breakpoints of chromosomal translocations disrupting CG-rich loci, we quantified epigenetic modifications at DLGAP4 (SAPAP4), a key post-synaptic density 95 (PSD95) associated gene, truncated by the chromosome translocation t(8;20)(p12;q11.23), co......-segregating with cerebellar ataxia in a five-generation family. We report significant epigenetic remodelling of the DLGAP4 locus triggered by the t(8;20)(p12;q11.23) translocation and leading to dysregulation of DLGAP4 expression in affected carriers. Disruption of DLGAP4 results in monoallelic hypermethylation...

  11. Recently emerging signaling landscape of ataxia-telangiectasia mutated (ATM) kinase.

    Science.gov (United States)

    Farooqi, Ammad Ahmad; Attar, Rukset; Arslan, Belkis Atasever; Romero, Mirna Azalea; ul Haq, Muhammad Fahim; Qadir, Muhammad Imran

    2014-01-01

    Research over the years has progressively and sequentially provided near complete resolution of regulators of the DNA repair pathways which are so important for cancer prevention. Ataxia-telangiectasia mutated kinase (ATM), a high-molecular-weight PI3K-family kinase has emerged as a master regulator of DNA damage signaling and extensive cross-talk between ATM and downstream proteins forms an interlaced signaling network. There is rapidly growing scientific evidence emphasizing newly emerging paradigms in ATM biology. In this review, we provide latest information regarding how oxidative stress induced activation of ATM can be utilized as a therapeutic target in different cancer cell lines and in xenografted mice. Moreover, crosstalk between autophagy and ATM is also discussed with focus on how autophagy inhibition induces apoptosis in cancer cells. PMID:25169474

  12. The preterm pig as a model of premature infant gait ataxia

    DEFF Research Database (Denmark)

    Bergström, A.; Ryom, K.; Vanden Hole, C.;

    Aims/background Compromised gait, balance and motor coordination (ataxia) as observed in cases of cerebral palsy is a serious complication to premature birth. The cerebellum is a central region with regards to these brain functions and its development shows high sensitivity to premature birth. Our...... group has over many years refined a pig model of premature birth focusing on gut and immune system development. Phenotypically, we have observed distinct motoric problems e.g. falls, tiptoe walking and swaying in preterm pigs relative to term born counterparts, indicating compromised brain function....... The aim of this study was to compare gait patterns and cerebellar neurodevelopmental gene expression of preterm and term piglets. Methods We compared gait patterns and T-maze performance of caesarean born preterm (3 litters, 90% gestation) and term born pigs (1 litter, 100% gestation) recorded at five...

  13. Possible role of chromatin alteration in the radiosensitivity of ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Hittelman, W.N. [Anderson (M.D.) Cancer Center, Houston, TX (United States); Pandita, T.K. [Columbia Univ., New York, NY (United States). Dept. of Radiation Oncology

    1994-12-01

    Cells derived from individuals with ataxia-telangiectasia (A-T) are known to exhibit increased sensitivity to ionizing radiation and certain radiomimetic chemical agents. Here we summarize our findings regarding the role of chromosome damage and repair in this radiosensitivity. Lymphoblastoid cells derived from A-T homozygotes were characterized for initial chromosome (premature chromosome condensation) and DNA (neutral filter elution) damage and repair kinetics in cells from G1 and G2 cell cycle phases. Despite initial levels of DNA damage being similar to normal controls, A-T cells exhibited nearly a two-fold higher initial amount of chromosome damage. Different A-T cell lines exhibited differing chromosome repair capacities compared with control lymphoblastoid cell lines. These results suggest that A-T cells have an altered chromatin structure whereby DNA double-strand breaks are apparently more efficiently converted into chromosome breaks. (author).

  14. Possible role of chromatin alteration in the radiosensitivity of ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Cells derived from individuals with ataxia-telangiectasia (A-T) are known to exhibit increased sensitivity to ionizing radiation and certain radiomimetic chemical agents. Here we summarize our findings regarding the role of chromosome damage and repair in this radiosensitivity. Lymphoblastoid cells derived from A-T homozygotes were characterized for initial chromosome (premature chromosome condensation) and DNA (neutral filter elution) damage and repair kinetics in cells from G1 and G2 cell cycle phases. Despite initial levels of DNA damage being similar to normal controls, A-T cells exhibited nearly a two-fold higher initial amount of chromosome damage. Different A-T cell lines exhibited differing chromosome repair capacities compared with control lymphoblastoid cell lines. These results suggest that A-T cells have an altered chromatin structure whereby DNA double-strand breaks are apparently more efficiently converted into chromosome breaks. (author)

  15. Early molecular events in the pathology of Machado-Joseph's disease or Spinocerebellar ataxia type 3

    OpenAIRE

    Tomé, Ricardo Jorge Ladeiro

    2012-01-01

    Desde a descrição inicial da doença de Machado-Joseph (MJD) ou Ataxia espinocerebelosa tipo 3 (SCA3) muitos foram os avanços, tanto no acumular de conhecimento como na compreensão dos mecanismos inerentes à doença. O gene afectado no estado patológico é transcrito em múltiplas variantes de ARN mensageiro, diferindo entre si no splicing alternativo de exões, recentemente descritas como tendo uma distribuição heterogénea nos vários tipos celulares humanos. O padrão de expressão destes ARN foi r...

  16. 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).

  17. A rare midbrain infarction presenting with plus-minus lid syndrome with ataxia: a case report

    Directory of Open Access Journals (Sweden)

    Sattin Justin A

    2011-10-01

    Full Text Available Abstract Introduction We present the case of a patient with midbrain infarction with an unusual clinical presentation, where clinical diagnosis and anatomical localization were valuable tools in deciding treatment. Case presentation Our patient was a 59-year-old, right-handed Caucasian man with hypertension who presented to our facility with acute diplopia that persisted until he developed complete right-sided ptosis. He also had difficulty walking and coordinating movements of his upper extremities bilaterally, but this was worse on his left side. Conclusions Plus-minus lid syndrome with ataxia is a rare presentation of midbrain infarction with a unique localization and anatomical description. This case highlights the importance of clinical skills for making a diagnosis in the absence of imaging to confirm the findings.

  18. 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).

  19. Lower limb antagonist muscle co-activation and its relationship with gait parameters in cerebellar ataxia.

    Science.gov (United States)

    Mari, Silvia; Serrao, Mariano; Casali, Carlo; Conte, Carmela; Martino, Giovanni; Ranavolo, Alberto; Coppola, Gianluca; Draicchio, Francesco; Padua, Luca; Sandrini, Giorgio; Pierelli, Francesco

    2014-04-01

    Increased antagonist muscle co-activation, seen in motor-impaired individuals, is an attempt by the neuromuscular system to provide mechanical stability by stiffening joints. The aim of this study was to investigate the co-activation pattern of the antagonist muscles of the ankle and knee joints during walking in patients with cerebellar ataxia, a neurological disease that strongly affects stability. Kinematic and electromyographic parameters of gait were recorded in 17 patients and 17 controls. Ankle and knee antagonist muscle co-activation indexes were measured throughout the gait cycle and during the sub-phases of gait. The indexes of ataxic patients were compared with those of controls and correlated with clinical and gait variables. Patients showed increased co-activity indexes of both ankle and knee muscles during the gait cycle as well as during the gait sub-phases. Both knee and ankle muscle co-activation indexes were positively correlated with disease severity, while ankle muscle co-activation was also positively correlated with stance and swing duration variability. Significant negative correlations were observed between the number of self-reported falls per year and knee muscle co-activation. The increased co-activation observed in these cerebellar ataxia patients may represent a compensatory strategy serving to reduce gait instability. Indeed, this mechanism allows patients to reduce the occurrence of falls. The need for this strategy, which results in excessive muscle co-contraction, increased metabolic costs and cartilage degeneration processes, could conceivably be overcome through the use of supportive braces specially designed to provide greater joint stability.

  20. Expression of Caytaxin protein in Cayman Ataxia mouse models correlates with phenotype severity.

    Directory of Open Access Journals (Sweden)

    Kristine M Sikora

    Full Text Available Caytaxin is a highly-conserved protein, which is encoded by the Atcay/ATCAY gene. Mutations in Atcay/ATCAY have been identified as causative of cerebellar disorders such as the rare hereditary disease Cayman ataxia in humans, generalized dystonia in the dystonic (dt rat, and marked motor defects in three ataxic mouse lines. While several lines of evidence suggest that Caytaxin plays a critical role in maintaining nervous system processes, the physiological function of Caytaxin has not been fully characterized. In the study presented here, we generated novel specific monoclonal antibodies against full-length Caytaxin to examine endogenous Caytaxin expression in wild type and Atcay mutant mouse lines. Caytaxin protein is absent from brain tissues in the two severely ataxic Atcay(jit (jittery and Atcay(swd (sidewinder mutant lines, and markedly decreased in the mildly ataxic/dystonic Atcay(ji-hes (hesitant line, indicating a correlation between Caytaxin expression and disease severity. As the expression of wild type human Caytaxin in mutant sidewinder and jittery mice rescues the ataxic phenotype, Caytaxin's physiological function appears to be conserved between the human and mouse orthologs. Across multiple species and in several neuronal cell lines Caytaxin is expressed as several protein isoforms, the two largest of which are caused by the usage of conserved methionine translation start sites. The work described in this manuscript presents an initial characterization of the Caytaxin protein and its expression in wild type and several mutant mouse models. Utilizing these animal models of human Cayman Ataxia will now allow an in-depth analysis to elucidate Caytaxin's role in maintaining normal neuronal function.

  1. Computational Insights into The Neuroprotective Action of Riluzole on 3-Acetylpyridine-Induced Ataxia in Rats

    Directory of Open Access Journals (Sweden)

    Mahyar Janahmadi

    2013-01-01

    Full Text Available Objective: Intra-peritoneal administration of riluzole has been shown to preserve the membrane properties and firing characteristics of Purkinje neurons in a rat model of cerebellar ataxia induced by 3-acetylpyridine (3-AP. However, the exact mechanism(s by which riluzole restores the normal electrophysiological properties of Purkinje neurons is not completely understood. Changes in the conductance of several ion channels, including the BK channels, have been proposed as a neuro protective target of riluzole. In this study, the possible cellular effects of riluzole on Purkinje cells from 3-AP-induced ataxic rats that could be responsible for its neuro protective action have been investigated by computer simulations.Materials and Methods: This is a computational stimulation study. The simulation environment enabled a change in the properties of the specific ion channels as the possible mechanism of action of riluzole. This allowed us to study the resulted changes in the firing activity of Purkinje cells without concerns about its other effects and interfering parameters in the experiments. Simulations were performed in the NEURON environment (Version 7.1 in a time step of 25 μs; analyses were conducted using MATLAB r2010a (The Mathworks. Data were given as mean ± SEM. Statistical analyses were performed by the student’s t test, and differences were considered significant if p<0.05.Results: The computational findings demonstrated that modulation of an individual ion channel current, as suggested by previous experimental studies, should not be considered as the only possible target for the neuro protective effects of riluzole to restore the normal firing activity of Purkinje cells from ataxic rats.Conclusion: Changes in the conductance of several potassium channels, including voltage-gated potassium (Kv1, Kv4 and big Ca2+-activated K+ (BK channels may be responsible for the neuro protective effect of riluzole against 3-AP induced alterations in

  2. 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.

  3. Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia.

    Science.gov (United States)

    Dantham, Subrahamanyam; Srivastava, Achal K; Gulati, Sheffali; Rajeswari, Moganty R

    2016-06-15

    Friedreich's ataxia (FRDA) is one of the most devastating childhood onset neurodegenerative disease affecting multiple organs in the course of progression. FRDA is associated with mitochondrial dysfunction due to deficit in a nuclear encoded mitochondrial protein, frataxin. Identification of disease-specific biomarker for monitoring the severity remains to be a challenging topic. This study was aimed to identify whether circulating cell-free nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in blood plasma can be a potential biomarker for FRDA. Clinical information was assessed using International Cooperative Ataxia Rating Scale and the disease was confirmed using Long-range PCR for GAA repeat expansion within the gene encoding frataxin. The frataxin expression was measured using Western blot. Plasma nDNA and mtDNA levels were quantified by Multiplex real-time PCR. The major observation is that the levels of nDNA found to be increased, whereas mtDNA levels were reduced significantly in the plasma of FRDA patients (n=21) as compared to healthy controls (n=21). Further, plasma mtDNA levels showed high sensitivity (90%) and specificity (76%) in distinguishing from healthy controls with optimal cutoff indicated at 4.1×10(5)GE/mL. Interestingly, a small group of follow-up patients (n=9) on intervention with, a nutrient supplement, omega-3 fatty acid (a known enhancer of mitochondrial metabolism) displayed a significant improvement in the levels of plasma mtDNA, supporting our hypothesis that plasma mtDNA can be a potential monitoring or prognosis biomarker for FRDA. PMID:27206881

  4. Nerve Growth Factor for the Treatment of Spinocerebellar Ataxia Type 3: An Open-label Study

    Institute of Scientific and Technical Information of China (English)

    Song Tan; Rui-Hao Wang; Hui-Xia Niu; Chang-He Shi; Cheng-Yuan Mao; Rui Zhang; Bo Song

    2015-01-01

    Background:Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA worldwide,and runs a slowly progressive and unremitting disease course.There is currently no curable treatment available.Growing evidence has suggested that nerve growth factor (NGF) may have therapeutic effects in neurodegenerative diseases,and possibly also in SCA3.The objective of this study was to test the efficacy of NGF in SCA3 patients.Methods:We performed an open-label prospective study in genetically confirmed adult (>18 years old) SCA3 patients.NGF was administered by intramuscular injection (18 μg once daily) for 28 days consecutively.All the patients were evaluated at baseline and 2 and 4 weeks after treatment using the Chinese version of the scale for assessment and rating of ataxia (SARA).Results:Twenty-one SCA3 patients (10 men and 11 women,mean age 39.14 ± 7.81 years,mean disease duration 4.14 ± 1.90 years,mean CAG repeats number 77.57 ± 2.27) were enrolled.After 28 days of NGF treatment,the mean total SARA score decreased significantly from a baseline of 8.48 ± 2.40 to 6.30 ± 1.87 (P < 0.001).Subsections SARA scores also showed significant improvements in stance (P =0.003),speech (P =0.023),finger chase (P =0.015),fast alternating hand movements (P =0.009),and heel-shin slide (P =0.001).Conclusions:Our preliminary data suggest that NGF may be effective in treating patients with SCA3.

