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Sample records for spinocerebellar ataxias scas

  1. 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

  2. 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

  3. Structural Insights Reveal the Dynamics of the Repeating r(CAG Transcript Found in Huntington's Disease (HD and Spinocerebellar Ataxias (SCAs.

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    Arpita Tawani

    Full Text Available In humans, neurodegenerative disorders such as Huntington's disease (HD and many spinocerebellar ataxias (SCAs have been found to be associated with CAG trinucleotide repeat expansion. An important RNA-mediated mechanism that causes these diseases involves the binding of the splicing regulator protein MBNL1 (Muscleblind-like 1 protein to expanded r(CAG repeats. Moreover, mutant huntingtin protein translated from expanded r(CAG also yields toxic effects. To discern the role of mutant RNA in these diseases, it is essential to gather information about its structure. Detailed insight into the different structures and conformations adopted by these mutant transcripts is vital for developing therapeutics targeting them. Here, we report the crystal structure of an RNA model with a r(CAG motif, which is complemented by an NMR-based solution structure obtained from restrained Molecular Dynamics (rMD simulation studies. Crystal structure data of the RNA model resolved at 2.3 Å reveals non-canonical pairing of adenine in 5´-CAG/3´-GAC motif samples in different syn and anti conformations. The overall RNA structure has helical parameters intermediate to the A- and B-forms of nucleic acids due to the global widening of major grooves and base-pair preferences near internal AA loops. The comprehension of structural behaviour by studying the spectral features and the dynamics also supports the flexible nature of the r(CAG motif.

  4. Inherited polyglutamine spinocerebellar ataxias in South Africa ...

    African Journals Online (AJOL)

    To determine the frequency and distribution of polyglutamine spinocerebellar ataxias (SCAs) from referrals over a 24-year period to the National Health Laboratory Service (NHLS) in South Africa (SA). Methods. Paper-based clinical reports in the University of. Cape Town laboratory and the NHLS electronic patient record

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

    Indian Academy of Sciences (India)

    Sowmya Devatha Venkatesh

    2018-03-13

    Mar 13, 2018 ... 5 Department of Psychology, Florida State University, Tallahassee, FL 32304, USA. 6 Department of ... Abstract. Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative syndromes, characterized by a wide range of muscular .... The age of FRDA mutation has been calculated to be ...

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

    NARCIS (Netherlands)

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

    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

  7. Spinocerebellar ataxia-10 with paranoid schizophrenia

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    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.

  8. Genetics Home Reference: spinocerebellar ataxia type 6

    Science.gov (United States)

    ... calcium channels . These channels transport positively charged calcium atoms (calcium ions) across cell membranes. The movement of ... Dysphagia Disease InfoSearch: Spinocerebellar ataxia 6 Johns Hopkins Medicine Department of Neurology and Neurosurgery: What is Ataxia? ...

  9. 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...

  10. Epilepsy and Spinocerebellar Ataxia

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    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.

  11. Genetics Home Reference: spinocerebellar ataxia type 2

    Science.gov (United States)

    ... Epub 2009 Dec 2. Citation on PubMed Lastres-Becker I, Rüb U, Auburger G. Spinocerebellar ataxia 2 ( ... spinocerebellar ataxias in Cuba: insights into SCA2 founder effect in Holguin. Neurosci Lett. 2009 Apr 24;454( ...

  12. 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

    2014-01-01

    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. PMID:25065913

  13. 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....... Even though a range of mechanisms contributing to polyQ diseases have been uncovered, there is still no treatment available. One of the more common polyQ diseases is SCA3, which is caused by a polyQ expansion in the ataxin-3 protein that normally functions as a deubiquitinating enzyme involved...

  14. Genetics Home Reference: spinocerebellar ataxia type 1

    Science.gov (United States)

    ... R, Giunti P. Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. Cerebellum. 2008;7( ... editing and CRISPR-Cas9? What is direct-to-consumer genetic testing? What is precision medicine? What is ...

  15. Axonal inclusions in spinocerebellar ataxia type 3

    NARCIS (Netherlands)

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

    2010-01-01

    Protein aggregation is a major pathological hallmark of many neurodegenerative disorders including polyglutamine diseases. Aggregation of the mutated form of the disease protein ataxin-3 into neuronal nuclear inclusions is well described in the polyglutamine disorder spinocerebellar ataxia type 3

  16. Mini-review: spinocerebellar ataxias: an update of SCA genes.

    Science.gov (United States)

    Trott, Alexis; Houenou, Lucien J

    2012-08-01

    Autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of debilitating and neurodegenerative diseases that affect the cerebellum and its main connections and characterized by a generalized incoordination of gait, speech, and limb movements. In general, the onset of SCAs occurs during adult life and shows great clinical heterogeneity. Currently, the mutations responsible for different types of SCAs have been localized in different regions of the genome, and most of them were already mapped and cloned. Several pieces of evidence suggest that all these diseases share the same molecular mechanism and physiopathological processes. CAG trinucleotide expansion is a common mutational basis of several of these disorders. An expanded polyglutamine tract may become a toxic product when located within the coding region of the gene. The SCA genes, recent patents and the molecular aspects of these disorders are presented in this review. Our knowledge of the molecular mechanisms of SCAs is rapidly expanding, and the development of important studies is bringing hope for effective therapies.

  17. 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.

  18. Vascular Risk Factors and Clinical Progression in Spinocerebellar Ataxias

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    Raymond Y. Lo

    2015-02-01

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

  19. Clinical neurogenetics: autosomal dominant spinocerebellar ataxia.

    Science.gov (United States)

    Shakkottai, Vikram G; Fogel, Brent L

    2013-11-01

    The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    Paradisi, Irene; Ikonomu, Vassiliki; Arias, Sergio

    2016-03-01

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

  1. 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

  2. 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.

  3. Spinocerebellar ataxia type 23: a genetic update.

    Science.gov (United States)

    Verbeek, Dineke S

    2009-06-01

    The spinocerebellar ataxia type 23 locus was identified in 2004 based on linkage analysis in a large, two-generation Dutch family. The age of onset ranged 43-56 years and the phenotype was characterized by a slowly progressive, isolated ataxia. Neuropathological examination revealed neuronal loss in the Purkinje cell layer, dentate nuclei, and inferior olives. Ubiquitin-positive intranuclear inclusions were found in nigral neurons, but were considered to be Marinesco bodies. The disease locus on chromosome 20p13-12.3 was found to span a region of approximately 6 Mb of genomic DNA, containing 97 known or predicted genes. To date, no other families have been described that also map to this SCA locus. Direct sequencing of the coding regions of 21 prioritized candidate genes did not reveal any disease-causing mutation. Apparently, the SCA23 gene is a disease gene with a different function than the genes that have been associated with other known SCA types. Work to elucidate the chromosomal organization of the SCA23 locus will eventually discover the responsible disease gene.

  4. 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

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

    Science.gov (United States)

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

    2017-12-01

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

  6. '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

  7. ‘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

  8. Spinocerebellar ataxia type 6: MRI of three Japanese patients

    International Nuclear Information System (INIS)

    Satoh, J.I.; Tokumoto, H.; Yukitake, M.; Matsui, M.; Kuroda, Y.; Matsuyama, Z.; Kawakami, H.; Nakamura, S.

    1998-01-01

    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 α 1A voltage-dependent P/Q-type Ca 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.)

  9. Ataxias and Cerebellar or Spinocerebellar Degeneration

    Science.gov (United States)

    ... SEARCH Definition Treatment ... a failure of muscle control in their arms and legs, resulting in a lack of balance and coordination or a disturbance of gait. While the term ataxia is primarily used to ...

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

    Indian Academy of Sciences (India)

    Mahesh

    Key words: SCA, Genotyping, CAG repeats, India. Introduction. The ataxia .... 2014), we also identified one SCA 12 positive case from southern India (Table 2). Out of the patients that tested positive for FRDA, 75% (N=15) were from southern India and 25% (N=5) from northern and eastern India. FRDA has been reported to ...

  11. Multimodal evoked potentials in spinocerebellar ataxia types 1, 2, and 3

    Directory of Open Access Journals (Sweden)

    Vijay Chandran

    2014-01-01

    Full Text Available Aims: Spinocerebellar ataxias (SCA are a clinically heterogeneous group of disorders that are characterized by ataxia and an autosomal dominant pattern of inheritance. The aim of our study was to describe the findings of evoked potentials (EPs among genetically proven SCA types 1, 2, and 3 and to additionally evaluate if EPs can be used to differentiate between them. Materials and Methods: Forty-three cases of genetically proven SCA (SCA1 = 19, SCA2 = 13, and SCA3 = 11 were evaluated with median somatosensory-EP (mSSEP, visual-EP (VEP, and brainstem auditory-evoked response (BAER by standard procedures and compared with normative laboratory data. An EP was considered abnormal if latency was prolonged (>mean + 3 standard deviation (SD of laboratory control data or the waveform was absent or poorly defined. The waves studied were as follows: mSSEP - N20, VEP - P100 and BAER - interpeak latency 1-3 and 3-5. Results: EPs were abnormal in at least one modality in 90.9% of patients. The most common abnormality was of BAER (86.1% followed by VEP (34.9% and mSSEP (30.2%. The degree of abnormality in VEP, mSSEP, and BAER among patients with SCA1 was 42.1, 41.2, and 73.3%, respectively; among patients with SCA2 was 38.5, 27.3, and 100%, respectively; and among patients with SCA3 was 18.2, 37.5, and 88.9%, respectively. The differences between the subgroups of SCAs were not statistically significant. Conclusions: BAER was the most frequent abnormality in SCA types 1, 2, and 3; abnormalities of mSSEP were comparable in the three SCAs; whereas, abnormality of VEP was less often noted in SCA3.

  12. 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

  13. Why do so many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia?

    Science.gov (United States)

    Huang, Miaozhen; Verbeek, Dineke S

    2018-02-05

    The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35 functionally diverse spinocerebellar ataxia genes have been identified. The main question that remains yet unsolved is why do some many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? To address this question it is important to identify intrinsic pathways important for Purkinje Cell function and survival. In this review, we discuss the current consensus on shared mechanisms underlying the pervasive Purkinje Cell loss in spinocerebellar ataxia. Additionally, using recently published cell type specific expression data, we identified several Purkinje Cell-specific genes and discuss how the corresponding pathways might underlie the vulnerability of Purkinje Cells in response to the diverse genetic insults causing spinocerebellar ataxia. Copyright © 2018. Published by Elsevier B.V.

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

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    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.

  15. 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...

  16. Progression of Dysphagia in Spinocerebellar Ataxia Type 6.

    Science.gov (United States)

    Isono, Chiharu; Hirano, Makito; Sakamoto, Hikaru; Ueno, Shuichi; Kusunoki, Susumu; Nakamura, Yusaku

    2017-06-01

    Spinocerebellar ataxia type 6 (SCA6), an autosomal dominant triplet repeat disease, predominantly affects the cerebellum with a late onset and generally good prognosis. Dysphagia is commonly associated with the outcomes of neurodegenerative diseases such as SCA6. Although the characteristics of dysphagia have been rarely reported in SCA6, our previous study indicated that dysphagia is generally milder in SCA6 than in SCA3, another inherited ataxia with multisystem involvement. However, abnormalities in the pharyngeal phase in SCA6 were indistinguishable from those in SCA3, with no explainable reason. To determine the reason, we repeatedly performed videofluoroscopic examinations (VF) in 14 patients with SCA6. The results showed that the gross progression of dysphagia was apparently slow, but four patients had progressive dysphagia at an early disease stage; dysphagia began within 10 years from the onset of ataxia and rapidly progressed. A common clinical feature of the four patients was a significantly older age at the onset of ataxia (74.0 vs. 60.3 years), associated with significantly shorter triplet repeats. This finding surprisingly indicated that patients who had shorter repeats and thereby later onset and potentially better prognoses were at risk for dysphagia-associated problems. Ischemic changes, homozygous mutation, and diabetes mellitus as well as aging might have contributed to the observed progressive dysphagia. We found that conventionally monitored somatosensory evoked potentials at least partly reflected progressive dysphagia. Despite the small study group, our findings suggest that clinicians should carefully monitor dysphagia in patients with SCA6 who are older at disease onset (>60 years).

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

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    Huang Lijia

    2012-09-01

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

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

    Science.gov (United States)

    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; Brunt, Ewout; Ippel, Elly; Kremer, Berry; Vlak, Monique; Adir, Noam; Wijmenga, Cisca; van de Warrenburg, Bart P C; Franke, Lude; Sinke, Richard J; Verbeek, Dineke S

    2017-11-01

    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 cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. 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.

  20. 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.

  1. Bergmann glia are reduced in spinocerebellar ataxia type 1.

    Science.gov (United States)

    Shiwaku, Hiroki; Yagishita, Saburo; Eishi, Yoshinobu; Okazawa, Hitoshi

    2013-08-07

    Non-cell-autonomous pathology involving glial cells has been implicated in Purkinje cell degeneration. We reported previously that mutant ataxin-1, a causative gene product of spinocerebellar ataxia type 1 (SCA1), prevents Bergmann glia proliferation in mutant ataxin-1 knockin mice and that suppressed Bergmann glia function leads to Purkinje cell degeneration. However, because reactive astrocytes are produced in response to brain injuries and diseases, Bergmann glia are also suspected to proliferate and increase in response to Purkinje cell degeneration, including during SCA1 pathogenesis. However, little is known about reactive Bergmann glia (Bergmann gliosis) and its beneficial or detrimental role. Given the lack of quantitative studies of Bergmann glia using specific molecular markers, we quantified Bergmann glia in human SCA1 brains with Bergmann glia-specific Sox2 staining and conventional hematoxylin and eosin staining. Our results showed reduced numbers of Bergmann glia in SCA1 patient brains and support the hypothesis that Bergmann glia loss contributes toward Purkinje cell degeneration in human SCA1.

