WorldWideScience

Sample records for ataxia

  1. Ataxia.

    Science.gov (United States)

    Ashizawa, Tetsuo; Xia, Guangbin

    2016-08-01

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

  2. Ataxia.

    Science.gov (United States)

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

    2013-01-01

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

  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. Ataxia - telangiectasia

    Science.gov (United States)

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

  5. 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 ...

  6. 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

  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, particularly younger than age 3, may occur several weeks after an illness caused by a virus. ...

  8. Friedreich ataxia.

    Science.gov (United States)

    Pandolfo, Massimo

    2008-10-01

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

  9. Cerebellar Ataxia.

    Science.gov (United States)

    Perlman

    2000-05-01

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

  10. Trial in Adult Subjects With Spinocerebellar Ataxia

    Science.gov (United States)

    2017-08-22

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

  11. Friedreich's Ataxia Research Alliance

    Science.gov (United States)

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

  12. Dystonia and ataxia progression in spinocerebellar ataxias.

    Science.gov (United States)

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

    2017-10-23

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

  13. Milestones in ataxia

    Science.gov (United States)

    Klockgether, Thomas; Paulson, Henry

    2010-01-01

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

  14. Genetics Home Reference: episodic ataxia

    Science.gov (United States)

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

  15. What Is Ataxia-Telangiectasia?

    Science.gov (United States)

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

  16. Canine hereditary ataxia.

    Science.gov (United States)

    Urkasemsin, Ganokon; Olby, Natasha J

    2014-11-01

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

  17. Speech in spinocerebellar ataxia.

    Science.gov (United States)

    Schalling, Ellika; Hartelius, Lena

    2013-12-01

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

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

    Science.gov (United States)

    2017-09-05

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

  19. Brain pathology of spinocerebellar ataxias

    NARCIS (Netherlands)

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

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

  20. Childhood Cerebellar Ataxia

    Science.gov (United States)

    Fogel, Brent L.

    2012-01-01

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

  1. 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.

  2. Ataxia-Telangiectasia

    OpenAIRE

    J Gordon Millichap

    1990-01-01

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

  3. Genetics Home Reference: ataxia-telangiectasia

    Science.gov (United States)

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

  4. Genetics Home Reference: ataxia-pancytopenia syndrome

    Science.gov (United States)

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

  5. Sleep disorders in cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    José L. Pedroso

    2011-04-01

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

  6. Spinocerebellar ataxia 13 and 25.

    Science.gov (United States)

    Stevanin, Giovanni; Dürr, Alexandra

    2012-01-01

    Spinocerebellar ataxia (SCA) types 13 and 25 are two genetic entities among the autosomal dominant cerebellar ataxias, initially mapped in two French families to chromosomes 19q and 2p, respectively. The SCA13 locus was confirmed by the identification of a second kindred of Filipino ancestry. SCA13 patients have cerebellar ataxia of adult onset, or of early onset when associated with mental impairment. SCA25 patients present with cerebellar ataxia with sensory neuropathy and frequent gastrointestinal features. While the gene responsible for SCA25 is still unknown, missense mutations affecting the potassium channel KCNC3 function have been identified. 2012 Elsevier B.V. All rights reserved.

  7. Rare forms of autosomal recessive neurodegenerative ataxia.

    Science.gov (United States)

    Koenig, Michel

    2003-09-01

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

  8. Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

    Science.gov (United States)

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

    2016-04-01

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

  9. Prevalence of ataxia in children

    Science.gov (United States)

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

    2014-01-01

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

  10. Cognition in Friedreich ataxia.

    Science.gov (United States)

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

    2012-12-01

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

  11. [Ataxias and hereditary spastic paraplegias].

    Science.gov (United States)

    Schüle, R; Schöls, L

    2017-07-01

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

  12. 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

  13. 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.

  14. Spinocerebellar ataxia type 7.

    Science.gov (United States)

    Martin, Jean-Jacques

    2012-01-01

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

  15. Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias.

    Science.gov (United States)

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

    2017-01-01

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

  16. 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...

  17. Genetics Home Reference: spinocerebellar ataxia type 1

    Science.gov (United States)

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

  18. Genetics Home Reference: spinocerebellar ataxia type 2

    Science.gov (United States)

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

  19. Genetics Home Reference: spinocerebellar ataxia type 3

    Science.gov (United States)

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

  20. Genetics Home Reference: spinocerebellar ataxia type 6

    Science.gov (United States)

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

  1. 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.

  2. Movement disorders in spinocerebellar ataxias

    NARCIS (Netherlands)

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

    2011-01-01

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

  3. Language Impairment in Cerebellar Ataxia

    NARCIS (Netherlands)

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

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

  4. 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…

  5. 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.

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

    Science.gov (United States)

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

    2017-04-01

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

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

    Science.gov (United States)

    Pearson, Toni S.

    2016-01-01

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

  8. [IOSCA - Infantile onset spinocerebellar ataxia].

    Science.gov (United States)

    Lönnqvist, Tuula

    2011-01-01

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

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

    Science.gov (United States)

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

  10. Genetics Home Reference: ataxia with vitamin E deficiency

    Science.gov (United States)

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

  11. Hepatic mitochondrial dysfunction in Friedreich Ataxia

    Directory of Open Access Journals (Sweden)

    Stüwe Sven H

    2011-11-01

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

  12. The Functional Role of the Ataxia Telangiectasia Gene

    National Research Council Canada - National Science Library

    Gautier, Jean

    2000-01-01

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

  13. The Functional Role of the Ataxia Telangiectasia Gene

    National Research Council Canada - National Science Library

    Gautier, Jean

    1999-01-01

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

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

    Science.gov (United States)

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

    2012-03-01

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

  15. Genes and genetic testing in hereditary ataxias.

    Science.gov (United States)

    Sandford, Erin; Burmeister, Margit

    2014-07-22

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

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

    NARCIS (Netherlands)

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

    2002-01-01

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

  17. 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.

  18. Emerging therapies in Friedreich's ataxia

    Science.gov (United States)

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

    2016-01-01

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

  19. Reviewing the genetic causes of spastic-ataxias

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Michael Bonello

    2016-01-01

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

  1. Paroxysmal ataxia and dysarthria in multiple sclerosis.

    Science.gov (United States)

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

    2014-01-01

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

  2. [Ataxia-opsoclonus-myoclonus syndrome].

    Science.gov (United States)

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

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

  3. Acute cerebellar ataxia in enteric fever.

    Science.gov (United States)

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

    1986-01-01

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

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

    National Research Council Canada - National Science Library

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

    2010-01-01

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

  5. Ataxias and Cerebellar or Spinocerebellar Degeneration

    Science.gov (United States)

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

  6. 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

  7. Vestibular ataxia and its measurement in man

    Science.gov (United States)

    Fregly, A. R.

    1974-01-01

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

  8. Acute Cerebellar Ataxia and Lyme Disease

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-06-01

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

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

    Science.gov (United States)

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

    1996-01-01

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

  10. 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

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

    NARCIS (Netherlands)

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

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

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

    NARCIS (Netherlands)

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

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

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

    NARCIS (Netherlands)

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

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

  14. 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

  15. Gluten-related disorders: gluten ataxia.

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Marcus Vinicius Cristino de Albuquerque

    2015-01-01

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

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

    Science.gov (United States)

    ... Twitter Home Health Conditions ARCA1 Autosomal recessive cerebellar ataxia type 1 Printable PDF Open All Close All ... the expand/collapse boxes. Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by ...

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

    Science.gov (United States)

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

  19. 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.

  20. Hereditary spastic paraplegia with cerebellar ataxia

    DEFF Research Database (Denmark)

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

    2004-01-01

    Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria...... in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance...... relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations....

  1. Paroxysmal movement disorders and episodic ataxias.

    Science.gov (United States)

    Fernández-Alvarez, Emilio; Perez-Dueñas, Belén

    2013-01-01

    This chapter summarizes clinical symptoms of some paroxysmal dyskinesias (PDs) of infancy and childhood, as well as episodic ataxias. PDs refer to a complex group of disorders whose main feature is the occurrence of sudden, intermittent attacks of abnormal postures and involuntary movements. PDs can sometimes be symptomatic (secondary PDs), but usually an underlying cerebral lesion is not present (primary PDs). Some of the primary PDs are transient, such as benign paroxysmal torticollis of infancy. Chronic PDs are subdivided into nonkinesigenic (Mount and Reback type), kinesigenic (Kertesz type), and exercise-induced (Lance type) but cases that overlap with these types are on record. They are autosomal dominant inherited conditions. The myofibrillogenesis regulator-1 gene is responsible for nonkinesigenic PDs. To date, the genetic basis of kinesigenic PDs remains unknown. Several clinical entities associated epilepsy with PDs, such as infantile convulsions and choreoathetosis (ICCA). Exercise-induced PD type can be produced by mutations in the SLC2A1 gene that encodes Glut1 (glucose transporter type1). Episodic ataxias are inherited disorders of intermittent ataxia. The attacks are brief and triggered by abrupt exercise and emotional stimulus. Between attacks, palpebral and hand muscle myokymia is often seen in episodic ataxia type 1 (EA1). In episodic ataxia type 2 (EA2) interictal nystagmus is usually present. Some of these latter patients develop progressive ataxia with vermian atrophy. This disorder is associated with mutations in the human Ca channel alfa 1 subunit CACN1A4 gene. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Ataxia with Vitamin E Deficiency in Norway

    Directory of Open Access Journals (Sweden)

    Areej Elkamil

    2015-01-01

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

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

    Science.gov (United States)

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

    2017-07-19

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

  4. Recent advances in hereditary spinocerebellar ataxias

    NARCIS (Netherlands)

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

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

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

    Indian Academy of Sciences (India)

    Mahesh

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

  6. 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.

  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...

  8. Friedreich ataxia: dysarthria profile and clinical data.

    Science.gov (United States)

    Brendel, Bettina; Ackermann, Hermann; Berg, Daniela; Lindig, Tobias; Schölderle, Theresa; Schöls, Ludger; Synofzik, Matthis; Ziegler, Wolfram

    2013-08-01

    Friedreich ataxia (FRDA) is the most frequent recessive ataxia in the Western world. Dysarthria is a cardinal feature of FRDA, often leading to severe impairments in daily functioning, but its exact characteristics are only poorly understood so far. We performed a comprehensive evaluation of dysarthria severity and the profile of speech motor deficits in 20 patients with a genetic diagnosis of FRDA based on a carefully selected battery of speaking tasks and two widely used paraspeech tasks, i.e., oral diadochokinesis and sustained vowel productions. Perceptual ratings of the speech samples identified respiration, voice quality, voice instability, articulation, and tempo as the most affected speech dimensions. Whereas vocal instability predicted ataxia severity, tempo turned out as a significant correlate of disease duration. Furthermore, articulation predicted the overall intelligibility score as determined by a systematic speech pathology assessment tool. In contrast, neurologists' ratings of intelligibility--a component of the "Scale for the Assessment and Rating of Ataxia"--were found to be related to perceived speech tempo. Obviously, clinicians are more sensitive to slowness of speech than to any other feature of spoken language during dysarthria evaluation. Our results suggest that different components of speech production and trunk/limb motor functions are differentially susceptible to FRDA pathology. Furthermore, evidence emerged that paraspeech tasks do not allow for an adequate scaling of speech deficits in FRDA.

  9. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia.

    Directory of Open Access Journals (Sweden)

    Ying-Hao Chen

    Full Text Available Adrenoleukodystrophy (ALD is a rare and progressive neurogenetic disease that may manifest disparate symptoms. The present study aims at investigating the role of ataxic variant of ALD (AVALD in patients with adult-onset cerebellar ataxia, as well as characterizing their clinical features that distinguish AVALD from other cerebellar ataxias. Mutations in the ATP binding cassette subfamily D member 1 gene (ABCD1 were ascertained in 516 unrelated patients with ataxia. The patients were categorized into three groups: molecularly unassigned hereditary ataxia (n = 118, sporadic ataxia with autonomic dysfunctions (n = 296, and sporadic ataxia without autonomic dysfunctions (n = 102. Brain MRIs were scrutinized for white matter hyperintensity (WMH in the parieto-occipital lobes, frontal lobes, corticospinal tracts, pons, middle cerebellar peduncles and cerebellar hemispheres. Two ABCD1 mutations (p.S108L and p.P623fs previously linked to cerebral ALD and adrenomyeloneuropathy but not AVALD were identified. ALD accounts for 0.85% (1/118 of the patients with molecularly unassigned hereditary ataxia and 0.34% (1/296 of the patients with sporadic ataxia with autonomic dysfunctions. WMH in the corticospinal tracts and WMH in the cerebellar hemispheres were strongly associated with AVALD rather than other ataxias. To conclude, ALD accounts for approximately 0.39% (2/516 of adult-onset cerebellar ataxias. This study expands the mutational spectrum of AVALD and underscores the importance of considering ALD as a potential etiology of cerebellar ataxia.

  10. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia.

    Science.gov (United States)

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

    2017-01-01

    Adrenoleukodystrophy (ALD) is a rare and progressive neurogenetic disease that may manifest disparate symptoms. The present study aims at investigating the role of ataxic variant of ALD (AVALD) in patients with adult-onset cerebellar ataxia, as well as characterizing their clinical features that distinguish AVALD from other cerebellar ataxias. Mutations in the ATP binding cassette subfamily D member 1 gene (ABCD1) were ascertained in 516 unrelated patients with ataxia. The patients were categorized into three groups: molecularly unassigned hereditary ataxia (n = 118), sporadic ataxia with autonomic dysfunctions (n = 296), and sporadic ataxia without autonomic dysfunctions (n = 102). Brain MRIs were scrutinized for white matter hyperintensity (WMH) in the parieto-occipital lobes, frontal lobes, corticospinal tracts, pons, middle cerebellar peduncles and cerebellar hemispheres. Two ABCD1 mutations (p.S108L and p.P623fs) previously linked to cerebral ALD and adrenomyeloneuropathy but not AVALD were identified. ALD accounts for 0.85% (1/118) of the patients with molecularly unassigned hereditary ataxia and 0.34% (1/296) of the patients with sporadic ataxia with autonomic dysfunctions. WMH in the corticospinal tracts and WMH in the cerebellar hemispheres were strongly associated with AVALD rather than other ataxias. To conclude, ALD accounts for approximately 0.39% (2/516) of adult-onset cerebellar ataxias. This study expands the mutational spectrum of AVALD and underscores the importance of considering ALD as a potential etiology of cerebellar ataxia.

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

    Science.gov (United States)

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

    2008-09-01

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

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

    Science.gov (United States)

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

    2014-01-07

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

  13. 'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization.

    Science.gov (United States)

    García-Murias, María; Quintáns, Beatriz; Arias, Manuel; Seixas, Ana I; Cacheiro, Pilar; Tarrío, Rosa; Pardo, Julio; Millán, María J; Arias-Rivas, Susana; Blanco-Arias, Patricia; Dapena, Dolores; Moreira, Ramón; Rodríguez-Trelles, Francisco; Sequeiros, Jorge; Carracedo, Angel; Silveira, Isabel; Sobrido, María J

    2012-05-01

    Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ~0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5-14 hexanucleotide repeats, expanded alleles range from ~650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ~1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is

  14. ‘Costa da Morte’ ataxia is spinocerebellar ataxia 36: clinical and genetic characterization

    Science.gov (United States)

    García-Murias, María; Quintáns, Beatriz; Arias, Manuel; Seixas, Ana I.; Cacheiro, Pilar; Tarrío, Rosa; Pardo, Julio; Millán, María J.; Arias-Rivas, Susana; Blanco-Arias, Patricia; Dapena, Dolores; Moreira, Ramón; Rodríguez-Trelles, Francisco; Sequeiros, Jorge; Carracedo, Ángel; Silveira, Isabel

    2012-01-01

    Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ∼0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5–14 hexanucleotide repeats, expanded alleles range from ∼650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ∼1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia

  15. Specific cerebellar and cortical degeneration correlates with ataxia severity in spinocerebellar ataxia type 7.

    Science.gov (United States)

    Hernandez-Castillo, Carlos R; Galvez, Victor; Diaz, Rosalinda; Fernandez-Ruiz, Juan

    2016-03-01

    Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder that is accompanied by loss of motor control and macular degeneration. Previous studies have shown cerebellar and pons atrophy as well as functional connectivity changes across the whole brain. Although different MRI modalities have been used to study the degenerative process, little is known about the relationship between the motor symptoms and cerebral atrophy. Twenty-four patients with molecular diagnosis of SCA7 where invited to participate in this study. Ataxia severity was evaluated using the scale for the assessment and rating of ataxia (SARA). Structural magnetic resonance imaging (MRI) brain images were used to obtain the grey matter volume of each participant. As expected, we found a significant negative correlation between the SARA score and the grey matter volume in distinct regions of the cerebellum in the patient group. Additionally, we found significant correlations between the ataxia degree and the degeneration of specific cortical areas in these patients. These findings provide a better understanding of the relationship between gray matter atrophy and ataxia related symptoms that result from the SCA7 mutation.

  16. Novel Diagnostic Paradigms for Friedreich Ataxia

    Science.gov (United States)

    Brigatti, Karlla W.; Deutsch, Eric C.; Lynch, David R.; Farmer, Jennifer M.