  5. Exploration of transitional life events in individuals with Friedreich ataxia: Implications for genetic counseling

    Directory of Open Access Journals (Sweden)

    Farmer Jennifer M

    2010-10-01

    Full Text Available Abstract Background Human development is a process of change, adaptation and growth. Throughout this process, transitional events mark important points in time when one's life course is significantly altered. This study captures transitional life events brought about or altered by Friedreich ataxia, a progressive chronic illness leading to disability, and the impact of these events on an affected individual's life course. Methods Forty-two adults with Friedreich ataxia (18-65y were interviewed regarding their perceptions of transitional life events. Data from the interviews were coded and analyzed thematically using an iterative process. Results Identified transitions were either a direct outcome of Friedreich ataxia, or a developmental event altered by having the condition. Specifically, an awareness of symptoms, fear of falling and changes in mobility status were the most salient themes from the experience of living with Friedreich ataxia. Developmental events primarily influenced by the condition were one's relationships and life's work. Conclusions Friedreich ataxia increased the complexity and magnitude of transitional events for study participants. Transitional events commonly represented significant loss and presented challenges to self-esteem and identity. Findings from this study help alert professionals of potentially challenging times in patients' lives, which are influenced by chronic illness or disability. Implications for developmental counseling approaches are suggested for genetic counseling. Background Human development can be described in terms of key transitional events, or significant times of change. Transitional events initiate shifts in the meaning or direction of life and require the individual to develop skills or utilize coping strategies to adapt to a novel situation 12. A successful transition has been defined as the development of a sense of mastery over the changed event 3. Transitions can be influenced by a variety

  6. 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.

  7. Episodic ataxia type 2 manifests as epileptiform electroencephalographic activity with no epileptic attacks in two family members.

    Science.gov (United States)

    Kaido, Misako; Furuta, Mitsuru; Nakamori, Masayuki; Yuasa, Yoshihito; Takahashi, Masanori P

    2016-04-28

    Here, we report two cases of episodic ataxia type 2 (EA2) in a 63-year-old woman and her 36-year-old daughter. The mother experienced recurrent attacks of cerebellar dysfunction lasting 4 to 5 hours since the age of 41 years. On several occasions, she was admitted to the emergency room, where she was diagnosed with epilepsy or stroke. Based on these diagnoses, she was treated with antiepileptic or anticoagulant drugs, but both treatments were eventually discontinued. The frequency of the attacks increased after the patient reached the age of 62. Interictal neurological examination demonstrated signs of slight cerebellar ataxia, i.e. saccadic eye movements, gaze-directed nystagmus, and mild truncal ataxia. Brain magnetic resonance imaging (MRI) showed cerebellar vermis atrophy. Electroencephalography (EEG) revealed various spike and wave patterns: solitary spikes, spike-and-slow wave complexes, and slow wave bursts. Photoparoxysmal response (PPR) type 3 was also observed. Treatment with acetazolamide abolished the patient's attacks almost completely. The daughter started experiencing 5- to 10-minute ataxic episodes at the age of 16 years. Based on her epileptiform EEG activities with PPR (type 2), antiepileptic drugs (valproate and zonisamide) were prescribed. Despite pharmacological treatment, the attacks recurred; however, their frequency gradually decreased with time, until they almost entirely disappeared when the patient was 33. Unfortunately, migraine-like headaches arose instead. Subtle truncal ataxia was observed during interictal periods. Sanger sequencing of the exons of the CACNA1A gene revealed a novel single base deletion (c.3575delA) in both patients. Despite the difference in age of onset and clinical course, both patients showed clearly epileptiform EEG activities without experiencing the concurrent epileptic episodes. Thus, EA2 is a disease that may be misdiagnosed as epilepsy or stroke in the field of emergency medicine. PMID:27025991

  8. Monoclonal Gammopathy of Undetermined Significance (MGUS) in a Man with Fragile X-associated Tremor/Ataxia Syndrome

    OpenAIRE

    Tri I. Winarni; Randi J Hagerman; Sumekar, Tanjung A.; Ashrani, Aneel A.

    2011-01-01

    We report the clinical presentation and laboratory findings of a 69-year-old man with fragile X-associated tremor ataxia syndrome (FXTAS), a progressive neurodegenerative disorder, who was noted to have monoclonal gammopathy of undetermined significance (MGUS), a plasma cell proliferative disorder and a precursor disease of multiple myeloma. Both MGUS and FXTAS are associated with microRNA (miRNA) dysregulation. We speculate that individuals with FXTAS may be predisposed to MGUS and further s...

  9. Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2

    OpenAIRE

    Fogel, Brent L.; Cho, Ellen; Wahnich, Amanda; Gao, Fuying; Becherel, Olivier J.; Wang, Xizhe; Fike, Francesca; Chen, Leslie; Criscuolo, Chiara; De Michele, Giuseppe; Filla, Alessandro; Collins, Abigail; Hahn, Angelika F.; Gatti, Richard A.; Konopka, Genevieve

    2014-01-01

    Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and ...

  10. Resonancia Magnética Nuclear de cráneo en primeras familias cubanas diagnosticadas con ataxia de Friedreich

    Directory of Open Access Journals (Sweden)

    Tania Cruz Mariño

    2011-01-01

    Full Text Available La ataxia de Friedreich se caracteriza por edad de comienzo antes de los 25 años, ataxia progresiva, disartria, ausencia de reflejos tendinosos profundos y alteraciones en el sentido de vibración. La presente investigación se realizó con el objetivo de describir las características imagenológicas de las estructuras del sistema nervioso central en las primeras familias cubanas diagnosticadas con la enfermedad. Mediante un equipo de 0.23 Teslas -PANORAMA-, Phylips Medical Systems, con una bobina estándar de cráneo, se obtuvieron cortes axiales de 5mm de grosor usando secuencias de FLAIR, T1 y T2, así como cortes sagitales en T1 y T2 en tres individuos con diagnóstico molecular confirmatorio de ataxia de Friedreich y seis controles saludables pareados mediante edad y sexo. Las estructuras con mayor afectación morfológica son la médula espinal cervical, el cerebelo y la protuberancia, lo cual provee evidencia in vivo de que la enfermedad conduce a atrofia de dichas estructuras.

  11. The Pointing Errors in Optic Ataxia Reveal the Role of “Peripheral Magnification” of the PPC

    Science.gov (United States)

    Vindras, Philippe; Blangero, Annabelle; Ota, Hisaaki; Reilly, Karen T.; Rossetti, Yves; Pisella, Laure

    2016-01-01

    Interaction with visual objects in the environment requires an accurate correspondence between visual space and its internal representation within the brain. Many clinical conditions involve some impairment in visuo-motor control and the errors created by the lesion of a specific brain region are neither random nor uninformative. Modern approaches to studying the neuropsychology of action require powerful data-driven analyses and error modeling in order to understand the function of the lesioned areas. In the present paper we carried out mixed-effect analyses of the pointing errors of seven optic ataxia patients and seven control subjects. We found that a small parameter set is sufficient to explain the pointing errors produced by unilateral optic ataxia patients. In particular, the extremely stereotypical errors made when pointing toward the contralesional visual field can be fitted by mathematical models similar to those used to model central magnification in cortical or sub-cortical structure(s). Our interpretation is that visual areas that contain this footprint of central magnification guide pointing movements when the posterior parietal cortex (PPC) is damaged and that the functional role of the PPC is to actively compensate for the under-representation of peripheral vision that accompanies central magnification. Optic ataxia misreaching reveals what would be hand movement accuracy and precision if the human motor system did not include elaborated corrective processes for reaching and grasping to non-foveated targets. PMID:27507938

  12. Novel frameshift mutation in the CACNA1A gene causing a mixed phenotype of episodic ataxia and familiar hemiplegic migraine.

    Science.gov (United States)

    Kinder, S; Ossig, C; Wienecke, M; Beyer, A; von der Hagen, M; Storch, A; Smitka, M

    2015-01-01

    Episodic ataxia type 2 (EA2, MIM#108500) is the most common form of EA and an autosomal-dominant inherited disorder characterized by paroxysmal episodes of ataxia. The disease causative gene CACNA1A encodes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel. We report on a family with a novel mutation in the CACNA1A gene. The clinical symptoms within the family varied from the typical clinical presentation of EA2 with dysarthria, gait ataxia and oculomotor symptoms to migraine and dystonia. A novel nonsense mutation of the CACNA1A gene was identified in all affected family members and is most likely the disease causing molecular defect. The pharmacological treatment with acetazolamide (AAA) was successful in three family members so far. Treatment with AAA led to a reduction of migraine attacks and an improvement of the dystonia. This relationship confirmed the hypothesis that this novel mutation results in a heterogeneous phenotype and confutes the coincidence with common migraine. Dystonia is potentially included as a further part of the phenotype spectrum of CACNA1A gene mutations.

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

    Science.gov (United States)

    Zampetti-Bosseler, F; Scott, D

    1981-05-01

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

  14. R-loops in proliferating cells but not in the brain: implications for AOA2 and other autosomal recessive ataxias.

    Directory of Open Access Journals (Sweden)

    Abrey J Yeo

    Full Text Available Disruption of the Setx gene, defective in ataxia oculomotor apraxia type 2 (AOA2 leads to the accumulation of DNA/RNA hybrids (R-loops, failure of meiotic recombination and infertility in mice. We report here the presence of R-loops in the testes from other autosomal recessive ataxia mouse models, which correlate with fertility in these disorders. R-loops were coincident in cells showing high basal levels of DNA double strand breaks and in those cells undergoing apoptosis. Depletion of Setx led to high basal levels of R-loops and these were enhanced further by DNA damage both in vitro and in vivo in tissues with proliferating cells. There was no evidence for accumulation of R-loops in the brains of mice where Setx, Atm, Tdp1 or Aptx genes were disrupted. These data provide further evidence for genome destabilization as a consequence of disrupted transcription in the presence of DNA double strand breaks arising during DNA replication or recombination. They also suggest that R-loop accumulation does not contribute to the neurodegenerative phenotype in these autosomal recessive ataxias.

  15. Familial periodic cerebellar ataxia without myokymia maps to a 19-cM region on 19p13

    Energy Technology Data Exchange (ETDEWEB)

    Teh, B.T.; Lindblad, K.; Betz, R. [Karolinska Hospital, Stockholm (Switzerland)] [and others

    1995-06-01

    Familial periodic cerebellar ataxia (FPCA) is a heterogenous group of rare autosomal dominant disorders characterized by episodic cerebellar disturbance. A potassium-channel gene (KCNA1) has been found to be responsible for one of its subgroups, familial periodic cerebellar ataxia with myokymia (FPCA/+M; MIM 160120). A different subgroup that is not associated with myokymia (FPCA/-M; MIM 108500) was recently mapped to chromosome 19p. Here we have performed linkage analysis in two large families with FPCA/-M that also demonstrated neurodegenerative pathology of the cerebellum. Three markers in 19p13 gave significant lod scores (>3.0), while linkage to KCNA1 and three known loci for spinocerebellar ataxia (SCA1, SCA2, and SCA3) was excluded. The highest lod score was obtained with the marker D19S413 (4.4 at recombination fraction 0), and identification of meiotic recombinants in affected individuals placed the locus between the flanking markers D19S406 and D19S226, narrowing the interval to 19 cM. A CAG trinucleotide-repeat expansion was detected in one family but did not consegregate with the disease. 30 refs., 3 figs., 1 tab.

  16. Mutation analysis of spinocerebellar ataxia type 1 (SCA1) in a large Iakut kinship of Eastern Siberia

    Energy Technology Data Exchange (ETDEWEB)

    Goldfarb, L.G.; Lunkes, A.; Vaconcelos, O. [and others

    1994-09-01

    We have studied 131 patients with autosomal dominant cerebellar ataxia clinically and pathologically expressed as olivopontocerebellar atrophy. The disease in this Siberian kinship has been genetically linked to the SCA1 gene on chromosome 6p, and the pedigree was screened for the recently described CAG repeat expansion in this gene using the GeneScan program (ABI). The normal allele in the affected individuals had 26 to 32 repeats, and among 424 analyzed normal alleles of the unaffected members of the kinship, unrelated controls and patients with other neurological disorders, the range of repeat numbers was 26 to 37, with 92% within 28 to 30 repeats. All 65 normal alleles in which the repeat area has been sequenced show a CAT or CATCAGCAT interruption between the first and the second stretches of 10 to 17 CAG repeats. The SCA1 allele was extended to 39 to 60 uninterrupted repeats in all fifty-nine analyzed ataxia patients. Repeat numbers of 40 to 55 were also found in thirty-nine of 105 tested unaffected first and second degree relatives. Two patients and an unaffected child were homozygous for the elongated allele. In seven of 10 paternal transmissions an increase of 2 to 11 repeats have occurred; in nine maternal transmissions the repeat numbers remained the same or grew for just one repeat. Mutation analysis provides new opportunities in diagnosis and risk assessment of spinocerebellar ataxia type 1.

  17. Édouard Manet's Tabes Dorsalis: From Painful Ataxia to Phantom Limb.