  2. Partial Body Weight-Supported Treadmill Training in Spinocerebellar Ataxia.

    Science.gov (United States)

    de Oliveira, Laura Alice Santos; Martins, Camilla Polonini; Horsczaruk, Carlos Henrique Ramos; da Silva, Débora Cristina Lima; Vasconcellos, Luiz Felipe; Lopes, Agnaldo José; Meira Mainenti, Míriam Raquel; Rodrigues, Erika de Carvalho

    2018-01-01

    The motor impairments related to gait and balance have a huge impact on the life of individuals with spinocerebellar ataxia (SCA). Here, the aim was to assess the possibility of retraining gait, improving cardiopulmonary capacity, and challenging balance during gait in SCA using a partial body weight support (BWS) and a treadmill. Also, the effects of this training over functionality and quality of life were investigated. Eight SCA patients were engaged in the first stage of the study that focused on gait training and cardiovascular conditioning. From those, five took part in a second stage of the study centered on dynamic balance training during gait. The first and second stages lasted 8 and 10 weeks, respectively, both comprising sessions of 50 min (2 times per week). The results showed that gait training using partial BWS significantly increased gait performance, treadmill inclination, duration of exercise, and cardiopulmonary capacity in individuals with SCA. After the second stage, balance improvements were also found. Combining gait training and challenging tasks to the postural control system in SCA individuals is viable, well tolerated by patients with SCA, and resulted in changes in capacity for walking and balance.

  3. 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.

  4. 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

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

    Science.gov (United States)

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

    2015-09-01

    Spinocerebellar ataxia type 23 is caused by mutations in PDYN, which encodes the opioid neuropeptide precursor protein, prodynorphin. Prodynorphin is processed into the opioid peptides, α-neoendorphin, and dynorphins A and B, that normally exhibit opioid-receptor mediated actions in pain signalling and addiction. Dynorphin A is likely a mutational hotspot for spinocerebellar ataxia type 23 mutations, and in vitro data suggested that dynorphin A mutations lead to persistently elevated mutant peptide levels that are cytotoxic and may thus play a crucial role in the pathogenesis of spinocerebellar ataxia type 23. To further test this and study spinocerebellar ataxia type 23 in more detail, we generated a mouse carrying the spinocerebellar ataxia type 23 mutation R212W in PDYN. Analysis of peptide levels using a radioimmunoassay shows that these PDYN(R212W) mice display markedly elevated levels of mutant dynorphin A, which are associated with climber fibre retraction and Purkinje cell loss, visualized with immunohistochemical stainings. The PDYN(R212W) mice reproduced many of the clinical features of spinocerebellar ataxia type 23, with gait deficits starting at 3 months of age revealed by footprint pattern analysis, and progressive loss of motor coordination and balance at the age of 12 months demonstrated by declining performances on the accelerating Rotarod. The pathologically elevated mutant dynorphin A levels in the cerebellum coincided with transcriptionally dysregulated ionotropic and metabotropic glutamate receptors and glutamate transporters, and altered neuronal excitability. In conclusion, the PDYN(R212W) mouse is the first animal model of spinocerebellar ataxia type 23 and our work indicates that the elevated mutant dynorphin A peptide levels are likely responsible for the initiation and progression of the disease, affecting glutamatergic signalling, neuronal excitability, and motor performance. Our novel mouse model defines a critical role for opioid

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

    Science.gov (United States)

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

    2016-08-01

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

  7. 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...

  8. 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...

  9. 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

  10. 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

  11. Degeneration of ingestion-related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7

    NARCIS (Netherlands)

    Rueb, U.; Brunt, E. R.; Petrasch-Parwez, E.; Schoels, L.; Theegarten, D.; Auburger, G.; Seidel, K.; Schultz, C.; Gierga, K.; Paulson, H.; van Broeckhoven, C.; Deller, T.; de Vos, R. A. I.

    2006-01-01

    Dysphagia, which can lead to nutritional deficiencies, weight loss and dehydration, represents a risk factor for aspiration pneumonia. Although clinical studies have reported the occurrence of dysphagia in patients with spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3), type 6 (SCA6) and type 7

  12. Spinocerebellar ataxia type 3 (Machado-Joseph disease) : severe destruction of the lateral reticular nucleus

    NARCIS (Netherlands)

    Rub, U; de Vos, RAI; Schultz, C; Brunt, ER; Paulson, H; Braak, H

    The lateral reticular nucleus (LRT) of the medulla oblongata is a precerebellar nucleus involved in proprioception and somatomotor automatisms. We investigated this nucleus in five individuals with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3, Machado-Joseph

  13. Spinocerebellar Ataxia Type 6 Protein Aggregates Cause Deficits in Motor Learning and Cerebellar Plasticity

    NARCIS (Netherlands)

    Mark, Melanie D; Krause, Martin; Boele, Henk-Jan; Kruse, Wolfgang; Pollok, Stefan; Kuner, Thomas; Dalkara, Deniz; Koekkoek, Sebastiaan; De Zeeuw, Chris I; Herlitze, Stefan

    2015-01-01

    Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca(2+) channels (Cav2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that

  14. 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 ce...

  15. Experience and outcome of 3 years of a European EQA scheme for genetic testing of the spinocerebellar ataxias.

    Science.gov (United States)

    Seneca, Sara; Morris, Michael A; Patton, Simon; Elles, Rob; Sequeiros, Jorge

    2008-08-01

    The European Molecular Genetics Quality Network (EMQN) has been organizing an external quality assessment (EQA) scheme for molecular genetic testing of trinucleotide repeat mutations in the spinocerebellar ataxias (SCAs) since 2004. DNA samples were validated by at least two independent labs and two different methods. Together with mock clinical case descriptions and requests for specific SCA gene analyses, these were sent to registered participants each year. Laboratories were asked to use their routine procedures and protocols. A panel of assessors reviewed the final returns, including genotype results and reports, to assess the quality of (1) genotyping and (2) interpretation and reporting. A description of methods and raw data were also requested and were very useful for the final analysis. Altogether, during 3 years, 239 reports were received from the laboratories. Overall genotype error rate ranged 1.1-5.2%, a significant cause of concern. Scores for interpretation and reporting also showed that there is still much room for progress, although performance has improved over this period of assessment. The consequences of suboptimal laboratory practices, genotyping errors and misdiagnosis and of incorrect or incomplete interpretation and reporting have wide implications for patient lives, as well as for health management and counselling of relatives. EQA schemes are an important part of quality assurance in molecular genetic laboratories, and their use should become a routine part of laboratory diagnostic practice. Current evidence shows also that it is important that laboratories participate on a yearly basis and that this becomes mandatory for reference laboratories.

  16. Understanding the Pathophysiology of Spinocerebellar Ataxias through genetics, neurophysiology, structural and functional neuroimaging

    Directory of Open Access Journals (Sweden)

    Pramod Kumar Pal

    2015-12-01

    Full Text Available Over the past 10 years a large cohort of 656 index patients with clinically suspected degenerative ataxias were clinically evaluated under various research projects. Of these, 625 index patients underwent genetic tests for the clinically suspected most probable diagnosis. A diagnosis could be achieved in 218 patients (34.9%. Among these 218 index patients, 82 each were SCA1 and SCA2, 32 were SCA3, 4 were SCA12, and 18 were Friedreich's Ataxia. Thus among the Autosomal Dominant Ataxias (SCAs there was equal prevalence of SCA1 and SCA2 (41% each followed by SCA3 (16% and SCA12 (2%. This high prevalence of SCA1 is in contrast to the available National and International literature. The rate of clinical disease progression, especially in SCA2, was dependent on the CAG repeat size, and may commence linearly from birth.Apart from cerebellar involvement, a comprehensive evaluation of the neuroaxis in various subsets of this genetically proved cohort showedsubclinicalinvolvement of the cerebral cortex, central motor and sensory pathways, peripheral nervous system and autonomic nervous system. Important findings include: (aAmixedsensorimotor and pure sensory neuropathy was seen in all the three subtypes of SCAs, while pure motor neuropathy was uncommon; (b There was reduced cortical excitability and prolonged central motor conduction time, most evident in SCA1 and least in SCA2; (c Cardiac autonomic dysfunction, predominantly parasympathetic, was seen in SCA, and the severity correlated with the duration of illness in SCA1; (d In SCA1 there was a global impairment of balance, with greater instability in anterior–posterior than medio–lateral directions; (e In all the three SCAs there was a significant loss of gray matter in both cerebellar hemispheres and vermis. Vermian atrophy was more pronounced in SCA3, while SCA1 and SCA2 had significant white matter atrophy. Pontine white matter atrophy was more pronounced in SCA2; (f Cerebellar activity was

  17. HLA-linked spinocerebellar ataxia: a clinical and genetic study of large Italian kindreds.

    Science.gov (United States)

    Spadaro, M; Giunti, P; Lulli, P; Frontali, M; Jodice, C; Cappellacci, S; Morellini, M; Persichetti, F; Trabace, S; Anastasi, R

    1992-04-01

    Five families with late onset autosomal dominant spinocerebellar ataxia, were studied. Linkage between the disease and HLA loci on the short arm of chromosome 6 was shown in the two largest pedigrees. Clinical study of 26 patients and neuropathological study in one are reported. The disease was characterized by cerebellar and pyramidal involvement variably associated with cranial nerve and peripheral nervous system disorders. A remarkable concordance of the main clinical features was observed in patients with similar disease duration. Comparison with previous reports of HLA-linked spinocerebellar ataxia kindreds showed differences in clinical phenotypes. Although these might be due to genetic variation, the hypothesis is suggested that the phenotype might appear more homogeneous if disease duration is taken into account.

  18. 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

  19. 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.

  20. Operation of a P300-based brain-computer interface by patients with spinocerebellar ataxia

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    Yoji Okahara

    Full Text Available Objective: We investigated the efficacy of a P300-based brain-computer interface (BCI for patients with spinocerebellar ataxia (SCA, which is often accompanied by cerebellar impairment. Methods: Eight patients with SCA and eight age- and gender-matched healthy controls were instructed to input Japanese hiragana characters using the P300-based BCI with green/blue flicker. All patients depended on some assistance in their daily lives (modified Rankin scale: mean 3.5. The chief symptom was cerebellar ataxia; no cognitive deterioration was present. A region-based, two-step P300-based BCI was used. During the P300 task, eight-channel EEG data were recorded, and a linear discriminant analysis distinguished the target from other nontarget regions of the matrix. Results: The mean online accuracy in BCI operation was 82.9% for patients with SCA and 83.2% for controls; no significant difference was detected. Conclusion: The P300-based BCI was operated successfully not only by healthy controls but also by individuals with SCA. Significance: These results suggest that the P300-based BCI may be applicable for patients with SCA. Keywords: BCI, BMI, P300, Visual stimuli, Spinocerebellar ataxia

  1. Machado-Joseph disease in Brazil: from the first descriptions to the emergence as the most common spinocerebellar ataxia

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    José Luiz Pedroso

    2012-08-01

    Full Text Available Machado-Joseph disease is an autosomal dominant inherited disorder of Azorean ancestry firstly described in 1972. Since then, several Brazilian researchers have studied clinical and genetic issues related to the disease. Nowadays, Machado-Joseph disease is considered the most common spinocerebellar ataxia worldwide. Machado-Joseph disease still has no specific therapy to arrest progression, but the unclear pathophysiological mechanism, features related to genetic characteristics, phenotype variability, apparently global involvement of the nervous system in the disease and the therapeutic challenges continue to attract investigators in the field of spinocerebellar ataxias. Brazilian researchers have distinguished themselves in the ongoing investigation seeking new knowledge about Machado-Joseph disease.

  2. Machado-Joseph disease in Brazil: from the first descriptions to the emergence as the most common spinocerebellar ataxia.

    Science.gov (United States)

    Pedroso, José Luiz; Braga-Neto, Pedro; Radvany, João; Barsottini, Orlando Graziani Povoas

    2012-08-01

    Machado-Joseph disease is an autosomal dominant inherited disorder of Azorean ancestry firstly described in 1972. Since then, several Brazilian researchers have studied clinical and genetic issues related to the disease. Nowadays, Machado-Joseph disease is considered the most common spinocerebellar ataxia worldwide. Machado-Joseph disease still has no specific therapy to arrest progression, but the unclear pathophysiological mechanism, features related to genetic characteristics, phenotype variability, apparently global involvement of the nervous system in the disease and the therapeutic challenges continue to attract investigators in the field of spinocerebellar ataxias. Brazilian researchers have distinguished themselves in the ongoing investigation seeking new knowledge about Machado-Joseph disease.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) is caused by a CAG-repeat expansion in the ATXN3 gene. In this study, induced pluripotent stem cell (iPSC) lines were established from two SCA3 patients. Dermal fibroblasts were reprogrammed using an integration-free method...... displaying synchronized spontaneous calcium oscillations within 28 days of maturation, and expressed the mature neuronal markers NeuN and Synapsin 1 implying a relatively advanced state of maturity, although not comparable to that of the adult human brain. Interestingly, we were not able to recapitulate...

  4. [Spinocerebellar ataxia type 8: the case of a Spanish family].

    Science.gov (United States)

    Mayo-Cabrero, D; Sánchez-Migallón, M; Cantarero, S; García-Ruiz Espiga, P J; Giménez-Pardo, A; Trujillo-Tiebas, M; Ayuso-García, C

    Dominant autosomic ataxias include a group of neurodegenerative diseases characterized by the abnormal expansion of triplets. Male aged 33, with expansion of the SCA 8 gene (100 repetitions), who presented a clinical picture compatible with a pancerebellar syndrome. The patient had been diagnosed 11 years earlier as suffering from previously of histiocytosis X. A clinico genetic study was conducted on the patient and several members of his family (parents and two sisters). Both sisters and the father were found to be carriers of the expansion (110 and 150 repetitions, respectively), and are currently asymptomatic. There is no relation between the number of repetitions and the age of onset of the disease. The normal interval in our population oscillates between 16 37 repetitions, and the pathological interval has not been well determined. There may be a relation between the SCA 8 form and histiocytosis X.