    2013-01-01

    Friedreich ataxia is the most common inherited ataxia, with a wide phenotypic spectrum. It is generally caused by GAA expansions on both alleles of FXN, but a small percentage of patients are compound heterozygotes for a pathogenic expansion and a point mutation. Two recent diagnostic innovations are further characterizing individuals with the phenotype but without the classic genotypes. First, lateral-flow immunoassay is able to quantify the frataxin protein, thereby further characterizing these atypical individuals as likely affected or not affected, and providing some correlation to phenotype. It also holds promise as a biomarker for clinical trials in which the investigative agent increases frataxin. Second, gene dosage analysis and the identification of affected individuals with gene deletions introduce a novel genetic mechanism of disease. Both tests are now clinically available and suggest a new diagnostic paradigm for the disorder. Genetic counseling issues and future diagnostic testing approaches are considered as well. PMID:22752491

  17. Friedreich's Ataxia – A Clinical Diagnosis

    Directory of Open Access Journals (Sweden)

    Md. Fekarul Islam

    2015-01-01

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

  18. Epigenetic-based therapies for Friedreich ataxia

    OpenAIRE

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

    2014-01-01

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

  19. Case of infantile onset spinocerebellar ataxia type 5.

    Science.gov (United States)

    Jacob, Francois-Dominique; Ho, Eugenia S; Martinez-Ojeda, Mayra; Darras, Basil T; Khwaja, Omar S

    2013-10-01

    Dominant spinocerebellar ataxias are a rare clinically and genetically heterogeneous group of neurodegenerative disorders. They are characterized by progressive cerebellar ataxia resulting in unsteady gait, clumsiness, dysarthria, and swallowing difficulty. The onset of symptoms is usually in the third or fourth decade of life; however, more subtle clinical manifestations can start in early childhood. Spinocerebellar ataxia type 5, a dominant spinocerebellar ataxia associated with mutations involving β-III spectrin (SPTBN2), has been described in 3 families. It typically consists of a slowly progressive spinocerebellar ataxia with onset in the third decade. The authors present the first case of infantile-onset spinocerebellar ataxia associated with a novel SPTBN2 mutation (transition C>T at nucleotide position 1438), the proband having a much more severe phenotype with global developmental delay, hypotonia, tremor, nystagmus, and facial myokymia.

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

    Science.gov (United States)

    Desai, Jay; Mitchell, Wendy G

    2012-11-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

    Gosalakkal, Jayaprakash A; Swamy, Puttamadaiah Mallikarjuna

    2006-04-01

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

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

    Science.gov (United States)

    ... with ataxia PRICKLE1-related progressive myoclonus epilepsy with ataxia Printable PDF Open All Close All Enable Javascript ... boxes. Description PRICKLE1 -related progressive myoclonus epilepsy with ataxia is a rare inherited condition characterized by recurrent ...

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

    Science.gov (United States)

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

    2012-11-13

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

  5. Fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Hoem, Gry; Koht, Jeanette

    2017-10-31

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

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

    African Journals Online (AJOL)

    TNHJOURNALPH

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

  7. Drug-induced cerebellar ataxia: a systematic review

    NARCIS (Netherlands)

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

    2014-01-01

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

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

    African Journals Online (AJOL)

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

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

    African Journals Online (AJOL)

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

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

    Science.gov (United States)

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

    2010-01-01

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

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

    NARCIS (Netherlands)

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

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

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

    NARCIS (Netherlands)

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

    2013-01-01

    The hereditary ataxias with onset in childhood are a group of heterogeneous disorders, usually with autosomal recessive inheritance. In many of them, magnetic resonance imaging (MRI) shows cerebellar atrophy. The most prominent exception to this is Friedreich's ataxia, where MRI shows normal

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

    NARCIS (Netherlands)

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

    2002-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1999-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Jin Zhang

    2013-01-01

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

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

    Science.gov (United States)

    Blaney, Bronagh; Hewlett, Nigel

    2007-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

    Tada, Masayoshi; Nishizawa, Masatoyo; Onodera, Osamu

    2015-08-01

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

  19. 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.

  20. Personality and Neuropsychological Profiles in Friedreich Ataxia.

    Science.gov (United States)

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

    2017-10-30

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

  1. 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.)

  2. 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,

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

    Science.gov (United States)

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

    2014-06-01

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

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

    Science.gov (United States)

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

    2016-02-01

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

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

    Science.gov (United States)

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

    2010-01-01

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

  8. Ataxia crónica en pediatría

    OpenAIRE

    Ricardo Erazo Torricelli

    2013-01-01

    Las ataxias crónicas constituyen un grupo heterogéneo de enfermedades, que afectan al niño a diferentes edades. Así las formas congénitas, generalmente no progresivas, se observan desde los primeros meses de vida y se expresan por hipotonía y retraso motor, mucho antes de que la ataxia se haga evidente. La resonancia magnética cerebral puede ser diagnóstica en algunos cuadros, como ocurre con el síndrome de Joubert. El grupo de ataxias hereditarias progresivas, en constante expansión, suelen ...

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

    Science.gov (United States)

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

    2011-10-01

    Among the hereditary ataxias, autosomal recessive cerebellar ataxias (ARCAs) encompass a diverse group of rare neurodegenerative disorders in which a cerebellar syndrome is the key clinical feature. The clinical overlap between the different cerebellar ataxias, the occasional atypical phenotypes, and the genetic heterogeneity often complicate the clinical management of such patients. Despite the steady increase in newly discovered ARCA genes, many patients with a putative ARCA cannot be genotyped yet, proving that more genes must be involved. This review presents an updated overview of the various ARCAs. The clinical and genetic characteristics of those forms with a known molecular genetic defect are discussed, along with the emerging insights in the underlying pathophysiological mechanisms.

  10. Ataxia with vitamin E deficiency associated with deafness.

    Science.gov (United States)

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

    2008-01-01

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

  11. 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

  12. Ataxia heredo-degenerativa associada a hipoacusia

    Directory of Open Access Journals (Sweden)

    José Antonio Levy

    1964-06-01

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

  13. Epigenetic-based therapies for Friedreich ataxia

    Directory of Open Access Journals (Sweden)

    Chiranjeevi eSandi

    2014-06-01

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

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

    Science.gov (United States)

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

    2014-09-01

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Andrew E. Becker

    2016-05-01

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

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

    OpenAIRE

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

    2017-01-01

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

  18. Myoclonus epilepsy and ataxia due to KCNC1 mutation

    DEFF Research Database (Denmark)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Breno José Alencar Pires Barbosa

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

  1. Harry Lee Parker and paroxysmal dysarthria and ataxia.

    Science.gov (United States)

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

    2013-01-15

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

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

    Directory of Open Access Journals (Sweden)

    Amene Saghazadeh

    2017-02-01

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

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

    Science.gov (United States)

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

    2014-10-28

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

  4. 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.

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

    Science.gov (United States)

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

    2011-08-01

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

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

    Science.gov (United States)

    Stoppa-Lyonnet, D; Aurias, A

    1992-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Joyce van de Leemput

    2007-06-01

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

  9. 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

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

    National Research Council Canada - National Science Library

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

    2013-01-01

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

  11. 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.

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

    Science.gov (United States)

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

    2012-03-01

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

  13. Vascular Risk Factors and Clinical Progression in Spinocerebellar Ataxias

    Directory of Open Access Journals (Sweden)

    Raymond Y. Lo

    2015-02-01

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

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

    Science.gov (United States)

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

    2013-04-01

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

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

    Science.gov (United States)

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

    1996-10-17

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

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

    Directory of Open Access Journals (Sweden)

    Wladimir Bocca Vieira de Rezende Pinto

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Wladimir Bocca Vieira de Rezende Pinto

    2015-10-01

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

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

    NARCIS (Netherlands)

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

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

  19. 2 SISTERS WITH MENTAL-RETARDATION, CATARACT, ATAXIA, PROGRESSIVE HEARING-LOSS, AND POLYNEUROPATHY

    NARCIS (Netherlands)

    BEGEER, JH; SCHOLTE, FA; VANESSEN, AJ

    1991-01-01

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

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

    Science.gov (United States)

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

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

    NARCIS (Netherlands)

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

    2017-01-01

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

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

    Science.gov (United States)

    Pinto, Wladimir Bocca Vieira de Rezende; Pedroso, José Luiz; Souza, Paulo Victor Sgobbi de; Albuquerque, Marcus Vinícius Cristino de; Barsottini, Orlando Graziani Povoas

    2015-10-01

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

  3. 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.

  4. ELOVL5 mutations cause spinocerebellar ataxia 38.

    Science.gov (United States)

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

    2014-08-07

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

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

    Science.gov (United States)

    Muthuswamy, Srinivasan; Agarwal, Sarita

    2015-09-01

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

  6. Infantile childhood onset of spinocerebellar ataxia type 2.

    Science.gov (United States)

    Di Fabio, Roberto; Santorelli, Filippo; Bertini, Enrico; Balestri, Martina; Cursi, Laura; Tessa, Alessandra; Pierelli, Francesco; Casali, Carlo

    2012-06-01

    Spinocerebellar ataxia type 2 (SCA2) is a late-onset autosomal dominant cerebellar ataxia caused by triplet CAG/CTG expansion in the ATX2 gene. The initial symptoms usually appear when subjects are in their 30s.Pediatric onset is less common and usually associated with larger triplet expansions. We here report the case of a 1-year-old girl who presented with facial dysmorphism,dystonic features, developmental delay, and retinitis pigmentosa.She was diagnosed as carrying an expanded CAG/CTG tract (92 repeats) before a molecular diagnosis of SCA2 was made in her father. Facial dysmorphism associated with developmental delay and retinitis pigmentosa in early childhood should prompt a careful family investigation for ataxia and study of ATX2.

  7. Diabetes mellitus as the presenting feature of Friedreich's ataxia

    Directory of Open Access Journals (Sweden)

    Meenal Garg

    2017-01-01

    Full Text Available Patients with Friedreich's ataxia (FA are at an increased risk of developing diabetes mellitus and glucose intolerance. Diabetes usually develops many years after the initial presentation. We report an 8-year-old girl who initially presented with diabetic ketoacidosis and was treated as a case of insulin-dependent diabetes mellitus. Around a year later, she developed gait problems and ataxia. Cardiac involvement was detected on echocardiography. Genetic testing confirmed the diagnosis of FA. FA should be a diagnostic consideration in children presenting with diabetes and neurological issues, even with early presentation of the former. Early occurrence of diabetes and rapid progression of ataxia in this patient needs a better understanding of underlying genetic mechanisms.

  8. 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.

  9. Deficits in peripheral visual attention in patients with optic ataxia.

    Science.gov (United States)

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

    2007-07-16

    Earlier research has suggested that optic ataxia, a deficit in reaching in peripheral vision, can be isolated from Balint's syndrome as it is primarily a visuomotor disorder, independent of perceptual or attentional deficits. Yet almost no research has examined the attentional abilities of these patients. We examined peripheral visual attention in two patients with unilateral optic ataxia. Results indicated that both patients were slower to respond to targets in their ataxic visual field, irrespective of cuing condition (i.e. validly, invalidly, and no cue conditions), consistent with an overall decrease in the salience of stimuli in the ataxic field. Attentional deficits in peripheral vision are therefore an important factor to consider when examining visuomotor control deficits in optic ataxia.

  10. Common Data Elements for Clinical Research in Friedreich Ataxia

    Science.gov (United States)

    Lynch, David R.; Pandolfo, Massimo; Schulz, Jorg B.; Perlman, Susan; Delatycki, Martin B.; Payne, R. Mark; Shaddy, Robert; Fischbeck, Kenneth H.; Farmer, Jennifer; Kantor, Paul; Raman, Subha V.; Hunegs, Lisa; Odenkirchen, Joanne; Miller, Kristy; Kaufmann, Petra

    2012-01-01

    Background To reduce study start-up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreich ataxia, a neurological disorder that involves multiple organ systems. Methods To develop Friedreich’s ataxia common data elements, Friedreich’s ataxia experts formed a working group and subgroups to define elements in: Ataxia and Performance Measures; Biomarkers; Cardiac and Other Clinical Outcomes; and Demographics, Laboratory Tests and Medical History. The basic development process included: Identification of international experts in Friedreich’s ataxia clinical research; Meeting via teleconference to develop a draft of standardized common data elements recommendations; Vetting of recommendations across the subgroups; Dissemination of recommendations to the research community for public comment. Results The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx. The Subgroups’ recommendations are classified as core, supplemental or exploratory. Template case report forms were created for many of the core tests. Conclusions The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new and ongoing studies will be assessed in an ongoing fashion to define their utility in Friedreich’s ataxia. PMID:23239403

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

    Science.gov (United States)

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

    2015-01-01

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

  12. Gly118Asp is a SCA14 founder mutation in the Dutch ataxia population

    NARCIS (Netherlands)

    Verbeek, DS; van de Warrenburg, BPC; Hennekam, FAM; Dooijes, D; Ippel, PF; Verschuuren-Bemelmans, CC; Kremer, HPH; Sinke, RJ

    Missense mutations in the PRKCG gene have recently been identified in spinocerebellar ataxia 14 (SCA14) patients; these include the Gly118Asp mutation that we found in a large Dutch autosomal dominant cerebellar ataxia (ADCA) family. We subsequently screened the current Dutch ataxia cohort

  13. Three novel KCNA1 mutations in episodic ataxia type I families

    NARCIS (Netherlands)

    Scheffer, H; Brunt, ERP; Mol, GJJ; van der Vlies, P; Stulp, RP; Verlind, E; Mantel, G; Averyanov, YN; Hofstra, RMW; Buys, CHCM

    Hereditary paroxysmal ataxia, or episodic ataxia (EA), is a rare, genetically heterogeneous neurological disorder characterized by attacks of generalized ataxia. By direct sequence analysis, a different missense mutation of the potassium channel gene (KCNA1) has been identified in three families

  14. 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

  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. Fisioterapia, aprendizagem e treino: teorema para viver com ataxia

    OpenAIRE

    Fernandes, Beatriz

    2013-01-01

    Caracterização da ataxia, sintomas relacionados com as alterações de movimento, objectivos da fisioterapia, importância do movimento. A fisioterapia pode ajudar as pessoas com ataxia a realizar as actividades funcionais para além da execução através de compensação; a aprendizagem motora é possível; treino de tarefas funcionais; repetição dos exercícios; exercícios que desafiem as capacidades do indivíduo.

  17. 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,

  18. 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,

  19. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

    Science.gov (United States)

    ... onset, and diagnostic criteria of the two conditions. Fragile X Syndrome (FXS) FXS is present (though often not diagnosed) ... long face (more common as children get older). Fragile X-associated Tremor Ataxia Syndrome (FXTAS) FXTAS develops in adulthood—usually after age ...

  20. Molecular Alterations in a Mouse Cardiac Model of Friedreich Ataxia

    DEFF Research Database (Denmark)

    Anzovino, Amy; Chiang, Shannon; Brown, Bronwyn E

    2017-01-01

    Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the antioxidant response. However, studies in models of Friedreich ataxia, a neurodegenerative and cardiodegenerative disease associated with oxidative stress, reported decreased Nrf2 expression attributable to unknown...

  1. 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…

  2. Progressive dysarthria and ataxia | McAlpine | South Sudan Medical ...

    African Journals Online (AJOL)

    South Sudan Medical Journal. Journal Home · ABOUT · Advanced Search · Current Issue · Archives · Journal Home > Vol 8, No 1 (2015) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Progressive dysarthria and ataxia. Lynsey McAlpine, Fiona Cran, Eluzai Hakim ...

  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. Studies on Molecular Mechanisms Underlying Spinocerebellar Ataxia Type 3

    DEFF Research Database (Denmark)

    Kristensen, Line Vildbrad

    The polyglutamine (polyQ) disorders comprise nine diseases characterized by an expanded polyQ tract within the respective proteins. These disorders are rare but include the well-known Huntington’s disease, and several spinocerebellar ataxias (SCAs). The diseases usually strike midlife and progress...

  5. Efavirenz as a cause of ataxia in children

    African Journals Online (AJOL)

    Background. A child presenting with ataxia may pose a diagnostic dilemma. After excluding the common causes, e.g. toxins, infection and tumours, one needs to consider, more carefully, a possible genetic cause, but with limited genetic testing facilities available in South Africa (SA) a definitive answer is not always found.

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

    Science.gov (United States)

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

    2014-09-01

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

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

    Science.gov (United States)

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

    2013-02-01

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

  8. 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.

  9. 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

  10. 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

  11. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond.

    Science.gov (United States)

    Durr, Alexandra

    2010-09-01

    Cerebellar ataxias with autosomal dominant transmission are rare, but identification of the associated genes has provided insight into the mechanisms that could underlie other forms of genetic or non-genetic ataxias. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes complex multisystemic neurological deficits. The designation of the loci, SCA for spinocerebellar ataxia, indicates the involvement of at least two systems: the spinal cord and the cerebellum. 11 of 18 known genes are caused by repeat expansions in the corresponding proteins, sharing the same mutational mechanism. All other SCAs are caused by either conventional mutations or large rearrangements in genes with different functions, including glutamate signalling (SCA5/SPTBN2) and calcium signalling (SCA15/16/ITPR1), channel function (SCA13/KCNC3, SCA14/PRKCG, SCA27/FGF14), tau regulation (SCA11/TTBK2), and mitochondrial activity (SCA28/AFG3L2) or RNA alteration (SCA31/BEAN-TK2). The diversity of underlying mechanisms that give rise to the dominant cerebellar ataxias need to be taken into account to identify therapeutic targets. Copyright 2010 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2014-12-01

    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, including those for internationally applicable Scale for Assessment and Rating of Ataxia (SARA) syllable repetition tasks (SARASRT). Three independent paediatric neurologists and a speech therapist scored speech in 52 healthy children (mean age 10y, range 4-16y) and 40 individuals with EOA (mean age 15y, range 5-34y). We compared ataxia speech subscores for the association with age and ataxia scores as well as interobserver reliability. In healthy children, ataxia speech subscores were moderately associated with age (International Cooperative Ataxia Rating Scale [ICARS]: r=-0.515; SARA: r=-0.321; pataxia scores (ICARS: r=0.552; SARA: r=0.336; pataxia scores (ICARS: r=0.735; SARA: r=0.730; pataxia speech subscores are associated with ataxia and also reveal high interobserver agreement, including those internationally applicable to SARASRT. We conclude that SARASRT appears to be applicable for EOA databases. However, before syllable repetition tasks are included, we would advise to wait for the results published by the international Childhood Ataxia and Cerebellar Group. © 2014 Mac Keith Press.

  13. 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.

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

    Science.gov (United States)

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

    2016-11-08

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

  15. 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.