    Science.gov (United States)

    Bogousslavsky, Julien; Tatu, Laurent

    2016-01-01

    Édouard Manet (1832-1883) is considered the 'father' of Impressionism and even of XXth century modern art. Manet's genius involved getting away from the classical narrative or historical topics and replacing them by the banality of daily life. Technically, he erased volumes into flat two-dimensional coloured planes, and distorted conventional perspective with often gross brushstrokes intentionally giving an 'unfinished' aspect to the work. It is little known that Manet had a very painful second part of his life, due to excruciating limb and chest pains, which developed in parallel with proprioceptive ataxia and gait imbalance. Manet always remained discreet about his private life, and we mainly know that his future wife was his family piano teacher, with whom he had a liaison already at age 17. Later, the great but platonic passion of his life was the painter Berthe Morisot (1841-1895), who got married to Manet's brother Eugène. In fact, we do not know whether he had any mistress at all, although he had several elegant 'flirts' in the mundane and artistic milieu. Thus, while Manet's progressive painful ataxia from age 40 yields little doubt on its tabetic origin, how he contracted syphilis at least 15-20 years before will probably remain a mystery. It is fascinating that Manet's daily struggle against pain and poor coordination may have led his art to become one of the most significant of modern times, opening the way to XXth century avant-gardes, along with another victim of syphilis, Paul Gauguin (1848-1903). Manet never showed any sign of General Paresis, and like his contemporary the writer Alphonse Daudet, his clinical picture remained dominated by paroxysmal pain and walking impairment. Difficult hand coordination made him quit watercolor painting, and during the last 2 years of his life, he had to focus on small format oil works, whose subject was nearly limited to modest bunches of fresh flowers, now often considered to be his maturity masterpieces

  18. Spinocerebellar ataxia type 7 in South Africa: Epidemiology, pathogenesis and therapy.

    Science.gov (United States)

    Watson, L; Smith, D C; Scholefield, J; Ballo, R; Kidson, S; Greenberg, L J; Wood, M J A

    2016-01-01

    Disorders of the nervous system represent a significant proportion of the global burden of non-communicable diseases, due to the trend towards ageing populations. The Department (now Division) of Human Genetics at the University of Cape Town (UCT) has been involved in pioneering research into these diseases since the appointment of Prof. Peter Beighton as Head of Department in 1972. Beighton's emphasis on understanding the genetic basis of disease laid the groundwork for investigations into several monogenic neurodegenerative conditions, including Huntington's disease and the polyglutamine spinocerebellar ataxias (SCAs). In particular, SCA7, which occurs at an unusually high frequency in the South African (SA) population, was identified as a target for further research and therapeutic development. Beginning with early epidemiological surveys, the SCA7 project progressed to molecular genetics-based investigations, leading to the identification of a founder effect in the SA SCA7 patient population in the mid-2000s. Capitalising on the founder haplotype shared by many SCA7 patients, UCT researchers went on to develop the first population-specific gene-silencing approach for the disease. More recently, efforts have shifted to the development of a more accurate model to decipher the precise mechanisms of neurodegeneration, using induced pluripotent stem cells derived from SA SCA7 patients. In many ways, the SA SCA7 journey reflects the legacy and vision of Prof. Peter Beighton, and his efforts to establish world-class, collaborative research into diseases affecting the African continent. PMID:27245542

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

    Directory of Open Access Journals (Sweden)

    Ninette Amariglio

    2009-02-01

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

  20. Role of glutathione S-transferases in the spinocerebellar ataxia type 2 clinical phenotype.

    Science.gov (United States)

    Almaguer-Gotay, D; Almaguer-Mederos, L E; Aguilera-Rodríguez, R; Estupiñán-Rodríguez, A; González-Zaldivar, Y; Cuello-Almarales, D; Laffita-Mesa, J M; Vázquez-Mojena, Y

    2014-06-15

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative and incurable hereditary disorder caused by a CAG repeat expansion mutation on ATXN2 gene. The identification of reliable biochemical markers of disease severity is of paramount significance for the development and assessment of clinical trials. In order to evaluate the potential use of glutathione-S-transferase (GST) activity as a biomarker for SCA2, a case-control study in 38 affected, presymptomatic individuals or healthy controls was conducted. An enlarged sample of 121 affected individuals was set to assess the impact of GST activity on SCA2 clinical expression. There was a significant increase in GST activity in affected individuals relative to controls, although sensibility and specificity were not high. GST activity was not significantly influenced by sex, age, disease duration or CAG repeat size and did not significantly influence disease severity markers. These findings show a disruption of in vivo GST activity in SCA2, suggesting a role for oxidative stress in the neurodegenerative process. PMID:24780439

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-01-01

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

  2. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome.

    Science.gov (United States)

    Todd, Peter K; Oh, Seok Yoon; Krans, Amy; He, Fang; Sellier, Chantal; Frazer, Michelle; Renoux, Abigail J; Chen, Kai-chun; Scaglione, K Matthew; Basrur, Venkatesha; Elenitoba-Johnson, Kojo; Vonsattel, Jean P; Louis, Elan D; Sutton, Michael A; Taylor, J Paul; Mills, Ryan E; Charlet-Berguerand, Nicholas; Paulson, Henry L

    2013-05-01

    Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 5' UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat-associated non-AUG-initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG. FMRpolyG accumulates in ubiquitin-positive inclusions in Drosophila, cell culture, mouse disease models, and FXTAS patient brains. CGG RAN translation occurs in at least two of three possible reading frames at repeat sizes ranging from normal (25) to pathogenic (90), but inclusion formation only occurs with expanded repeats. In Drosophila, CGG repeat toxicity is suppressed by eliminating RAN translation and enhanced by increased polyglycine protein production. These studies expand the growing list of nucleotide repeat disorders in which RAN translation occurs and provide evidence that RAN translation contributes to neurodegeneration. PMID:23602499

  3. Ataxia telangiectasia: A report of two cousins and review of literature

    Directory of Open Access Journals (Sweden)

    Anjali Sharma

    2011-01-01

    Full Text Available Ataxia telangiectasia (AT is a rare multisystem, neurodegenerative genetic disorder. Due to its wide clinical heterogeneity, it often leads physicians to an incorrect or missed diagnosis, and insight into this rare disease is important. Here is a case report of two cousins from the same family who showed salient characteristic features of AT along with the incidental finding of co-inheritance of hemoglobin E trait. Though both of them were from the same family, they showed differences in the type of humoral immune deficiencies, laboratory findings, and their susceptibility to develop different types of malignancies. One of them developed T cell acute lymphoblastic leukemia, isolated immunoglobulin A deficiency, and normal serum carcinoembryonic antigen (CEA and carbohydrate antigen 19.9 (CA 19.9 levels. He expired at the age of nine years. The other, though a year older, has still got normal blood counts, normal immunoglobulin levels, and elevated serum CEA and CA 19.9 levels. Thus, insight into this disease is very important as AT patients require protection from unnecessary exposure to ionizing radiation to prevent malignancies. Diagnosis of AT allows appropriate genetic counseling for the family.

  4. [Neuropsychological profile in opsoclonus-myoclonus-ataxia syndrome presenting as neuroblastic tumours].

    Science.gov (United States)

    Bravo, Jezabel; López-Almaraz, Ricardo; Mateos, Mercedes; Díaz, Leticia; Hernández-Expósito, Sergio

    2016-03-16

    Introduccion. Las mejoras sociosanitarias experimentadas en la sociedad occidental han incrementado de forma significativa la supervivencia de los pacientes con el sindrome opsoclono-mioclono-ataxia (SOMA). Sin embargo, diversos estudios han informado de deficits neurologicos, cognitivo-conductuales y de desarrollo persistentes en el 70-80% de estos pacientes. Pacientes y metodos. Se revisan los casos de tumores neuroblasticos diagnosticados en un periodo total de 13 años y seis meses (desde enero de 2000 a mayo de 2013) y su asociacion a SOMA en el servicio de pediatria de un hospital general de tercer nivel. Ademas, se lleva a cabo la evaluacion neuropsicologica exhaustiva de tres niños diagnosticados de SOMA. Resultados. Hemos objetivado deficits en inteligencia, atencion, velocidad de procesamiento, memoria, lenguaje, habilidades visuoespaciales y visuoconstructivas, motricidad fina y funciones ejecutivas. Ademas, hemos comprobado alteraciones en el perfil psicologico. Conclusiones. Se aportan datos que enfatizan el papel del cerebelo en el procesamiento cognitivo complejo en poblacion infantil, probablemente vinculado a alteraciones neuromadurativas de esta estructura motivadas por deficiencias del sistema inmunologico. Los resultados encontrados son interpretados en el marco conceptual de la neuropsicologia Infantil y su interes por estudiar las relaciones cerebro-conducta en el contexto dinamico del desarrollo cerebral.

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

    International Nuclear Information System (INIS)

    The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. We conducted a nested case–control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (χ2 = 3.43, five degrees of freedom, P = 0.63). There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk

  6. Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3.

    Science.gov (United States)

    Boy, Jana; Schmidt, Thorsten; Wolburg, Hartwig; Mack, Andreas; Nuber, Silke; Böttcher, Martin; Schmitt, Ina; Holzmann, Carsten; Zimmermann, Frank; Servadio, Antonio; Riess, Olaf

    2009-11-15

    Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a CAG repeat tract that affects the MJD1 gene which encodes the ataxin-3 protein. In order to analyze whether symptoms caused by ataxin-3 with an expanded repeat are reversible in vivo, we generated a conditional mouse model of SCA3 using the Tet-Off system. We used a full-length human ataxin-3 cDNA with 77 repeats in order to generate the responder mouse line. After crossbreeding with a PrP promoter mouse line, double transgenic mice developed a progressive neurological phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired Rotarod performance and lower body weight gain. When ataxin-3 expression was turned off in symptomatic mice in an early disease state, the transgenic mice were indistinguishable from negative controls after 5 months of treatment. These results show that reducing the production of pathogenic ataxin-3 indeed may be a promising approach to treat SCA3, provided that such treatment is applied before irreversible damage has taken place and that it is continued for a sufficiently long time. PMID:19666958

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

    Science.gov (United States)

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

    2013-01-01

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

  8. The fragile X-associated tremor ataxia syndrome (FXTAS) in Indonesia.

    Science.gov (United States)

    Winarni, T I; Mundhofir, F E P; Ediati, A; Belladona, M; Nillesen, W M; Yntema, H G; Hamel, B C J; Faradz, S M H; Hagerman, R J

    2013-03-01

    Fragile X-associated disorders caused by the premutation of the FMR1 gene, includes the fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS affects more than 40% of premutation males over the age of 50 and 75% over the age of 80. FMR1 molecular analysis was done using PCR and confirmed by Southern Blot. Three premutation males were diagnosed FXTAS using quantification based on the standard neurological examination. Cognitive impairment was assessed using Raven and WAIS-R test. MRI was done to identify the middle cerebellar peduncle (MCP) sign, white matter disease and/or cerebral atrophy. Three cases of FXTAS are identified, of five individuals older than 50 years in one family tree two met criteria for definite FXTAS and the third with sub-clinical symptoms, although cognitive and radiological criteria are met. These cases are the first identified FXTAS cases in rural Indonesia. In addition with lack of routine medical follow-up, complications of FXTAS, such as hypertension may go unrecognized and untreated, which may further exacerbate the central nervous system (CNS) findings of FXTAS. PMID:22568721

  9. 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.

  10. Characteristics of gait ataxia in δ2 glutamate receptor mutant mice, ho15J.

    Directory of Open Access Journals (Sweden)

    Eri Takeuchi

    Full Text Available The cerebellum plays a fundamental, but as yet poorly understood, role in the control of locomotion. Recently, mice with gene mutations or knockouts have been used to investigate various aspects of cerebellar function with regard to locomotion. Although many of the mutant mice exhibit severe gait ataxia, kinematic analyses of limb movements have been performed in only a few cases. Here, we investigated locomotion in ho15J mice that have a mutation of the δ2 glutamate receptor. The cerebellum of ho15J mice shows a severe reduction in the number of parallel fiber-Purkinje synapses compared with wild-type mice. Analysis of hindlimb kinematics during treadmill locomotion showed abnormal hindlimb movements characterized by excessive toe elevation during the swing phase, and by severe hyperflexion of the ankles in ho15J mice. The great trochanter heights in ho15J mice were lower than in wild-type mice throughout the step cycle. However, there were no significant differences in various temporal parameters between ho15J and wild-type mice. We suggest that dysfunction of the cerebellar neuronal circuits underlies the observed characteristic kinematic abnormality of hindlimb movements during locomotion of ho15J mice.

  11. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia

    Energy Technology Data Exchange (ETDEWEB)

    Filla, A.; De Michele, G.; Cavalcanti, F. [Federico II Univ., Naples (Italy)] [and others

    1996-09-01

    Friedreich ataxia (FA) is associated with the expansion of a GAA trinucleotide repeat in the first intron of the X25 gene. We found both alleles expanded in 67 FA patients from 48 Italian families. Five patients from three families were compound heterozygotes with expansion on one allele and an isoleucine{r_arrow}phenylalanine change at position 154 on the other one. We found neither expansions nor point mutations in three patients. The length of FA alleles ranged from 201 to 1,186 repeat units, with no overlap with the normal range, and showed a negatively skewed distribution with a peak between 800 and 1,000 repeats. The FA repeat showed meiotic instability with a median variation of 150 repeats. The lengths of both larger and smaller alleles in each patient inversely correlated with age at onset of the disorder. Smaller alleles showed the best correlation, accounting for {approximately}50% of the variation of age at onset. Mean allele length was significantly higher in patients with diabetes and in those with cardiomyopathy. 16 refs., 3 figs., 1 tab.

  12. The Contribution of the Cerebellum to Cognition in Spinocerebellar Ataxia Type 6

    Directory of Open Access Journals (Sweden)

    Freya E. Cooper

    2010-01-01

    Full Text Available This study sought evidence for a specific cerebellar contribution to cognition by characterising the cognitive phenotype of Spinocerebellar Ataxia Type 6 (SCA-6; an autosomal dominant genetic disease which causes a highly specific late-onset cerebellar degeneration. A comprehensive neuropsychological assessment was administered to 27 patients with genetically confirmed SCA-6. General intellectual ability, memory and executive function were examined using internationally standardised tests (Wechsler Adult Intelligence Scale-III, Wechsler Memory Scale-III, Delis and Kaplan Executive Function System, Brixton Spatial Anticipation test. The patient group showed no evidence of intellectual or memory decline. However, tests of executive function involving skills of cognitive flexibility, inhibition of response and verbal reasoning and abstraction demonstrated significant impairment at the group level with large effect sizes. The results demonstrate an executive deficit due to SCA-6 that can be conceptualised as parallel to the motor difficulties suffered by these patients: the data support a role for the cerebellum in the regulation and coordination of cognitive, as well as motor processes that is relevant to individual performance.