  5. 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

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

    Science.gov (United States)

    2014-01-01

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

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

    NARCIS (Netherlands)

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

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

  8. Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains

    NARCIS (Netherlands)

    Evert, BO; Vogt, IR; Kindermann, C; Ozimek, L; de Vos, RAI; Brunt, ERP; Schmitt, [No Value; Klockgether, T; Wullner, U

    2001-01-01

    Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3, we performed PCR-based cDNA subtractive hybridization in a cell culture

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

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    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.

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

    Science.gov (United States)

    Mascalchi, Mario; Diciotti, Stefano; Giannelli, Marco; Ginestroni, Andrea; Soricelli, Andrea; Nicolai, Emanuele; Aiello, Marco; Tessa, Carlo; Galli, Lucia; Dotti, Maria Teresa; Piacentini, Silvia; Salvatore, Elena; Toschi, Nicola

    2014-01-01

    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.

  11. Pontine atrophy precedes cerebellar degeneration in spinocerebellar ataxia 7: MRI-based volumetric analysis

    Science.gov (United States)

    Bang, O; Lee, P; Kim, S; Kim, H; Huh, K

    2004-01-01

    Background and objective: Spinocerebellar ataxia 7 (SCA7) is characterised by cerebellar ataxia and visual loss. The aim of the present study was to elucidate the magnetic resonance imaging (MRI) findings characteristic of patients with SCA7. Methods: Twenty patients with SCA (eight SCA3, three SCA6, and nine SCA7) and 20 control subjects underwent an MRI-based volumetric analysis. Results: The pontine volume in patients with SCA7 was decreased by a greater amount than in patients with other types of SCA (p0.05). Pontine atrophy was a consistent finding in all patients with SCA7 regardless of the degree of cerebellar atrophy or the severity or duration of illness. In contrast, cerebellar atrophy was not found in those with a short duration of illness or mild ataxia, but became prominent as the severity and duration of illness progressed. Conclusions: Our study suggests that neurodegeneration is ongoing during the life of individuals with SCA7, and that the primary pathology in these individuals involves the brainstem rather than the cerebellum. In addition, pontine atrophy is a prominent, consistent finding in SCA7, and may help in establishing the clinical diagnosis of SCA7. PMID:15377695

  12. 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

  13. RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration.

    Directory of Open Access Journals (Sweden)

    Pavitra S Ramachandran

    Full Text Available Spinocerebellar ataxia type 7 (SCA7 is an autosomal dominant neurodegenerative disease characterized by loss of motor coordination and retinal degeneration with no current therapies in the clinic. The causative mutation is an expanded CAG repeat in the ataxin-7 gene whose mutant protein product causes cerebellar and brainstem degeneration and retinal cone-rod dystrophy. Here, we reduced the expression of both mutant and wildtype ataxin-7 in the SCA7 mouse retina by RNA interference and evaluated retinal function 23 weeks post injection. We observed a preservation of normal retinal function and no adverse toxicity with ≥50% reduction of mutant and wildtype ataxin-7 alleles. These studies address an important safety concern regarding non-allele specific silencing of ataxin-7 for SCA7 retinal therapy.

  14. Major Depressive Disorder Complicated with Spinocerebellar Ataxia: Report of 2 Cases

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    Nagahisa Okamoto

    2010-05-01

    Full Text Available Background: It is known that patients with spinocerebellar ataxia (SCA tend to exhibit depressive symptoms. But the pathology of depressive symptoms complicated with SCA, including the reaction to the stress resulting from decreased motor function and central dysfunction due to neurodegeneration, is controversial and remains to be elucidated. To our knowledge, there have been hardly any reports on treatment methods of major depressive disorder (MDD complicated with SCA. Case Reports: We report 2 cases in which selective serotonin reuptake inhibitors (SSRIs were effective against MDD complicated with SCA. Interestingly, one of the patients developed the symptoms of spinocerebellar degeneration (SCD during the course of the MDD, and the other patient developed the symptoms of MDD during the course of SCA, but complete remission of the MDD occurred in both cases. In our cases, the depressive symptoms may have been caused mainly by an abnormality of reversible neural transmission including serotonin transmission due to central dysfunction, and there is the unlikely possibility that the depressive symptoms are reactive to the stress due to decreased motor function, because the depressive symptoms decreased with SSRIs. Conclusion: Although cerebellar degeneration is irreversible in SCA patients, our cases suggest that MDD complicated with SCA may be reversible and treatable using antidepressants such as SSRIs with few adverse events. Therefore, it is important for neurologists to detect MDD complicated with SCA early and consult a psychiatrist in order to improve quality of life of SCA patients.

  15. Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures

    Science.gov (United States)

    McFarland, Karen N.; Liu, Jilin; Landrian, Ivette; Zeng, Desmond; Raskin, Salmo; Moscovich, Mariana; Gatto, Emilia M.; Ochoa, Adriana; Teive, Hélio A. G.; Rasmussen, Astrid; Ashizawa, Tetsuo

    2014-01-01

    Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed “ATCCT interruptions,” experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confers a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling. PMID:24318420

  16. Spinocerebellar Ataxia Type 2: Clinicogenetic Aspects, Mechanistic Insights, and Management Approaches

    Directory of Open Access Journals (Sweden)

    Luis C. Velázquez-Pérez

    2017-09-01

    Full Text Available Spinocerebellar ataxia type 2 (SCA2 is an autosomal dominant cerebellar ataxia that occurs as a consequence of abnormal CAG expansions in the ATXN2 gene. Progressive clinical features result from the neurodegeneration of cerebellum and extra-cerebellar structures including the pons, the basal ganglia, and the cerebral cortex. Clinical, electrophysiological, and imaging approaches have been used to characterize the natural history of the disease, allowing its classification into four distinct stages, with special emphasis on the prodromal stage, which is characterized by a plethora of motor and non-motor features. Neuropathological investigations of brain tissue from SCA2 patients reveal a widespread involvement of multiple brain systems, mainly cerebellar and brainstem systems. Recent findings linking ataxin-2 intermediate expansions to other neurodegenerative diseases such as amyotrophic lateral sclerosis have provided insights into the ataxin-2-related toxicity mechanism in neurodegenerative diseases and have raised new ethical challenges to molecular predictive diagnosis of SCA2. No effective neuroprotective therapies are currently available for SCA2 patients, but some therapeutic options such as neurorehabilitation and some emerging neuroprotective drugs have shown palliative benefits.

  17. Spinocerebellar Ataxia Type 2: Clinicogenetic Aspects, Mechanistic Insights, and Management Approaches

    Science.gov (United States)

    Velázquez-Pérez, Luis C.; Rodríguez-Labrada, Roberto; Fernandez-Ruiz, Juan

    2017-01-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia that occurs as a consequence of abnormal CAG expansions in the ATXN2 gene. Progressive clinical features result from the neurodegeneration of cerebellum and extra-cerebellar structures including the pons, the basal ganglia, and the cerebral cortex. Clinical, electrophysiological, and imaging approaches have been used to characterize the natural history of the disease, allowing its classification into four distinct stages, with special emphasis on the prodromal stage, which is characterized by a plethora of motor and non-motor features. Neuropathological investigations of brain tissue from SCA2 patients reveal a widespread involvement of multiple brain systems, mainly cerebellar and brainstem systems. Recent findings linking ataxin-2 intermediate expansions to other neurodegenerative diseases such as amyotrophic lateral sclerosis have provided insights into the ataxin-2-related toxicity mechanism in neurodegenerative diseases and have raised new ethical challenges to molecular predictive diagnosis of SCA2. No effective neuroprotective therapies are currently available for SCA2 patients, but some therapeutic options such as neurorehabilitation and some emerging neuroprotective drugs have shown palliative benefits. PMID:28955296

  18. Spinocerebellar ataxia type 3/Machado-Joseph disease starting before adolescence.

    Science.gov (United States)

    Donis, Karina Carvalho; Saute, Jonas Alex Morales; Krum-Santos, Ana Carolina; Furtado, Gabriel Vasata; Mattos, Eduardo Preusser; Saraiva-Pereira, Maria Luiza; Torman, Vanessa Leotti; Jardim, Laura Bannach

    2016-04-01

    Onset of Machado-Joseph disease (SCA3/MJD) before adolescence has been rarely reported. This study aims to describe a cohort of SCA3/MJD with onset before 12 years of age, comparing their disease progression with the progression observed in patients with usual disease onset. We identified all cases from our cohort whose onset was before adolescence. After consent, patients were examined with clinical scales Scale for the Assessment and Rating of Ataxia (SARA) and Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). Gender, age, age at onset, disease duration, CAG expanded repeats, transmitting parent, and anticipation of cases with infantile and adult onset were studied. Progression of NESSCA and SARA scores was estimated through a mixed model, and was compared with a historical group with onset after adolescence. Between 2000 and 2014, 461 symptomatic individuals from our region were diagnosed as SCA3/MJD. Onset of eight cases (2.2%), all heterozygotes, was before adolescence: seven were females (p = 0.054). CAG expanded repeats--75 ± 3 versus 84 ± 4--and anticipations--7 ± 9.7 versus 14.4 ± 7.2 years--were different between early childhood and adult onset groups (p < 0.03). The median survival of early childhood onset group was 23 years of age. The annual progression of SARA--2.3 and 0.6 points/year (p = 0.001)--and NESSCA--2.04 and 0.88 points/year (p = 0.043)--was faster in childhood than in adult onset group. Onset of SCA3/MJD before adolescence was related to larger expanded CAG repeats in heterozygosis; females seemed to be at higher risk. Disease progression was faster than in SCA3/MJD starting after 12 years.

  19. CAG repeats determine brain atrophy in spinocerebellar ataxia 17: a VBM study.

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    Kathrin Reetz

    2011-01-01

    Full Text Available Abnormal repeat length has been associated with an earlier age of onset and more severe disease progression in the rare neurodegenerative disorder spinocerebellar ataxia 17 (SCA17.To determine whether specific structural brain degeneration and rate of disease progression in SCA17 might be associated with the CAG repeat size, observer-independent voxel-based morphometry was applied to high-resolution magnetic resonance images of 16 patients with SCA17 and 16 age-matched healthy controls. The main finding contrasting SCA17 patients with healthy controls demonstrated atrophy in the cerebellum bilaterally. Multiple regression analyses with available genetic data and also post-hoc correlations revealed an inverse relationship again with cerebellar atrophy. Moreover, we found an inverse relationship between the CAG repeat length and rate of disease progression.Our results highlight the fundamental role of the cerebellum in this neurodegenerative disease and support the genotype-phenotype relationship in SCA17 patients. Genetic factors may determine individual susceptibility to neurodegeneration and rate of disease progression.

  20. Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7.

    Science.gov (United States)

    Trang, Heather; Stanley, Sabrina Y; Thorner, Paul; Faghfoury, Hannaneh; Schulze, Andreas; Hawkins, Cynthia; Pearson, Christopher E; Yoon, Grace

    2015-02-01

    We report the first case to date of maternally transmitted infantile spinocerebellar ataxia type 7 (SCA7), in which a tract of (CAG)45 expands to lengths as large as (CAG)92-250. A 38-year-old woman with classic SCA7 (and a son, who died at age 3 years) had pronounced cerebellar atrophy and a renal biopsy specimen that showed focal segmental glomerulosclerosis with abnormal podocytes containing cytoplasmic inclusions. Polymerase chain reaction amplification across the SCA7 repeat tract assessed expansion levels in tissues of the affected son. High levels of somatic CAG instability were observed in blood, kidney, and skeletal muscle. This transmitted expansion is considerably larger than previously reported maternal transmission expansions of 5 to 10 gained repeats. We document the first intertissue CAG instability reported to date in patients with SCA7, similar to SCA7 mouse models. Infantile SCA7, which is often paternally transmitted, can rarely arise by maternal transmission, which has implications for diagnosis and counseling among families of patients with SCA7.

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

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    Susanne K. Hansen

    2016-09-01

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

  2. Visual Suppression is Impaired in Spinocerebellar Ataxia Type 6 but Preserved in Benign Paroxysmal Positional Vertigo

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    Masahiko Kishi

    2012-10-01

    Full Text Available Positional vertigo is a common neurologic emergency and mostly the etiology is peripheral. However, central diseases may mimic peripheral positional vertigo at their initial presentation. We here describe the results of a visual suppression test in six patients with spinocerebellar ataxia type 6 (SCA6, a central positional vertigo, and nine patients with benign paroxysmal positional vertigo (BPPV, the major peripheral positional vertigo. As a result, the visual suppression value of both diseases differed significantly; e.g., 22.5% in SCA6 and 64.3% in BPPV (p < 0.001. There was a positive correlation between the visual suppression value and disease duration, cerebellar atrophy, and CAG repeat length of SCA6 but they were not statistically significant. In conclusion, the present study showed for the first time that visual suppression is impaired in SCA6, a central positional vertigo, but preserved in BPPV, the major peripheral positional vertigo, by directly comparing both groups. The abnormality in the SCA6 group presumably reflects dysfunction in the central visual fixation pathway at the cerebellar flocculus and nodulus. This simple test might aid differential diagnosis of peripheral and central positional vertigo at the earlier stage of disease.disease.