  16. 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.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2014-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Parmar R

    2000-07-01

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

  20. Cognitive Functions in Ataxia with Oculomotor Apraxia Type 2

    OpenAIRE

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

    2012-01-01

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

  1. Cognitive Functions in Ataxia with Oculomotor Apraxia Type 2

    OpenAIRE

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

    2012-01-01

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

  2. Kinematic discrimination of ataxia in horses is facilitated by blindfolding.

    Science.gov (United States)

    Olsen, E; FouchÉ, N; Jordan, H; Pfau, T; Piercy, R J

    2017-08-10

    Agreement among experienced clinicians is poor when assessing the presence and severity of ataxia, especially when signs are mild. Consequently, objective gait measurements might be beneficial for assessment of horses with neurological diseases. To assess diagnostic criteria using motion capture to measure variability in spatial gait-characteristics and swing duration derived from ataxic and non-ataxic horses, and to assess if variability increases with blindfolding. Cross-sectional. A total of 21 horses underwent measurements in a gait laboratory and live neurological grading by multiple raters. In the gait laboratory, the horses were made to walk across a runway surrounded by a 12-camera motion capture system with a sample frequency of 240 Hz. They were made to walk normally and with a blindfold in at least three trials each. Displacements of reflective markers on head, fetlock, hoof, fourth lumbar vertebra, tuber coxae and sacrum derived from three to four consecutive strides were processed and descriptive statistics, receiver operator characteristics (ROC) to determine the diagnostic sensitivity, specificity and area under the curve (AUC), and correlation between median ataxia grade and gait parameters were determined. For horses with a median ataxia grade ≥2, coefficient of variation for the location of maximum vertical displacement of pelvic and thoracic distal limbs generated good diagnostic yield. The hoofs of the thoracic limbs yielded an AUC of 0.81 with 64% sensitivity and 90% specificity. Blindfolding exacerbated the variation for ataxic horses compared to non-ataxic horses with the hoof marker having an AUC of 0.89 with 82% sensitivity and 90% specificity. The low number of consecutive strides per horse obtained with motion capture could decrease diagnostic utility. Motion capture can objectively aid the assessment of horses with ataxia. Furthermore, blindfolding increases variation in distal pelvic limb kinematics making it a useful clinical tool

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

    Directory of Open Access Journals (Sweden)

    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.

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

    OpenAIRE

    Sarvesh Kumar Singh; Kshipra Rajoria

    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 disabi...

  5. Huntington’s disease masquerading as spinocerebellar ataxia

    OpenAIRE

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Stephan Marianne Anke

    2011-01-01

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

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

    Science.gov (United States)

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

    2007-08-01

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

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

    Science.gov (United States)

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

    2017-01-01

    Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.

  9. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations.

    Science.gov (United States)

    Bockenhauer, Detlef; Feather, Sally; Stanescu, Horia C; Bandulik, Sascha; Zdebik, Anselm A; Reichold, Markus; Tobin, Jonathan; Lieberer, Evelyn; Sterner, Christina; Landoure, Guida; Arora, Ruchi; Sirimanna, Tony; Thompson, Dorothy; Cross, J Helen; van't Hoff, William; Al Masri, Omar; Tullus, Kjell; Yeung, Stella; Anikster, Yair; Klootwijk, Enriko; Hubank, Mike; Dillon, Michael J; Heitzmann, Dirk; Arcos-Burgos, Mauricio; Knepper, Mark A; Dobbie, Angus; Gahl, William A; Warth, Richard; Sheridan, Eamonn; Kleta, Robert

    2009-05-07

    Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy). Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice. Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families. These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents. Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting. Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate that KCNJ10 plays a major role in renal salt handling and, hence, possibly also in blood-pressure maintenance and its regulation. 2009 Massachusetts Medical Society

  10. hiPSC Disease Modeling of Rare Hereditary Cerebellar Ataxias.

    Science.gov (United States)

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

    2016-10-01

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

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

    Science.gov (United States)

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

    2014-11-01

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

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

    Science.gov (United States)

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

    2011-04-01

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

  13. Miller-Fisher Syndrome: Is the ataxia central or peripheral?

    Science.gov (United States)

    Sandler, Robert D; Hoggard, Nigel; Hadjivassiliou, Marios

    2015-01-01

    A 50-year-old man presented with a brief history of slurred speech, unsteadiness, double vision and paraesthesia. He had been unwell for 12 days with campylobacter gastroenteritis. On examination, there was ophthalmoplegia, nystagmus, areflexia and lower limb and gait ataxia. Serological testing was positive for GQ1b antibody in keeping with the diagnosis of Miller Fisher Syndrome (MFS). He was treated with two courses of intravenous immunoglobulins and made a good recovery, only displaying mild gait ataxia when reviewed in clinic 2.5 months later. There has long been a debate as to whether the ataxia in MFS originates in the cerebellum or it is more peripheral. In this case, magnetic resonance spectroscopy (MRS) revealed a reduced NAA/Cr ratio in the cerebellar vermis and right cerebral hemisphere, suggestive of cerebellar dysfunction. The NAA/Cr normalised 2.5 months later reflecting the clinical recovery. The findings on MRS suggest that the cerebellum is involved in MFS.

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

    Science.gov (United States)

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

    2013-02-01

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

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

    Science.gov (United States)

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

    2006-05-01

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

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

    Science.gov (United States)

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

    2015-05-01

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

  17. SACS gene-related autosomal recessive spastic ataxia of Charlevoix-Saguenay from South India

    Directory of Open Access Journals (Sweden)

    M Suraj Menon

    2016-01-01

    Full Text Available Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS is a neurodegenerative disorder characterized by late infantile onset spastic ataxia and other neurological features. Initially described in the Charlevoix-Saguenay region of Quebec, Canada, it is being increasingly reported from many other countries. Here, we present the case of a 20-year-old male from South India, who presented with progressive ataxia, spasticity, and peripheral neuropathy with imaging features and genetic testing suggestive of SACS gene-related ARSACS. The phenotypic variability from other cases and occurrence in a geographically distinct region is stressed upon to alert the clinicians to consider ARSACS in progressive ataxias.

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

    Science.gov (United States)

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

    2015-08-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

    Marquer, A; Barbieri, G; Pérennou, D

    2014-03-01

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

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

    Science.gov (United States)

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

    2016-07-01

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

  4. Mutations in KCND3 cause spinocerebellar ataxia type 22

    Science.gov (United States)

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

    2014-01-01

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

  5. 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

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

    NARCIS (Netherlands)

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

    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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive neurodegeneration and cerebellar ataxia. A-T is causally linked to defects in ATM, a master regulator of the response to and repair of DNA double-strand breaks. The molecular basis of cerebellar atrophy...

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

    Science.gov (United States)

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

    2014-07-01

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

  10. 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…

  11. 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

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

    Science.gov (United States)

    Sato, Kenji; Nanri, Kazunori

    2017-08-01

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

  13. [Review of the pathogenetic problem of hereditary ataxia].

    Science.gov (United States)

    Gurgone, G; Gaglio, R M; Piccoli, F

    1984-01-01

    In the inherited ataxias, a heterogeneous group of relatively rare and progressive neurological disorders, abnormalities in pyruvate metabolism have been described. Pyruvate is involved in the glycolitic pathway as an important step, and utilized in the Krebs cycle, the main energy source in the brain. Furthermore, pyruvate and other intermediates in the Krebs cycle, can also serve as a precursors of amino acids for which a role as a neurotransmitter has been shown. The explanation of the basic biochemistry may serve as a basis for a more steady knowledge of the clinical and pathological findings of such diseases.

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

    National Research Council Canada - National Science Library

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

    2008-01-01

    Infantile-onset spinocerebellar ataxia (IOSCA) is a severe neurodegenerative disorder caused by the recessive mutation in PEO1, leading to an Y508C change in the mitochondrial helicase Twinkle, in its helicase domain...

  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

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

    Science.gov (United States)

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

    2007-05-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2017-06-28

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

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

    Science.gov (United States)

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

    2017-08-15

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

  20. Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways.

    Science.gov (United States)

    Synofzik, Matthis; Schüle, Rebecca

    2017-03-01

    Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene. The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development. © 2017 International Parkinson and Movement Disorder Society. © 2017 International

  1. 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.

  2. Anti-oxidative capacity in patients with ataxia telangiectasia

    Science.gov (United States)

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

    1999-01-01

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

  3. 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).

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

    Directory of Open Access Journals (Sweden)

    Ricardo Nitrini

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

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

    Science.gov (United States)

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

    2016-07-01

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

  6. 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.)

  7. 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.

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

    Science.gov (United States)

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

    2016-01-12

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

  9. 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

  10. 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.

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

    Science.gov (United States)

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

    2014-02-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2015-11-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Huang Lijia

    2012-09-01

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

  16. The reciprocal cerebellar circuitry in human hereditary ataxia.

    Science.gov (United States)

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

    2013-08-01

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

  17. Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T-->C mutation.

    Science.gov (United States)

    Rantamäki, Maria T; Soini, Heidi K; Finnilä, Saara M; Majamaa, Kari; Udd, Bjarne

    2005-08-01

    The 8993T-->C mutation in mitochondrial DNA (mtDNA) has been described previously to be associated with infantile- or childhood-onset phenotypes, ranging from Leigh's syndrome to neurogenic weakness, ataxia, and retinitis pigmentosa syndrome. We report a kindred with adult-onset slowly progressive ataxia and polyneuropathy and with the heteroplasmic 8993T-->C mutation. Our findings suggest that the 8993T-->C mtDNA mutation should be considered in the differential diagnosis of nondominant adult-onset ataxia and axonal neuropathy.

  18. 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...

  19. Avances en el tratamiento de las ataxias crónicas

    OpenAIRE

    María Celeste Buompadre

    2013-01-01

    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 esta...

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

    OpenAIRE

    Salman, Michael S.; Chodirker, Bernard N.

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Antonios Mammis

    2012-07-01

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

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

    Science.gov (United States)

    Bourke, T; Keane, D

    2011-12-01

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

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

    Science.gov (United States)

    Punga, Tanel; Bühler, Marc

    2010-04-01

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

  4. Sun1 deficiency leads to cerebellar ataxia in mice

    Directory of Open Access Journals (Sweden)

    Jing-Ya Wang

    2015-08-01

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

  5. 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.

  6. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia.

    Science.gov (United States)

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

    2014-01-01

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

  7. 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.

  8. Sun1 deficiency leads to cerebellar ataxia in mice.

    Science.gov (United States)

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

    2015-08-01

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

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Sarvesh Kumar Singh

    2016-01-01

    Full Text Available 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 Balaādi ksiāra basti (enema with medicated milk with Aśvagandhā taila anuvaāsana(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 Brahadvaātacintaāmanirasa – 125 mg, Vasantaāmaltiā rasa- 125 mg, Daśamūla kvātha- 40 ml, Aśvagandhā cūrṃa(powder of Withania somnifera DUNAL- 3g, Amrtaā cūrṃa (powder of Tinospora cordifolia Willd.- 500 mg, Muktāśukti pisti – 500 mg, Yogaraāja 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.

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

    Directory of Open Access Journals (Sweden)

    Genko Oyama

    2014-07-01

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

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

    Science.gov (United States)

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

    2016-04-28

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

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

    Science.gov (United States)

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

    2010-01-01

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

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

    National Research Council Canada - National Science Library

    Shala Ghaderi Berntsson; Anne-Marie Landtblom; Gullvi Flensner

    2017-01-01

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

  15. Identification of a novel mutation in theAPTXgene associated with ataxia-oculomotor apraxia.

    Science.gov (United States)

    Inlora, Jingga; Sailani, M Reza; Khodadadi, Hamidreza; Teymurinezhad, Ahmad; Takahashi, Shinichi; Bernstein, Jonathan A; Garshasbi, Masoud; Snyder, Michael P

    2017-11-01

    Hereditary ataxias are a clinically and genetically heterogeneous family of disorders defined by the inability to control gait and muscle coordination. Given the nonspecific symptoms of many hereditary ataxias, precise diagnosis relies on molecular genetic testing. To this end, we conducted whole-exome sequencing (WES) on a large consanguineous Iranian family with hereditary ataxia and oculomotor apraxia. WES in five affected and six unaffected individuals resulted in the identification of a homozygous novel stop-gain mutation in the APTX gene (c.739A>T; p.Lys247*) that segregates with the phenotype. Mutations in the APTX (OMIM 606350) gene are associated with ataxia with oculomotor apraxia type 1 (OMIM 208920). © 2017 Inlora et al.; Published by Cold Spring Harbor Laboratory Press.

  16. An autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy, and seizures

    NARCIS (Netherlands)

    Straussberg, R; Basel-Vanagaite, L; Kivity, S; Dabby, R; Cirak, S; Nurnberg, P; Voit, T; Mahajnah, M; Inbar, D; Saifi, GM; Lupski, [No Value; Delague, [No Value; Megarbane, A; Richter, A; Leshinsky, E; Berkovic, SF

    2005-01-01

    The authors describe three siblings born to consanguineous parents with early onset ataxia, dysarthria, myoclonic, generalized tonic clonic seizures, upward gaze palsy, extensor plantar reflexes, sensory neuropathy, and normal cognition. Direct screening excluded mutations in FRDA, TDP1, and SACS

  17. 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.

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

    Science.gov (United States)

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

    2014-06-01

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

  19. The sharpened Romberg test for assessing ataxia in mild acute mountain sickness.

    Science.gov (United States)

    Johnson, Brian G; Wright, Alex D; Beazley, Margaret F; Harvey, Timothy C; Hillenbrand, Peter; Imray, Christopher H E

    2005-01-01

    To evaluate the Sharpened Romberg Test (SRT) as a measure of ataxia in subjects with mild acute mountain sickness in order to determine its sensitivity and specificity. The SRT was performed in 23 subjects during ascent to 5260 m. The SRT was more often abnormal than the traditional heel-to-toe test, and at the highest altitude it was related to higher median Lake Louise symptom scores with predictive values of 60% sensitivity and 89% specificity. Our evaluation of the SRT appears to agree with similar studies on ataxia showing a lack of correlation between ataxia and symptoms of acute mountain sickness at altitudes below 5260 m. The SRT was easy to perform and provided a quantitative assessment of truncal ataxia in the field without the need for specialized equipment.

  20. The Sharpened Romberg Test for Assessing Ataxia in Mild Acute Mountain Sickness

    National Research Council Canada - National Science Library

    Brian G. Johnson; Alex D. Wright; Margaret F. Beazley; Timothy C. Harvey; Peter Hillenbrand; Christopher H. E. Imray

    2005-01-01

    Abstract Objective.—To evaluate the Sharpened Romberg Test (SRT) as a measure of ataxia in subjects with mild acute mountain sickness in order to determine its sensitivity and specificity. Methods...

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    Science.gov (United States)

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

    2014-04-01

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2000-01-01

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

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

    Science.gov (United States)

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

    2013-06-01

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

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

    OpenAIRE

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

    2002-01-01

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

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

    Science.gov (United States)

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

    2017-04-01

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

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

    Science.gov (United States)

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

    2014-01-01

    Ataxia-telangiectasia is a recessive genetic disorder (ATM is the mutated gene) of childhood with severe motor impairments and whereas homozygotes manifest the disorder, heterozygotes are asymptomatic. Structural brain imaging and post-mortem studies in individuals with ataxia-telangiectasia have reported cerebellar atrophy; but abnormalities of motor control characteristic of extrapyramidal dysfunction suggest impairment of broader motor networks. Here, we investigated possible dysfunction in other brain areas in individuals with ataxia-telangiectasia and tested for brain changes in asymptomatic relatives to assess if heterozygocity affects brain function. We used positron emission tomography and 18F-fluorodeoxyglucose to measure brain glucose metabolism (quantified as µmol/100 g/min), which serves as a marker of brain function, in 10 adults with ataxia-telangiectasia, 19 non-affected adult relatives (12 siblings, seven parents) and 29 age-matched healthy controls. Statistical parametric mapping and region of interest analyses were used to compare individuals with ataxia-telangiectasia, asymptomatic relatives, and unrelated controls. We found that participants with ataxia-telangiectasia had lower metabolism in cerebellar hemispheres (14%, P ataxia-telangiectasia also had higher metabolism in globus pallidus (16%, P = 0.05), which correlated negatively with motor performance. Asymptomatic relatives had lower metabolism in anterior vermis (12%; P = 0.01) and hippocampus (19%; P = 0.002) than controls. Our results indicate that, in addition to the expected decrease in cerebellar metabolism, participants with ataxia-telangiectasia had widespread changes in metabolic rates including hyperactivity in globus pallidus indicative of basal ganglia involvement. Changes in basal ganglia metabolism offer potential insight into targeting strategies for therapeutic deep brain stimulation. Our finding of decreased metabolism in vermis and hippocampus of asymptomatic relatives

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Sergio Carmona

    2016-08-01

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

  11. [Ataxia with ophthalmoplegia: Miller-Fisher syndrome with anti-GQ1b antibody positivity].

    Science.gov (United States)

    Guilloton, L; Camarasa, C; Agard, E; Tondeur, G; Dot, C; Drouet, A

    2014-02-01

    Miller-Fisher syndrome is defined as ophthalmoplegia, ataxia and areflexia. Considered as a variant of Guillain-Barré syndrome, it differs in its clinical presentation and by anti-GQ1b antibody positivity. The authors report a case of Miller-Fisher syndrome characterized by ataxia and complete ophthalmoplegia. Through this example, the range of ophthalmologic clinical manifestations are discussed. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  12. 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.

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

    Science.gov (United States)

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

    2014-06-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  15. 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.