  13. Chinese patients with spinocerebellar ataxia type 3 presenting with rare clinical symptoms.

    Science.gov (United States)

    Dong, Yi; Sun, Yi-Min; Ni, Wang; Gan, Shi-Rui; Wu, Zhi-Ying

    2013-01-15

    Clinical heterogeneity is the prominent feature of spinocerebellar ataxia type 3 (SCA3) which is sometimes neglected and often impedes the timely diagnosis of patients. In this study, the clinical data of 201 unrelated Chinese SCA3 patients were retrospectively studied. The rare clinical features were summarized and the underlying genetic mutations were screened by direct DNA sequencing. Three patients were found primarily presenting with the rare clinical features, including dystonic phenotype without response to levodopa, chorea and memory decline, and hearing impairment, respectively. We firstly reported three diverse heterogeneities of SCA3 patients, which are quite uncommon in the Chinese SCA3 patients. Our results expanded the variable phenotypes of SCA3 and provided the explicit information for the rare and special SCA3 manifestations. Based on this new knowledge, we suggested that when the presentation was consistent with HD or DRD while negative in the corresponding genetic testing, SCA3 should be considered, and clinicians should divert partial attention to the examinations on the auditory system of SCA3 patients. PMID:23174085

  14. A randomized controlled pilot trial of lithium in spinocerebellar ataxia type 2.

    Science.gov (United States)

    Saccà, Francesco; Puorro, Giorgia; Brunetti, Arturo; Capasso, Giovambattista; Cervo, Amedeo; Cocozza, Sirio; de Leva, Mariafulvia; Marsili, Angela; Pane, Chiara; Quarantelli, Mario; Russo, Cinzia Valeria; Trepiccione, Francesco; De Michele, Giuseppe; Filla, Alessandro; Morra, Vincenzo Brescia

    2015-01-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder. Lithium is able to stimulate autophagy, and to reduce Ca(2+) efflux from the inositol-1,4,5-triphosphate receptor. We designed a phase II, randomized, placebo-controlled, double-blind, 48-week trial with lithium carbonate in 20 patients with SCA2. The primary objective was to determine safety and tolerability of lithium. The secondary objectives were to determine disease progression, quality of life, mood, and brain volume change. Sixteen patients completed the trial, 8 randomized to lithium, 8 to placebo. Forty adverse events (AEs) were reported during the trial, twenty-eight in the lithium and 12 in the placebo group (p = 0.11). Mean AE duration was 57.4 ± 60.8 and 77.4 ± 68.5 days (p = 0.37). Non-significant differences were observed for the SARA and for brain volume change, whereas a significant reduction in the BDI-II was observed for lithium group (p bipolar disorder patients. A correctly powered phase III trial is needed to assess if lithium may slow disease progression in SCA2. PMID:25346067

  15. Impaired Spatio-Temporal Predictive Motor Timing Associated with Spinocerebellar Ataxia Type 6.

    Science.gov (United States)

    Broersen, Robin; Onuki, Yoshiyuki; Abdelgabar, Abdel R; Owens, Cullen B; Picard, Samuel; Willems, Jessica; Boele, Henk-Jan; Gazzola, Valeria; Van der Werf, Ysbrand D; De Zeeuw, Chris I

    2016-01-01

    Many daily life activities demand precise integration of spatial and temporal information of sensory inputs followed by appropriate motor actions. This type of integration is carried out in part by the cerebellum, which has been postulated to play a central role in learning and timing of movements. Cerebellar damage due to atrophy or lesions may compromise forward-model processing, in which both spatial and temporal cues are used to achieve prediction for future motor states. In the present study we sought to further investigate the cerebellar contribution to predictive and reactive motor timing, as well as to learning of sequential order and temporal intervals in these tasks. We tested patients with spinocerebellar ataxia type 6 (SCA6) and healthy controls for two related motor tasks; one requiring spatio-temporal prediction of dynamic visual stimuli and another one requiring reactive timing only. We found that healthy controls established spatio-temporal prediction in their responses with high temporal precision, which was absent in the cerebellar patients. SCA6 patients showed lower predictive motor timing, coinciding with a reduced number of correct responses during the 'anticipatory' period on the task. Moreover, on the task utilizing reactive motor timing functions, control participants showed both sequence order and temporal interval learning, whereas patients only showed sequence order learning. These results suggest that SCA6 affects predictive motor timing and temporal interval learning. Our results support and highlight cerebellar contribution to timing and argue for cerebellar engagement during spatio-temporal prediction of upcoming events. PMID:27571363

  16. 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.

  17. [{sup 123}I]-IMP SPECT findings in spinocerebellar ataxia type 6

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Yasuhiko; Nakabayashi, Haruo; Iguchi, Yasuyuki; Suzuki, Masahiko; Kobayashi, Masayuki [Jikei Univ., Chiba (Japan). Kashiwa Hospital; Nakajima, Takashi

    2000-01-01

    To study the dynamics of metabolic function in the cerebellar hemispheres, vermis and brain stem of patients with spinocerebellar ataxia type 6 (SCA6), we used single photon emission computed tomography (SPECT) with N-isopropyl-p-[{sup 123}I] iodoamphetamine (IMP) to measure regional cerebral blood flow (rCBF) in six Japanese patients with SCA6 and nine normal control subjects. All patients with SCA6 were found to have expanded CAG repeats (from 22 to 24 repeats). The SPECT data were also analyzed semiquantitatively. The rCBF in the cerebellar hemisphere, vermis and brain stem was not significantly lower in patients with SCA6 than in normal controls. However, the ratio of the cerebellar hemisphere to occipital lobe (C/O ratio) was significantly lower in patients. The ratio of the vermis and brain stem to occipital lobe (V/O, P/O ratio) were not significantly lower in patients. The C/O, V/O and P/O ratio were especially sensitive indexes for regional cerebral function in patients with SCA6. Results of this study suggest that the functional decrease in SCA6 may begin in the cerebellar hemispheres. IMP SPECT was useful for evaluating rCBF in patients with SCA6. (author)

  18. A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins.

    Science.gov (United States)

    Chapdelaine, Pierre; Coulombe, Zoé; Chikh, Amina; Gérard, Catherine; Tremblay, Jacques P

    2013-09-03

    TALEs targeting a promoter sequence and fused with a transcription activation domain (TAD) may be used to specifically induce the expression of a gene as a potential treatment for haploinsufficiency. This potential therapeutic approach was applied to increase the expression of frataxin in fibroblasts of Friedreich ataxia (FRDA) patients. FRDA fibroblast cells were nucleofected with a pCR3.1 expression vector coding for TALEFrat#8 fused with VP64. A twofold increase of the frataxin mRNA (detected by quantitative reverse transcription-PCR (qRT-PCR)) associated with a similar increase of the mature form of the frataxin protein was observed. The frataxin mRNA and protein were also increased by this TALE in the fibroblasts of the YG8R mouse model. The addition of 5-aza-2'-deoxycytidine (5-Aza-dC) or of valproic acid (VPA) to the TALE treatment did not produce significant improvement. Other TADs (i.e., p65, TFAP2α, SRF, SP1, and MyoD) fused with the TALEFrat#8 gene did not produce a significant increase in the frataxin protein. Thus the TALEFrat#8-VP64 recombinant protein targeting the frataxin promoter could eventually be used to increase the frataxin expression and alleviate the FRDA symptoms.Molecular Therapy-Nucleic Acids (2013) 2, e119; doi:10.1038/mtna.2013.41; published online 3 September 2013.

  19. Inferior cerebellar hypoplasia resembling a Dandy-Walker-like malformation in purebred Eurasier dogs with familial non-progressive ataxia: a retrospective and prospective clinical cohort study.

    Directory of Open Access Journals (Sweden)

    Filipa Bernardino

    Full Text Available Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5-6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance.

  20. Inferior cerebellar hypoplasia resembling a Dandy-Walker-like malformation in purebred Eurasier dogs with familial non-progressive ataxia: a retrospective and prospective clinical cohort study.

    Science.gov (United States)

    Bernardino, Filipa; Rentmeister, Kai; Schmidt, Martin J; Bruehschwein, Andreas; Matiasek, Kaspar; Matiasek, Lara A; Lauda, Alexander; Schoon, Heinz A; Fischer, Andrea

    2015-01-01

    Cerebellar malformations can be inherited or caused by insults during cerebellar development. To date, only sporadic cases of cerebellar malformations have been reported in dogs, and the genetic background has remained obscure. Therefore, this study`s objective was to describe the clinical characteristics, imaging features and pedigree data of a familial cerebellar hypoplasia in purebred Eurasier dogs. A uniform cerebellar malformation characterized by consistent absence of the caudal portions of the cerebellar vermis and, to a lesser degree, the caudal portions of the cerebellar hemispheres in association with large retrocerebellar fluid accumulations was recognized in 14 closely related Eurasier dogs. Hydrocephalus was an additional feature in some dogs. All dogs displayed non-progressive ataxia, which had already been noted when the dogs were 5-6 weeks old. The severity of the ataxia varied between dogs, from mild truncal sway, subtle dysmetric gait, dysequilibrium and pelvic limb ataxia to severe cerebellar ataxia in puppies and episodic falling or rolling. Follow-up examinations in adult dogs showed improvement of the cerebellar ataxia and a still absent menace response. Epileptic seizures occurred in some dogs. The association of partial vermis agenesis with an enlarged fourth ventricle and an enlarged caudal (posterior) fossa resembled a Dandy-Walker-like malformation in some dogs. Pedigree analyses were consistent with autosomal recessive inheritance. PMID:25668516

  1. Increasing cutaneous afferent feedback improves proprioceptive accuracy at the knee in patients with sensory ataxia.

    Science.gov (United States)

    Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Goulding, Niamh; Palma, Jose-Alberto; Fuente Mora, Cristina; Kaufmann, Horacio

    2016-02-01

    Hereditary sensory and autonomic neuropathy type III (HSAN III) features disturbed proprioception and a marked ataxic gait. We recently showed that joint angle matching error at the knee is positively correlated with the degree of ataxia. Using intraneural microelectrodes, we also documented that these patients lack functional muscle spindle afferents but have preserved large-diameter cutaneous afferents, suggesting that patients with better proprioception may be relying more on proprioceptive cues provided by tactile afferents. We tested the hypothesis that enhancing cutaneous sensory feedback by stretching the skin at the knee joint using unidirectional elasticity tape could improve proprioceptive accuracy in patients with a congenital absence of functional muscle spindles. Passive joint angle matching at the knee was used to assess proprioceptive accuracy in 25 patients with HSAN III and 9 age-matched control subjects, with and without taping. Angles of the reference and indicator knees were recorded with digital inclinometers and the absolute error, gradient, and correlation coefficient between the two sides calculated. Patients with HSAN III performed poorly on the joint angle matching test [mean matching error 8.0 ± 0.8° (±SE); controls 3.0 ± 0.3°]. Following application of tape bilaterally to the knee in an X-shaped pattern, proprioceptive performance improved significantly in the patients (mean error 5.4 ± 0.7°) but not in the controls (3.0 ± 0.2°). Across patients, but not controls, significant increases in gradient and correlation coefficient were also apparent following taping. We conclude that taping improves proprioception at the knee in HSAN III, presumably via enhanced sensory feedback from the skin.

  2. KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function

    Science.gov (United States)

    Reichold, Markus; Zdebik, Anselm A.; Lieberer, Evelyn; Rapedius, Markus; Schmidt, Katharina; Bandulik, Sascha; Sterner, Christina; Tegtmeier, Ines; Penton, David; Baukrowitz, Thomas; Hulton, Sally-Anne; Witzgall, Ralph; Ben-Zeev, Bruria; Howie, Alexander J.; Kleta, Robert; Bockenhauer, Detlef; Warth, Richard

    2010-01-01

    Mutations of the KCNJ10 (Kir4.1) K+ channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome. We investigated the localization of KCNJ10 and the homologous KCNJ16 in kidney and the functional consequences of KCNJ10 mutations found in our patients with EAST syndrome. Kcnj10 and Kcnj16 were found in the basolateral membrane of mouse distal convoluted tubules, connecting tubules, and cortical collecting ducts. In the human kidney, KCNJ10 staining was additionally observed in the basolateral membrane of the cortical thick ascending limb of Henle's loop. EM of distal tubular cells of a patient with EAST syndrome showed reduced basal infoldings in this nephron segment, which likely reflects the morphological consequences of the impaired salt reabsorption capacity. When expressed in CHO and HEK293 cells, the KCNJ10 mutations R65P, G77R, and R175Q caused a marked impairment of channel function. R199X showed complete loss of function. Single-channel analysis revealed a strongly reduced mean open time. Qualitatively similar results were obtained with coexpression of KCNJ10/KCNJ16, suggesting a dominance of KCNJ10 function in native renal KCNJ10/KCNJ16 heteromers. The decrease in the current of R65P and R175Q was mainly caused by a remarkable shift of pH sensitivity to the alkaline range. In summary, EAST mutations of KCNJ10 lead to impaired channel function and structural changes in distal convoluted tubules. Intriguingly, the metabolic alkalosis present in patients carrying the R65P mutation possibly improves residual function of KCNJ10, which shows higher activity at alkaline pH. PMID:20651251

  3. 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 the disease

  4. Parallel fiber to Purkinje cell synaptic impairment in a mouse model of spinocerebellar ataxia type 27

    Directory of Open Access Journals (Sweden)

    Filippo eTempia

    2015-06-01

    Full Text Available Genetically inherited mutations in the fibroblast growth factor 14 (FGF14 gene lead to spinocerebellar ataxia type 27 (SCA27, an autosomal dominant disorder characterized by severe heterogeneous motor and cognitive impairments. Consistently, genetic deletion of Fgf14 in Fgf14-/- mice recapitulates salient features of the SCA27 human disease. In vitro molecular studies in cultured neurons indicate that the FGF14F145S SCA27 allele acts as a dominant negative mutant suppressing the FGF14 wild type function and resulting in inhibition of voltage-gated Na+ and Ca2+ channels. To gain insights in the cerebellar deficits in the animal model of the human disease, we applied whole-cell voltage-clamp in the acute cerebellar slice preparation to examine the properties of parallel fibers (PF to Purkinje neuron synapses in Fgf14-/- mice and wild type littermates. We found that the AMPA receptor-mediated excitatory postsynaptic currents evoked by PF stimulation (PF-EPSCs were significantly reduced in Fgf14-/- animals, while short-term plasticity, measured as paired-pulse facilitation (PPF, was enhanced. Measuring Sr2+-induced release of quanta from stimulated synapses, we found that the size of the PF-EPSCs was unchanged, ruling out a postsynaptic deficit. This phenotype was corroborated by decreased expression of VGLUT1, a specific presynaptic marker at PF-Purkinje neuron synapses. We next examined the mGluR1 receptor-induced response (mGluR1-EPSC that under normal conditions requires a gradual build-up of glutamate concentration in the synaptic cleft, and found no changes in these responses in Fgf14-/- mice. These results provide evidence of a critical role of FGF14 in maintaining presynaptic function at PF-Purkinje neuron synapses highlighting critical target mechanisms to recapitulate the complexity of the SCA27 disease.