  3. Misclassification of Patients with Spinocerebellar Ataxia as having Psychogenic Postural Instability based on Computerized Dynamic Posturography

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    Susan J Herdman

    2011-04-01

    Full Text Available Specific criteria have been developed based on computerized dynamic posturography (CDP to assist clinicians in identifying patients with psychogenic balance problems1-4. Patients with known Spinocerebellar Ataxia (SCA meet several of the criteria for psychogenic balance problem and risk being misclassified as having imbalance of psychogenic origin. However, our research shows that patients with SCA may be distinguished from patients with psychogenic balance problems in several ways. We compared test performance on CDP and the observation of specific behaviors that are associated with psychogenic balance problems in patients with SCA (n = 43 and patients with known psychogenic balance problems (n = 40. Chi square analysis was used to determine if there were significant differences between the groups for the frequency of each criterion for psychogenic CDP and Observed Behaviors. Level of significance was Bonferroni corrected for multiple comparisons. Sensitivity, specificity, and positive likelihood ratios were calculated for each criterion. Hierarchical cluster analysis was used to examine whether the two patient groups demonstrated similar groupings of criteria. Comparison of the results of these analyses identified two criteria that were significantly more frequent in the Psychogenic group than in the SCA group: Regular Periodicity of sway and Circular Sway. Sensitivity, specificity and positive likelihood ratios identified two additional criteria, Inconsistent Motor Responses and Large lateral Sway that also seem to suggest a psychogenic component to a person’s imbalance. Prospective studies are needed to validate the usefulness of these findings.

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

    Science.gov (United States)

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

    2017-04-01

    The progressive deterioration of patients with spinocerebellar ataxia (SCA) has a major impact on their health-related quality of life (HRQOL). This study evaluates HRQOL in a sample of patients diagnosed with SCA and aims to estimate the predictive ability of a set of sociodemographic variables for the different dimensions of the General Health Questionnaire. A total of 80 patients diagnosed with SCA were assessed using a sociodemographic questionnaire and the SF-36 General Health Questionnaire. The sociodemographic variables studied were sex, age, presence of a carer, employment status, and time elapsed from diagnosis of the disease. The 8 subscales of the SF-36 show positive and significant correlations to one another. Mean scores obtained on each SF-36 subscale differ between women and men, although this difference is significant only on the general health subscale, with men scoring higher than women. We found significant age differences on the vitality and social function subscales, with higher scores among younger patients (< 34 years). The variable 'presence of a carer' accounts for most of the total variance of the questionnaire. The SF-36 is a valid and useful instrument for evaluating HRQOL in patients diagnosed with SCA. Presence of a carer seems to be a determinant of self-perceived quality of life in these patients. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Impact of gene patents on diagnostic testing: a new patent landscaping method applied to spinocerebellar ataxia.

    Science.gov (United States)

    Berthels, Nele; Matthijs, Gert; Van Overwalle, Geertrui

    2011-11-01

    Recent reports in Europe and the United States raise concern about the potential negative impact of gene patents on the freedom to operate of diagnosticians and on the access of patients to genetic diagnostic services. Patents, historically seen as legal instruments to trigger innovation, could cause undesired side effects in the public health domain. Clear empirical evidence on the alleged hindering effect of gene patents is still scarce. We therefore developed a patent categorization method to determine which gene patents could indeed be problematic. The method is applied to patents relevant for genetic testing of spinocerebellar ataxia (SCA). The SCA test is probably the most widely used DNA test in (adult) neurology, as well as one of the most challenging due to the heterogeneity of the disease. Typically tested as a gene panel covering the five common SCA subtypes, we show that the patenting of SCA genes and testing methods and the associated licensing conditions could have far-reaching consequences on legitimate access to this gene panel. Moreover, with genetic testing being increasingly standardized, simply ignoring patents is unlikely to hold out indefinitely. This paper aims to differentiate among so-called 'gene patents' by lifting out the truly problematic ones. In doing so, awareness is raised among all stakeholders in the genetic diagnostics field who are not necessarily familiar with the ins and outs of patenting and licensing.

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

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    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.

  7. Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia.

    Science.gov (United States)

    Cadieux-Dion, Maxime; Turcotte-Gauthier, Maude; Noreau, Anne; Martin, Caroline; Meloche, Caroline; Gravel, Micheline; Drouin, Christian Allen; Rouleau, Guy A; Nguyen, Dang Khoa; Cossette, Patrick

    2014-04-01

    The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described. To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations. Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers. We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome β-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.

  8. Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1 Características clínicas e moleculares de uma família Brasileira com ataxia espinocerebelar tipo 1

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    Iscia Lopes-Cendes

    1996-09-01

    Full Text Available The spinocerebellar ataxias (SCAs are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped: SCA1, SCA2, Machado-Joseph disease (MJD/SCA3, SCA4, SCA5, SCA7 and dentatorubropallidoluysian atrophy (DRPLA. Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.As ataxias espinocerebelares (AECs fazem parte de um grupo de doenças neurodegenerativas que apresentam grande heterogeneidade clínica e genética. Existem até o momento sete genes mapeados responsáveis pelas AECs de transmissão autossômica dominante: SCA1, SCA2, doença de Machado-Joseph (DA/7 ou SCA3, SCA4, SCA5, SCA7 e atrofia dentatorubropalidoluisiana (ADRPL. Uma expansão de um trínucletídeo CAG foi identificada como a mutação responsável na SCA], DMJ e ADRPL. Estudamos uma família brasileira com uma forma autossômica dominante de AEC. Dez indivíduos foram examinados e

  9. Spinocerebellar ataxia type 8 larger triplet expansion alters histone modification and induces RNA foci

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    Wu Yih-Ru

    2009-02-01

    Full Text Available Abstract Background Spinocerebellar ataxia type 8 (SCA8 involves the expression of an expanded CTG/CAG combined repeats (CR from opposite strands producing CUG expansion transcripts (ataxin 8 opposite strand, ATXN8OS and a polyglutamine expansion protein (ataxin 8, ATXN8. The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad. Results Using stably induced cell models expressing 0, 23, 88 and 157 CR, we study the role of ATXN8OS transcripts in SCA8 pathogenesis. In the absence of doxycycline, the stable ATXN8OS CR cell lines exhibit low levels of ATXN8OS expression and a repeat length-related increase in staurosporine sensitivity and in the number of annexin positive cells. A repeat length-dependent repression of ATXN8OS expression was also notable. Addition of doxycycline leads to 25~50 times more ATXN8OS RNA expression with a repeat length-dependent increase in fold of ATXN8OS RNA induction. ChIP-PCR assay using anti-dimethyl-histone H3-K9 and anti-acetyl-histone H3-K14 antibodies revealed increased H3-K9 dimethylation and reduced H3-K14 acetylation around the ATXN8OS cDNA gene in 157 CR line. The repeat length-dependent increase in induction fold is probably due to the increased RNA stability as demonstrated by monitoring ATXN8OS RNA decay in cells treated with the transcriptional inhibitor, actinomycin D. In cells stably expressing ATXN8OS, RNA FISH experiments further revealed ribonuclear foci formation in cells carrying expanded 88 and 157 CR. Conclusion The present study demonstrates that the expanded CUG-repeat tracts are toxic to human cells and may affect ATXN8OS RNA expression and stability through epigenetic and post-transcriptional mechanisms.

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

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    Ma Wei-Hsien

    2011-08-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

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    Roberto Emmanuele Mercadillo

    2015-06-01

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

  13. A strategy for multimodal data integration: application to biomarkers identification in spinocerebellar ataxia.

    Science.gov (United States)

    Garali, Imene; Adanyeguh, Isaac M; Ichou, Farid; Perlbarg, Vincent; Seyer, Alexandre; Colsch, Benoit; Moszer, Ivan; Guillemot, Vincent; Durr, Alexandra; Mochel, Fanny; Tenenhaus, Arthur

    2017-07-03

    The growing number of modalities (e.g. multi-omics, imaging and clinical data) characterizing a given disease provides physicians and statisticians with complementary facets reflecting the disease process but emphasizes the need for novel statistical methods of data analysis able to unify these views. Such data sets are indeed intrinsically structured in blocks, where each block represents a set of variables observed on a group of individuals. Therefore, classical statistical tools cannot be applied without altering their organization, with the risk of information loss. Regularized generalized canonical correlation analysis (RGCCA) and its sparse generalized canonical correlation analysis (SGCCA) counterpart are component-based methods for exploratory analyses of data sets structured in blocks of variables. Rather than operating sequentially on parts of the measurements, the RGCCA/SGCCA-based integrative analysis method aims at summarizing the relevant information between and within the blocks. It processes a priori information defining which blocks are supposed to be linked to one another, thus reflecting hypotheses about the biology underlying the data blocks. It also requires the setting of extra parameters that need to be carefully adjusted.Here, we provide practical guidelines for the use of RGCCA/SGCCA. We also illustrate the flexibility and usefulness of RGCCA/SGCCA on a unique cohort of patients with four genetic subtypes of spinocerebellar ataxia, in which we obtained multiple data sets from brain volumetry and magnetic resonance spectroscopy, and metabolomic and lipidomic analyses. As a first step toward the extraction of multimodal biomarkers, and through the reduction to a few meaningful components and the visualization of relevant variables, we identified possible markers of disease progression. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Mangifera indica L. extract (Vimang improves the aversive memory in spinocerebellar ataxia type 2 transgenic mice.

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    Natasha Maurmann

    2014-06-01

    Full Text Available Context: The spinocerebellar ataxia type 2 (SCA-2 is a progressive neurodegenerative disorder without specific therapy identified, and it is related to the loss of function in the cerebellum, mitochondrial dysfunction, oxidative stress and neurotoxic processes. Scientific evidence indicates that Mangifera indica L. aqueous extract (MiE and its major constituent (mangiferin display antioxidant, anti-inflammatory and neuroprotective actions. Aims: To investigate the MiE and mangiferin effects on behavioral outcomes of neurological function in SCA-2 transgenic mice. Methods: The SCA-2 transgenic mice were daily and orally administered during 12 months with MiE (10, 50, and 100 mg/kg, mangiferin (10 mg/kg or vehicle. It was evaluated locomotion (open-field, aversive memory (inhibitory avoidance and declarative memory (object recognition. To explore possible cellular mechanisms underlying the in vivo effects was also evaluated their effects on nerve grow factor (NGF and tumor necrosis factor-α (TNF-α levels in the human glioblastoma cell line U138-MG supernatant. Results: MiE administration did not affect the object recognition memory, but mangiferin did. The natural extract improved selectively the aversive memory in SCA-2 mice, indicating that MiE can affect behavioral parameters regarding fear-related memory. MiE also induced a significant increase in supernatant levels of NGF and TNF-α in vitro in human U138-MG glioblastoma cells. Conclusions: The results suggest that MiE enhances the aversive memory through a mechanism that might involve an increase in neurotrophin and cytokine levels. These findings constitute the basis for the use of the natural extract in the prevention/treatment of memory deficits in SCA-2.

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

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    Jian-Wen Chen

    2015-01-01

    Conclusions: Collectively our study is a systematic research on SCAs in China, which may help for the clinical diagnosis and prenatal screening of this disease, and it may also aid toward better understanding of this disease.

  16. Automated home cage assessment shows behavioral changes in a transgenic mouse model of spinocerebellar ataxia type 17.

    Science.gov (United States)

    Portal, Esteban; Riess, Olaf; Nguyen, Huu Phuc

    2013-08-01

    Spinocerebellar Ataxia type 17 (SCA17) is an autosomal dominantly inherited, neurodegenerative disease characterized by ataxia, involuntary movements, and dementia. A novel SCA17 mouse model having a 71 polyglutamine repeat expansion in the TATA-binding protein (TBP) has shown age related motor deficit using a classic motor test, yet concomitant weight increase might be a confounding factor for this measurement. In this study we used an automated home cage system to test several motor readouts for this same model to confirm pathological behavior results and evaluate benefits of automated home cage in behavior phenotyping. Our results confirm motor deficits in the Tbp/Q71 mice and present previously unrecognized behavioral characteristics obtained from the automated home cage, indicating its use for high-throughput screening and testing, e.g. of therapeutic compounds. Copyright © 2013 Elsevier B.V. All rights reserved.

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

    International Nuclear Information System (INIS)

    De Rosa, Anna; De Leva, Maria Fulvia; Maddaluno, Gennaro; Filla, Alessandro; De Michele, Giuseppe; Pappata, Sabina; Pellegrino, Teresa; Fiumara, Giovanni; Carotenuto, Raffaella; Cuocolo, Alberto; Petretta, Mario

    2013-01-01

    Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia, supranuclear ophthalmoplegia, and peripheral neuropathy. Autonomic nervous system dysfunction is often present. This study evaluated the cardiac sympathetic function in patients with SCA2 using 123 I-metaiodobenzylguanidine (MIBG) in comparison with patients with Parkinson's disease (PD) and control subjects. Nine patients with SCA2, nine patients with PD, and nine control subjects underwent 123 I-MIBG imaging studies from which early and late heart-to-mediastinum (H/M) ratios and myocardial washout rates were calculated. Early (F = 12.3, p 123 I-MIBG myocardial scintigraphy demonstrated an impairment of cardiac sympathetic function in patients with SCA2, which was less marked than in PD patients. These results suggest that 123 I-MIBG cardiac imaging could become a useful tool for analysing the pathophysiology of SCA2. (orig.)

  18. Consistent affection of the central somatosensory system in spinocerebellar ataxia type 2 and type 3 and its significance for clinical symptoms and rehabilitative therapy

    NARCIS (Netherlands)

    Rueb, Udo; Seidel, Kay; Ozerden, Inci; Gierga, Kristin; Brunt, Ewout R.; Schoels, Ludger; de Vos, Rob A. I.; den Dunnen, Wilfred; Schultz, Christian; Auburger, Georg; Deller, Thomas

    The spinocerebellar ataxias type 2 (SCA2) and type 3 (SCA3) are progressive, currently untreatable and ultimately fatal ataxic disorders, which belong to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Since knowledge regarding the involvement of the central

  19. Involvement of the auditory brainstem system in spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7)

    NARCIS (Netherlands)

    Hoche, F.; Seidel, K.; Brunt, E. R.; Auburger, G.; Schoels, L.; Buerk, K.; de Vos, R. A.; den Dunnen, W.; Bechmann, I.; Egensperger, R.; Van Broeckhoven, C.; Gierga, K.; Deller, T.; Rueb, U.