  16. Posterior fossa imaging in 158 children with ataxia.

    Science.gov (United States)

    Boddaert, N; Desguerre, I; Bahi-Buisson, N; Romano, S; Valayannopoulos, V; Saillour, Y; Seidenwurm, D; Grevent, D; Berteloot, L; Lebre, A-S; Zilbovicius, M; Puget, S; Salomon, R; Attie-Bitach, T; Munnich, A; Brunelle, F; de Lonlay, P

    2010-10-01

    To propose a MRI cerebellar algorithm that may be applied to guide genetic/malformative or biochemical investigations for patients with cerebellar ataxia. Cerebral MRI of 158 patients with cerebellar ataxia and no supratentorial abnormality were examined according to a new categorization system based on posterior fossa imaging. The clinical and radiological findings were confronted to biochemical and/or genetic results using the MR cerebellar algorithm. Seven groups of cerebellar MRI pattern were described: vermian dysgenesis (n=27), cerebellar hypoplasia (n=15), hemispheric cerebellar dysgenesis (n=6), unilateral hemispheric atrophy (n=5), global cerebellar atrophy (n=84), signal abnormalities (n=11) and normal MRI (n=10). Cerebellar hypoplasia, vermian dysgenesis and hemispheric cerebellar dysgenesis groups were classified as malformative disorders. Global atrophy and signal abnormality groups were classified as metabolic disorders. In the vermian dysgenesis group, a specific genetic diagnosis was obtained in eight children (8/27) and all of the mutated genes (AHI1 (JBS3), CEP290 (JBS5), TMEM67 (JBS6), and RPGRIP1L (JBS7)) are involved in primary cilia function. In the group of pontocerebellar hypoplasia specific genetic diagnosis was obtained in one patient (PCH2) (1/15). Thus, nine of 42 children classified as malformative disorder had a molecular diagnosis. Global atrophy and signal abnormality groups were classified as metabolic disorders, specific biochemical was obtained in 46/95 children. In global atrophy group, respiratory chain deficiency was diagnosed in 18 children (18/84). In 21 children a congenital disorders of glycosylation type 1a (CDG Ia) was diagnosed (21/84) and infantile neuroaxonale dystrophy (INAD) was diagnosed in one child. In signal abnormalities group, specific biochemical diagnosis was obtained in six out of 11 children, five children with respiratory chain deficiency and one child with sulphite oxidase deficiency. In hemispheric

  17. 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.

  18. Progressive ataxia due to central demyelination in Rottweiler dogs.

    Science.gov (United States)

    Wouda, W; van Nes, J J

    1986-04-01

    A clinicopathological study of a neurologic disease in Rottweiler dogs was conducted. Clinical data were available on 16 dogs, 11 of which were examined pathologically. All dogs had a history of progressive gait abnormalities, which had commenced insidiously at an age varying from 1.5 to 3.5 years. In most dogs the fore limbs were affected prior to the hind limbs. At neurologic examination ataxia of all 4 limbs was seen, in some instances accompanied by an apparent paresis. Proprioceptive positioning was delayed whereas spinal reflexes were often hyperactive. Plain and contrast radiographs of the spine did not reveal any compressive lesions in 5 dogs examined. Cerebrospinal fluid analysis in 4 dogs was normal. Electrodiagnostic testing in 3 dogs revealed no abnormalities. At pathologic examination demyelinating lesions were found in the central nervous system. These were largely confined to the cervical spinal cord and brain stem and had a rather characteristic more or less symmetric distribution. Pedigree data suggested that the disease is transmitted genetically.

  19. Effects of genetic severity on glucose homeostasis in Friedreich ataxia.

    Science.gov (United States)

    Isaacs, Charles J; Brigatti, Karlla W; Kucheruk, Olena; Ratcliffe, Sarah; Sciascia, Tom; McCormack, Shana E; Willi, Steven M; Lynch, David R

    2016-11-01

    Friedreich ataxia (FRDA) leads to increased risk of diabetes. Less is known regarding the dynamics of glucose homeostasis in FRDA, the influence of disease features, and the utility of oral-based metrics for capturing metabolic dysfunction. To examine these dynamics, we analyzed oral and intravenous glucose tolerance test data in 42 non-diabetic patients with FRDA. Patients showed high insulin responsiveness to glucose and low insulin sensitivity. Genetic severity predicted overall metabolic impairment: individuals with longer guanine-adenine-adenine (GAA) repeats on the shorter allele showed a lower disposition index. Genetic severity did not predict any other variables. Measures of disposition index from intravenous and oral glucose tolerance testing did not correlate well, possibly reflecting divergent responses to oral and intravenous glucose loads. FRDA patients demonstrate abnormal compensatory activity for managing glucose. Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient to patient. Muscle Nerve 54: 887-894, 2016. © 2016 Wiley Periodicals, Inc.

  20. False-Positive Head-Impulse Test in Cerebellar Ataxia

    Science.gov (United States)

    Kremmyda, Olympia; Kirchner, Hanni; Glasauer, Stefan; Brandt, Thomas; Jahn, Klaus; Strupp, Michael

    2012-01-01

    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, vestibuloocular reflex (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 80 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 identified 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. PMID:23162531

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

    Science.gov (United States)

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

    2013-04-12

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

  2. 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.

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

    Science.gov (United States)

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

    2014-01-01

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

  4. Ethical considerations in presymptomatic diagnosis of autosomal dominant spinocerebellar ataxias.

    Science.gov (United States)

    Orozco-Gutiérrez, M H; Cervantes-Aragón, I; García-Cruz, D

    2017-09-01

    Information on achieving presymptomatic diagnosis of spinocerebellar ataxia (SCA) is limited. The advent of molecular diagnosis makes it possible to identify the carriers of different diseases and has also introduced the prospect of detecting diseases even before their onset. This has drawn attention to the ethical implications that must be considered in these subjects with a view to preserving their physical and psychological well-being. SCA is composed of a group of neurodegenerative disorders with autosomal dominant inheritance. Only a few publications have described the genetic counselling processes and guidelines to be followed during the process of presymptomatic diagnosis (PSD). The size of the multidisciplinary teams, their areas of expertise, and the number of counselling sessions are different for each of the studies analysed here. However, the basis of presymptomatic diagnosis originates in common guidelines to which members of our team have contributed recently. Presymptomatic diagnosis should be performed according to guidelines that safeguard the subjects' welfare. The diagnostic process is only recommended for patients over 18 years old with symptoms suggesting SCA, and a minimum risk of 50%. Genetic counselling programmes must be available in all centres that offer presymptomatic diagnosis of SCA. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Gait ataxia--specific cerebellar influences and their rehabilitation.

    Science.gov (United States)

    Ilg, Winfried; Timmann, Dagmar

    2013-09-15

    It is well known that the cerebellum is important for movement control and plays a critical role in balance and locomotion. As such, one of the most characteristic and sensitive signs of cerebellar damage is gait ataxia. However, characterizing ataxic gait is no easy task, because gait patterns are highly variable. This variability seems to result from the interaction of different factors, namely, (1) the primary motor deficits in balance control and multi-joint coordination and oculomotor dysfunction, (2) the safety strategies used, and (3) inaccurate adjustments in patients with loss of balance. In this report, we review different approaches to analyzing ataxic gait and studies to identify and quantify the different factors contributing to this movement disorder. We also discuss the influence of the cerebellum in adaptive locomotor control, the interaction between cognitive load and gait in dual-task paradigms, and the recent advances in rehabilitation of gait and posture for patients with cerebellar degeneration. In the second part, we discuss open questions concerning cerebellar mechanisms in multi-joint coordination during different walking conditions. Furthermore, we point out potential future directions in motor rehabilitation, with the objective of identifying predictors of rehabilitation outcome and the development of individualized training programs that potentially involve rehabilitation technology. © 2013 Movement Disorder Society.

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

    Science.gov (United States)

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

    2014-01-01

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

  7. 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.

  8. Molecular genetics of a Chinese family with spinocerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Dan-dan WU

    2015-10-01

    Full Text Available Objective To study the genotype of the members of a Chinese family with spinocerebellar ataxia (SCA. Methods The peripheral blood samples of 6 patients and 40 asymptomatic people belonged to the family were collected. Referring to the clinical manifestations of the proband and second-generation sequencing results, the CAG trinucleotide repeats of the pathogenic gene ATXN2 were amplified by polymerase chain reaction (PCR. The repeated times of the trinucleotide in normally and abnormally amplified alleles were defined by agarose gel electrophoresis and PCR products sequencing. Results Autosomal dominant heredity was the cause of the SCA in this family. Six out of 46 in the fourth-generation were SCA2 patients, 7 were the carriers of pathogenic allele. The repeated times of CAG trinucleotide were within the normal range in one of the two alleles of ATXN2, but they were in abnormal range in the another one. The repeated times of CAG trinucleotide were 40-46 in abnormal alleles of patients. Conclusion Autosomal dominant heredity SCA2 has been diagnosed in this family caused by the dynamic nutation of CAG trinucleotide repeats, and 7 pathogenic allele carriers in this family were confirmed by genetic diagnosis. DOI: 10.11855/j.issn.0577-7402.2015.08.07

  9. Pulmonary function in children and young adults with ataxia telangiectasia.

    Science.gov (United States)

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

    2014-01-01

    Pulmonary disease contributes to significant morbidity and mortality in people with ataxia telangiectasia (A-T). To determine the association between age and lung function in children and young adults with A-T and to identify factors associated with decreased lung function, pulmonary function tests were performed in 100 consecutive people with A-T. Children and adults ranging from 6 to 29 years of age and with the diagnosis of A-T were recruited, and underwent pulmonary function tests. The mean forced vital capacity % predicted (FVC %) in the population was 56.6 ± 20.0. Males and females between 6 and 10 years of age had similar pulmonary function. Older females were found to have significantly lower FVCs % than both older males (P pulmonary function testing on two or more occasions over an average of 2 years. In children and young adults with A-T, older females and people who required supplemental gamma globulin had significantly lower lung function by cross-sectional analysis. Stable lung function is possible over a 2-year period. Recognition of groups who are at higher risk for lower pulmonary function may help direct care and improve clinical outcomes in people with A-T. © 2013 Wiley Periodicals, Inc.

  10. Kv3.3 potassium channels and spinocerebellar ataxia.

    Science.gov (United States)

    Zhang, Yalan; Kaczmarek, Leonard K

    2016-08-15

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

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

    Science.gov (United States)

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

    2017-08-15

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

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2016-05-01

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

  14. 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.

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

    Science.gov (United States)

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

    2016-11-01

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

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

    Science.gov (United States)

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

    2010-03-15

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

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Science.gov (United States)

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

    2012-09-01

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

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

    Science.gov (United States)

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

    2017-09-05

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

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

    Science.gov (United States)

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

    2017-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Simindokht Hosseini Seyede

    2009-12-01

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

  2. Pure Cerebellar Ataxia with Homozygous Mutations in the PNPLA6 Gene.

    Science.gov (United States)

    Wiethoff, Sarah; Bettencourt, Conceição; Paudel, Reema; Madon, Prochi; Liu, Yo-Tsen; Hersheson, Joshua; Wadia, Noshir; Desai, Joy; Houlden, Henry

    2017-02-01

    Autosomal-recessive cerebellar ataxias (ARCA) are clinically and genetically heterogeneous conditions primarily affecting the cerebellum. Mutations in the PNPLA6 gene have been identified as the cause of hereditary spastic paraplegia and complex forms of ataxia associated with retinal and endocrine manifestations in a field where the genotype-phenotype correlations are rapidly expanding. We identified two cousins from a consanguineous family belonging to a large Zoroastrian (Parsi) family residing in Mumbai, India, who presented with pure cerebellar ataxia without chorioretinal dystrophy or hypogonadotropic hypogonadism. We used a combined approach of clinical characterisation, homozygosity mapping, whole-exome and Sanger sequencing to identify the genetic defect in this family. The phenotype in the family was pure cerebellar ataxia. Homozygosity mapping revealed one large region of shared homozygosity at chromosome 19p13 between affected individuals. Within this region, whole-exome sequencing of the index case identified two novel homozygous missense variants in the PNPLA6 gene at c.3847G>A (p.V1283M) and c.3929A>T (p.D1310V) in exon 32. Both segregated perfectly with the disease in this large family, with only the two affected cousins being homozygous. We identified for the first time PNPLA6 mutations associated with pure cerebellar ataxia in a large autosomal-recessive Parsi kindred. Previous mutations in this gene have been associated with a more complex phenotype but the results here suggest an extension of the associated disease spectrum.

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

    Science.gov (United States)

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

    2017-02-01

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

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

    Science.gov (United States)

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

    2016-10-01

    This cross-sectional investigation aimed to assess the value of non-invasive measures of temporal respiratory-swallow coupling in individuals with ataxic swallowing. Twenty participants (11 males, 9 females; range 9-21y) with ataxia telangiectasia were presented with water and pudding boluses. Their 193 swallows were compared with 2200 swallows from 82 age-matched healthy controls. The two components of airway protection during swallowing that were analyzed were: direction of peri-deglutitive airflow and duration of deglutitive inhibition of respiratory airflow (DIORA). Safe expiratory patterns of peri-deglutitive airflow occurred significantly less often in participants with ataxia telangiectasia than in age-matched control participants (younger pdeglutitive airflow increased with age in participants in the comparison group (p=0.006), but not in those with ataxia telangiectasia (p=0.234). With age, mean duration of DIORA decreased in controls (p<0.001) but was unchanged in participants with ataxia telangiectasia (p=0.164). Non-invasive quantitative measures of respiratory-swallow coupling capture temporal relationships that plausibly contribute to airway compromise from dysphagia. Changes in respiratory-swallow coupling observed with advancing age in control participants were not seen in participants with ataxia telangiectasia. Measures of perturbations may herald swallowing problems prior to development of pulmonary and nutritional sequelae. © 2016 Mac Keith Press.

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

    Directory of Open Access Journals (Sweden)

    Tiago Silva Aguiar

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

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

    Science.gov (United States)

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

    2017-03-13

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

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

    NARCIS (Netherlands)

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

    2004-01-01

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

  8. Phosphomannomutase deficiency (PMM2-CDG): ataxia and cerebellar assessment.

    Science.gov (United States)

    Serrano, Mercedes; de Diego, Víctor; Muchart, Jordi; Cuadras, Daniel; Felipe, Ana; Macaya, Alfons; Velázquez, Ramón; Poo, M Pilar; Fons, Carmen; O'Callaghan, M Mar; García-Cazorla, Angels; Boix, Cristina; Robles, Bernabé; Carratalá, Francisco; Girós, Marisa; Briones, Paz; Gort, Laura; Artuch, Rafael; Pérez-Cerdá, Celia; Jaeken, Jaak; Pérez, Belén; Pérez-Dueñas, Belén

    2015-10-26

    Phosphomannomutase deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. The cerebellum is nearly always affected in PMM2-CDG patients, a cerebellar atrophy progression is observed, and cerebellar dysfunction is their main daily functional limitation. Different therapeutic agents are under development, and clinical evaluation of drug candidates will require a standardized score of cerebellar dysfunction. We aim to assess the validity of the International Cooperative Ataxia Rating Scale (ICARS) in children and adolescents with genetically confirmed PMM2-CDG deficiency. We compare ICARS results with the Nijmegen Pediatric CDG Rating Scale (NPCRS), neuroimaging, intelligence quotient (IQ) and molecular data. Our observational study included 13 PMM2-CDG patients and 21 control subjects. Ethical permissions and informed consents were obtained. Three independent child neurologists rated PMM2-CDG patients and control subjects using the ICARS. A single clinician administered the NPCRS. All patients underwent brain MRI, and the relative diameter of the midsagittal vermis was measured. Psychometric evaluations were available in six patients. The Mann-Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients' ICARS ratings, intraclass correlation coefficients (ICC) were calculated. ICARS internal consistency was evaluated using Cronbach's alpha. Spearman's rank correlation coefficient test was used to correlate ICARS with NPCRS, midsagittal vermis relative diameter and IQ. ICARS and ICARS subscores differed between patients and controls (p cerebellar assessment, IQ and neuroimaging. For the first a correlation between ICARS, neuroimaging and IQ in PMM2-CDG patients has been demonstrated.

  9. RNA gain-of-function in spinocerebellar ataxia type 8.

    Directory of Open Access Journals (Sweden)

    Randy S Daughters

    2009-08-01

    Full Text Available Microsatellite expansions cause a number of dominantly-inherited neurological diseases. Expansions in coding-regions cause protein gain-of-function effects, while non-coding expansions produce toxic RNAs that alter RNA splicing activities of MBNL and CELF proteins. Bi-directional expression of the spinocerebellar ataxia type 8 (SCA8 CTG CAG expansion produces CUG expansion RNAs (CUG(exp from the ATXN8OS gene and a nearly pure polyglutamine expansion protein encoded by ATXN8 CAG(exp transcripts expressed in the opposite direction. Here, we present three lines of evidence that RNA gain-of-function plays a significant role in SCA8: 1 CUG(exp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons in the brain; 2 loss of Mbnl1 enhances motor deficits in SCA8 mice; 3 SCA8 CUG(exp transcripts trigger splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4. In vivo optical imaging studies in SCA8 mice confirm that Gabt4 upregulation is associated with the predicted loss of GABAergic inhibition within the granular cell layer. These data demonstrate that CUG(exp transcripts dysregulate MBNL/CELF regulated pathways in the brain and provide mechanistic insight into the CNS effects of other CUG(exp disorders. Moreover, our demonstration that relatively short CUG(exp transcripts cause RNA gain-of-function effects and the growing number of antisense transcripts recently reported in mammalian genomes suggest unrecognized toxic RNAs contribute to the pathophysiology of polyglutamine CAG CTG disorders.

  10. Growth and nutrition in children with ataxia telangiectasia.

    Science.gov (United States)

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

    2016-12-01

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

  11. 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.

  12. 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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Samin Alavi

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Vujić Dragana S.