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

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    Kevin Kemp

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

  6. Generation and characterisation of Friedreich ataxia YG8R mouse fibroblast and neural stem cell models.

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    Chiranjeevi Sandi

    Full Text Available BACKGROUND: Friedreich ataxia (FRDA is an autosomal recessive neurodegenerative disease caused by GAA repeat expansion in the first intron of the FXN gene, which encodes frataxin, an essential mitochondrial protein. To further characterise the molecular abnormalities associated with FRDA pathogenesis and to hasten drug screening, the development and use of animal and cellular models is considered essential. Studies of lower organisms have already contributed to understanding FRDA disease pathology, but mammalian cells are more related to FRDA patient cells in physiological terms. METHODOLOGY/PRINCIPAL FINDINGS: We have generated fibroblast cells and neural stem cells (NSCs from control Y47R mice (9 GAA repeats and GAA repeat expansion YG8R mice (190+120 GAA repeats. We then differentiated the NSCs in to neurons, oligodendrocytes and astrocytes as confirmed by immunocytochemical analysis of cell specific markers. The three YG8R mouse cell types (fibroblasts, NSCs and differentiated NSCs exhibit GAA repeat stability, together with reduced expression of frataxin and reduced aconitase activity compared to control Y47R cells. Furthermore, YG8R cells also show increased sensitivity to oxidative stress and downregulation of Pgc-1α and antioxidant gene expression levels, especially Sod2. We also analysed various DNA mismatch repair (MMR gene expression levels and found that YG8R cells displayed significant reduction in expression of several MMR genes, which may contribute to the GAA repeat stability. CONCLUSIONS/SIGNIFICANCE: We describe the first fibroblast and NSC models from YG8R FRDA mice and we confirm that the NSCs can be differentiated into neurons and glia. These novel FRDA mouse cell models, which exhibit a FRDA-like cellular and molecular phenotype, will be valuable resources to further study FRDA molecular pathogenesis. They will also provide very useful tools for preclinical testing of frataxin-increasing compounds for FRDA drug therapy

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

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    Ma Wei-Hsien

    2011-08-01

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

  8. Spinocerebellar ataxias type 8, 12, and 17 and dentatorubro-pallidoluysian atrophy in Czech ataxic patients.

    Science.gov (United States)

    Musova, Zuzana; Sedlacek, Zdenek; Mazanec, Radim; Klempir, Jiri; Roth, Jan; Plevova, Pavlina; Vyhnalek, Martin; Kopeckova, Marta; Apltova, Ludmila; Krepelova, Anna; Zumrova, Alena

    2013-04-01

    Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders currently associated with 27 genes. The most frequent types are caused by expansions in coding CAG repeats. The frequency of SCA subtypes varies among populations. We examined the occurrence of rare SCAs, SCA8, SCA12, SCA17 and dentatorubro-pallidoluysian atrophy (DRPLA), in the Czech population from where the data were missing. We analyzed causal gene expansions in 515 familial and sporadic ataxic patients negatively tested for SCA1-3 and SCA6-7. Pathogenic SCA8 and SCA17 expansions were identified in eight and five patients, respectively. Tay-Sachs disease was later diagnosed in one patient with an SCA8 expansion and the diagnosis of multiple sclerosis (MS) was suspected in two other patients with SCA8 expansions. These findings are probably coincidental, although the participation of SCA8 expansions in the susceptibility to MS and disease progression cannot be fully excluded. None of the patients had pathogenic SCA12 or DRPLA expansions. However, three patients had intermediate SCA12 alleles out of the normal range with 36 and 43 CAGs. Amyotrophic lateral sclerosis (ALS) was probable in the patient with 43 CAGs. This coincidence is remarkable, especially in the context with the recently identified predisposing role of longer SCA2 alleles in ALS. Five families with SCA17 represent a significant portion of ataxic patients and this should be reflected in the diagnostics of SCAs in the Czech population. SCA8 expansions must be considered after careful clinical evaluation. PMID:22872568

  9. Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases.

    Science.gov (United States)

    Kolnagou, Annita; Kontoghiorghe, Christina N; Kontoghiorghes, George J

    2014-12-26

    Thalassaemia major (TM) and Friedreich's ataxia (FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients. Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in

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

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    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

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

    Science.gov (United States)

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

    2013-11-01

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

  12. Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

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    Sara Anjomani Virmouni

    Full Text Available Friedreich ataxia (FRDA is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats, YG8R (90 and 190 GAA repeats and YG22R (190 GAA repeats.We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R.Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.

  13. A novel GAA-repeat-expansion-based mouse model of Friedreich’s ataxia

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    Sara Anjomani Virmouni

    2015-03-01

    Full Text Available Friedreich’s ataxia (FRDA is an autosomal recessive neurodegenerative disorder caused by a GAA repeat expansion mutation within intron 1 of the FXN gene, resulting in reduced levels of frataxin protein. We have previously reported the generation of human FXN yeast artificial chromosome (YAC transgenic FRDA mouse models containing 90–190 GAA repeats, but the presence of multiple GAA repeats within these mice is considered suboptimal. We now describe the cellular, molecular and behavioural characterisation of a newly developed YAC transgenic FRDA mouse model, designated YG8sR, which we have shown by DNA sequencing to contain a single pure GAA repeat expansion. The founder YG8sR mouse contained 120 GAA repeats but, due to intergenerational expansion, we have now established a colony of YG8sR mice that contain ~200 GAA repeats. We show that YG8sR mice have a single copy of the FXN transgene, which is integrated at a single site as confirmed by fluorescence in situ hybridisation (FISH analysis of metaphase and interphase chromosomes. We have identified significant behavioural deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8sR FRDA mice compared with control Y47R and wild-type (WT mice. We have also detected increased somatic GAA repeat instability in the brain and cerebellum of YG8sR mice, together with significantly reduced expression of FXN, FAST-1 and frataxin, and reduced aconitase activity, compared with Y47R mice. Furthermore, we have confirmed the presence of pathological vacuoles within neurons of the dorsal root ganglia (DRG of YG8sR mice. These novel GAA-repeat-expansion-based YAC transgenic FRDA mice, which exhibit progressive FRDA-like pathology, represent an excellent model for the investigation of FRDA disease mechanisms and therapy.

  14. Development of frataxin gene expression measures for the evaluation of experimental treatments in Friedreich's ataxia.

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    Heather L Plasterer

    Full Text Available BACKGROUND: Friedreich ataxia is a progressive neurodegenerative disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene and, ultimately, a deficiency in the levels of functional frataxin protein. Heterozygous carriers of the expansion express approximately 50% of normal frataxin levels yet manifest no clinical symptoms, suggesting that therapeutic approaches that increase frataxin may be effective even if frataxin is raised only to carrier levels. Small molecule HDAC inhibitor compounds increase frataxin mRNA and protein levels, and have beneficial effects in animal models of FRDA. METHODOLOGY/PRINCIPAL FINDINGS: To gather data supporting the use of frataxin as a therapeutic biomarker of drug response we characterized the intra-individual stability of frataxin over time, determined the contribution of frataxin from different components of blood, compared frataxin measures in different cell compartments, and demonstrated that frataxin increases are achieved in peripheral blood mononuclear cells. Frataxin mRNA and protein levels were stable with repeated sampling over four and 15 weeks. In the 15-week study, the average CV was 15.6% for protein and 18% for mRNA. Highest levels of frataxin in blood were in erythrocytes. As erythrocytes are not useful for frataxin assessment in many clinical trial situations, we confirmed that PBMCs and buccal swabs have frataxin levels equivalent to those of whole blood. In addition, a dose-dependent increase in frataxin was observed when PBMCs isolated from patient blood were treated with HDACi. Finally, higher frataxin levels predicted less severe neurological dysfunction and were associated with slower rates of neurological change. CONCLUSIONS/SIGNIFICANCE: Our data support the use of frataxin as a biomarker of drug effect. Frataxin levels are stable over time and as such a 1.5 to 2-fold change would be detectable over normal biological fluctuations. Additionally, our data support

  15. 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

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

    Science.gov (United States)

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

    1989-09-01

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

  17. Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after myocardial infarction.

    Science.gov (United States)

    Daniel, Laura L; Scofield, Stephanie L C; Thrasher, Patsy; Dalal, Suman; Daniels, Christopher R; Foster, Cerrone R; Singh, Mahipal; Singh, Krishna

    2016-08-01

    Ataxia telangiectasia-mutated kinase (ATM), a cell cycle checkpoint protein, is activated in response to DNA damage and oxidative stress. We have previously shown that ATM deficiency is associated with increased apoptosis and fibrosis and attenuation of cardiac dysfunction early (1-7 days) following myocardial infarction (MI). Here, we tested the hypothesis that enhanced fibrosis and apoptosis, as observed early post-MI during ATM deficiency, exacerbate cardiac dysfunction and remodeling in ATM-deficient mice late post-MI. MIs were induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Left ventricular (LV) structural and functional parameters were assessed by echocardiography 14 and 28 days post-MI, whereas biochemical parameters were measured 28 days post-MI. hKO-MI mice exhibited exacerbated LV dysfunction as observed by increased LV end-systolic volume and decreased percent fractional shortening and ejection fraction. Infarct size and thickness were not different between the two genotypes. Myocyte cross-sectional area was greater in hKO-MI group. The hKO-MI group exhibited increased fibrosis in the noninfarct and higher expression of α-smooth muscle actin (myofibroblast marker) in the infarct region. Apoptosis and activation of GSK-3β (proapoptotic kinase) were significantly lower in the infarct region of hKO-MI group. Matrix metalloproteinase 2 (MMP-2) expression was not different between the two genotypes. However, MMP-9 expression was significantly lower in the noninfarct region of hKO-MI group. Thus ATM deficiency exacerbates cardiac remodeling late post-MI with effects on cardiac function, fibrosis, apoptosis, and myocyte hypertrophy. PMID:27288435

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

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    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.

  19. Pharmacometabolomic signature of ataxia SCA1 mouse model and lithium effects.

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    Bertrand Perroud

    Full Text Available We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1 disease mouse model (Sca1(154Q/+. To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+ mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1(154Q/+ mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1(154Q/+ cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1(154Q/+ mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002, with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1(154Q/+ mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1(154Q/+ mice and restored upon lithium treatment, might relate to lithium neuroprotective properties.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-11-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1982-01-01

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

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

    LENUS (Irish Health Repository)

    Anheim, M

    2009-10-01

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

  3. A novel frameshift mutation in the AFG3L2 gene in a patient with spinocerebellar ataxia.

    Science.gov (United States)

    Musova, Zuzana; Kaiserova, Michaela; Kriegova, Eva; Fillerova, Regina; Vasovcak, Peter; Santava, Alena; Mensikova, Katerina; Zumrova, Alena; Krepelova, Anna; Sedlacek, Zdenek; Kanovsky, Petr

    2014-06-01

    Spinocerebellar ataxia type 28 (SCA28) is an autosomal dominant neurodegenerative disorder caused by missense AFG3L2 mutations. To examine the occurrence of SCA28 in the Czech Republic, we screened 288 unrelated ataxic patients with hereditary (N = 49) and sporadic or unknown (N = 239) form of ataxia for mutations in exons 15 and 16, the AFG3L2 mutation hotspots. A single significant variant, frameshift mutation c.1958dupT leading to a premature termination codon, was identified in a patient with slowly progressive speech and gait problems starting at the age of 68 years. Neurological examination showed cerebellar ataxia, mild Parkinsonian features with predominant bradykinesia, polyneuropathy of the lower limbs, and cognitive decline. However, other common SCA28 features like pyramidal tract signs (lower limb hyperreflexia, positive Babinski sign), ophthalmoparesis or ptosis were absent. The mutation was also found in a patient's unaffected daughter in whom a targeted examination at 53 years of age revealed mild imbalance signs. RNA analysis showed a decreased ratio of the transcript from the mutated AFG3L2 allele relative to the normal transcript in the peripheral lymphocytes of both patients. The ratio was increased by puromycin treatment, indicating that the mutated transcript can be degraded via nonsense-mediated RNA decay. The causal link between the mutation and the phenotype of the patient is currently unclear but a pathogenic mechanism based on AFG3L2 haploinsufficiency rather than the usual dominant-negative effect of missense AFG3L2 mutations reported in SCA28, cannot be excluded.

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

    Science.gov (United States)

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

    2012-03-01

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

  5. Localization of the candidate gene d-amino acid oxidase outside the refined 1-cM region of spinocerebellar ataxia 2

    Energy Technology Data Exchange (ETDEWEB)

    Auburger, G.; Gispert, S.; Lunkes, A. [Univ. Hospital, Duesseldorf (Germany)] [and others

    1995-10-01

    Spinocerebellar ataxia 2 (SCA2) is one form of the neurodegenerative autosomal dominant cerebellar ataxias and has been linked to chromosome 12q in 25 previously described and 13 new families from a founder collective of {ge}500 patients in Holguin, Cuba. Although SCA2 in most patients cannot be distinguished from other spinocerebellar ataxias by clinical criteria, in some patients it exhibits a particular phenotype with early neuropathy/late slow saccades and late myoclonus. Autopsy in 11 patients demonstrated olivo-ponto-cerebellar atrophy with a selective sparing of the dentate nucleus. Complete allelic association within the Holguin population was established with the microsatellite D12S105, and the candidate region was determined to be within a 6-cM region distal to the marker D12S84, contrasting previous reports by Pulst and Lopes-Cendes and according to preliminary data between D12S84 and D12S1329. 17 refs., 1 fig., 1 tab.

  6. Inverted duplication of JH associated with chromosome 14 translocation and T-cell leukemia in ataxia-telangiectasia.

    OpenAIRE

    Johnson, J P; Gatti, R A; Sears, T S; White, R. L.

    1986-01-01

    A specific 14q32 breakpoint is observed in a homologous chromosome 14 translocation [t(14;14)q12q32] occurring in the T-cells of about 10% of patients with ataxia-telangiectasia (AT). To investigate whether the 14q32 breakpoint in AT occurs within the immunoglobulin gene cluster as is frequently detected in B-cell lymphoma, immunoglobulin clones were hybridized to Southern blots of DNA isolated from the T-cells of two AT patients with this chromosome 14 translocation. The 14q32 translocation ...