    2008-01-01

    Aims: The spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3) and type 7 (SCA7) are clinically characterized by progressive and severe ataxic symptoms, dysarthria, dysphagia, oculomotor impairments, pyramidal and extrapyramidal manifestations and sensory deficits. Although recent clinical studies

  20. Capillary electrophoresis fragment analysis and clone sequencing in detection of dynamic mutations of spinocerebellar ataxia

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    Yuan-yuan CHEN

    2018-04-01

    Full Text Available Objective To estimate the accuracy and stability of capillary electrophoresis fragment analysis and clone sequencing in detecting dynamic mutations of spinocerebellar ataxia (SCA. Methods Capillary electrophoresis fragment analysis and clone sequencing were used in detecting trinucleotide repeated sequence of 14 SCA patients (3 cases of SCA2, 2 cases of SCA7, 7 cases of SCA8 and 2 cases of SCA17. Results Capillary electrophoresis fragment analysis of 3 SCA2 cases showed the expanded cytosine-adenine-guanine (CAG repeats were 31, 30 and 32, and the copy numbers of 3 clone sequencing for 3 colonies in each case were 37/40/40, 37/38/39 and 38/39/40 respectively. Capillary electrophoresis fragment analysis of 2 SCA7 cases showed the expanded CAG repeats were 57 and 34, and the copy numbers of repeats were 69, 74, 75 in 3 colonies of one case, and was 45 in the other case. For the 7 SCA8 cases with the expanded cytosine-thymine-adenine (CTA/cytosine-thymine-guanine (CTG repeats of 99, 111, 104, 92, 89, 104 and 75, the results of clone sequencing were 97, 116, 104, 90, 90, 102 and 76 respectively. For 2 SCA17 cases with the short/expanded CAG repeats of 37/50 and 36/45, the results of clone sequencing were 51/50/52 and 45/44 for 3 and 2 colonies. Conclusions Although the higher mobility of polymerase chain reaction (PCR products containing dynamic mutation in the capillary electrophoresis fragment analysis might cause the deviation for analysis of copy numbers, the deviation was predictable and the results were repeatable. The clone sequencing results showed obvious instability, especially for SCA2 and SCA7 genes, which might owing to their simple CAG repeats. Consequently, clone sequencing is not suited for detection of dynamic mutation, not to mention the quantitative criteria of dynamic mutation sequencing. DOI: 10.3969/j.issn.1672-6731.2018.03.008

  1. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis.

    Science.gov (United States)

    Galatolo, Daniele; Tessa, Alessandra; Filla, Alessandro; Santorelli, Filippo M

    2018-01-01

    One of the hardest challenges in medical genetics is to reach a molecular diagnosis in the presence of rare brain disorders. Hereditary spinocerebellar ataxia (HA), characterized by high clinical and genetic heterogeneity, is among the diseases that present this challenge. HA can have features overlapping with those of other neurological diseases, especially hereditary spastic paraplegia (HSP), as routine clinical application of next generation sequencing (NGS) has confirmed. This article reviews different NGS methods applied in heterogeneous cohorts of patients with suspected HA and suggests that exome sequencing should be considered the first-tier genetic approach in this setting. Its application lends support to the hypothesis of HA and HSP as two extremes of a continuous spectrum.

  2. Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7.

    Science.gov (United States)

    Rüb, Udo; Schöls, Ludger; Paulson, Henry; Auburger, Georg; Kermer, Pawel; Jen, Joanna C; Seidel, Kay; Korf, Horst-Werner; Deller, Thomas

    2013-05-01

    The spinocerebellar ataxias type 1 (SCA1), 2 (SCA2), 3 (SCA3), 6 (SCA6) and 7 (SCA7) are genetically defined autosomal dominantly inherited progressive cerebellar ataxias (ADCAs). They belong to the group of CAG-repeat or polyglutamine diseases and share pathologically expanded and meiotically unstable glutamine-encoding CAG-repeats at distinct gene loci encoding elongated polyglutamine stretches in the disease proteins. In recent years, progress has been made in the understanding of the pathogenesis of these currently incurable diseases: Identification of underlying genetic mechanisms made it possible to classify the different ADCAs and to define their clinical and pathological features. Furthermore, advances in molecular biology yielded new insights into the physiological and pathophysiological role of the gene products of SCA1, SCA2, SCA3, SCA6 and SCA7 (i.e. ataxin-1, ataxin-2, ataxin-3, α-1A subunit of the P/Q type voltage-dependent calcium channel, ataxin-7). In the present review we summarize our current knowledge about the polyglutamine ataxias SCA1, SCA2, SCA3, SCA6 and SCA7 and compare their clinical and electrophysiological features, genetic and molecular biological background, as well as their brain pathologies. Furthermore, we provide an overview of the structure, interactions and functions of the different disease proteins. On the basis of these comprehensive data, similarities, differences and possible disease mechanisms are discussed. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Depression as the Primary Cause of Insomnia and Excessive Daytime Sleepiness in a Family with Multiple Cases of Spinocerebellar Ataxia.

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    Hsu, Chun-Hsien; Chen, Yen-Lin; Pei, Dee; Yu, Shu-Man; Liu, I-Chao

    2016-07-15

    Spinocerebellar ataxia (SCA) is a hereditary disease characterized by central nervous system-related motor dysfunctions. Sleep disorders and frequent non-motor manifestations are commonly comorbid with SCA. To elucidate this relationship, we present three cases in a family that included multiple SCA type 2 patients with various sleep disorders. Complete physical examination, and genetic and imaging studies were performed. Anti-parkinsonism medications were prescribed after neurological examination. Clonazepam and/or quetiapine were administered for sleep disorders but failed to resolve insomnia and excessive daytime sleepiness (EDS). Based on DSM-5 criteria, all cases were diagnosed with depression. After treatment with serotonin-norepinephrine reuptake inhibitors and noradrenergic and specific serotonergic antidepressants, symptoms of insomnia and EDS, which are strongly associated with depression in SCA type 2 patients, improved significantly. It is crucial to recognize insomnia and EDS in neurodegenerative diseases, not only for earlier diagnosis, but also to improve quality of life. © 2016 American Academy of Sleep Medicine.

  4. 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

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    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.

  5. Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1.

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    Platonov, Fedor A; Tyryshkin, Kathrin; Tikhonov, Dmitriy G; Neustroyeva, Tatyana S; Sivtseva, Tatyana M; Yakovleva, Natalya V; Nikolaev, Valerian P; Sidorova, Oksana G; Kononova, Sardana K; Goldfarb, Lev G; Renwick, Neil M

    2016-07-01

    Spinocerebellar ataxia type 1 (SCA1) is the major and likely the only type of autosomal dominant cerebellar ataxia in the Sakha (Yakut) people of Eastern Siberia. The prevalence rate of SCA1 has doubled over the past 21 years peaking at 46 cases per 100,000 rural population. The age at death correlates closely with the number of CAG triplet repeats in the mutant ATXN1 gene (r = -0.81); most patients with low-medium (39-55) repeat numbers survived until the end of reproductive age. The number of CAG repeats expands in meiosis, particularly in paternal transmissions; the average total increase in intergenerational transmissions in our cohort was estimated at 1.6 CAG repeats. The fertility rates of heterozygous carriers of 39-55 CAG repeats in women were no different from those of the general Sakha population. Overall, the survival of mutation carriers through reproductive age, unaltered fertility rates, low childhood mortality in SCA1-affected families, and intergenerational transmission of increasing numbers of CAG repeats in the ATXN1 gene indicate that SCA1 in the Sakha population will be maintained at high prevalence levels. The low (0.19) Crow's index of total selection intensity in our SCA1 cohort implies that this mutation is unlikely to be eliminated through natural selection alone.

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

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    Khalaf Bushara

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

  7. Double-blind crossover trial of trimethoprim-sulfamethoxazole in spinocerebellar ataxia type 3/Machado-Joseph disease.

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    Schulte, T; Mattern, R; Berger, K; Szymanski, S; Klotz, P; Kraus, P H; Przuntek, H; Schöls, L

    2001-09-01

    To evaluate the efficiency of a combination of trimethoprim and sulfamethoxazole in patients with spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). Placebo-controlled, double-blind crossover trial in 22 patients with genetically confirmed SCA3/MJD. Study phases of 6 months were separated by a washout period of 4 weeks. Dosages were a combination of trimethoprim, 160 mg, and sulfamethoxazole, 800 mg, twice daily for 2 weeks, followed by a combination of trimethoprim, 80 mg, and sulfamethoxazole, 400 mg, twice daily for 5.5 months. Outpatient department of the Neurological Clinic, Ruhr-University, Bochum, Germany. Ataxia ranking scale, self-assessment score, static posturography, and results of motor performance testing. Effects on the visual system were studied using the achromatic Vision Contrast Test System and the Farnsworth-Munsell 100-hue test for color discrimination. Physical and mental health were documented using the Medical Outcomes Study 36-Item Short-Form Health Survey. Subgroup analyses assessed the influence of age, sex, age at onset, duration of the disease, phenotype, and CAG repeat length on test performance. Twenty of 22 patients completed the study. Dropouts were due to a rash (placebo phase) and an attempted suicide in a family conflict. Trimethoprim-sulfamethoxazole therapy had no significant effect in SCA3/MJD patients in the short-term analysis (2 weeks) or in the long-term interval (6 months). In contrast to previous reports that studied smaller groups of patients, treatment with trimethoprim-sulfamethoxazole did not improve the diverse and complex movement disorders caused by SCA3/MJD. Trimethoprim-sulfamethoxazole had no effect on the visual system and cannot be recommended as a continuous treatment for SCA3/MJD patients.

  8. Incidentalome in Neurogenetics: Pathogenic Variant of NSD1 in a Patient With Spinocerebellar Ataxia (SCA).

    Science.gov (United States)

    Velasco, Harvy; Ramírez-Montaño, Diana

    2018-01-01

    Background: Genetic studies of late-onset sporadic ataxias (>40 years of age) are not routinely indicated. For unresolved cases, next-generation sequencing (NGS) tools, such as whole-exome sequencing (WES), are available for a definitive diagnosis. Case presentation: Our patient is a woman with a usual facial phenotype and anthropometry, who developed ataxia at 45 years of age, with no relevant family history and an initial clinical approach that ruled out common aetiologies. WES was performed when the patient was 54 years old. The results identified the heterozygous pathogenic variant c.248delA (p.N83MfsX4) in the nuclear receptor-binding SET domain protein 1 ( NSD1 ; MIM 606681) gene (related to Sotos syndrome), which was not associated with ataxia and is not related to the patient's phenotype. Sanger sequencing of NSD1 in two different laboratories confirmed the variant. Conclusions: NGS findings generally offer valuable information that can be used for clinical decision-making. However, an incidental finding that leads to defining new clinical and bioethical actions is also possible. Consequently, the biological importance of this type of genetic "incidentalome" must be determined.

  9. Incidentalome in Neurogenetics: Pathogenic Variant of NSD1 in a Patient With Spinocerebellar Ataxia (SCA

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    Harvy Velasco

    2018-03-01

    Full Text Available Background: Genetic studies of late-onset sporadic ataxias (>40 years of age are not routinely indicated. For unresolved cases, next-generation sequencing (NGS tools, such as whole-exome sequencing (WES, are available for a definitive diagnosis.Case presentation: Our patient is a woman with a usual facial phenotype and anthropometry, who developed ataxia at 45 years of age, with no relevant family history and an initial clinical approach that ruled out common aetiologies. WES was performed when the patient was 54 years old. The results identified the heterozygous pathogenic variant c.248delA (p.N83MfsX4 in the nuclear receptor-binding SET domain protein 1 (NSD1; MIM 606681 gene (related to Sotos syndrome, which was not associated with ataxia and is not related to the patient's phenotype. Sanger sequencing of NSD1 in two different laboratories confirmed the variant.Conclusions: NGS findings generally offer valuable information that can be used for clinical decision-making. However, an incidental finding that leads to defining new clinical and bioethical actions is also possible. Consequently, the biological importance of this type of genetic “incidentalome” must be determined.

  10. Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions.

    Science.gov (United States)

    Souza, G N; Kersting, N; Krum-Santos, A C; Santos, A S P; Furtado, G V; Pacheco, D; Gonçalves, T A; Saute, J A; Schuler-Faccini, L; Mattos, E P; Saraiva-Pereira, M L; Jardim, L B

    2016-08-01

    Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta-CAGexp from parent-offspring pairs, and delta-CAGexp between siblings were obtained. One hundred and fifty-nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta-CAGexp among 115 direct parent-offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta-CAGexp between 269 siblings correlated with their delta-of-age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Polyglutamine length-dependent toxicity from α1ACT in Drosophila models of spinocerebellar ataxia type 6

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    Wei-Ling Tsou

    2016-12-01

    Full Text Available Spinocerebellar ataxia type 6 (SCA6 is a neurodegenerative disease that results from abnormal expansion of a polyglutamine (polyQ repeat. SCA6 is caused by CAG triplet repeat expansion in the gene CACNA1A, resulting in a polyQ tract of 19-33 in patients. CACNA1A, a bicistronic gene, encodes the α1A calcium channel subunit and the transcription factor, α1ACT. PolyQ expansion in α1ACT causes degeneration in mice. We recently described the first Drosophila models of SCA6 that express α1ACT with a normal (11Q or hyper-expanded (70Q polyQ. Here, we report additional α1ACT transgenic flies, which express full-length α1ACT with a 33Q repeat. We show that α1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, α1ACT33Q-expressing adults die earlier than flies expressing the normal allele. α1ACT33Q causes retinal degeneration and leads to aggregated species in an age-dependent manner, but at a slower pace than the 70Q counterpart. According to western blots, α1ACT33Q localizes less readily in the nucleus than α1ACT70Q, providing clues into the importance of polyQ tract length on α1ACT localization and its site of toxicity. We expect that these new lines will be highly valuable for future work on SCA6.