    2013-01-01

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

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

    Science.gov (United States)

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

    2015-12-01

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

  17. Optic ataxia: from Balint’s syndrome to the parietal reach region

    Science.gov (United States)

    Andersen, Richard A.; Andersen, Kristen N.; Hwang, EunJung; Hauschild, Markus

    2014-01-01

    Optic ataxia is a high order deficit in reaching to visual goals that occurs with posterior parietal cortex (PPC) lesions. It is a component of Balint’s syndrome that also includes attentional and gaze disorders. Aspects of optic ataxia are misreaching in the contralesional visual field, difficulty preshaping the hand for grasping, and an inability to correct reaches online. Recent research in non-human primates (NHPs) suggests that many aspects of Balint’s syndrome and optic ataxia are a result of damage to specific functional modules for reaching, saccades, grasp, attention, and state estimation. The deficits from large lesions in humans are likely composite effects from damage to combinations of these functional modules. Interactions between these modules, either within posterior parietal cortex or downstream within frontal cortex, may account for more complex behaviors such as hand-eye coordination and reach-to-grasp. PMID:24607223

  18. Acute Cerebellar Ataxia Associated with Anti-glutamic Acid Decarboxylase Antibodies Mimicking Miller Fisher Syndrome.

    Science.gov (United States)

    Nakamura, Yoshitsugu; Nakajima, Hideto; Hosokawa, Takafumi; Yamane, Kazushi; Ishida, Shimon; Kimura, Fumiharu

    2018-01-15

    We herein report the case of a 53-year-old man with cerebellar ataxia with anti-glutamic acid decarboxylase antibody (GAD-Ab) who mimicked Miller Fisher syndrome (MFS). He developed ophthalmoplegia, diplopia, and gait ataxia for one week. The serum and cerebrospinal fluid GAD-Ab titers were greatly increased, and the GAD-Ab index suggesting intrathecal antibody synthesis was elevated, while GQ1b-Ab was negative. After steroid pulse therapy and following prednisolone, his symptoms dramatically improved over the course of 11 months with the simultaneous decline of GAD-Ab titers. This case indicates that cerebellar ataxia with GAD-Ab can present with acute neurological findings mimicking MFS, and that steroid therapy has an excellent therapeutic effect.

  19. 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.

  20. 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.

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

    Science.gov (United States)

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

    2016-12-15

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

  2. 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.

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

    Science.gov (United States)

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

    2017-09-15

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

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

    Science.gov (United States)

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

    2012-01-01

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

  5. Structural and Functional Magnetic Resonance Imaging of the Cerebellum: Considerations for Assessing Cerebellar Ataxias.

    Science.gov (United States)

    Deistung, Andreas; Stefanescu, Maria R; Ernst, Thomas M; Schlamann, Marc; Ladd, Mark E; Reichenbach, Jürgen R; Timmann, Dagmar

    2016-02-01

    Magnetic resonance imaging (MRI) of the brain is of high interest for diagnosing and understanding degenerative ataxias. Here, we present state-of-the-art MRI methods to characterize structural alterations of the cerebellum and introduce initial experiments to show abnormalities in the cerebellar nuclei. Clinically, T1-weighted MR images are used to assess atrophy of the cerebellar cortex, the brainstem, and the spinal cord, whereas T2-weighted and PD-weighted images are typically employed to depict potential white matter lesions that may be associated with certain types of ataxias. More recently, attention has also focused on the characterization of the cerebellar nuclei, which are discernible on spatially highly resolved iron-sensitive MR images due to their relatively high iron content, including T2 (*)-weighted images, susceptibility-weighted images (SWI), effective transverse relaxation rate (R2 (*)) maps, and quantitative susceptibility maps (QSM). Among these iron-sensitive techniques, QSM reveals the best contrast between cerebellar nuclei and their surroundings. In particular, the gyrification of the dentate nuclei is prominently depicted, even at the clinically widely available field strength of 3 T. The linear relationship between magnetic susceptibility and local iron content allows for determination of iron deposition in cerebellar nuclei non-invasively. The increased signal-to-noise ratio of ultrahigh-field MRI (B0 ≥ 7 T) and advances in spatial normalization methods enable functional MRI (fMRI) at the level of the cerebellar cortex and cerebellar nuclei. Data from initial fMRI studies are presented in three common forms of hereditary ataxias (Friedreich's ataxia, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6). Characteristic changes in the fMRI signal are discussed in the light of histopathological data and current knowledge of the underlying physiology of the fMRI signal in the cerebellum.

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

    Science.gov (United States)

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

    2015-10-01

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

  7. The sword of Damocles: the psychosocial impact of familial spinocerebellar ataxia in South Africa.

    Science.gov (United States)

    de Villiers, C; Weskamp, K; Bryer, A

    1997-05-31

    A survey was conducted on 30 unaffected individuals from a family with autosomal dominant late onset spinocerebellar ataxia in South Africa. The psychological impact of the disorder on individual lives, risk awareness, attitudes towards affected kin and reproduction were evaluated. Respondents employed various psychological strategies to deal with the threat of developing the disorder. In a comparison of "assigned" risk with "perceived" risk, 80% of unaffected persons reported incorrect perceptions of personal risk status. The disorder had little impact on attitudes concerning reproduction; the majority of individuals at risk wanted more children. These issues need to be addressed in the genetic and predictive testing service for familial ataxia in South Africa.

  8. Late Presentation of Ataxia, Areflexia, and Electrophysiological Abnormalities as Part of Miller Fisher Syndrome: Case Report.

    Science.gov (United States)

    Somer, Deniz; Yilmaz, Arzu; Tiras Teber, Serap; Cinar, Fatma Gul

    2016-08-01

    Miller Fisher syndrome (MFS) is characterised by the triad of ophthalmoplegia, ataxia, and areflexia. A case with external ophthalmoplegia and absence of ataxia and areflexia until the end of second week is presented. Electrophysiological findings became apparent after the third week and showed reduced amplitudes of sensory nerve action potentials and prolonged latencies of F with no evidence of conduction blocks. There was no response to intravenous immunoglobulin, but there was response to corticosteroids. This case may represent an atypical MFS with late presenting electrophysiological abnormalities. Corticosteroids can be a therapeutic option when intravenous immunoglobulin fails to control clinical symptoms.

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

    Science.gov (United States)

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

    2017-11-01

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

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

    Science.gov (United States)

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

    2014-06-15

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

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

    Science.gov (United States)

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

    2013-04-01

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

  12. 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

    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...... of these paroxysms, but the underlying mechanisms are poorly understood. Normal ion channels are crucial for coordinating neuronal firing in response to facilitatory input. Thus, we hypothesized that channel dysfunction in episodic ataxia type 2 and familial hemiplegic migraine may impair the ability to adjust...... set the stage for the emergence of paroxysmal neural dysfunction in this disorder....

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

    Science.gov (United States)

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

    2017-06-01

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

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

    Directory of Open Access Journals (Sweden)

    Mohammad Ehlayel

    2014-01-01

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

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

    Science.gov (United States)

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

    2010-07-01

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

  16. Cardiopatía dilatada en ataxia de Friedreich: el punto sin retorno Dilated cardiomyopathy in Friedreich's ataxia: point of no return

    Directory of Open Access Journals (Sweden)

    Luis E Silva

    2012-04-01

    Full Text Available Las cardiopatías infiltrativas se caracterizan por el depósito de sustancias en el miocardio que causan un impacto negativo en la arquitectura de la pared ventricular. La ataxia espino-cerebelosa de Friedreich es una enfermedad degenerativa, heredada, con carácter autosómico recesivo. Clínicamente se caracteriza por ataxia de extremidades y tronco, hiporreflexia, neuropatía periférica, retinopatía y cardiopatía, entre otros. La afectación cardíaca es muy frecuente y se detectan alteraciones en estudios pos-mortem en 95% a 100% de los pacientes. La tasa de mortalidad es elevada y se considera una enfermedad incurable, a pesar de la existencia actual de múltiples medicamentos en estudio basados en los fundamentos fisiopatológicos de esta afección.Infiltrative heart diseases are characterized by deposit of substances in the myocardium that cause a negative impact on the architecture of the ventricular wall. Friedreich's spino-cerebellar ataxia is a degenerative disease, inherited in an autosomal recessive pattern. Clinically it is characterized by limb and trunk ataxia, hyporeflexia, peripheral neuropathy, retinopathy and heart disease among others. Cardiac involvement is common and on post-mortem studies cardiac abnormalities are found in 95% to 100% of patients. The mortality rate is high and it is considered an incurable disease, despite the current existence of multiple medications being studied, based on the pathophysiological basis of this condition.

  17. 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.

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

    Science.gov (United States)

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

    2008-12-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    NARCIS (Netherlands)

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

    2010-01-01

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

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

    Science.gov (United States)

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

    2014-04-01

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

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

    Science.gov (United States)

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

    2018-02-05

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

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

    Science.gov (United States)

    Keller, Jennifer L; Bastian, Amy J

    2014-10-01

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

  4. 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

  5. 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…

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  7. 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.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-02-17

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

  10. 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...

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  14. 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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

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

    NARCIS (Netherlands)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2009-08-28

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

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

    Directory of Open Access Journals (Sweden)

    Ishani Sahama

    2015-01-01

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

  19. 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…

  20. Mucocutaneous leishmaniasis in an 11-year-old girl with ataxia ...

    African Journals Online (AJOL)

    LETTER TO THE EDITOR. Mucocutaneous leishmaniasis in an 11-year-old girl with ataxia telangectasia Бcase report. Leishmaniasis is a protozoal disease caused by flagellates of the genus Leishmania and transmit- ted by sand fly. The reservoir hosts are humans, dogs, and rodents. It has three different morphological.

  1. The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia Type 6

    NARCIS (Netherlands)

    Seidel, K.; Brunt, E. R. P.; de Vos, R. A. I.; Dijk, F.; van der Want, H. J. L.; Kampinga, H. H.; Rueb, U.; den Dunnen, W. F. A.

    2009-01-01

    Neuronal protein aggregates are considered as pathological hallmarks of various human neurodegenerative diseases, including the so-called CAG-repeat disorders, such as spinocerebellar ataxia Type 6 (SCA6). Since the immunocytochemical findings of an initial post-mortem study using a specific

  2. Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6.

    NARCIS (Netherlands)

    Globas, C.; Montcel, S.T. du; Baliko, L.; Boesch, S.; Depondt, C.; DiDonato, S.; Durr, A.; Filla, A.; Klockgether, T.; Mariotti, C.; Melegh, B.; Rakowicz, M.; Ribai, P.; Rola, R.; Schmitz-Hubsch, T.; Szymanski, S.; Timmann, D.; Warrenburg, B.P.C. van de; Bauer, P.; Schols, L.

    2008-01-01

    Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We

  3. Functional Analysis Helps to Define KCNC3 Mutational Spectrum in Dutch Ataxia Cases

    NARCIS (Netherlands)

    Duarri, Anna; Nibbeling, Esther A. R.; Fokkens, Michiel R.; Meijer, Michel; Boerrigter, Melissa; Verschuuren - Bemelmans, Corien C.; Kremer, Berry P. H.; van de Warrenburg, Bart P.; Dooijes, Dennis; Boddeke, Erik; Sinke, Richard J.; Verbeek, Dineke S.

    2015-01-01

    Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominantly inherited neurodegenerative disorder of the cerebellum caused by mutations in the voltage gated potassium channel KCNC3. To identify novel pathogenic SCA13 mutations in KCNC3 and to gain insights into the disease prevalence in the

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1983-07-01

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

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

    Science.gov (United States)

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

    2017-04-01

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

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

    Science.gov (United States)

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

    2017-06-01

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

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

    Science.gov (United States)

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

    2014-02-01

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

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

    Science.gov (United States)

    2011-01-01

    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 examination, genetic molecular

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

    Directory of Open Access Journals (Sweden)

    Fujioka Shinsuke

    2011-05-01

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

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

    Science.gov (United States)

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

    2014-04-17

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

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

    Science.gov (United States)

    2013-01-01

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

  12. Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13).

    Science.gov (United States)

    Figueroa, Karla P; Waters, Michael F; Garibyan, Vartan; Bird, Thomas D; Gomez, Christopher M; Ranum, Laura P W; Minassian, Natali A; Papazian, Diane M; Pulst, Stefan M

    2011-03-29

    Gain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3) were recently identified as a cause of autosomal dominant spinocerebellar ataxia. Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial ataxia presenting to three US ataxia clinics at academic medical centers. DNA sequence analysis of the coding region of the KCNC3 gene was performed in 327 index cases with ataxia. Analysis of channel function was performed by expression of DNA variants in Xenopus oocytes. Sequence analysis revealed two non-synonymous substitutions in exon 2 and five intronic changes, which were not predicted to alter splicing. We identified another pedigree with the p.Arg423His mutation in the highly conserved S4 domain of this channel. This family had an early-onset of disease and associated seizures in one individual. The second coding change, p.Gly263Asp, subtly altered biophysical properties of the channel, but was unlikely to be disease-associated as it occurred in an individual with an expansion of the CAG repeat in the CACNA1A calcium channel. Mutations in KCNC3 are a rare cause of spinocerebellar ataxia with a frequency of less than 1%. The p.Arg423His mutation is recurrent in different populations and associated with early onset. In contrast to previous p.Arg423His mutation carriers, we now observed seizures and mild mental retardation in one individual. This study confirms the wide phenotypic spectrum in SCA13.

  13. Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13.

    Directory of Open Access Journals (Sweden)

    Karla P Figueroa

    2011-03-01

    Full Text Available Gain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3 were recently identified as a cause of autosomal dominant spinocerebellar ataxia. Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial ataxia presenting to three US ataxia clinics at academic medical centers.DNA sequence analysis of the coding region of the KCNC3 gene was performed in 327 index cases with ataxia. Analysis of channel function was performed by expression of DNA variants in Xenopus oocytes.Sequence analysis revealed two non-synonymous substitutions in exon 2 and five intronic changes, which were not predicted to alter splicing. We identified another pedigree with the p.Arg423His mutation in the highly conserved S4 domain of this channel. This family had an early-onset of disease and associated seizures in one individual. The second coding change, p.Gly263Asp, subtly altered biophysical properties of the channel, but was unlikely to be disease-associated as it occurred in an individual with an expansion of the CAG repeat in the CACNA1A calcium channel.Mutations in KCNC3 are a rare cause of spinocerebellar ataxia with a frequency of less than 1%. The p.Arg423His mutation is recurrent in different populations and associated with early onset. In contrast to previous p.Arg423His mutation carriers, we now observed seizures and mild mental retardation in one individual. This study confirms the wide phenotypic spectrum in SCA13.

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

    Science.gov (United States)

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

    2010-02-01

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

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

    Science.gov (United States)

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

    2009-01-01

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

  16. Supporting a Youth with Cerebellar Ataxia into Adolescence.

    Science.gov (United States)

    Meneses, Veronica; Gonzalez-Castillo, Zurisadai; Edgar, Veronica B; Augustyn, Marilyn

    2017-04-01

    Zoe, a 13-year-old white girl, presents as a new patient to your pediatric clinic with complaints of frequent emesis, anxiety, and learning problems, and previous diagnosis of cerebellar ataxia. Parents accompany Zoe and state, "it is really hard for her to go out, she gets sick and falls easily." She was born full term by vaginal delivery without complications. Given globally delayed milestones, she received early intervention services. Feeding problems began at infancy, including gastroesophageal reflux and aspiration pneumonia.At age 2, Zoe saw a neurologist and brain MRI revealed cerebellar atrophy. She recently saw a geneticist and genetic studies are pending. Parents report receiving "little" information regarding prognosis; through their own research, they read about individuals having similar symptoms in adulthood, with a degenerative pattern. They worry that Zoe is "still very young and we do not know what her future will be like."Despite ongoing speech and feeding challenges, the parents report difficulty finding a speech and language therapist in their area. Zoe does see an otolaryngologist for frequent otitis media and hearing loss and an ophthalmologist for vision problems. Still, she continues to fall further behind in school. Furthermore, she is intensely afraid of falling at school and has few friends, resulting in the family being at a loss regarding "what to do about school."She lives with both parents and 2 healthy older sisters. Her mother has Crohn's disease and has been unable to work. Her maternal aunt is close to Zoe and has hypothyroidism. Her father works as an insurance agent and resources have been "tight." Zoe's mother describes "making" Zoe go out to the movies, "otherwise she just stays home." Zoe usually needs assistance to walk in public, to keep from stumbling. Parents share that simply being in a public place or meeting a new physician may trigger emesis. Zoe does enjoy interacting with neighborhood children and says she wants to

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

    National Research Council Canada - National Science Library

    Offit, Kenneth

    1998-01-01

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

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

    National Research Council Canada - National Science Library

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

    2011-01-01

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

  19. 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.

  20. Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model.

    Science.gov (United States)

    Németh, Andrea H; Kwasniewska, Alexandra C; Lise, Stefano; Parolin Schnekenberg, Ricardo; Becker, Esther B E; Bera, Katarzyna D; Shanks, Morag E; Gregory, Lorna; Buck, David; Zameel Cader, M; Talbot, Kevin; de Silva, Rajith; Fletcher, Nicholas; Hastings, Rob; Jayawant, Sandeep; Morrison, Patrick J; Worth, Paul; Taylor, Malcolm; Tolmie, John; O'Regan, Mary; Valentine, Ruth; Packham, Emily; Evans, Julie; Seller, Anneke; Ragoussis, Jiannis

    2013-10-01

    Many neurological conditions are caused by immensely heterogeneous gene mutations. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the 'diagnostic odyssey' for many of these patients. We performed a pilot study using heterogeneous ataxias as a model neurogenetic disorder to assess the introduction of next-generation sequencing into clinical practice. We captured 58 known human ataxia genes followed by Illumina Next-Generation Sequencing in 50 highly heterogeneous patients with ataxia who had been extensively investigated and were refractory to diagnosis. All cases had been tested for spinocerebellar ataxia 1-3, 6, 7 and Friedrich's ataxia and had multiple other biochemical, genetic and invasive tests. In those cases where we identified the genetic mutation, we determined the time to diagnosis. Pathogenicity was assessed using a bioinformatics pipeline and novel variants were validated using functional experiments. The overall detection rate in our heterogeneous cohort was 18% and varied from 8.3% in those with an adult onset progressive disorder to 40% in those with a childhood or adolescent onset progressive disorder. The highest detection rate was in those with an adolescent onset and a family history (75%). The majority of cases with detectable mutations had a childhood onset but most are now adults, reflecting the long delay in diagnosis. The delays were primarily related to lack of easily available clinical testing, but other factors included the presence of atypical phenotypes and the use of indirect testing. In the cases where we made an eventual diagnosis, the delay was 3-35 years (mean 18.1 years). Alignment and coverage metrics indicated that the capture and sequencing was highly efficient and the consumable cost

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

    Science.gov (United States)

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

    2017-06-01

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

  2. 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.