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

    DEFF Research Database (Denmark)

    Duno, Morten; Wibrand, Flemming; Baggesen, Kirsten;

    2013-01-01

    The archetypal NARP syndrome is almost exclusively associated with the m.8993T>C/G mutation in the sixth subunit of the mitochondrial ATP synthase, whereas other mutations in the MT-ATP6 gene primarily associate with Leigh syndrome or Leber's hereditary optic neuropathy (LHON). We report a novel...... mitochondrial point mutation, m.8989G>C, in a patient presenting with neuropathy, ataxia and retinitis pigmentosa constituting the classical NARP phenotype. This mutation alters the amino acid right next to canonical NARP mutation. We suggest that classic NARP syndrome relates to a defined dysfunction of p...

  8. Monoclonal Gammopathy of Undetermined Significance (MGUS in a Man with Fragile X-associated Tremor/Ataxia Syndrome

    Directory of Open Access Journals (Sweden)

    Tanjung A. Sumekar

    2011-01-01

    Full Text Available We report the clinical presentation and laboratory findings of a 69-year-old man with fragile X-associated tremor ataxia syndrome (FXTAS, a progressive neurodegenerative disorder, who was noted to have monoclonal gammopathy of undetermined significance (MGUS, a plasma cell proliferative disorder and a precursor disease of multiple myeloma. Both MGUS and FXTAS are associated with microRNA (miRNA dysregulation. We speculate that individuals with FXTAS may be predisposed to MGUS and further studies are warranted regarding this association.

  9. Delayed-onset ataxia in mice lacking α-tocopherol transfer protein: Model for neuronal degeneration caused by chronic oxidative stress

    OpenAIRE

    Yokota, Takanori; Igarashi, Keiji; Uchihara, Toshiki; Jishage, Kou-ichi; Tomita, Hiroshi; Inaba, Akira; Li, Yi; Arita, Makoto; Suzuki, Hiroshi; Mizusawa, Hidehiro; Arai, Hiroyuki

    2001-01-01

    α-Tocopherol transfer protein (α-TTP) maintains the concentration of serum α-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating α-tocopherol export from the liver. Mutations of the α-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED). We produced a model mouse of AVED by deleting the α-TTP gene, which showed ataxia and retinal degeneration after 1 year of age. Because the brain α-TTP functions in maintainin...

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

    Directory of Open Access Journals (Sweden)

    Kaisa Kyöstilä

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

  11. TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia

    Science.gov (United States)

    Calap-Quintana, Pablo; Soriano, Sirena; Llorens, José Vicente; Al-Ramahi, Ismael; Botas, Juan; Moltó, María Dolores; Martínez-Sebastián, María José

    2015-01-01

    Friedreich’s ataxia (FRDA), the most common inherited ataxia in the Caucasian population, is a multisystemic disease caused by a significant decrease in the frataxin level. To identify genes capable of modifying the severity of the symptoms of frataxin depletion, we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. Furthermore, rapamycin reduced the altered levels of malondialdehyde + 4-hydroxyalkenals and total glutathione of the model flies. The rapamycin-mediated protection against oxidative stress is due in part to an increase in the transcription of antioxidant genes mediated by cap-n-collar (Drosophila ortholog of Nrf2). Our results suggest that autophagy is indeed necessary for the protective effect of rapamycin in hyperoxia. Rapamycin increased the survival and aconitase activity of model flies subjected to high oxidative insult, and this improvement was abolished by the autophagy inhibitor 3-methyladenine. These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment. PMID:26158631

  12. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

    Science.gov (United States)

    Gulsuner, Suleyman; Stapleton, Gail A.; Walsh, Tom; Lee, Ming K.; Mandell, Jessica B.; Morales, Augusto; Klevit, Rachel E.; King, Mary-Claire; Rogers, R. Curtis

    2016-01-01

    Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder. PMID:27551684

  13. Taltirelin improves motor ataxia independently of monoamine levels in rolling mouse nagoya, a model of spinocerebellar atrophy.

    Science.gov (United States)

    Nakamura, Tomoka; Honda, Motoko; Kimura, Satoko; Tanabe, Mitsuo; Oda, Sen-ichi; Ono, Hideki

    2005-12-01

    To examine the relationship between motor ataxia and monoamine levels in the central nervous system, the contents and concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the cerebellum, brain stem and spinal cord were measured in rolling mouse Nagoya (RMN), a murine model of spinocerebellar atrophy. The tissue weight of the cerebellum and spinal cord, but not that of the brain stem was significantly lower in RMN than in the control group. In RMN, the NA content of the brain stem and spinal cord, but not the cerebellum were decreased relative to the control, and the concentration of NA in the spinal cord was also lower, but not significant. The DA and 5-HT contents in each tissue did not differ from those of the control, but the concentrations of monoamines, except for DA, were elevated in the brain stem and spinal cord in RMN. In particular, the concentrations of NA, DA and 5-HT in the cerebellum were significantly increased in RMN. Repeated administration of tartilerin hydrate, an analog of thyrotropin-releasing hormone, improved the ataxia of RMN, and elicited no obvious changes in either monoamine content or concentration of cerebellum, brain stem and spinal cord. These results indicate that the concentration of DA, as well as NA and 5-HT, increased in the RMN cerebellum, and that tartilerin improves the motor function of these mice via mechanisms other than changes in the levels of NA, DA and 5-HT in the central nervous system.

  14. A gamma-ray-resistant derivative of an ataxia telangiectasia cell line obtained following DNA-mediated gene transfer

    International Nuclear Information System (INIS)

    Genomic DNA from normal human or mouse cells was transfected together with the selectable market gpt into the simian virus 40-transformed ataxia telangiectasia fibroblast line, AT5BIVA. From a series of experiments involving over 400 000 clones selected for the gpt marker, one unambiguously radiation-resistant clone (clone 67) was recovered following selection with repeated cyles of gamma irradiation. The normal level of radiation resistance of clone 67 has been maintained for at least 11 months in the absence of further selection by radiation. The resistant clone contains one copy of the gpt gene. Its DNA synthesis following gamma-radiation is inhibited to an extent intermediate between that of ataxia telangiectasia and normal cells. Three out of four thioguanine-resistant derivatives of clone 67 have either lost or do not express the gpt sequence and show almost the same sensitivity to gamma irradiation as the original AT5BIVA line. This suggests that the radiation resistance of clone 67 may be linked to the gpt sequence and may have arisen as a consequence of the transfection, rather than as the result of an independent mutation to radiation resistance. (author)

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

    Directory of Open Access Journals (Sweden)

    Zhao Chen

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

  16. Impaired vestibulo-ocular reflex (VOR) in spinocerebellar ataxia type 3 (SCA3): bedside and search coil evaluation.

    Science.gov (United States)

    Gordon, Carlos R; Zivotofsky, Ari Z; Caspi, Avi

    2014-01-01

    Vestibulo-Ocular Reflex (VOR) abnormalities in cerebellar ataxias are a matter of renewed interest. We have previously reported vestibular areflexia in a group of Yemenite-Jews with Spinocerebellar Ataxia Type 3 (SCA3) who had clear bilateral pathological horizontal Head Impulse Test (HIT). The objective of this study was to evaluate the VOR of ten SCA3 patients who have variable bedside HIT responses by recording their eye movements using magnetic search coils and to correlate these results with their clinical and genetic data. Eight out of the ten patients have abnormal horizontal HIT detected by both clinical bedside examination and laboratory tests. Results of bedside HIT testing were significantly correlated with the VOR gain recorded using magnetic search coils. No significant correlations were found between VOR gain and other clinical or genetic data. Our study confirms the presence of defective VOR in SCA3 patients and corroborates the useful of the HIT as a reliable bedside test for diagnosis of VOR deficits.

  17. Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1.

    Science.gov (United States)

    Platonov, Fedor A; Tyryshkin, Kathrin; Tikhonov, Dmitriy G; Neustroyeva, Tatyana S; Sivtseva, Tatyana M; Yakovleva, Natalya V; Nikolaev, Valerian P; Sidorova, Oksana G; Kononova, Sardana K; Goldfarb, Lev G; Renwick, Neil M

    2016-07-01

    Spinocerebellar ataxia type 1 (SCA1) is the major and likely the only type of autosomal dominant cerebellar ataxia in the Sakha (Yakut) people of Eastern Siberia. The prevalence rate of SCA1 has doubled over the past 21 years peaking at 46 cases per 100,000 rural population. The age at death correlates closely with the number of CAG triplet repeats in the mutant ATXN1 gene (r = -0.81); most patients with low-medium (39-55) repeat numbers survived until the end of reproductive age. The number of CAG repeats expands in meiosis, particularly in paternal transmissions; the average total increase in intergenerational transmissions in our cohort was estimated at 1.6 CAG repeats. The fertility rates of heterozygous carriers of 39-55 CAG repeats in women were no different from those of the general Sakha population. Overall, the survival of mutation carriers through reproductive age, unaltered fertility rates, low childhood mortality in SCA1-affected families, and intergenerational transmission of increasing numbers of CAG repeats in the ATXN1 gene indicate that SCA1 in the Sakha population will be maintained at high prevalence levels. The low (0.19) Crow's index of total selection intensity in our SCA1 cohort implies that this mutation is unlikely to be eliminated through natural selection alone. PMID:27106293

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

    Science.gov (United States)

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

    2016-08-01

    Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes. PMID:26662178

  19. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease.

    Science.gov (United States)

    Pierce, Sarah B; Gulsuner, Suleyman; Stapleton, Gail A; Walsh, Tom; Lee, Ming K; Mandell, Jessica B; Morales, Augusto; Klevit, Rachel E; King, Mary-Claire; Rogers, R Curtis

    2016-07-01

    Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder. PMID:27551684

  20. Identifying Niemann-Pick type C in early-onset ataxia: two quick clinical screening tools.

    Science.gov (United States)

    Synofzik, Matthis; Fleszar, Zofia; Schöls, Ludger; Just, Jennifer; Bauer, Peter; Torres Martin, Juan V; Kolb, Stefan

    2016-10-01

    Niemann-Pick disease type C (NP-C) is a rare multisystemic lysosomal disorder which, albeit treatable, is still starkly underdiagnosed. As NP-C features early onset ataxia (EOA) in 85-90 % of cases, EOA presents a promising target group for undiagnosed NP-C patients. Here, we assessed the ability of the previously established NP-C suspicion index (SI) and a novel abbreviated '2/3 SI' tool for rapid appraisal of suspected NP-C in unexplained EOA. This was a retrospective observational study comparing 'NP-C EOA' cases (EOA patients with confirmed NP-C) with non-NP-C EOA controls (EOA patients negative for NP-C gene mutations). NP-C risk prediction scores (RPS) from both the original and 2/3 SIs were calculated and their discriminatory performance evaluated. Among 133 patients (47 NP-C EOA cases; 86 non-NP-C EOA controls), moderate (40-69 points) and high (≥70 points) RPS were common based on original SI assessments in non-NP-C EOA controls [16 (19 %) and 8 (9 %), respectively], but scores ≥70 points were far more frequent [46 (98 %)] among NP-C EOA cases. RPS cut-off values provided 98 % sensitivity and 91 % specificity for NP-C at 70-point cut-off, and ROC analysis revealed an AUC of 0.982. Using the 2/3 SI, 90 % of NP-C EOA cases had scores of 2 or 3, and RPS analysis showed an AUC of 0.961. In conclusion, the NP-C SI and the new, quick-to-apply 2/3 SI distinguished well between NP-C and non-NP-C patients, even in EOA populations with high background levels of broadly NPC-compatible multisystemic disease features. While the original SI showed the greatest sensitivity, both tools reliably aided identification of patients with unexplained EOA who warranted further investigation for NP-C.

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

    Science.gov (United States)

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

    2007-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Zamba-Papanicolaou Eleni

    2008-04-01

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

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

    NARCIS (Netherlands)

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

    1995-01-01

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

  4. Advance in Molecular Genetics on Spinocerebellar Ataxia%脊髓小脑性共济失调的分子遗传学研究进展

    Institute of Scientific and Technical Information of China (English)

    谢春格; 谢秋幼; 李洵桦

    2008-01-01

    脊髓小脑性共济失调是一类单基因常染色体显性遗传病,不同的基因突变将导致不同的遗传亚型.随着分子遗传学技术的飞速发展,目前已经获得基因定位的有近30种亚型,多数是由于三核苷酸重复序列异常扩增引起.其中部分亚型的致病基因已被克隆.本文主要就新近发现的几种亚型作简要综述.%Spinocerebellar ataxia is a group of autosomal dominant and heterogeneous neurodegenerative disease. Different genetic mutation may cause different subtypes of spinocerbellar ataxia. Up to now, with the rapid development of molecular genetic study, nearly 30 mutated genes associated with various subtypes of spinocerebella ataxias have been located and some of them have been identified. Most of the mutated genes are caused by the abnormal expansion of trinucleotide. In this review, the clinical and genetic features of the recently identified spinocerebellar ataxias will be described.

  5. Ocular-motor profile and effects of memantine in a familial form of adult cerebellar ataxia with slow saccades and square wave saccadic intrusions.

    Science.gov (United States)

    Rosini, Francesca; Federighi, Pamela; Pretegiani, Elena; Piu, Pietro; Leigh, R John; Serra, Alessandro; Federico, Antonio; Rufa, Alessandra

    2013-01-01

    Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI) and macrosaccadic oscillations (MSO). A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI). We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°-18°) and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly), but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich's, in which saccadic intrusions are prominent.

  6. Ocular-motor profile and effects of memantine in a familial form of adult cerebellar ataxia with slow saccades and square wave saccadic intrusions.

    Directory of Open Access Journals (Sweden)

    Francesca Rosini

    Full Text Available Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI and macrosaccadic oscillations (MSO. A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI. We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°-18° and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly, but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich's, in which saccadic intrusions are prominent.

  7. Canine hereditary ataxia in old english sheepdogs and gordon setters is associated with a defect in the autophagy gene encoding RAB24.

    Directory of Open Access Journals (Sweden)

    Caryline Agler

    2014-02-01

    Full Text Available Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.