  12. Epigallocatechin-3-gallate and tetracycline differently affect ataxin-3 fibrillogenesis and reduce toxicity in spinocerebellar ataxia type 3 model.

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    Bonanomi, Marcella; Natalello, Antonino; Visentin, Cristina; Pastori, Valentina; Penco, Amanda; Cornelli, Giuseppina; Colombo, Giorgio; Malabarba, Maria G; Doglia, Silvia M; Relini, Annalisa; Regonesi, Maria E; Tortora, Paolo

    2014-12-15

    The polyglutamine (polyQ)-containing protein ataxin-3 (AT3) triggers the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3) when its polyQ tract is expanded beyond a critical length. This results in protein aggregation and generation of toxic oligomers and fibrils. Currently, no effective treatment is available for such and other polyQ diseases. Therefore, plenty of investigations are being carried on to assess the mechanism of action and the therapeutic potential of anti-amyloid agents. The polyphenol compound epigallocatechin-3-gallate (EGCG) and tetracycline have been shown to exert some effect in preventing fibrillogenesis of amyloidogenic proteins. Here, we have incubated an expanded AT3 variant with either compound to assess their effects on the aggregation pattern. The process was monitored by atomic force microscopy and Fourier transform infrared spectroscopy. Whereas in the absence of any treatment, AT3 gives rise to amyloid β-rich fibrils, whose hallmark is the typical glutamine side-chain hydrogen bonding, when incubated in the presence of EGCG it generated soluble, SDS-resistant aggregates, much poorer in β-sheets and devoid of any ordered side-chain hydrogen bonding. These are off-pathway species that persist until the latest incubation time and are virtually absent in the control sample. In contrast, tetracycline did not produce major alterations in the structural features of the aggregated species compared with the control, but substantially increased their solubility. Both compounds significantly reduced toxicity, as shown by the MTT assay in COS-7 cell line and in a transgenic Caenorhabditis elegans strain expressing in the nervous system an AT3 expanded variant in fusion with GFP. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Fatigue and Its Associated Factors in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.

    Science.gov (United States)

    Martinez, Alberto R M; Nunes, Marcelo B; Faber, Ingrid; D'Abreu, Anelyssa; Lopes-Cendes, Íscia; França, Marcondes C

    2017-02-01

    Fatigue has been described in several neurodegenerative diseases, reducing quality of life. A systematic evaluation of this clinical feature is lacking in SCA3/MJD. The aim of this study was to evaluate the frequency and the factors associated with fatigue in SCA3/MJD. Patients with SCA3/MJD and matched healthy controls answered the Modified Fatigue Impact Scale (MFIS), Beck Inventory Depression (BDI) and Epworth Sleepiness Scale (ESS). Scale for the assessment and rating of ataxia (SARA) was used to determine ataxia severity. We used Mann-Whitney and Fisher exact tests to compare mean scores and proportions between groups. Linear regression analyses were employed to investigate factors associated with fatigue in SCA3/MJD. Seventy-four patients were included with a mean age and disease duration of 47.2 ± 12.8 and 9.5 ± 6.37 years, respectively. There were 38 men and 36 women. Mean (CAG)n was 72.2 ± 3.8. Mean MFIS score was higher in patients with SCA3/MJD (41.4 ± 16.2 vs 18.4 ± 12.9, p < 0.001). According to BDI scores, relevant depressive symptoms were found in 69.4 % of patients but only in 10.4 % of controls (p < 0.001). The proportion of patients with ESS scores indicating excessive daytime somnolence was also higher than controls (37.5 vs 22.3 %, p = 0.05). In the multiple regression analysis, both BDI and ESS scores were associated with fatigue (r = 0.67, p < 0.001 and p = 0.01). Fatigue is frequent and strongly associated with depression and excessive daytime somnolence in SCA3/MJD.

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

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    Iscia Lopes-Cendesi

    1997-09-01

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

  15. Novel selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2

    Science.gov (United States)

    Kasumu, AW; Hougaard, C; Rode, F; Jacobsen, TA; Sabatier, JM; Eriksen, BL; Strøbæk, D; Liang, X; Egorova, P; Vorontsova, D; Christophersen, P; Rønn, LCB; Bezprozvanny, I

    2012-01-01

    Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from transgenic SCA2 mice we demonstrate that SK channel modulators restore regular pacemaker activity of SCA2 PCs. Furthermore, we also show that oral delivery of a novel selective positive modulator of SK2/3 channels (NS13001) alleviates behavioural and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a novel target for SCA2 treatment and that the developed selective SK2/3 modulator NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias. PMID:23102227

  16. Spinocerebellar ataxia type 2 neurodegeneration differentially affects error-based and strategic-based visuomotor learning.

    Science.gov (United States)

    Vaca-Palomares, Israel; Díaz, Rosalinda; Rodríguez-Labrada, Roberto; Medrano-Montero, Jacqeline; Vázquez-Mojena, Yaimé; Velázquez-Pérez, Luis; Fernandez-Ruiz, Juan

    2013-12-01

    There are different types of visuomotor learning. Among the most studied is motor error-based learning where the sign and magnitude of the error are used to update motor commands. However, there are other instances where individuals show visuomotor learning even if the sign or magnitude of the error is precluded. Studies with patients suggest that the former learning is impaired after cerebellar lesions, while basal ganglia lesions disrupt the latter. Nevertheless, the cerebellar role is not restricted only to error-based learning, but it also contributes to several cognitive processes. Therefore, here, we tested if cerebellar ataxia patients are affected in two tasks, one that depends on error-based learning and the other that prevents the use of error-based learning. Our results showed that cerebellar patients have deficits in both visuomotor tasks; however, while error-based learning tasks deficits correlated with the motor impairments, the motor error-dependent task did not correlate with any motor measure.

  17. Spinocerebellar ataxia type 7 (SCA7) : widespread brain damage in an adult-onset patient with progressive visual impairments in comparison with an adult-onset patient without visual impairments

    NARCIS (Netherlands)

    Rueb, U.; Brunt, E. R.; Seidel, K.; Gierga, K.; Mooy, C. M.; Kettner, M.; Van Broeckhoven, C.; Bechmann, I.; La Spada, A. R.; Schoels, L.; den Dunnen, W.; de Vos, R. A. I.; Deller, T.

    Spinocerebellar ataxia type 7 (SCA7) represents a rare and severe autosomal dominantly inherited ataxic disorder and is among the known CAG-repeat, or polyglutamine, diseases. In contrast to other currently known autosomal dominantly inherited ataxic disorders, SCA7 may manifest itself with

  18. 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.

  19. Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.

    Science.gov (United States)

    Rodríguez-Cueto, Carmen; Hernández-Gálvez, Mariluz; Hillard, Cecilia J; Maciel, Patricia; García-García, Luis; Valdeolivas, Sara; Pozo, Miguel A; Ramos, José A; Gómez-Ruiz, María; Fernández-Ruiz, Javier

    2016-12-17

    Spinocerebellar ataxia type-3 (SCA-3) is a rare disease but it is the most frequent type within the autosomal dominant inherited ataxias. The disease lacks an effective treatment to alleviate major symptoms and to modify disease progression. Our recent findings that endocannabinoid receptors and enzymes are significantly altered in the post-mortem cerebellum of patients affected by autosomal-dominant hereditary ataxias suggest that targeting the endocannabinoid signaling system may be a promising therapeutic option. Our goal was to investigate the status of the endocannabinoid signaling system in a transgenic mouse model of SCA-3, in the two CNS structures most affected in this disease - cerebellum and brainstem. These animals exhibited progressive motor incoordination, imbalance, abnormal gait, muscle weakness, and dystonia, in parallel to reduced in vivo brain glucose metabolism, deterioration of specific neuron subsets located in the dentate nucleus and pontine nuclei, small changes in microglial morphology, and reduction in glial glutamate transporters. Concerning the endocannabinoid signaling, our data indicated no changes in CB 2 receptors. By contrast, CB 1 receptors increased in the Purkinje cell layer, in particular in terminals of basket cells, but they were reduced in the dentate nucleus. We also measured the levels of endocannabinoid lipids and found reductions in anandamide and oleoylethanolamide in the brainstem. These changes correlated with an increase in the FAAH enzyme in the brainstem, which also occurred in some cerebellar areas, whereas other endocannabinoid-related enzymes were not altered. Collectively, our results in SCA-3 mutant mice confirm a possible dysregulation in the endocannabinoid system in the most important brain structures affected in this type of ataxia, suggesting that a pharmacological manipulation addressed to correct these changes could be a promising option in SCA-3. Copyright © 2016 IBRO. Published by Elsevier Ltd. All

  20. Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.

    Science.gov (United States)

    Kanack, Adam J; Newsom, Oliver J; Scaglione, Kenneth Matthew

    2018-02-23

    The accumulation of misfolded proteins promotes protein aggregation and neuronal death in many neurodegenerative diseases. To counteract misfolded protein accumulation, neurons have pathways that recognize and refold or degrade aggregation-prone proteins. One U-box-containing E3 ligase, C terminus of Hsc70-interacting protein (CHIP), plays a key role in this process, targeting misfolded proteins for proteasomal degradation. CHIP plays a protective role in mouse models of neurodegenerative disease, and in humans, mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability. Here, we systematically analyzed CHIP mutations that cause SCAR16 and found that most SCAR16 mutations destabilize CHIP. This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells. Consistent with decreased CHIP stability promoting its dysfunction in SCAR16, most mutant proteins recovered activity when the assays were performed below the mutants' melting temperature. Together, our results have uncovered the molecular basis of genetic defects in CHIP function that cause SCAR16. Our insights suggest that compounds that improve the thermostability of genetic CHIP variants may be beneficial for treating patients with SCAR16. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Clinical analysis of the treatment of spinocerebellar ataxia and multiple system atrophy-cerebellar type with umbilical cord mesenchymal stromal cells.

    Science.gov (United States)

    Dongmei, Han; Jing, Liu; Mei, Xue; Ling, Zhu; Hongmin, Yan; Zhidong, Wang; Li, Ding; Zikuan, Guo; Hengxiang, Wang

    2011-09-01

    The aims of this study were to observe the safety and effectiveness of umbilical cord mesenchymal stromal cells (UC-MSC) in the treatment of spinocerebellar ataxia (SCA) and multiple system atrophy-cerebellar type (MSA-C). From October 2009 to September 2010, 14 cases of SCA and 10 cases of MSA-C were given UC-MSC by weekly intrathecal injection, at a dose of 1 × 10(6)/kg four times as one course. All the patients received one course of treatment, except three patients who received two courses. The movement ability and quality of daily life were evaluated with the International Cooperative Ataxia Rating Scale (ICARS) and Activity of Daily Living Scale (ADL) and the scores compared with those before cell therapy. A follow-up of 6-15 months was carried out for all of the patients. The results showed that the ICARS and ADL scores were significantly decreased 1 month after treatment (P pain (two cases) and headache (one case), which disappeared within 1-3 days. During the follow-up, 10 cases remained stable for half a year or longer, while 14 cases had regressed to the status prior to the treatment within 1-14 months (an average of 3 months). Intrathecal injection of UC-MSC is safe and can delay the progression of neurologic deficits for SCA and MSA-C patients.

  2. Challenges in sleep stage R scoring in patients with autosomal dominant spinocerebellar ataxias (SCA1, SCA2 and SCA3) and oculomotor abnormalities: a whole night polysomnographic evaluation.

    Science.gov (United States)

    Seshagiri, Doniparthi Venkata; Sasidharan, Arun; Kumar, Gulshan; Pal, Pramod Kumar; Jain, Sanjeev; Kutty, Bindu M; Yadav, Ravi

    2018-02-01

    Spinocerebellar ataxias are progressive neurodegenerative disorders characterized by progressive cerebellar features with additional neuro-axis involvement. Oculomotor abnormality is one of the most frequent manifestations. This study was done to assess the polysomnographic abnormalities in patients with Spinocerebellar ataxia (SCA1, SCA2 and SCA3) and also to evaluate whether oculomotor abnormalities interfere with sleep stage R scoring. The study was carried out using 36 genetically positive SCA patients. All patients underwent neurological examination with special focus on oculomotor function (optokinetic nystagmus-OKN and extraocular movement restriction-EOM). The sleep quality was measured with Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Disease severity was assessed with International Cooperative Ataxia Rating Scale (ICARS). All the patients underwent over-night video-polysomnography (VPSG). Out of 36 patients studied, the data of 34 patients [SCA1 (n = 12), SCA2 (n = 13), SCA3 (n = 9)] were used for final analysis. Patients from SCA1, SCA2, and SCA3 category did not show significant differences in age and diseases severity (ICARS). All patients had vertical OKN impairment. Oculomotor impairment was higher in SCA2 patients. Sleep macro-architecture analysis showed absent stage R sleep, predominantly in SCA2 (69%) followed by SCA3 (44%) and SCA1 (8%). Patients showed a strong negative correlation of stage R sleep percentage with disease severity and oculomotor dysfunction. Voluntary saccadic eye movement velocity and rapid eye movements (REMs) in sleep are strongly correlated. The more severe the saccadic velocity impairment, the less likely was it to generate REMs (rapid eye movements) during stage R. Accordingly 69% of SCA2 patients with severe occulomotor impairments showed absent stage R as per the AASM sleep scoring. We presume that the impaired REMs generation in sleep could be due to oculomotor abnormality and has

  3. Clinical validity of MR based program for analysis of fluid/brain index of posterior cranial fossa structures in patients with spinocerebellar ataxia

    International Nuclear Information System (INIS)

    Boguslawska, R.; Lechowicz, W.