  3. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: typical clinical and neuroimaging features in a Brazilian family

    Directory of Open Access Journals (Sweden)

    J L Pedroso

    2011-01-01

    Full Text Available Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS is a neurodegenerative disorder characterized by late-infantile onset spastic ataxia and other neurological features. ARSACS has a high prevalence in northeastern Quebec, Canada. Several ARSACS cases have been reported outside Canada in recent decades. This is the first report of typical clinical and neuroimaging features in a Brazilian family with probable diagnosis of ARSACS.

  4. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): typical clinical and neuroimaging features in a Brazilian family.

    Science.gov (United States)

    Pedroso, José Luiz; Braga-Neto, Pedro; Abrahão, Agessandro; Rivero, René Leandro Magalhães; Abdalla, Carolina; Abdala, Nitamar; Barsottini, Orlando Graziani Povoas

    2011-01-01

    Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder characterized by late-infantile onset spastic ataxia and other neurological features. ARSACS has a high prevalence in northeastern Quebec, Canada. Several ARSACS cases have been reported outside Canada in recent decades. This is the first report of typical clinical and neuroimaging features in a Brazilian family with probable diagnosis of ARSACS.

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

    Science.gov (United States)

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

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

  6. Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis

    OpenAIRE

    Pondarre, Corinne; Campagna, Dean R.; Antiochos, Brendan; Sikorski, Lindsay; Mulhern, Howard; Fleming, Mark D.

    2007-01-01

    X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare syndromic form of inherited sideroblastic anemia associated with spinocerebellar ataxia, and is due to mutations in the mitochondrial ATP-binding cassette transporter Abcb7. Here, we show that Abcb7 is essential for hematopoiesis and formally demonstrate that XLSA/A is due to partial loss of function mutations in Abcb7 that directly or indirectly inhibit heme biosynthesis.

  7. Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis.

    Science.gov (United States)

    Pondarre, Corinne; Campagna, Dean R; Antiochos, Brendan; Sikorski, Lindsay; Mulhern, Howard; Fleming, Mark D

    2007-04-15

    X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare syndromic form of inherited sideroblastic anemia associated with spinocerebellar ataxia, and is due to mutations in the mitochondrial ATP-binding cassette transporter Abcb7. Here, we show that Abcb7 is essential for hematopoiesis and formally demonstrate that XLSA/A is due to partial loss of function mutations in Abcb7 that directly or indirectly inhibit heme biosynthesis.

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

    Science.gov (United States)

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

    2002-08-01

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

  9. The effects of sleep dysfunction on cognition, affect, and quality of life in individuals with cerebellar ataxia.

    Science.gov (United States)

    Sonni, Akshata; Kurdziel, Lauri B F; Baran, Bengi; Spencer, Rebecca M C

    2014-05-15

    Cerebellar ataxia comprises a group of debilitating diseases that are the result of progressive cerebellar degeneration. Recent studies suggest that, like other neurodegenerative diseases, sleep impairments are common in cerebellar ataxia. In light of the role of sleep in mood regulation and cognition, we sought to assess interactions between sleep, cognition, and affect in individuals with cerebellar ataxia. A survey of 176 individuals with cerebellar ataxia was conducted. The battery of instruments included a modified International Cooperative Ataxia Rating Scale, Pittsburgh Sleep Quality Index, Restless Leg Syndrome Questionnaire, REM Behavior Disorder Questionnaire, Beck Depression Inventory, Epworth Sleepiness Scale, and a Composite Cognitive Questionnaire. Fifty-one percent of individuals indicated significant sleep disturbances on the Pittsburgh Sleep Quality Index, 73% of participants had two or more symptoms of restless leg syndrome, and 88% had two or more symptoms of REM behavior disorder. Ataxia severity, based on the modified International Cooperative Ataxia Rating Scale, predicted scores on the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale and REM Behavior Disorder Questionnaire. Median split analyses revealed that cognitive function appeared to be reduced and depressive symptoms were greater for those individuals with poor subjective sleep quality and severe RLS. Importantly, sleep appears to play a mediatory role between disease severity and depressive symptoms. These results suggest that disturbed sleep may have detrimental effects on cognition and affect in individuals with cerebellar ataxia. While objective measures are needed, such results suggest that treating sleep deficits in these individuals may improve cognitive and mental health as well as overall quality of life.

  10. Identification of a novel Twinkle mutation in a family with infantile onset spinocerebellar ataxia by whole exome sequencing.

    Science.gov (United States)

    Dündar, Halil; Ozgül, Rıza Köksal; Yalnızoğlu, Dilek; Erdem, Sevim; Oğuz, Kader Karlı; Tuncel, Deniz; Temuçin, Cağrı Mesut; Dursun, Ali

    2012-03-01

    Whole exome sequencing combined with homozygosity mapping comprises a genetic diagnostic tool to identify genetic defects in families with multiple affected members, compatible with presumed autosomal recessively inherited neurometabolic/neurogenetic disease. These tools were applied to a family with two individuals manifesting ataxia, associated with peripheral sensory neuropathy, athetosis, seizures, deafness, and ophthalmoplegia. A novel homozygous missense mutation c.1366C>G (L456V) in C10orf2 (the Twinkle gene) was identified, confirming infantile onset spinocerebellar ataxia in the probands. Signs in infantile onset spinocerebellar ataxia follow a fairly distinct pattern, affecting early development, followed by ataxia and loss of skills. However, this very rare disease was previously reported only in Finland. We suggest that infantile onset spinocerebellar ataxia should be more frequently considered in the differential diagnosis of neurometabolic diseases in childhood. Next-generation sequencing and its use along with homozygosity mapping offer highly promising techniques for molecular diagnosis, especially in small families affected with very rare neurometabolic disorders such as infantile onset spinocerebellar ataxia. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2014-10-01

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

  12. Prolonged Type 1 Metabotropic Glutamate Receptor Dependent Synaptic Signaling Contributes to Spino-Cerebellar Ataxia Type 1.

    Science.gov (United States)

    Power, Emmet M; Morales, Adrienne; Empson, Ruth M

    2016-05-04

    Type 1 metabotropic glutamate receptor (mGluR1)-dependent signaling at parallel fiber to Purkinje neuron synapses is critical for cerebellar function. In a mouse model of human spino-cerebellar ataxia type 1 (early SCA1, 12 weeks) we find prolonged parallel fiber mGluR1-dependent synaptic currents and calcium signaling. Acute treatment with a low dose of the potent and specific activity-dependent mGluR1-negative allosteric modulator JNJ16259685 shortened the prolonged mGluR1 currents and rescued the moderate ataxia. Our results provide exciting new momentum for developing mGluR1-based pharmacology to treat ataxia. Ataxia is a progressive and devastating degenerative movement disorder commonly associated with loss of cerebellar function and with no known cure. In the early stages of a mouse model of human spinocerebellar ataxia type 1, SCA1, where mice exhibit only moderate motor impairment, we detect excess "gain of function" of metabotropic glutamate receptor signaling at an important cerebellar synapse. Because careful control of this type of signaling is critical for cerebellar function in mice and humans, we sought to remove the excess signaling with a powerful, readily available pharmacological modulator. Remarkably, this pharmacological treatment acutely restored normal motor function in the ataxic mice. Our results pave the way for exploring a new avenue for early treatment of human ataxias. Copyright © 2016 the authors 0270-6474/16/364910-07$15.00/0.

  13. Novel GFAP Variant in Adult-onset Alexander Disease With Progressive Ataxia and Palatal Tremor.

    Science.gov (United States)

    Gass, Jennifer M; Cheema, Anvir; Jackson, Jessica; Blackburn, Patrick R; Van Gerpen, Jay; Atwal, Paldeep S

    2017-11-01

    Alexander disease is a rare neurodegenerative disease caused by variants in the glial fibrillary acidic protein gene (GFAP). This disorder can develop as an infantile, juvenile or adult-onset form and is characterized by several clinical features, including macrocephaly, seizures, ataxia, and bulbar/pseudobulbar signs. While the majority of these patients have the more progressive infantile form which causes severe leukodystrophy and early death; the less common adult form is more variable (ie, onset age, symptoms), with bulbar dysfunction as the primary feature. In our investigation, we describe a patient with progressive neuromuscular issues including dyspnea, dysphagia, dysarthria and progressive ataxia with palatal tremor. Through genetic testing, we determined that our patient has a novel variant in GFAP typical of Alexander disease.

  14. Introducing treatment strategy for cerebellar ataxia in mutant med mice: combination of acetazolamide and 4-aminopyridine.

    Science.gov (United States)

    Abbasi, Samira; Abbasi, Ataollah; Sarbaz, Yashar

    2014-02-01

    Purkinje neurons are the sole output neuron of the cerebellar cortex, and they generate high-frequency action potentials. Electrophysiological dysfunction of Purkinje neurons causes cerebellar ataxia. Mutant med mice have the lack of expression of the Scn8a gene. This gene encodes the NaV1.6 protein. In med Purkinje neurons, regular high-frequency firing is slowed, and med mice are ataxic. The aim of this study was to propose the neuroprotective drugs which could be useful for ataxia treatment in med mice, and to investigate the neuroprotective effects of these drugs by simulation. Simulation results showed that Kv4 channel inhibitors and BK channel activators restored the normal electrophysiological properties of the med Purkinje neurons. 4-Aminopyridine (4-AP) and acetazolamide (ACTZ) were proposed as neuroprotective drugs for Kv4 channel inhibitor and BK channel activator, respectively. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. 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.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

    Becker, Esther B E

    2014-10-01

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

  18. 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.

  19. Proposed diagnostic criteria for cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS)

    Science.gov (United States)

    Roberts, Leslie; McLean, Catriona A.; MacDougall, Hamish G.; Halmagyi, G. Michael; Storey, Elsdon

    2016-01-01

    Abstract Purpose of review: Diagnosis of ataxic disorders is an important clinical challenge upon which prognostication, management, patient solace, and, above all, the hope of future treatment all rely. Heritable diseases and the possibility of affected offspring carry the added burden of portending adverse health, social and financial ramifications. Recent findings: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited multisystem ataxia compromising cerebellar, vestibular, and sensory function. It is not uncommon, but despite early attempts the genetic defect is yet to be identified. As the search for the causative gene continues, we have found it useful to further define this syndrome in terms of its likely phenotype. Summary: We propose staged diagnostic criteria based on the identified pathology in CANVAS. We envisage that these criteria will aid the clinician in diagnosing CANVAS and the researcher in further elucidating this complex disorder. PMID:26918204

  20. Cardiopatía dilatada en ataxia de Friedreich: El punto sin retorno

    Directory of Open Access Journals (Sweden)

    Luis E. Silva, MD

    2012-02-01

    Full Text Available Las cardiopatías infiltrativas se caracterizan por el depósito de sustancias en el miocardio que causan un impacto negativo en la arquitectura de la pared ventricular. La ataxia espino-cerebelosa de Friedreich es una enfermedad degenerativa, heredada, con carácter autosómico recesivo. Clínicamente se caracteriza por ataxia de extremidades y tronco, hiporreflexia, neuropatía periférica, retinopatía y cardiopatía, entre otros. La afectación cardíaca es muy frecuente y se detectan alteraciones en estudios pos-mortem en 95% a 100% de los pacientes. La tasa de mortalidad es elevada y se considera una enfermedad incurable, a pesar de la existencia actual de múltiples medicamentos en estudio basados en los fundamentos fisiopatológicos de esta afección.

  1. Spinocerebellar ataxia type 13 is an uncommon SCA subtype in the Chinese Han population.

    Science.gov (United States)

    Peng, Lan; Wang, Chunrong; Chen, Zhao; Wang, Jun-Ling; Tang, Bei-Sha; Jiang, Hong

    2013-07-01

    The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders, among which SCA subtype 13 (SCA13) was found associated with mutations in the KCNC3 gene. Among 522 Chinese Han SCA patients (including familial and sporadic) we have collected since 1995, approximately 40% of them have not yet been assigned genotype. To investigate the mutation frequency of KCNC3 in SCA patients from mainland Chinese Han population, we analyzed the KCNC3 gene in 201 unrelated patients diagnosed with dominantly inherited cerebellar ataxia using the denaturing high-performance liquid chromatography (DHPLC) method. All analyzed samples displayed the normal elution profile, which denoted that no disease-related mutation was identified, suggesting that SCA13 be a rare form of SCA in mainland China.

  2. A novel locus for episodic ataxia:UBR4 the likely candidate

    OpenAIRE

    Conroy, Judith; McGettigan, Paul; Murphy, Raymond; Webb, David; Murphy, Sinéad M.; McCoy, Blathnaid; Albertyn, Christine; McCreary, Dara; McDonagh, Cara; Walsh, Orla; Lynch, SallyAnn; Ennis, Sean

    2013-01-01

    Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may ...

  3. Inmunodeficiencia con ataxia telangiectasia: presentación de 4 casos

    Directory of Open Access Journals (Sweden)

    Ma. Victoria Guntiñas Zamora

    2004-03-01

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

  4. Novel Autosomal Recessive c10orf2 Mutations Causing Infantile-Onset Spinocerebellar Ataxia

    OpenAIRE

    Hartley, Jessica N.; Booth, Frances A.; Del Bigio, Marc R.; Mhanni, Aizeddin A.

    2012-01-01

    Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene, c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA ...

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

    Science.gov (United States)

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

    2017-08-15

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

  6. 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.

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

    Science.gov (United States)

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

    2014-10-21

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

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

    Science.gov (United States)

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

    2015-01-01

    Our understanding of the effect of ataxia-telangiectasia mutated gene mutations on brain structure and function is limited. In this study, white matter motor pathway integrity was investigated in ataxia telangiectasia patients using diffusion MRI and probabilistic tractography. Diffusion MRI were obtained from 12 patients (age range: 7-22 years, mean: 12 years) and 12 typically developing age matched participants (age range 8-23 years, mean: 13 years). White matter fiber tracking and whole tract statistical analyses were used to assess quantitative fractional anisotropy and mean diffusivity differences along the cortico-ponto-cerebellar, cerebellar-thalamo-cortical, somatosensory and lateral corticospinal tract length in patients using a linear mixed effects model. White matter tract streamline number and apparent fiber density in patient and control tracts were also assessed. Reduced fractional anisotropy along all analyzed patient tracts were observed (p < 0.001). Mean diffusivity was significantly elevated in anterior tract locations but was reduced within cerebellar peduncle regions of all patient tracts (p < 0.001). Reduced tract streamline number and tract volume in the left and right corticospinal and somatosensory tracts were observed in patients (p < 0.006). In addition, reduced apparent fiber density in the left and right corticospinal and right somatosensory tracts (p < 0.006) occurred in patients. Whole tract analysis of the corticomotor, corticospinal and somatosensory pathways in ataxia telangiectasia showed significant white matter degeneration along the entire length of motor circuits, highlighting that ataxia-telangiectasia gene mutation impacts the cerebellum and multiple other motor circuits in young patients.

  9. 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.

  10. Detection of interruptions in the GAA trinucleotide repeat expansion in the FXN gene of Friedreich ataxia.

    Science.gov (United States)

    Holloway, Timothy P; Rowley, Simone M; Delatycki, Martin B; Sarsero, Joseph P

    2011-03-01

    Friedreich ataxia is a neurodegenerative disorder caused by the expansion of a GAA trinucleotide repeat sequence within the first intron of the FXN gene. Interruptions in the GAA repeat may serve to alleviate the inhibitory effects of the GAA expansion on FXN gene expression and to decrease pathogenicity. We have developed a simple and rapid PCR- and restriction enzyme-based assay to assess the purity of GAA repeat sequences.

  11. Gait ataxia in humans: vestibular and cerebellar control of dynamic stability.

    Science.gov (United States)

    Schniepp, Roman; Möhwald, Ken; Wuehr, Max

    2017-10-01

    During human locomotion, vestibular feedback control is fundamental for maintaining dynamic stability and adapting the gait pattern to external circumstances. Within the supraspinal locomotor network, the cerebellum represents the key site for the integration of vestibular feedback information. The cerebellum is further important for the fine-tuning and coordination of limb movements during walking. The aim of this review article is to highlight the shared structural and functional sensorimotor principles in vestibular and cerebellar locomotion control. Vestibular feedback for the maintenance of dynamic stability is integrated into the locomotor pattern via midline, caudal cerebellar structures (vermis, flocculonodular lobe). Hemispheric regions of the cerebellum facilitate feed-forward control of multi-joint coordination and higher locomotor functions. Characteristic features of the gait disorder in patients with vestibular deficits or cerebellar ataxia are increased levels of spatiotemporal gait variability in the fore-aft and the medio-lateral gait dimension. In the fore-aft dimension, pathologic increases of gait fluctuations critically depend on the locomotion speed and predominantly manifest during slow walking velocities. This feature is associated with an increased risk of falls in both patients with vestibular hypofunction as well as patients with cerebellar ataxia. Pharmacological approaches for the treatment of vestibular or cerebellar gait ataxia are currently not available. However, new promising options are currently tested in randomized, controlled trials (fampridine/FACEG; acetyl-DL-leucine/ALCAT).

  12. Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease.