  8. Clinical Analysis of 13 Cases with Cerebellar Ataxia%小脑性共济失调13例病例报道

    Institute of Scientific and Technical Information of China (English)

    施韵; 干静; 陈伟; 刘振国

    2011-01-01

    目的:探讨以进行性小脑性共济失调为主要临床症状的疾病诊断.方法:回顾性分析13例以慢性进行性小脑共济失调为主要临床表现患者的临床资料、实验室、影像学和基因检查结果.结果:13例患者中,脊髓小脑性共济失调3例,多系统萎缩-小脑型6例,小脑肿瘤1例,桥小脑结合臂脓肿1例,小脑梗死后遗症2例.结论:对于以进行性小脑共济失调为主要体征的患者,临床上首先要排除占位性病变,其次多系统萎缩和脊髓小脑性共济失调为主要的遗传变性病因.%Aim: To investigate the diagnosis for the diseases that present with progressive cerebellar ataxia Methods : The data of 13 cases manifesting with cerebellar ataxia as a main clinical feature, including clinical data laboratory data and images, were analyzed. Results: Among 13 cases, 3 cases were spinocerebellar ataxia (SCA) , 6 cases MSA with predominant cerebellar ataxia (MSA-C) , 1 case cerebellar tumor, 1 case pontocerebellar brachium abscess and 2 cases with sequela of cerebellar infarction. Conclusion : For the patients with cerebellar ataxia as the main signs, space-occupying lesions should be first excluded. And then MSA and SCA may be the main degenerative and genetic causes.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-15

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

  10. Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1 Características clínicas e moleculares de uma família Brasileira com ataxia espinocerebelar tipo 1

    Directory of Open Access Journals (Sweden)

    Iscia Lopes-Cendes

    1996-09-01

    Full Text Available The spinocerebellar ataxias (SCAs are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped: SCA1, SCA2, Machado-Joseph disease (MJD/SCA3, SCA4, SCA5, SCA7 and dentatorubropallidoluysian atrophy (DRPLA. Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.As ataxias espinocerebelares (AECs fazem parte de um grupo de doenças neurodegenerativas que apresentam grande heterogeneidade clínica e genética. Existem até o momento sete genes mapeados responsáveis pelas AECs de transmissão autossômica dominante: SCA1, SCA2, doença de Machado-Joseph (DA/7 ou SCA3, SCA4, SCA5, SCA7 e atrofia dentatorubropalidoluisiana (ADRPL. Uma expansão de um trínucletídeo CAG foi identificada como a mutação responsável na SCA], DMJ e ADRPL. Estudamos uma família brasileira com uma forma autossômica dominante de AEC. Dez indivíduos foram examinados e

  11. A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze Family.

    Science.gov (United States)

    Delague, Valérie; Bareil, Corinne; Bouvagnet, Patrice; Salem, Nabiha; Chouery, Eliane; Loiselet, Jacques; Mégarbané, André; Claustres, Mireille

    2002-03-01

    Congenital cerebellar ataxias are a heterogeneous group of non-progressive disorders characterized by hypotonia and developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We report the mapping of a disease gene in a large inbred Lebanese Druze family, with five cases of a new form of non-progressive autosomal recessive congenital ataxia associated with optic atrophy, severe mental retardation, and structural skin abnormalities, to a 3.6-cM interval on chromosome 15q24-15q26.

  12. A Mutation in the Golgi Qb-SNARE Gene GOSR2 Causes Progressive Myoclonus Epilepsy with Early Ataxia

    Science.gov (United States)

    Corbett, Mark A.; Schwake, Michael; Bahlo, Melanie; Dibbens, Leanne M.; Lin, Meng; Gandolfo, Luke C.; Vears, Danya F.; O'Sullivan, John D.; Robertson, Thomas; Bayly, Marta A.; Gardner, Alison E.; Vlaar, Annemarie M.; Korenke, G. Christoph; Bloem, Bastiaan R.; de Coo, Irenaeus F.; Verhagen, Judith M.A.; Lehesjoki, Anna-Elina; Gecz, Jozef; Berkovic, Samuel F.

    2011-01-01

    The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi. PMID:21549339

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

    Directory of Open Access Journals (Sweden)

    Susanne K. Hansen

    2016-05-01

    Full Text Available 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, SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of genomically integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vitro and retained the disease-causing ATXN3 mutation. This iPSC line could be useful for the investigation of SCA3 disease mechanisms.

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

    Directory of Open Access Journals (Sweden)

    Susanne K. Hansen

    2016-05-01

    Full Text Available 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-MYC, LIN28, SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vitro and retained the disease-causing ATXN3 mutation. Potentially, this iPSC line could be a useful tool for the investigation of SCA3 disease mechanisms.

  15. Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.

    Science.gov (United States)

    Haack, Tobias B; Ignatius, Erika; Calvo-Garrido, Javier; Iuso, Arcangela; Isohanni, Pirjo; Maffezzini, Camilla; Lönnqvist, Tuula; Suomalainen, Anu; Gorza, Matteo; Kremer, Laura S; Graf, Elisabeth; Hartig, Monika; Berutti, Riccardo; Paucar, Martin; Svenningsson, Per; Stranneheim, Henrik; Brandberg, Göran; Wedell, Anna; Kurian, Manju A; Hayflick, Susan A; Venco, Paola; Tiranti, Valeria; Strom, Tim M; Dichgans, Martin; Horvath, Rita; Holinski-Feder, Elke; Freyer, Christoph; Meitinger, Thomas; Prokisch, Holger; Senderek, Jan; Wredenberg, Anna; Carroll, Christopher J; Klopstock, Thomas

    2016-09-01

    SQSTM1 (sequestosome 1; also known as p62) encodes a multidomain scaffolding protein involved in various key cellular processes, including the removal of damaged mitochondria by its function as a selective autophagy receptor. Heterozygous variants in SQSTM1 have been associated with Paget disease of the bone and might contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using exome sequencing, we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation. Our findings expand the SQSTM1-associated phenotypic spectrum and lend further support to the concept of disturbed selective autophagy pathways in neurodegenerative diseases. PMID:27545679

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

    DEFF Research Database (Denmark)

    Bech, Sara; Petersen, Thor; Nørremølle, Anne;

    2010-01-01

    tract in the respective proteins. SCA17 is caused by a CAG/CAA repeat expansion in the TATA box-binding protein-gene (TBP). In some cases the clinical phenotype of SCA17 overlaps that of Huntington's disease (HD), hence the use of the term Huntington's disease-like. We screened 89 patients...... with a Huntington's disease-like phenotype without the HD-gene mutation and 178 patients with genetically unclassified cerebellar ataxia for the mutation in TBP. A 33-year old woman presenting with an HD like phenotype with a de novo 54 CAG/CAA repeat expansion was identified. Her normal allele included 38 repeats....... The patient's mother and father both carried normal range repeats, 38/38 and 33/39 respectively. Analysis of the repeat structures revealed that the expansion had occurred upon expansion of the longer paternal allele. We conclude that, however rare, SCA17 must be considered as a cause of Huntington's disease...

  17. Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase.

    Science.gov (United States)

    Degorce, Sébastien L; Barlaam, Bernard; Cadogan, Elaine; Dishington, Allan; Ducray, Richard; Glossop, Steven C; Hassall, Lorraine A; Lach, Franck; Lau, Alan; McGuire, Thomas M; Nowak, Thorsten; Ouvry, Gilles; Pike, Kurt G; Thomason, Andrew G

    2016-07-14

    A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model. PMID:27259031

  18. Does Ataxia Telangiectasia Mutated (ATM) protect testicular and germ cell DNA integrity by regulating the redox status?

    Science.gov (United States)

    Godschalk, Roger W L; Vanhees, Kimberly; Maas, Lou; Drittij, Marie-Jose; Pachen, Daniëlle; van Doorn-Khosrovani, Sahar van Waalwijk; van Schooten, Frederik J; Haenen, Guido R M M

    2016-08-01

    A balanced redox homeostasis in the testis is essential for genetic integrity of sperm. Reactive oxygen species can disturb this balance by oxidation of glutathione, which is regenerated using NADPH, formed by glucose-6-phosphate dehydrogenase (G6PDH). G6PDH is regulated by the Ataxia Telangiectasia Mutated (Atm) protein. Therefore, we studied the redox status and DNA damage in testes and sperm of mice that carried a deletion in Atm. The redox status in heterozygote mice, reflected by glutathione levels and antioxidant capacity, was lower than in wild type mice, and in homozygotes the redox status was even lower. The redox status correlated with oxidative DNA damage that was highest in mice that carried Atm deletions. Surprisingly, G6PDH activity was highest in homozygotes carrying the deletion. These data indicate that defective Atm reduces the redox homeostasis of the testis and genetic integrity of sperm by regulating glutathione levels independently from G6PDH activity. PMID:27318254

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

    International Nuclear Information System (INIS)

    The production and repair of double strand breaks induced by γ-rays in the DNA of human fibroblasts have been measured by sedimentation in sucrose gradients under non-denaturing conditions. Unirradiated DNA formed a rapidly sedimenting gel. Low doses of radiation released freely sedimenting DNA molecules from this gel. Higher doses reduced the rate of sedimentation of the free DNA due to the introduction of double strand breaks. The breakage efficiency was 1 break/1.3x1010 daltons of DNA/krad. Postirradiation incubation after a high dose of radiation resulted in an increase in molecular weight of the free DNA molecules, and after a low dose the rapidly-sedimenting gel was reformed. These data suggest that double strand breaks are repaired in human fibroblasts. No significant differences were found between fibroblasts from two normal donors and four patients with the radiosensitive disorder, ataxia telangiectasia, in either the production or repair of double strand breaks

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

    International Nuclear Information System (INIS)

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

  1. Occupational therapy intervention to inspire self-efficacy in a patient with spinal ataxia and visual disturbance.

    Science.gov (United States)

    Tohyama, Satsuki; Usuki, Fusako

    2015-02-09

    We report a case of a patient with severe ataxia and visual disturbance due to vitamin E deficiency, whose self-efficacy was inspired by intervention with an appropriate occupational therapy activity. Before the handloom intervention, her severe neurological deficits decreased her activities of daily living (ADL) ability, which made her feel pessimistic and depressed. The use of a handloom, however, inspired her sense of accomplishment because she could perform the weft movement by using her residual physical function, thereby relieving her pessimistic attitude. This perception of capability motivated her to participate in further rehabilitation. Finally, her eager practice enhanced her ADL ability and quality of life (QOL). The result suggests that it is important to provide an appropriate occupational therapy activity that can inspire self-efficacy in patients with chronic refractory neurological disorders because the perception of capability can enhance the motivation to improve performance in general activities, ADL ability and QOL.

  2. 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.

  3. 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)

  4. 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.

  5. Síndrome opsoclono-mioclono-atáxico paraneoplásico Paraneoplastic opsoclonus myoclonus ataxia syndrome

    Directory of Open Access Journals (Sweden)

    S. Aguilera

    2009-04-01

    Full Text Available El síndrome opsoclono-mioclono-atáxico (SOMA es un trastorno del movimiento muy infrecuente, de origen autoinmune y de aparición a cualquier edad, más probable entre los 6-36 meses. Se presenta el caso de una niña de 30 meses, previamente sana, que desarrolló progresivamente en cuatro días marcha inestable, temblor intencional, habla escandida, irritabilidad y trastorno del sueño. El resto de la exploración física y neurológica era normal. Presentó exantema leve tres semanas antes. Al ingreso, la analítica general, cultivos, tóxicos en orina, serologías, electroencefalograma y tomografía cerebral (TC fueron normales. La punción lumbar mostró linforraquia leve. Al quinto día desde el inicio, la ataxia impedía la sedestación y el temblor era generalizado agravado probablemente por mioclonias intencionales. Aparecieron entonces movimientos oculares rápidos, sacádicos, multidireccionales, aunque conjugados. Ante el diagnóstico de opsoclono, se solicitó radiografía de tórax observando una masa torácica paravertebral, corroborada en la TC torácica. La cirugía confirmó un ganglioneuroblastoma localizado. La enolasa neuronal específica en sangre y catecolaminas en orina fueron normales. El opsoclono desapareció con prednisona oral a altas dosis y tras cirugía. Un año después precisaba dosis mínima de corticoide por aparición de leve inestabilidad de la marcha e irritabilidad al suspender la medicación.Opsoclonus myoclonus ataxia syndrome (OMAS is a very infrequent paraneoplastic or postinfectious movement disorder, which may occur at any age, most commonly between 6 and 36 months of age. In four days, a previously healthy 30-month-old girl progressively developed gait instability, intention tremor, dysarthric speech, irritability and altered sleep. Physical and neurological examination did not reveal additional deficits. She had had a transient exanthema without fever three weeks before. Basic blood analysis

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

    Directory of Open Access Journals (Sweden)

    Dörte Poburski

    2016-05-01

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

  7. The Walk on Floor Eyes Closed Tandem Step Test as a Quantitative Measure of Ataxia After Space Flight

    Science.gov (United States)

    Fisher, E. A.; Reschke, M. F.; Kofman, I. S.; Cerisano, J. M.; Lawrence, E. L.; Peters, B. T.; Bloomberg, J. J.; Harm, D. L.

    2010-01-01

    INTRODUCTION Posture and locomotion are among the functions most affected by space flight. Postflight ataxia can be quantified easily by using the walk on the floor line test with the eyes closed (WOFEC). Data from a modified WOFEC were obtained as part of an ongoing interdisciplinary pre- and postflight study (Functional Task Test, FTT) designed to evaluate both postflight functional performance of astronauts and related physiological changes. METHODS Five astronauts with flight durations of 12 to 16 days participated in this study. Performance measurements were obtained in 2 preflight sessions, on landing day, and 1, 6, and 30 days after landing. The WOFEC test consisted of walking with the feet placed heel to toe in tandem, arms folded across the chest and eyes closed, for 10 steps. A trial was initiated after the eyes were closed and the front foot was aligned with the rear foot. The performance metric was the average percentage of correct steps completed over 3 trials. A step was not counted as correct if the crewmember sidestepped, opened eyes, or paused for more than 3 seconds between steps. Step accuracy was scored independently by 3 examiners. RESULTS Immediately after landing subjects seemed to be unaware of their foot position relative to their body or the floor. The percentage of correct steps was significantly decreased on landing day. Partial recovery was observed the next day, and full recovery to baseline on the sixth day post landing. CONCLUSION These data clearly demonstrate the sensorimotor challenges facing crewmembers after they return from space flight. Although this simple test is intended to complement the FTT battery of tests, it has some stand-alone value as it provides investigators with a means to quantify vestibular ataxia as well as provide instant feedback on postural stability without the use of complex test equipment.