    2008-01-01

    Spinocerebellar ataxia type 1 (SCA1) and type 2 (SCA2) belong to the group of neurodegenerative disorders of autosomal dominant inheritance, genetically and clinically heterogeneous, caused by CAG trinucleotide repeat expansion, which leads to productions of protein carrying the abnormal polyglutamine chain (polyQ). Molecular abnormalities cause degenerative changes - atrophy of posterior cranial fossa structures. The clinical symptoms typical of this disorder include progressive gait and limb ataxia, dysarthria, occulomotor disturbances, pyramidal tract and peripheral nerves involvement. The aim of the study is to evaluate the usefulness of a computer program prepared in our department for volumetric measurements of posterior cranial fossa structures (the pons, vermis and cerebellar hemispheres) in a group of SCA patients. MR examinations of 22 patients suffering from SCA were used to calculate the value of fluid/brain index of posterior cranial fossa structures and compared with the results of group of 10 healthy volunteers. The degree of atrophy of posterior cranial fossa structures can be objectively evaluated by special volumetric measurements. We found fluid/brain index (FBI) of posterior cranial fossa structures in group of SCA patients to vary from 0.1411 to 0.3929 (mean 0.2456 SD±0.601). 1. MR-based calculation of fluid/brain index of posterior fossa structures is a valuable tool for morphological assessment of SCA-related changes in brain structures. 2. The presented software enables objective evaluation of the course and stage of posterior fossa structures atrophy. 3. Our self-made computer program to calculate the fluid/brain index of posterior cranial fossa structures is easy to use on a personal computer- it is a good tool in everyday radiological practice. (author)

  4. A novel nuclear DnaJ protein, DNAJC8, can suppress the formation of spinocerebellar ataxia 3 polyglutamine aggregation in a J-domain independent manner

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Norie [Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556 (Japan); Department of Neurology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556 (Japan); Kamiguchi, Kenjiro; Nakanishi, Katsuya; Sokolovskya, Alice; Hirohashi, Yoshihiko; Tamura, Yasuaki; Murai, Aiko; Yamamoto, Eri; Kanaseki, Takayuki; Tsukahara, Tomohide; Kochin, Vitaly [Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556 (Japan); Chiba, Susumu [Department of Neurology, Clinical Brain Research Laboratory, Toyokura Memorial Hall, Sapporo Yamano-ue Hospital (Japan); Shimohama, Shun [Department of Neurology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556 (Japan); Sato, Noriyuki [Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556 (Japan); Torigoe, Toshihiko, E-mail: torigoe@sapmed.ac.jp [Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556 (Japan)

    2016-06-10

    Polyglutamine (polyQ) diseases comprise neurodegenerative disorders caused by expression of expanded polyQ-containing proteins. The cytotoxicity of the expanded polyQ-containing proteins is closely associated with aggregate formation. In this study, we report that a novel J-protein, DNAJ (HSP40) Homolog, Subfamily C, Member 8 (DNAJC8), suppresses the aggregation of polyQ-containing protein in a cellular model of spinocerebellar ataxia type 3 (SCA3), which is also known as Machado-Joseph disease. Overexpression of DNAJC8 in SH-SY5Y neuroblastoma cells significantly reduced the polyQ aggregation and apoptosis, and DNAJC8 was co-localized with the polyQ aggregation in the cell nucleus. Deletion mutants of DNAJC8 revealed that the C-terminal domain of DNAJC8 was essential for the suppression of polyQ aggregation, whereas the J-domain was dispensable. Furthermore, 22-mer oligopeptide derived from C-termilal domain could suppress the polyQ aggregation. These results indicate that DNAJC8 can suppress the polyQ aggregation via a distinct mechanism independent of HSP70-based chaperone machinery and have a unique protective role against the aggregation of expanded polyQ-containing proteins such as pathogenic ataxin-3 proteins.

  5. Spinocerebellar ataxia (SCA1) in two large Italian kindreds: evidence in favour of a locus position distal to GLO1 and the HLA cluster.

    Science.gov (United States)

    Frontali, M; Iodice, C; Lulli, P; Spadaro, M; Cappellacci, S; Giunti, P; Malaspina, P; Morellini, M; Morocutti, C; Novelletto, A

    1991-01-01

    Two large Italian pedigrees with HLA-linked spinocerebellar ataxia (SCA1) were typed for HLA-A, -B and -DR as well as for markers either distal (F13A, D6S8) or proximal (D6S29, GLO1) to HLA. Pairwise linkage analyses of SCA1 vs. HLA-A, -B, and -DR showed peak lodscores of 5.3, 5.6 and 3.3 respectively at 7% recombination. Negative lodscores significantly excluded linkage with F13A at less than 5% and with GLO1 at less than 10%. The lodscores with D6S8 and D6S29 had only low peaks. Recombination events in the two pedigrees and the estimated genetic distances of SCA1 from GLO1 and HLA favour the hypothesis of a SCA1 location distal to both of them. An order cen-GLO1-HLA-SCA1-tel appears therefore most likely with present data. These results are discussed in relation to previous reports placing SCA1 distal to HLA in two families and

  6. The SCA1 (Spinocerebellar ataxia type 1 and MJD (Machado-Joseph disease CAG repeats in normal individuals: segregation analysis and allele frequencies

    Directory of Open Access Journals (Sweden)

    Wiezel Cláudia Emília Vieira

    2003-01-01

    Full Text Available Spinocerebellar ataxia type 1 (SCA1 and Machado-Joseph disease (MJD/SCA3 are autosomal dominant neurodegenerative diseases caused by expansions of a CAG trinucleotide repeat in the SCA1 and MJD genes. These expanded sequences are unstable upon transmission, leading to an intergeneration increase in the number of repeats (dynamic mutation. The transmission of the CAG repeat was studied in normal mother-father-child trios, referred for paternity testing (SCA1, n = 367; MJD, n = 879. No segregation distortion was detected. The CAG allele frequencies were determined in 330 unrelated individuals (fathers from couples tested for paternity. The allele frequency distributions did not differ from those previously reported for European populations. The estimated values for the statistic parameters indicating diversity at the SCA1 locus did not differ much from those reported previously for other STRs in the Brazilian population, while those for the MJD locus were close to or higher than the maximum values of previous reports. This shows that SCA1 and MJD are highly informative loci for applications in genetic and population studies and for forensic analysis.

  7. Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach.

    Science.gov (United States)

    Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

    2016-01-01

    Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient ( r 2 ) value of 0.6774, cross-validated correlation coefficient ( q 2 ) of 0.6157 and co-relation coefficient for external test set ( pred _ r 2 ) of 0.7570. A high F -test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of -10.097 and -9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-12-15

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

  9. Home-cage anxiety levels in a transgenic rat model for Spinocerebellar ataxia type 17 measured by an approach-avoidance task: The light spot test.

    Science.gov (United States)

    Kyriakou, Elisavet I; Nguyen, Huu Phuc; Homberg, Judith R; Van der Harst, Johanneke E

    2017-08-18

    Measuring anxiety in a reliable manner is essential for behavioural phenotyping of rodent models such as the rat model for Spinocerebellar ataxia type 17 (SCA17) where anxiety is reported in patients. An automated tool for assessing anxiety within the home cage can minimize human intervention, stress of handling, transportation and novelty. We applied the anxiety test "light spot" (LS) (white led directed at the food-hopper) to our transgenic SCA17 rat model in the PhenoTyper 4500 ® to extend the knowledge of this automated tool for behavioural phenotyping and to verify an anxiety-like phenotype at three different disease stages for use in future therapeutic studies. Locomotor activity was increased in SCA17 rats at 6 and 9 months during the first 15min of the LS, potentially reflecting increased risk assessment. Both genotypes responded to the test with lower duration in the LS zone and higher time spent inside the shelter compared to baseline. We present the first data of a rat model subjected to the LS. The LS can be considered more biologically relevant than a traditional test as it measures anxiety in a familiar situation. The LS successfully evoked avoidance and shelter-seeking in rats. SCA17 rats showed a stronger approach-avoidance conflict reflected by increased activity in the area outside the LS. This home cage test, continuously monitoring pre- and post-effects, provides the opportunity for in-depth analysis, making it a potentially useful tool for detecting subtle or complex anxiety-related traits in rodents. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins.

    Science.gov (United States)

    Pakdaman, Yasaman; Sanchez-Guixé, Monica; Kleppe, Rune; Erdal, Sigrid; Bustad, Helene J; Bjørkhaug, Lise; Haugarvoll, Kristoffer; Tzoulis, Charalampos; Heimdal, Ketil; Knappskog, Per M; Johansson, Stefan; Aukrust, Ingvild

    2017-04-30

    Spinocerebellar ataxia, autosomal recessive 16 (SCAR16) is caused by biallelic mutations in the STIP1 homology and U-box containing protein 1 ( STUB1 ) gene encoding the ubiquitin E3 ligase and dimeric co-chaperone C-terminus of Hsc70-interacting protein (CHIP). It has been proposed that the disease mechanism is related to CHIP's impaired E3 ubiquitin ligase properties and/or interaction with its chaperones. However, there is limited knowledge on how these mutations affect the stability, folding, and protein structure of CHIP itself. To gain further insight, six previously reported pathogenic STUB1 variants (E28K, N65S, K145Q, M211I, S236T, and T246M) were expressed as recombinant proteins and studied using limited proteolysis, size-exclusion chromatography (SEC), and circular dichroism (CD). Our results reveal that N65S shows increased CHIP dimerization, higher levels of α-helical content, and decreased degradation rate compared with wild-type (WT) CHIP. By contrast, T246M demonstrates a strong tendency for aggregation, a more flexible protein structure, decreased levels of α-helical structures, and increased degradation rate compared with WT CHIP. E28K, K145Q, M211I, and S236T also show defects on structural properties compared with WT CHIP, although less profound than what observed for N65S and T246M. In conclusion, our results illustrate that some STUB1 mutations known to cause recessive SCAR16 have a profound impact on the protein structure, stability, and ability of CHIP to dimerize in vitro. These results add to the growing understanding on the mechanisms behind the disorder. © 2017 The Author(s).

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

    NARCIS (Netherlands)

    Smeets, C J L M; Verbeek, D S

    2014-01-01

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

  12. Transcranial sonography findings in spinocerebellar ataxia type 3 (Machado-Joseph disease): a cross-sectional study.

    Science.gov (United States)

    Pedroso, José Luiz; Bor-Seng-Shu, Edson; Felício, Andre Carvalho; Braga-Neto, Pedro; Teixeira, Manoel Jacobsen; Barsottini, Orlando Graziani

    2011-10-24

    Few studies on transcranial brain sonography have been performed in hereditary and non-hereditary ataxias. The objective of the present study was to report transcranial brain sonography findings in a sample of clinically and molecularly proven Machado-Joseph disease patients and to compare these data against those of an age- and gender-matched control group. A cross-sectional study on transcranial brain sonography was conducted in 30 Machado-Joseph disease patients. Transcranial brain sonography was performed by an experienced sonographer blinded to the clinical, genetic, and neuroimaging data. The results were compared with those of a control group of 44 healthy subjects matched for age and gender. The sonographic findings were also correlated with clinical features and genetic data in Machado-Joseph disease group. A significantly higher frequency of substantia nigra and lenticular nucleus hyperechogenicity was found in the Machado-Joseph disease group compared to an age- and gender-matched healthy control group (pMachado-Joseph disease patients than in the control subjects. No significant correlations were found between transcranial brain sonography findings and Machado-Joseph disease demographic/clinical data. Transcranial brain sonography findings in Machado-Joseph disease patients differed significantly to those in age- and gender-matched controls. Substantia nigra hyperechogenicity occurred frequently in Machado-Joseph disease patients and was found to be the best predictor for differentiating cases from controls. Additionally, this data describes the occurrence of brain atrophy in Machado-Joseph disease group. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. Deregulation of the actin cytoskeleton and macropinocytosis in response to phorbol ester by the mutant protein kinase C gamma that causes spinocerebellar ataxia type 14.