    Science.gov (United States)

    Velázquez-Pérez, Luis; Rodríguez-Labrada, Roberto; Cruz-Rivas, Edilia M; Fernández-Ruiz, Juan; Vaca-Palomares, Israel; Lilia-Campins, Jandy; Cisneros, Bulmaro; Peña-Acosta, Arnoy; Vázquez-Mojena, Yaimeé; Diaz, Rosalinda; Magaña-Aguirre, Jonathan J; Cruz-Mariño, Tania; Estupiñán-Rodríguez, Annelié; Laffita-Mesa, José M; González-Piña, Rigoberto; Canales-Ochoa, Nalia; González-Zaldivar, Yanetza

    2014-10-01

    The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches. Thirty-seven non-ataxic SCA2 mutation carriers and its age- and sex-matched controls underwent clinical assessments, including standardized neurological exam, structured interviews and clinical scales, and looking for somatic and autonomic features, as well as a neuropsychological battery, antisaccadic recordings, and MRI scans. Main clinical somatic features of non-ataxic mutation carriers were cramps, sensory symptoms, sleep disorders, and hyperreflexia, whereas predominating autonomic symptoms were pollakiuria/nocturia, constipation, and frequent throat clearing. Cognitive impairments included early deficits of executive functions and visual memory, suggesting the involvement of cerebro-cerebellar-cerebral loops and/or reduced cholinergic basal forebrain input to the cortex. Antisaccadic task revealed impaired oculomotor inhibitory control but preserved ability for error correction. Cognitive and antisaccadic deficits were higher as carriers were closer to the estimated onset of ataxia, whereas higher Scale for the Assessment and Rating of Ataxia (SARA) scores were associated most notably to vermis atrophy. The recognition of early features of SCA2 offers novel insights into the prodromal phase and physiopathological base of the disease, allowing the assessment of its progression and the efficacy of treatments, in particular at early phases when therapeutical options should be most effective.

  13. Keys to overcoming the challenge of diagnosing autosomal recessive spinocerebellar ataxia.

    Science.gov (United States)

    Arias, M

    2016-07-23

    Autosomal recessive spinocerebellar ataxia refers to a large group of diseases affecting the cerebellum and/or its connections, although they may also involve other regions of the nervous system. These diseases are accompanied by a wide range of systemic manifestations (cardiopathies, endocrinopathies, skeletal deformities, and skin abnormalities). This study reviews current knowledge of the most common forms of autosomal recessive spinocerebellar ataxia in order to provide tips that may facilitate diagnosis. A thorough assessment of clinical phenotype (pure cerebellar or cerebellar-plus syndrome, with or without systemic manifestations), laboratory tests (vitamin E, acanthocytosis, albumin, cholesterol, phytanic acid, lactic acid, creatine kinase, cholestanol, coenzyme Q10, alpha-fetoprotein, copper, ceruloplasmin, chitotriosidase), nerve conduction studies (presence and type of neuropathy), and an magnetic resonance imaging study (presence of cerebellar atrophy, presence and location of signal alterations) may help establish a suspected diagnosis, which should be confirmed by detecting the underlying genetic mutation. A positive genetic test result is necessary to determine prognosis and provide adequate genetic counselling, and will also permit appropriate treatment of some entities (abetalipoproteinaemia, ataxia with vitamin E deficiency, Refsum disease, cerebrotendinous xanthomatosis, Niemann-Pick disease type C, Wilson disease). Without a genetic diagnosis, conducting basic research and therapeutic trials will not be possible. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

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

    Science.gov (United States)

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

    2016-01-01

    AIM This cross-sectional investigation aimed to assess the value of non-invasive measures of temporal respiratory–swallow coupling in individuals with ataxic swallowing. METHOD Twenty participants with ataxia telangiectasia were presented with water and pudding boluses. Their 193 swallows were compared with 2200 swallows from 82 age-matched healthy controls. The two components of airway protection during swallowing that were analyzed were: direction of peri-deglutitive airflow and duration of deglutitive inhibition of respiratory airflow (DIORA). RESULTS Safe expiratory patterns of peri-deglutitive airflow occurred significantly less often in participants with ataxia telangiectasia than in age-matched control participants (younger pataxia telangiectasia (p=0.234). With age, mean duration of DIORA decreased in controls (pataxia telangiectasia (p=0.164). INTERPRETATION Non-invasive quantitative measures of respiratory–swallow coupling capture temporal relationships that plausibly contribute to airway compromise from dysphagia. Changes in respiratory–swallow coupling observed with advancing age in control participants were not seen in participants with ataxia telangiectasia. Measures of perturbations may herald swallowing problems prior to development of pulmonary and nutritional sequelae. PMID:27214374

  15. 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.

  16. 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. Copyright © 2016 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  17. Understanding the genetic and molecular pathogenesis of Friedreich's ataxia through animal and cellular models.

    Science.gov (United States)

    Martelli, Alain; Napierala, Marek; Puccio, Hélène

    2012-03-01

    In 1996, a link was identified between Friedreich's ataxia (FRDA), the most common inherited ataxia in men, and alterations in the gene encoding frataxin (FXN). Initial studies revealed that the disease is caused by a unique, most frequently biallelic, expansion of the GAA sequence in intron 1 of FXN. Since the identification of this link, there has been tremendous progress in understanding frataxin function and the mechanism of FRDA pathology, as well as in developing diagnostics and therapeutic approaches for the disease. These advances were the subject of the 4th International Friedreich's Ataxia Conference held on 5th-7th May in the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. More than 200 scientists gathered from all over the world to present the results of research spanning all areas of investigation into FRDA (including clinical aspects, FRDA pathogenesis, genetics and epigenetics of the disease, development of new models of FRDA, and drug discovery). This review provides an update on the understanding of frataxin function, developments of animal and cellular models of the disease, and recent advances in trying to uncover potential molecules for therapy.

  18. Identification and quantification of differentially expressed proteins in plasma of spinocerebellar ataxia type 12.

    Science.gov (United States)

    Swarup, Vishnu; Srivastava, Achal K; Rajeswari, Moganty R

    2012-06-01

    Spinocerebellar ataxia 12 (SCA12) is a unique dominant type of ataxia characterized by early and prominent action tremors, memory deficit, neuropathy, dysarthria, etc. The expansion of DNA triplet (CAG) repeats in 5'UTR of PPP2R2B gene appears to be the cause for the pathogenesis of the neurodegenerative disorder, SCA12. The objective of the current study was to identify the aberrantly expressed plasma proteins for their potential application in therapy or diagnosis/prognosis of SCA12. Sixty-two clinically suspected patients were assessed using International Co-operative Ataxia Rating Scale (ICARS) and genetic confirmation was done using PCR followed by DNA sequencing. Twenty patients who were genetically confirmed were included in the study. 2D-DIGE analyses of plasma proteins of SCA12 patients revealed 14 differentially expressed protein spots, which were confirmed as nine proteins by LC-MS/MS. The 6 downregulated and 3 upregulated proteins are known to have physiological role in transport (thyroxin and retinol to brain), lipid metabolism, memory, scavenging of free haemoglobin, etc. Altered expression of some of the proteins of interest, transthyretin, haptaglobin, apolipoprotein C-II, apolipoprotein C-III are indicative of clinical manifestations such as neuropathy, cognitive impairment and altered lipid metabolism in SCA12. Copyright © 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  19. 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.

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2017-02-01

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

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

    Science.gov (United States)

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

    2017-01-10

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

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

    Science.gov (United States)

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

    2015-06-01

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

  4. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features.

    Science.gov (United States)

    Dürr, A; Stevanin, G; Cancel, G; Duyckaerts, C; Abbas, N; Didierjean, O; Chneiweiss, H; Benomar, A; Lyon-Caen, O; Julien, J; Serdaru, M; Penet, C; Agid, Y; Brice, A

    1996-04-01

    Patients with spinocerebellar ataxia 3 (SCA3) and Machado-Joseph disease (MJD) carry an expanded CAG repeat in the MJD1 gene. One hundred twenty families of different geographic origin with autosomal dominant cerebellar ataxia (ADCA) type I were tested. Thirty-four families (126 patients) carried an expanded CAG repeat. The expanded and the normal allele did not overlap and the repeat was unstable during transmission, with variation in the size of the CAG length ranging from -8 to +5 and a mean expansion of 0.86 repeats without differences according to the parental sex. There was a combined effect of the number of CAG repeats of the expanded and normal allele on the age at onset, which accounted for 70% of its variability. The length of the CAG repeat influenced the frequency of clinical signs associated with cerebellar ataxia, such as abnormal tendon reflexes or decreased vibration sense, whereas the interindividual variation of supranuclear ophthalmoplegia, sphincter and swallowing difficulties, and amyotrophy was mostly determined by different disease durations. We compared the clinical profile of 91 SCA3/MJD patients with 51 SCA1 and 32 SCA2 patients. There were striking differences between the SCA3/MJD and SCA2 but not with SCA1 groups of patients. Despite their clinical similarities, distinct neuropathological features were observed in 2 SCA3/MJD and 2 SCA1 patients.

  5. Understanding the genetic and molecular pathogenesis of Friedreich’s ataxia through animal and cellular models

    Science.gov (United States)

    Martelli, Alain; Napierala, Marek; Puccio, Hélène

    2012-01-01

    In 1996, a link was identified between Friedreich’s ataxia (FRDA), the most common inherited ataxia in men, and alterations in the gene encoding frataxin (FXN). Initial studies revealed that the disease is caused by a unique, most frequently biallelic, expansion of the GAA sequence in intron 1 of FXN. Since the identification of this link, there has been tremendous progress in understanding frataxin function and the mechanism of FRDA pathology, as well as in developing diagnostics and therapeutic approaches for the disease. These advances were the subject of the 4th International Friedreich’s Ataxia Conference held on 5th–7th May in the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. More than 200 scientists gathered from all over the world to present the results of research spanning all areas of investigation into FRDA (including clinical aspects, FRDA pathogenesis, genetics and epigenetics of the disease, development of new models of FRDA, and drug discovery). This review provides an update on the understanding of frataxin function, developments of animal and cellular models of the disease, and recent advances in trying to uncover potential molecules for therapy. PMID:22382366

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

    Science.gov (United States)

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

    2017-01-05

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

  7. 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.

  8. Progressive impairment of cerebellar mGluR signalling and its therapeutic potential for cerebellar ataxia in spinocerebellar ataxia type 1 model mice.

    Science.gov (United States)

    Shuvaev, Anton N; Hosoi, Nobutake; Sato, Yamato; Yanagihara, Dai; Hirai, Hirokazu

    2017-01-01

    Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a gene defect, leading to movement disorder such as cerebellar ataxia. It remains largely unknown which functional defect contributes to the cerebellar ataxic phenotype in SCA1. In this study, we report progressive dysfunction of metabotropic glutamate receptor (mGluR) signalling, which leads to smaller slow synaptic responses, reduced dendritic Ca2+ signals and impaired synaptic plasticity at cerebellar synapses, in the early disease stage of SCA1 model mice. We also show that enhancement of mGluR signalling by a clinically available drug, baclofen, leads to improvement of motor performance in SCA1 mice. SCA1 is an incurable disease with no effective treatment, and our results may provide mechanistic grounds for targeting mGluRs and a novel drug therapy with baclofen to treat SCA1 patients in the future. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that presents with cerebellar ataxia and motor learning defects. Previous studies have indicated that the pathology of SCA1, as well as other ataxic diseases, is related to signalling pathways mediated by the metabotropic glutamate receptor type 1 (mGluR1), which is indispensable for proper motor coordination and learning. However, the functional contribution of mGluR signalling to SCA1 pathology is unclear. In the present study, we show that SCA1 model mice develop a functional impairment of mGluR signalling which mediates slow synaptic responses, dendritic Ca2+ signals, and short- and long-term synaptic plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in a progressive manner from the early disease stage (5 postnatal weeks) prior to PC death. Notably, impairment of mGluR-mediated dendritic Ca2+ signals linearly correlated with a reduction of PC capacitance (cell surface area) in disease progression. Enhancement of mGluR signalling by baclofen, a clinically available GABAB receptor

  9. The Yield of Neuroimaging in Children Presenting to the Emergency Department With Acute Ataxia in the Post-Varicella Vaccine Era.

    Science.gov (United States)

    Rudloe, Tiffany; Prabhu, Sanjay P; Gorman, Mark P; Nigrovic, Lise E; Harper, Marvin B; Landschaft, Assaf; Kimia, Amir A

    2015-09-01

    To determine the yield of neuroimaging in children presenting to the emergency department with acute ataxia in the post-varicella vaccine era, we conducted a cross-sectional study between 1995 and 2013 at a single pediatric tertiary care center. We included children aged 1-18 years evaluated for acute ataxia of ataxia. Neuroimaging may be deferred in younger children with short duration of symptoms contingent on close follow-up. © The Author(s) 2014.

  10. 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.

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

    Science.gov (United States)

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

    2015-11-01

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

  12. Fragile X-Associated Tremor Ataxia Syndrome: The Expanding Clinical Picture, Pathophysiology, Epidemiology, and Update on Treatment

    Directory of Open Access Journals (Sweden)

    Deborah A. Hall

    2012-05-01

    Full Text Available Fragile X-associated tremor/ataxia syndrome (FXTAS is a progressive degenerative movement disorder characterized by kinetic tremor, cerebellar gait ataxia, parkinsonism, and cognitive decline. This disorder occurs in both males and females, frequently in families with children who have fragile X syndrome. The clinical features of this disorder, both classic and newly described, are summarized in this paper. In screening studies, fragile X mental retardation 1 (FMR1 gene premutation (55–200 CGG expansions are most frequently seen in men with ataxia who have tested negative for spinocerebellar ataxias. Since the original description, the classic FXTAS phenotype has now been reported in females and in carriers of smaller (45–54 CGG and larger (>200 CGG expansions in FMR1. Premutation carriers may present with a Parkinson disease phenotype or hypotension, rather than with tremor and/or ataxia. Parkinsonism and gait ataxia may also be seen in individuals with gray zone (41–54 CGG expansions. Studies regarding medication to treat the symptoms in FXTAS are few in number and suggest that medications targeted to specific symptoms, such as kinetic tremor or gait ataxia, may be most beneficial. Great progress has been made in regards to FXTAS research, likely given the readily available gene test and the screening of multiple family members, including parents and grandparents, of fragile X syndrome children. Expansion of genotypes and phenotypes in the disorder may suggest that a broader disease definition might be necessary in the future.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-02-01

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

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

    Science.gov (United States)

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

    2017-01-01

    Congenital ataxias are nonprogressive neurological disorders characterized by neonatal hypotonia, developmental delay and ataxia, variably associated with intellectual disability and other neurological or extraneurological features. We performed trio-based whole-exome sequencing of 12 families with congenital cerebellar and/or vermis atrophy in parallel with targeted next-generation sequencing of known ataxia genes (CACNA1A, ITPR1, KCNC3, ATP2B3 and GRM1) in 12 additional patients with a similar phenotype. Novel pathological mutations of ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) were found in seven patients from four families (4/24, ∼16.8%) all localized in the IRBIT (inositol triphosphate receptor binding protein) domain which plays an essential role in the regulation of neuronal plasticity and development. Our study expands the mutational spectrum of ITPR1-related congenital ataxia and indicates that ITPR1 gene screening should be implemented in this subgroup of ataxias. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

    Science.gov (United States)

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

    2014-01-01

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

  17. Computational analysis of calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons associated with ataxia

    Directory of Open Access Journals (Sweden)

    Brown Sherry-Ann

    2012-06-01

    Full Text Available Abstract Background Mutations in the smooth endoplasmic reticulum (sER calcium channel Inositol Trisphosphate Receptor type 1 (IP3R1 in humans with the motor function coordination disorders Spinocerebellar Ataxia Types 15 and 16 (SCA15/16 and in a corresponding mouse model, the IP3R1delta18/delta18 mice, lead to reduced IP3R1 levels. We posit that increasing IP3R1 sensitivity to IP3 in ataxias with reduced IP3R1 could restore normal calcium response. On the other hand, in mouse models of the human polyglutamine (polyQ ataxias, SCA2, and SCA3, the primary finding appears to be hyperactive IP3R1-mediated calcium release. It has been suggested that the polyQ SCA1 mice may also show hyperactive IP3R1. Yet, SCA1 mice show downregulated gene expression of IP3R1, Homer, metabotropic glutamate receptor (mGluR, smooth endoplasmic reticulum Ca-ATP-ase (SERCA, calbindin, parvalbumin, and other calcium signaling proteins. Results We create a computational model of pathological alterations in calcium signaling in cerebellar Purkinje neurons to investigate several forms of spinocerebellar ataxia associated with changes in the abundance, sensitivity, or activity of the calcium channel IP3R1. We find that increasing IP3R1 sensitivity to IP3 in computational models of SCA15/16 can restore normal calcium response if IP3R1 abundance is not too low. The studied range in IP3R1 levels reflects variability found in human and mouse ataxic models. Further, the required fold increases in sensitivity are within experimental ranges from experiments that use IP3R1 phosphorylation status to adjust its sensitivity to IP3. Results from our simulations of polyglutamine SCAs suggest that downregulation of some calcium signaling proteins may be partially compensatory. However, the downregulation of calcium buffer proteins observed in the SCA1 mice may contribute to pathology. Finally, our model suggests that the calcium-activated voltage-gated potassium channels may provide an

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

    Science.gov (United States)

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

    2017-12-01

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

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

    Science.gov (United States)

    Hall, Deborah A; Berry-Kravis, Elizabeth

    2018-01-01

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

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

    Science.gov (United States)

    Silva, R C R; Saute, J A M; Silva, A C F; Coutinho, A C O; Saraiva-Pereira, M L; Jardim, L B

    2010-06-01

    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.

  1. 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.

  2. Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3.

    Directory of Open Access Journals (Sweden)

    Carmen Rodríguez-Cueto

    Full Text Available Spinocerebellar ataxia type-3 (SCA-3 is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia, we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem. These data open the way to search for drugs that might correct these changes.

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

    Science.gov (United States)

    Perkins, Emma; Suminaite, Daumante

    2016-01-01

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

  4. In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.

    Science.gov (United States)

    Tomlinson, Susan E; Tan, S Veronica; Burke, David; Labrum, Robyn W; Haworth, Andrea; Gibbons, Vaneesha S; Sweeney, Mary G; Griggs, Robert C; Kullmann, Dimitri M; Bostock, Hugh; Hanna, Michael G

    2016-02-01

    Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

  5. Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1.