  8. The insulin-like growth factor pathway is altered in Spinocerebellar ataxia type 1 and type 7

    Energy Technology Data Exchange (ETDEWEB)

    Gatchel, Jennifer R.; Watase, Kei; Thaller, Christina; Carson, James P.; Jafar-Nejad, Paymaan; Shaw, Chad A.; Zu, Tao; Orr, Harry T.; Zoghbi, Huda Yahya

    2008-01-29

    Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG trinucleotide repeats encoding a polyglutamine tract in the disease-causing proteins. There are nine of these disorders each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with corresponding degeneration of Purkinje cells. Given this common phenotype, we asked whether the two disorders share common molecular pathogenic events. To address this question we studied two genetically accurate mouse models of SCA1 and SCA7—Sca1154Q/2Q and Sca7266Q/5Q knock-in mice—that express the glutamine-expanded proteins from the respective endogenous loci. We found common transcriptional changes in early symptomatic mice, with downregulation of Insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust transcriptional changes that closely correlates with disease state. Interestingly, down-regulation of Igfbp5 occurred in granule neurons through a non-cell autonomous mechanism and was concomitant with activation of the Insulin-like growth factor I (Igf-I) pathway, and, in particular, the Igf-I receptor, expressed in part on Purkinje cells (PC). These data define a possible common pathogenic response in SCA1 and SCA7 and reveal the importance of neuron-neuron interactions in SCA1 and SCA7 pathogenesis. The sensitivity of Igfbp5 levels to disease state could render it and other components of its effector pathway useful as biomarkers in this class of diseases.

  9. Clinical Insights on Adult-onset Sporadic Ataxias%成人发病的散发性共济失调症临床诊疗

    Institute of Scientific and Technical Information of China (English)

    张颖冬

    2015-01-01

    Adult-onset sporadic ataxias are a group of disorders manifested predominantly with ataxia, due to a variety of the potential causes including intoxication, immune-mediation, vitamins deifciencies, infections, neurodegeneration, and even some hereditary conditions. The clinical spectrum of these disorders is diverse, and their diagnosis remains a challenge. Compared with hereditary ataxias, most ataxias in this group respond the treatment well, that means the signiifcance of timely and correct diagnosis. The advanced biochemical, immune and imaging tools will help the perception and management on those ataxias. Different categories of adult-onset sporadic ataxia were elucidated with the highlight on their clinical features, neuro-imagingand diagnostic criteria.%成人发病的散发性共济失调症是由多种原因所致,临床表现以共济失调为主要的多种疾病。致病原因包括中毒、免疫介导性、维生素缺乏、感染性疾病、变性病以及遗传性疾患等。散发性共济失调临床谱具有明显异质性,临床正确诊断极具挑战性。但相比于遗传性共济失调症,此类疾患多数治疗效果较好,及时、正确诊断尤为重要。现代生化、免疫以及影像学技术有助于此类疾患的认识和诊治。文中综述并讨论可致成人发病的散发性共济失调的不同疾病分类,并着重其临床和神经影像学表现及诊断标准。

  10. Preserved Glucose Metabolism of Deep Cerebellar Nuclei in a Case of Multiple System Atrophy with Predominant Cerebellar Ataxia: F-18 Fluorodeoxyglucose Positron Emission Tomography Study

    Directory of Open Access Journals (Sweden)

    Oh Dae Kwon

    2010-10-01

    Full Text Available The cerebellar glucose metabolism of multiple system atrophy with predominant cerebellar ataxia (MSA-C is known to be decreased but is not defined among areas of cerebellum. We encountered a 54-year-old man who developed dizziness and progressive ataxia followed by urinary incontinence and orthostatic hypotension, all of those symptoms progressed relentlessly and the symptoms responded poorly to levodopa therapy. Visual analysis and statistical parametric mapping analysis of F-18 fluorodeoxyglucose positron emission tomography showed hypometabolism of both cerebellar hemisphere, severe at cortical area, and pons. There was clear sparing of deep cerebellar nuclei. Our report, as we know, shows the first case of preserved glucose metabolism of deep cerebellar nuclei relative to cerebellar cortex in an MSA-C patient.

  11. An enzyme activity in normal and ataxia telangiectasia cell lines which is involved in the repair of γ-irradiation-induced DNA damage

    International Nuclear Information System (INIS)

    An enzyme that enhances the activity of DNA polymerase I (EC 2.7.7.7) for γ-irradiated calf thymus DNA was demonstrated in cellular extracts of normal human fibroblasts and lymphoid-cell lines. This enzyme was found to be deficient in all cellular extracts of fibroblasts and lymphoid-cell lines examined from patients with the autosomal recessive disease ataxia telangiectasia. The activity in cellular extracts from normal fibroblasts was removed when heated to 1000C for 2 min or when the assay was performed at 40C. No significant deficiency in primer activating enzyme activity was observed in cell-free extracts of lymphoid lines from patients with xeroderma pigmentosum, Huntington's chorea or neurofibromatosis, or from an ataxia telangiectasia heterozygote. (author)

  12. 脊髓小脑性共济失调一家系的遗传学研究%Genetics of a Chinese family with spinocerebellar ataxia

    Institute of Scientific and Technical Information of China (English)

    刘丹; 郭洪; 王凯; 白云

    2011-01-01

    Objective To do genetic diagnosis of an autosomal dominant spinocerebellar ataxia family and discuss its clinical characteristics. Methods Familial investigation and pedigree analysis were per formed. The duplicate number of tri-nucleotides in pathogenic CAG was detected by polymerase chain reaction (PCR) and direct DNA sequencing in the family members. Results Autosomal dominant heredity was found in this family. Clinical symptoms such as gait, dysphagia and slurred speech occurred in three spinocerebellar ataxia patients of the family at the age of over 30 years. Genetic diagnosis of spinocerebellar ataxia showed that the CAG duplicate number of SCA2 and SCA3 was normal in all the family members of spinocerebellar ataxia patients, and abnormal allelic gene SCA1 was detected in 3 spinocerebellar ataxia patients. The CAG was amplified 43, 48, and 51 times, respectively, and amplified 53 and 50 times for another 2 members of the family who were diagnosed as presymptomatic SCA1. Conclusion Type 1 spinocerebellar ataxia can be diagnosed in the family members of spinocerebellar ataxia patients according to their autosomal dominant heredity caused by dynamic mutations. Genetic diagnosis can be established in 2 presymptomatic SCA1 patients of the family.%目的 对一个常染色体显性遗传的脊髓小脑共济失调家系(spinocerebellar ataxias,SCA)进行基因诊断并探讨其临床特点.方法 完成家系调查和系谱分析,通过聚合酶链式反应和直接测序的方法 对收集到的家系成员进行脊髓小脑性共济失调致病基因CAG三核苷酸重复数目的 检测.结果 该家系呈常染色体显性遗传模式,家系中3名患者均于30岁后逐渐表现为行走不稳、饮水呛咳、言语不清等共济失调的临床特征.对所有家系成员进行基因诊断,结果 发现,SCA2和SCA3致病基因的CAG重复数目均在正常范围内;而家系中3名患者SCA1致病基因出现异常等位基因,CAG扩增次数分别为43、48

  13. Location of the spinal cerebellar ataxia 2 locus to a 1 cM interval on chromsome 12q23-24.1

    Energy Technology Data Exchange (ETDEWEB)

    Allotey, R.; Twells, R.; Orozco, G. [Imperial College, London (United Kingdom)] [and others

    1994-09-01

    Spinocerebellar ataxia 2 (SCA2) is a dominantly inherited neurodegenerative disorder characterised by progressive ataxia, dysarthria, dysmetria and dysdiadochokinesia. We have previously assigned the disease locus to chromosome 12q23-24.1 in a population from the Holguin province, Cuba, within a 31 cM interval flanked by the anonymous marker D12S53 and the phospholipase A2 gene (PLA2). Clinical as much as genealogical and geographical evidence indicate that the Cuban pedigrees are homogeneous and descend from a common ancestor. We now report fine genetic mapping of the disease locus with fourteen microsatellite loci known to span this region, which positions SCA2 in a 1 cM interval defined by the loci D12S84-AFM291xe9. Observation of a common haplotype segregating with the disease supports the existence of a founder effect in the Holguin pedigrees.

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

    OpenAIRE

    Graaf, A. de; De Jong, G; Kleijer, Wim

    1995-01-01

    textabstractWe report a family of 4 siblings from a non-consanguineous marriage, presenting with an early onset recessive cerebellar ataxia and progressive distal limb wasting. Ocular or other telangiectasias were absent. There were neither frequent infections nor immunodeficiencies. The two youngest patients exhibited an incapacitating myoclonus which abated markedly after 20 years. Late onset diabetes was demonstrated in 3 patients. Hypogonadism was not a feature and there was a prolonged s...

  15. A derivative of an ataxia-telangiectasia (A-T) cell line with normal radiosensitivity but A-T-like inhibition of DNA synthesis

    International Nuclear Information System (INIS)

    Ataxia-telangiectasia (A-T) cells are hypersensitive to the lethal effects of ionizing radiation and fail to inhibit DNA synthesis following radiation exposure. A cell line derived from an A-T line following DNA-mediated gene transfer has normal radiation sensitivity, but the kinetics of DNA synthesis after γ-irradiation are similar to those of A-T cells. (author)

  16. Increased Prevalence 12308 A > G mutation in Mitochondrial tRNALeu (CUN Gene Associated with earlier Age of Onset in Friedreich Ataxia

    Directory of Open Access Journals (Sweden)

    Mohammad Medhi HEIDARI

    2011-12-01

    Full Text Available How to Cite this Article: Heidari MM, Khatami M, Houshmand M, Mahmoudi E, Nafissi Sh .Increased Prevalence 12308 A > G mutation in MitochondrialtRNALeu (CUN Gene Associated with earlier Age of Onset in Friedreich Ataxia. Iranian Journal of Child Neurology 2011;5(4:25-31.Objective Friedreich ataxia (FRDA is an inherited recessive disorder. Mitochondrial DNA is a candidate modifying factor for FRDA.The purpose of this study was to investigate the relationship between the tRNALeu (CUN 12308 A> G mutation and age of onset in Friedreich ataxia.Materials & Methods The 12308 A> G substitution in mitochondrial tRNALeu (CUN was examined in DNA samples from 30 Friedreich ataxia patients and 48 control subjects by temporal temperature gradient gel electrophoresis (TTGE and sequencing. Logistic regression was used to determine of cutoff age of onset.ResultsTwenty-two patients had the 12308 A> G mutation, and we found that its overall prevalence was significantly higher in 20 patients aged 17 years or younger than in 2 patients aged over 17 years (90% versus 10%. The 12308 A> G mutation lies in a region that has been highly conserved between species.Conclusion Our results show that the 12308 A > G mutation is associated with earlier age of onset in Friedreich ataxia. Thus, this mutation might cause the younger age of onset in FRDA.References Grabczyk E, Usdin K. The GAA*TTC triplet repeat expanded in Friedreich ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner. Nucleic Acids Res 2000;28(14:2815-22.Sakamoto N, Chastain PD, Parniewski P, Ohshima K, Pandolfo M, Griffith JD, et al. Sticky DNA: self association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich ataxia. Mol Cell1999;3(4:465-75.Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ, et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A 1999

  17. Treatment for Hereditary Spinocerebellar Ataxia from Spleen and Stomach%从脾胃论治遗传性脊髓小脑其济失调

    Institute of Scientific and Technical Information of China (English)

    郑倩茹; 白金凤; 黄慧

    2013-01-01

    遗传性脊髓小脑共济失调属神经系统遗传性疾病,西医学目前尚无有效治疗方法,针刺作为治疗该病的手段之一,取得了一定的临床疗效.近年来针刺治疗共济失调的文献报道较多,但是针对遗传性共济失调的研究则相对较少.本文从脾胃立论,阐释脾胃与脑的关系,提出从脾胃论治该病,针刺选穴以调节脾胃气机升降为主,兼顾调理大小肠功能,为临床治疗遗传性共济失调提供思路,也为临床治疗遗传性脑病提供参考.%Genetic spinocerebellar ataxia is a kind of genetic disease of the nervous system, western medicine has no effective treatment method for this disease at present. Acupuncture is as one of the treatment methods, which has obtained a certain effect. A lot of reports about acupuncture therapy for ataxia have been published in recent years, but the reports which emphasize on genetic spinocerebellar ataxia is relatively less. This article focuses on spleen and stomach, expounding the relationship of spleen, stomach and cerebrum, putting forward the conclusion that emphasize on spleen and stomach to treat this disease. Treatment principle is regulating the movement of spleen Qi and stomach Qi, adjusting the function of large intestine and small intestine at the same time. We expect to provide a method for clinic to treat genetic spinocerebellar ataxia, and offer a reference to treat the genetic cerebrum disease.

  18. 遗传性小脑共济失调的MRI表现附2个家系报告%MRI Findings of Hereditary Cerebellar Ataxia

    Institute of Scientific and Technical Information of China (English)

    董江宁; 刘啸峰; 马力

    2004-01-01

    遗传性小脑共济失调(hereditary cerebellar ataxia,HCA),又称遗传性痉挛性共济失调(hereditary spastic ataxia,HSA),属介于脊髓型至脑干小脑型及小脑型之间的遗传性共济失调(hereditary ataxia,HA),包括Sanger-Brown型、橄榄桥脑小脑萎缩(olivopontocerebellar atrophy,

  19. "ATP1A3" Mutations in Infants: A New Rapid-Onset Dystonia-Parkinsonism Phenotype Characterized by Motor Delay and Ataxia

    Science.gov (United States)

    Brashear, Allison; Mink, Jonathan W.; Hill, Deborah F.; Boggs, Niki; McCall, W. Vaughn; Stacy, Mark A.; Snively, Beverly; Light, Laney S.; Sweadner, Kathleen J.; Ozelius, Laurie J.; Morrison, Leslie

    2012-01-01

    We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the "ATP1A3" gene. In adults, mutations in "ATP1A3" cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and…

  20. An altered GABA-A receptor function in spinocerebellar ataxia type 6 and familial hemiplegic migraine type 1 associated with the CACNA1A gene mutation

    Directory of Open Access Journals (Sweden)

    Satoshi Kono

    2014-12-01

    General significance: An altered GABA-A receptor function has previously been reported in models of inherited murine cerebellar ataxia caused by a mutation in the CACNA1A gene. This study showed novel clinical characteristics of alteration in the GABA-A receptor in vivo, which may provide clinical evidence indicating a pathological mechanism common to neurological disorders associated with CACNA1A gene mutation.