    Science.gov (United States)

    Tomlinson, Susan Elizabeth; Rajakulendran, Sanjeev; Tan, Stella Veronica; Graves, Tracey Dawn; Bamiou, Doris-Eva; Labrum, Robyn W; Burke, David; Sue, Carolyn M; Giunti, Paola; Schorge, Stephanie; Kullmann, Dimitri M; Hanna, Michael G

    2013-10-01

    Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations. 15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry. Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of K(v)1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia. The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of K(v)1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between K(v)1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1.

  6. 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.

  7. Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia.

    Science.gov (United States)

    Wecker, L; Engberg, M E; Philpot, R M; Lambert, C S; Kang, C W; Antilla, J C; Bickford, P C; Hudson, C E; Zesiewicz, T A; Rowell, Peter P

    2013-10-01

    Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. 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.

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

    Science.gov (United States)

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

    2016-06-01

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

  10. 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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  12. 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

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

    Science.gov (United States)

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

    2015-10-01

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

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

    Science.gov (United States)

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

    2013-06-01

    The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective genes leading to pathogenic expansions of polyglutamine stretches in the encoded proteins. In general, unstable CAG repeats have an uninterrupted CAG repeat, whereas stable CAG repeats are either short or interrupted by CAA codons, which - like CAG codons - code for glutamine. Here we report on an infantile SCA2 patient who, due to germ-line CAG repeat instability in her father, inherited an extremely expanded CAG repeat in the SCA2 locus. Surprisingly, the expanded allele of the father was an interrupted CAG repeat sequence. Furthermore, analyses of single spermatozoa showed a high frequency of paternal germ-line repeat sequence instability of the expanded SCA2 locus.

  15. 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...... in those individuals who were clinically affected by a complex phenotype consisting of HSP and cerebellar ataxia. Other features noted in this kindred including epilepsy, cognitive impairment, depression, and migraine did not segregate with the HSP phenotype or mutation, and therefore the significance...... relatively decreased regional cerebral blood flow in most of the cerebellum. We conclude that this kindred demonstrates a considerable overlap between cerebellar ataxia and spastic paraplegia, emphasizing the marked clinical heterogeneity of HSP associated with spastin mutations...

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

    Science.gov (United States)

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

    2015-03-01

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

  17. 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.

  18. Spontaneous thrombosis of developmental venous anomaly (DVA) with venous infarct and acute cerebellar ataxia.

    Science.gov (United States)

    Agarwal, Amit; Kanekar, Sangam; Kalapos, Paul; Vijay, Kanupriya

    2014-08-01

    Developmental venous anomaly (DVA), formally known as venous angioma, is a congenital anatomic variant of the venous drainage of the brain. Although they typically have a benign clinical course and a low symptomatic rate, thrombosis of a drainage vein may occur, leading to potentially debilitating complications. We report a unique case of spontaneous thrombosis of a posterior fossa developmental venous anomaly with cerebellar infarct in a 61-year-old man who presented with acute onset cerebellar ataxia. DVA thrombosis was well-depicted on CT and MR studies. Patient was put on anticoagulant therapy and complete recanalization was seen on follow-up imaging.

  19. Ipsilesional limb ataxia and truncal ipsipulsion in isolated infarction of the superior cerebellar peduncle.

    Science.gov (United States)

    Lee, Sun-Uk; Bae, Hee-Joon; Kim, Ji-Soo

    2015-02-15

    The clinical features of a lesion confined to the superior cerebellar peduncle (SCP) have not been defined well in human. A 92-year-old woman suddenly developed mild dysarthria and severe imbalance from an isolated unilateral SCP infarction, and examination showed ipsiversive ocular torsion, severe ipsilesional limb ataxia, and truncal ipsipulsion. These findings are well consistent with those observed in monkeys when the SCP was severed. In addition to the dentate-rubro-thalamic projections, the SCP appears to contain the fibers involved in the control of eye motion in the roll plane. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Novel SIL1 mutations cause cerebellar ataxia and atrophy in a French-Canadian family.

    Science.gov (United States)

    Noreau, Anne; La Piana, Roberta; Marcoux, Camille; Dion, Patrick A; Brais, Bernard; Bernard, Geneviève; Rouleau, Guy A

    2015-10-01

    Two French-Canadian sibs with cerebellar ataxia and dysarthria were seen in our neurogenetics clinic. The older brother had global developmental delay and spastic paraplegia. Brain MRIs from these two affected individuals showed moderate to severe cerebellar atrophy. To identify the genetic basis for their disease, we conducted a whole exome sequencing (WES) investigation using genomic DNA prepared from the affected sibs and their healthy father. We identified two mutations in the SIL1 gene, which is reported to cause Marinesco-Sjögren syndrome. This study emphasizes how the diagnosis of patients with ataxic gait and cerebellar atrophy may benefit from WES to identify the genetic cause of their condition.

  1. Absence of PAX6 gene mutations in Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation)

    Energy Technology Data Exchange (ETDEWEB)

    Glaser, T.; Maas, R.L. (Harvard Medical School, Boston, MA (United States)); Ton, C.C.T.; Housman, D.E. (Massachusetts Institute of Technology, Cambridge, MA (United States)); Mueller, R.; Oliver, C. (Leeds General Infirmary (United Kingdom)); Petzl-Erler, M.L. (Federal Univ. of Parana, Curitiba (Brazil)); Nevin, N.C. (Queen' s Univ. of Belfast (Ireland))

    1994-01-01

    The PAX6 gene is expressed at high levels in the developing eye and cerebellum and is mutated in patients with autosomal dominant aniridia. The authors have tested the role of PAX6 mutations in three families with Gillespie syndrome, a rare autosomal recessive condition consisting of partial aniridia, cerebellar ataxia, and mental retardation. Single-strand conformational polymorphism analysis of affected individuals revealed no alteration of PAX6 sequences. In two families, the disease trait segregates independently from chromosome 11p markers flanking PAX6. The authors conclude that Gillespie syndrome is genetically distinct from autosomal dominant aniridia. 28 refs., 2 figs., 1 tab.

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

    OpenAIRE

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

    1998-01-01

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

  3. Ataxia por intoxicación crónica con fenitoina

    OpenAIRE

    Moris, M.; Mazza, Alejandro; Nuñez Vivas, J.; Mosca, M.; Vilela, Pablo José María; Chaumeil, Pedro Oscar; Miller, Alejandro

    2016-01-01

    El objetivo de este trabajo es describir un caso de ataxia adquirida del adulto por intoxicación crónica por fenitoína. Presentamos el caso de una paciente de 20 años de edad que consultó al servicio de Neurología en el año 2012, por cuadro de trastornos de la marcha y en la emisión de la palabra de 18 meses de evolución progresiva.

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

    Directory of Open Access Journals (Sweden)

    Dickerson Jennifer A

    2008-04-01

    Full Text Available 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 absent at rest. Epicardial coronaries were free of disease by invasive angiography; together, these findings support the notion of impaired myocardial perfusion reserve in FA.

  5. Spinal anaesthesia for a caesarean section in a patient with paraneoplastic cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    Ayca Tas Tuna

    2017-01-01

    Full Text Available Paraneoplastic cerebellar ataxia (PCA is most frequently observed in gynaecological cancers, small cell lung cancer, breast cancer, Hodgkin's lymphoma, cancer testis or malignant thymoma. In the literature, there is no data related to the effects of PCA during pregnancy or reports on the effects of anaesthesia in patients with PCA. We present management of a pregnant woman with PCA who was suddenly unable to walk with PCA and for whom effective spinal anaesthesia was performed for an elective caesarean section with no complications.

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

    Science.gov (United States)

    Jonveaux, P; Berger, R

    1993-04-01

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

  7. Delayed cerebellar ataxia: A rare self limiting complication of plasmodium falciparum malaria

    Directory of Open Access Journals (Sweden)

    Amit K Sakaria

    2013-01-01

    Full Text Available The classic presentation of malaria with paroxysms of fever is seen only in 50-70% of the patients. The development of immunity, the increasing resistance to anti-malarial drugs, and the indiscriminate use of anti-malarial drugs have led to malaria with the presentation of unusual features. Cerebellar ataxia, extrapyramidal rigidity and various psychiatric symptoms have been described either as early manifestations of cerebral malaria or as a part of post malaria neurological syndrome. In this case report, we will discuss one such patient of falciparum malaria infection who developed midline cerebellar signs, and responded to anti-malarial treatment.

  8. Abordagem fisioterapêutica da ataxia espinocerebelar: uma revisão sistemática

    OpenAIRE

    Martins,Camilla Polonini; Rodrigues,Erika de Carvalho; Oliveira,Laura Alice Santos de

    2013-01-01

    A ataxia espinocerebelar (SCA) é uma afecção hereditária que cursa com a degeneração progressiva do cerebelo e suas vias, causando alterações do equilíbrio e de outras funções. O efeito das abordagens da fisioterapia no tratamento da SCA e a qualidade metodológica desses estudos foram analisados. Foi investigado ainda se os benefícios alcançados com o tratamento são retidos. As intervenções encontradas incluem treino do equilíbrio, marcha e coordenação; fortalecimento; caneleiras nos membros ...

  9. 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...

  10. 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.

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

    OpenAIRE

    Roberta Passos Palazzo

    2010-01-01

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

  12. Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)(n) Repeats by PNA or LNA Targeting

    DEFF Research Database (Denmark)

    Bergquist, Helen; Rocha, Cristina S. J.; Alvarez-Asencio, Ruben

    2016-01-01

    Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigen......Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated...

  13. X-linked sideroblastic anemia and ataxia: a new family with identification of a fourth ABCB7 gene mutation.

    Science.gov (United States)

    D'Hooghe, Marc; Selleslag, Dominik; Mortier, Geert; Van Coster, Rudy; Vermeersch, Pieter; Billiet, Johan; Bekri, Soumeya

    2012-11-01

    X-linked sideroblastic anemia and ataxia (XLSA-A) is a rare cause of early onset ataxia, which may be overlooked due to the usually mild asymptomatic anemia. The genetic defect has been identified as a mutation in the ABCB7 gene at Xq12-q13. The gene encodes a mitochondrial ATP-binding cassette (ABC) transporter protein involved in iron homeostasis. Until now only three families have been reported, each with a distinct missense mutation in this gene. We describe a fourth family with XLSA-A and a novel mutation in the ABCB7 gene. Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2010-01-01

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

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

    Science.gov (United States)

    2014-01-01

    Background Mutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts. Methods 300 subjects with degenerative ataxia (n = 167) or spastic paraplegia (n = 133) were screened for STUB1 variants by whole-exome-sequencing (n = 204) or shotgun-fragment-library-sequencing (n = 96). To control for the specificity of STUB1 variants, we screened an additional 1707 exomes from 891 index families with other neurological diseases. Results We identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1, including 3 mutations in its tetratricopeptide-repeat domain. All patients showed evidence of pyramidal tract damage. Cognitive impairment was present only in one and hypogonadism in none of them. Ataxia did not start before age 48 years in one subject. No recessive STUB1 variants were identified in families with other neurological diseases, demonstrating that STUB1 variants are not simply rare polymorphisms ubiquitous in neurodegenerative disease. Conclusions STUB1-disease occurs also in Caucasian ataxia populations (1.8%). Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain. Moreover, they further delineate the phenotypic core features of STUB1-ataxia. Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity, thus adding STUB1-ataxia to the differential diagnosis of “spastic ataxias”. However, STUB1 is rare in subjects with predominant spastic paraplegia (0/133). In contrast to previous reports, STUB1-ataxia can start even above age 40

  16. [A family of hereditary spastic paraplegia with dementia, ataxia, and dystonia].

    Science.gov (United States)

    Maruta, K; Kondo, I

    2001-10-01

    We reported three siblings with complicated hereditary spastic paraplegia. The striking features in these patients were characterized by early onset of gait disturbance, mental deficiency, and dystonia. The most likely diagnosis was Mast syndrome. Patient 1: A 44 years-old woman. She first developed gait disturbances at age of 8. She was admitted in our hospital because of progressive spastic paraplegia. Neurological examination revealed mental deficiency, saccadic pursuit eye movement, speech disturbance of cerebellar type, ataxia, and spastic paraplegia. She showed also dystonia in the face, tongue, and trunk. MRI showed cerebellar atrophy. Patient 2: A 51 years-old brother of the patient 1. He had mentally retarded. Late teens he developed gait disturbance. Gradually he manifested spastic paraplegia, dysarthria, dysphasia, mental deficiency, and ataxia. He also showed incontinence of urine and feces. Then he became bedridden, apathetic, and showed forced crying. MRI showed diffuse brain atrophy. Patient 3: A 48 year-old woman. This woman, a sister of the patient 1, showed progressive gait disturbance and dysarthria. She also developed incontinence, apathy, and dystonia. She became bedridden, responding to simple questions with only occasional single-word answers. Her speech was slurred, and spastic paraplegia was noted. MRI showed diffuse brain atrophy including marked atrophy of the cerebellum.

  17. Trinucleotide repeat expansion of spinocerebellar ataxia (SCA1) found in a Chinese family.

    Science.gov (United States)

    Cai, T; Yu, P; Chen, X; Lopa, M

    1998-02-01

    To investigate the gene mutation and the ratio of the spinocerebellar ataxia type 1 (SCA1) in Chinese patients with autosomal dominant spinocerebellar ataxia (ADSCA). The family material and DNA samples were collected from thirteen families with ADSCA. To determine the characteristics of the CAG trinucleotide repeats in SCA1 gene, the PCR products of the Rep1 and Rep2 primers were analyzed, and the bands with CAG repeat expansion were cloned by PCR2. 1 vector and sequenced. One family was found to have an expanded CAG repeat in the 13 families with ADSCA. The clinically affected individual was heterozygous with one disease allele being 55 CAG repeats, whereas the mean size of the CAG repeats on 104 chromosomes generated from unrelated control Chinese individuals is 29.3 (ranging from 18 to 34). The frequency of the SCA1 mutation is about 7% in the 13 Chinese families with ADSCA, suggesting that this type of genetic defect is not the main cause involved in the pathogenesis of ADSCA in China. Since the mutation has also been found in Caucasian, Japanese, Malaysian, and Bangladeshi kindreds, it is suggested that this genetic defect may well have multiple origins in different ethnic groups.

  18. A splice-site variant in FLVCR1 produces retinitis pigmentosa without posterior column ataxia.

    Science.gov (United States)

    Yusuf, Imran H; Shanks, Morag E; Clouston, Penny; MacLaren, Robert E

    2017-12-01

    FLVCR1 (feline leukemia virus subgroup c receptor 1) is a transmembrane protein involved in the trafficking of intracellular heme. Homozygous variants in FLVCR1 have been described in association with a clinical syndrome of posterior column ataxia with retinitis pigmentosa (PCARP). Here, we describe a patient with non-syndromic retinitis pigmentosa homozygous for a splice-site variant in FLVCR1 (c.1092 + 5G>A) without evidence of posterior column ataxia or cerebellar degeneration. We suggest an association between intronic splice-site variants in FLVCR1 and the absence of posterior column degeneration and suggest a hypothesis to explain this observation. Should this association be proven, it would provide valuable prognostic information for patients. Retinal degeneration appears to be the sole clinical manifestation of this FLVCR1 variant; gene therapy approaches using an adeno-associated viral vector with sub-retinal delivery may therefore represent a therapeutic approach to halting retinal degeneration in this patient group.

  19. Walking in circles: navigation deficits from Parkinson's disease but not from cerebellar ataxia

    Science.gov (United States)

    Paquette, Caroline; Franzén, Erika; Jones, Geoffrey Melvill; Horak, Fay B

    2011-01-01

    Little is known on the role of neuronal structures for spatial navigation. Our goal was to examine how Parkinson's disease (PD) and cerebellar ataxia, as human lesion models of the basal ganglia and cerebellum, affect spatial navigation round a circular walking path, blindfolded. Twelve subjects with idiopathic PD (ON and OFF medication), 8 subjects with cerebellar ataxia and a control group of 20 age-matched healthy subjects participated. All groups performed well when walking around the circle with eyes open. In the eyes-closed condition, control subjects overshot the outlined trajectory but returned to their initial position, thus walking a further distance with eyes closed than with eyes open. When OFF medication, PD subjects navigated a larger radius than controls with eyes closed. When ON levodopa, PD subjects walked a similar distance as controls but with even larger errors in endpoint. Surprisingly, cerebellar patients navigated the circular walking task in the eyes closed condition with even more accuracy (i.e. following the outlined circle) than control and PD subjects. We conclude that blindfolded navigation around a previously seen circle requires intact basal ganglia, but not cerebellar input. PMID:21704129

  20. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain.

    Science.gov (United States)

    Liao, Y; Anttonen, A-K; Liukkonen, E; Gaily, E; Maljevic, S; Schubert, S; Bellan-Koch, A; Petrou, S; Ahonen, V E; Lerche, H; Lehesjoki, A-E

    2010-10-19

    Inherited and de novo mutations in sodium channel genes underlie a variety of channelopathies. Mutations in SCN2A, encoding the brain sodium channel Na(V)1.2, have previously been reported to be associated with benign familial neonatal infantile seizures, febrile seizures plus, and intractable epilepsy of infancy. We evaluated the clinical characteristics in a patient with a neonatal-onset complex episodic neurologic phenotype. We screened SCN2A for mutations and carried out in vitro electrophysiologic analyses to study the consequences of the identified mutation. We studied the developmental expression of Na(V)1.2 in cerebellum by immunohistochemical analysis. The patient presented with neonatal-onset seizures and variable episodes of ataxia, myoclonia, headache, and back pain after 18 months of age. The patient carries a de novo missense mutation (p.Ala263Val) in SCN2A, which leads to a pronounced gain-of-function, in particular an increased persistent Na(+) current. Immunohistochemical studies suggest a developmentally increasing expression of Na(V)1.2 in granule cell axons projecting to Purkinje neurons. These results can explain a neuronal hyperexcitability resulting in seizures and other episodic symptoms extending the spectrum of SCN2A-associated phenotypes. The developmentally increasing expression of Na(V)1.2 in cerebellum may be responsible for the later onset of episodic ataxia.