    Science.gov (United States)

    Yamamoto, Kazuhiro; Seki, Takahiro; Yamamoto, Hikaru; Adachi, Naoko; Tanaka, Shigeru; Hide, Izumi; Saito, Naoaki; Sakai, Norio

    2014-01-01

    Several missense mutations in the protein kinase Cγ (γPKC) gene have been found to cause spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. γPKC is a neuron-specific member of the classical PKCs and is activated and translocated to subcellular regions as a result of various stimuli, including diacylglycerol synthesis, increased intracellular Ca(2+) and phorbol esters. We investigated whether SCA14 mutations affect the γPKC-related functions by stimulating HeLa cells with TPA (12-O-tetradecanoylpholbol 13-acetate), a type of phorbol ester. Wild-type (WT) γPKC-GFP was translocated to the plasma membrane within 10 min of TPA stimulation, followed by its perinuclear translocation and cell shrinkage, in a PKC kinase activity- and microtubule-dependent manner. On the other hand, although SCA14 mutant γPKC-GFP exhibited a similar translocation to the plasma membrane, the subsequent perinuclear translocation and cell shrinkage were significantly impaired in response to TPA. Translocated WT γPKC colocalized with F-actin and formed large vesicular structures in the perinuclear region. The uptake of FITC-dextran, a marker of macropinocytosis, was promoted by TPA stimulation in cells expressing WT γPKC, and FITC-dextran was surrounded by γPKC-positive vesicles. Moreover, TPA induced the phosphorylation of MARCKS, which is a membrane-substrate of PKC, resulting in the translocation of phosphorylated MARCKS to the perinuclear region, suggesting that TPA induces macropinocytosis via γPKC activation. However, TPA failed to activate macropinocytosis and trigger the translocation of phosphorylated MARCKS in cells expressing the SCA14 mutant γPKC. These findings suggest that γPKC is involved in the regulation of the actin cytoskeleton and macropinocytosis in HeLa cells, while SCA14 mutant γPKC fails to regulate these processes due to its reduced kinase activity at the plasma membrane. This property might be involved in pathogenesis

  14. Deregulation of the actin cytoskeleton and macropinocytosis in response to phorbol ester by the mutant protein kinase C gamma that causes spinocerebellar ataxia type 14

    Directory of Open Access Journals (Sweden)

    Kazuhiro eYamamoto

    2014-04-01

    Full Text Available Several missense mutations in the protein kinase Cγ (γPKC gene have been found to cause spinocerebellar ataxia type 14 (SCA14, an autosomal dominant neurodegenerative disease. γPKC is a neuron-specific member of the classical PKCs and is activated and translocated to subcellular regions as a result of various stimuli, including diacylglycerol synthesis, increased intracellular Ca2+ and phorbol esters. We investigated whether SCA14 mutations affect the γPKC-related functions by stimulating HeLa cells with TPA (12-O-tetradecanoylpholbol 13-acetate, a type of phorbol ester. Wild-type (WT γPKC-GFP was translocated to the plasma membrane within 10 min of TPA stimulation, followed by its perinuclear translocation and cell shrinkage, in a PKC kinase activity- and microtubule-dependent manner. On the other hand, although SCA14 mutant γPKC-GFP exhibited a similar translocation to the plasma membrane, the subsequent perinuclear translocation and cell shrinkage were significantly impaired in response to TPA. Translocated WT γPKC colocalized with F-actin and formed large vesicular structures in the perinuclear region. The uptake of FITC-dextran, a marker of macropinocytosis, was promoted by TPA stimulation in cells expressing WT γPKC, and FITC-dextran was surrounded by γPKC-positive vesicles. Moreover, TPA induced the phosphorylation of MARCKS, which is a membrane-substrate of PKC, resulting in the translocation of phosphorylated MARCKS to the perinuclear region, suggesting that TPA induces macropinocytosis via γPKC activation. However, TPA failed to activate macropinocytosis and trigger the translocation of phosphorylated MARCKS in cells expressing the SCA14 mutant γPKC. These findings suggest that γPKC is involved in the regulation of the actin cytoskeleton and macropinocytosis in HeLa cells, while SCA14 mutant γPKC fails to regulate these processes due to its reduced kinase activity at the plasma membrane. This property might be involved in

  15. Synergistic Toxicity of Polyglutamine-Expanded TATA-Binding Protein in Glia and Neuronal Cells: Therapeutic Implications for Spinocerebellar Ataxia 17.

    Science.gov (United States)

    Yang, Yang; Yang, Su; Guo, Jifeng; Cui, Yiting; Tang, Beisha; Li, Xiao-Jiang; Li, Shihua

    2017-09-20

    Spinocerebellar ataxia 17 (SCA17) is caused by polyglutamine (polyQ) repeat expansion in the TATA-binding protein (TBP) and is among a family of neurodegenerative diseases in which polyQ expansion leads to preferential neuronal loss in the brain. Although previous studies have demonstrated that expression of polyQ-expanded proteins in glial cells can cause neuronal injury via noncell-autonomous mechanisms, these studies investigated animal models that overexpress transgenic mutant proteins. Since glial cells are particularly reactive to overexpressed mutant proteins, it is important to investigate the in vivo role of glial dysfunction in neurodegeneration when mutant polyQ proteins are endogenously expressed. In the current study, we generated two conditional TBP-105Q knock-in mouse models that specifically express mutant TBP at the endogenous level in neurons or in astrocytes. We found that mutant TBP expression in neuronal cells or astrocytes alone only caused mild neurodegeneration, whereas severe neuronal toxicity requires the expression of mutant TBP in both neuronal and glial cells. Coculture of neurons and astrocytes further validated that mutant TBP in astrocytes promoted neuronal injury. We identified activated inflammatory signaling pathways in mutant TBP-expressing astrocytes, and blocking nuclear factor κB (NF-κB) signaling in astrocytes ameliorated neurodegeneration. Our results indicate that the synergistic toxicity of mutant TBP in neuronal and glial cells plays a critical role in SCA17 pathogenesis and that targeting glial inflammation could be a potential therapeutic approach for SCA17 treatment. SIGNIFICANCE STATEMENT Mutant TBP with polyglutamine expansion preferentially affects neuronal viability in SCA17 patients. Whether glia, the cells that support and protect neurons, contribute to neurodegeneration in SCA17 remains mostly unexplored. In this study, we provide both in vivo and in vitro evidence arguing that endogenous expression of mutant

  16. Autosomal dominant hereditary ataxia in Sri Lanka

    OpenAIRE

    Sumathipala, Dulika S; Abeysekera, Gayan S; Jayasekara, Rohan W; Tallaksen, Chantal ME; Dissanayake, Vajira HW

    2013-01-01

    Background Spinocerebellar ataxias (SCA) are a group of hereditary neurodegenerative disorders. Prevalence of SCA subtypes differ worldwide. Autosomal dominant ataxias are the commonest types of inherited ataxias seen in Sri Lanka. The aim of the study is to determine the genetic etiology of patients with autosomal dominant ataxia in Sri Lanka and to describe the clinical features of each genetic subtype. Methods ...

  17. Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders.

    Science.gov (United States)

    Robertson, Erin E; Hall, Deborah A; McAsey, Andrew R; O'Keefe, Joan A

    2016-08-01

    The purpose of this paper is to review the typical cognitive and motor impairments seen in fragile X-associated tremor/ataxia syndrome (FXTAS), essential tremor (ET), Parkinson disease (PD), spinocerebellar ataxias (SCAs), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in order to enhance diagnosis of FXTAS patients. We compared the cognitive and motor phenotypes of FXTAS with each of these other movement disorders. Relevant neuropathological and neuroimaging findings are also reviewed. Finally, we describe the differences in age of onset, disease severity, progression rates, and average lifespan in FXTAS compared to ET, PD, SCAs, MSA, and PSP. We conclude with a flow chart algorithm to guide the clinician in the differential diagnosis of FXTAS. By comparing the cognitive and motor phenotypes of FXTAS with the phenotypes of ET, PD, SCAs, MSA, and PSP we have clarified potential symptom overlap while elucidating factors that make these disorders unique from one another. In summary, the clinician should consider a FXTAS diagnosis and testing for the Fragile X mental retardation 1 (FMR1) gene premutation if a patient over the age of 50 (1) presents with cerebellar ataxia and/or intention tremor with mild parkinsonism, (2) has the middle cerebellar peduncle (MCP) sign, global cerebellar and cerebral atrophy, and/or subcortical white matter lesions on MRI, or (3) has a family history of fragile X related disorders, intellectual disability, autism, premature ovarian failure and has neurological signs consistent with FXTAS. Peripheral neuropathy, executive function deficits, anxiety, or depression are supportive of the diagnosis. Distinct profiles in the cognitive and motor domains between these movement disorders may guide practitioners in the differential diagnosis process and ultimately lead to better medical management of FXTAS patients.

  18. Congo red, an amyloid-inhibiting compound, alleviates various types of cellular dysfunction triggered by mutant protein kinase cγ that causes spinocerebellar ataxia type 14 (SCA14) by inhibiting oligomerization and aggregation.

    Science.gov (United States)

    Seki, Takahiro; Takahashi, Hideyuki; Yamamoto, Kazuhiro; Ogawa, Kota; Onji, Tomoya; Adachi, Naoko; Tanaka, Shigeru; Hide, Izumi; Saito, Naoaki; Sakai, Norio

    2010-01-01

    Several missense mutations in the protein kinase Cγ (γPKC) gene have been found to cause spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that the mutant γPKC found in SCA14 is susceptible to aggregation that induces apoptotic cell death. Congo red is widely used as a histological dye for amyloid detection. Recent evidence has revealed that Congo red has the property to inhibit amyloid oligomers and fibril formation of misfolded proteins. In the present study, we examine whether Congo red inhibits aggregate formation and cytotoxicity of mutant γPKC. Congo red likely inhibits aggregate formation of mutant γPKC – green fluorescent protein (GFP) without affecting its expression level in SH-SY5Y cells. Congo red counteracts the insolubilization of recombinant mutant γPKC, suggesting that the dye inhibits aggregation of mutant γPKC by a direct mechanism. Congo red also inhibits aggregation and oligomerization of mutant γPKC-GFP in primary cultured cerebellar Purkinje cells. Moreover, the dye reverses the improper development of dendrites and inhibits apoptotic cell death in Purkinje cells that express mutant γPKC-GFP. These results indicate that amyloid-inhibiting compounds like Congo red may be novel therapeutics for SCA14.

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

    Directory of Open Access Journals (Sweden)

    Juan I. Rojas

    2007-04-01

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

  20. 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

  1. Sleep disorders in cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    José L. Pedroso

    2011-04-01

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

  2. 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

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

    Indian Academy of Sciences (India)

    Mahesh

    Cuba and south Asia) population could have important implications in studying the population flow, and prevalence of inherited late-onset disorders. Evidence for a founder effect at the SCA12 loci has been suggested specifically from northern ...

  4. Genetics Home Reference: spinocerebellar ataxia type 3

    Science.gov (United States)

    ... time, individuals with SCA3 may develop loss of sensation and weakness in the limbs (peripheral neuropathy), muscle cramps, muscle twitches (fasciculations), and swallowing difficulties. Individuals with SCA3 may have problems with memory, planning, and problem solving. Signs and symptoms of ...

  5. 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

  6. Delayed-onset Friedreich's ataxia revisited.

    Science.gov (United States)

    Lecocq, Claire; Charles, Perrine; Azulay, Jean-Philippe; Meissner, Wassilios; Rai, Myriam; N'Guyen, Karine; Péréon, Yann; Fabre, Nelly; Robin, Elsa; Courtois, Sylvie; Guyant-Maréchal, Lucie; Zagnoli, Fabien; Rudolf, Gabrielle; Renaud, Mathilde; Sévin-Allouet, Mathieu; Lesne, Fabien; Alaerts, Nick; Goizet, Cyril; Calvas, Patrick; Eusebio, Alexandre; Guissart, Claire; Derkinderen, Pascal; Tison, Francois; Brice, Alexis; Koenig, Michel; Pandolfo, Massimo; Tranchant, Christine; Dürr, Alexandra; Anheim, Mathieu

    2016-01-01

    Friedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25 and 40 years, respectively. We describe the clinical, functional, and molecular findings from a large series of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia and compare them with typical-onset Friedreich's ataxia. Phenotypic and genotypic comparison of 44 late-onset Friedreich's ataxia, 30 very late-onset Friedreich's ataxia, and 180 typical Friedreich's ataxia was undertaken. Delayed-onset Friedreich's ataxia (late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia) had less frequently dysarthria, abolished tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, ganglionopathy, cerebellar atrophy, scoliosis, and cardiomyopathy than typical-onset Friedreich's ataxia, along with less severe functional disability and shorter GAA expansion on the smaller allele (P < 0.001). Delayed-onset Friedreich's ataxia had lower scale for the assessment and rating of ataxia and spinocerebellar degeneration functional scores and longer disease duration before wheelchair confinement (P < 0.001). Both GAA expansions were negatively correlated to age at disease onset (P < 0.001), but the smaller GAA expansion accounted for 62.9% of age at onset variation and the larger GAA expansion for 15.6%. In this comparative study of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, no differences between these phenotypes were demonstrated. Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as "delayed-onset Friedreich's ataxia." As the most frequently inherited ataxia, Friedreich's ataxia should be considered

  7. 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, ...

  8. Friedreich's Ataxia

    Science.gov (United States)

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

  9. 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…

  10. Cerebellar ataxia of early onset

    International Nuclear Information System (INIS)

    Yamashita, Sumimasa; Miyake, Shota; Yamada, Michiko; Iwamoto, Hiroko; Yamada, Kazuhiko.

    1989-01-01

    Eight cases of childhood cerebellar ataxia were reported. All these cases showed chronic cerebellar ataxia with early onset, and the other diseases of cerebellum such as infections, neoplasms and storage diseases were excluded by clinical symptoms and laboratory findings including blood counts, blood chemistry, lactate, pyruvate, ceruloplasmine, urinalysis, serum immunoglobulins, amino acid analysis in blood and urine, CSF analysis, leukocyte lysosomal enzymes, MCV, EMG, EEG and brain X-CT. Two pairs of siblings were included in this study. The clinical diagnosis were cerebellar type (5), spinocerebellar type (1), one Marinesco-Sjoegren syndrome and undetermined type (1). The age of onset was 1 to 5 years. The chief complaint was motor developmental delay in 6 cases; among them 5 patients could walk alone at the ages of 2 to 3 years'. Mental retardation was observed in 7 cases and epilepsy in 2. TRH was effective in 5 cases. The MRI study revealed that the area of medial sagittal slice of the cerebellum was reduced significantly in all cases and also that of pons was reduced in 5 cases. Different from typical adult onset spinocerebellar degenerations, most of the present cases have achieved slow developmental milestones and the clinical course was not progressive. Genetic factors are suspected in the pathogenesis of this disease in some cases. (author)

  11. Ataxia - telangiectasia

    Science.gov (United States)

    ... or absent physical and sexual development Growth failure Mask-like face Multiple skin coloring and texture changes ... Foundation (NAF): www.ataxia.org Outlook (Prognosis) Early death is common, but life expectancy varies. Because people ...

  12. Ataxia Telangiectasia

    Science.gov (United States)

    ... A-T usually have normal or above normal intelligence. × Definition Ataxia-telangiectasia is a rare, childhood neurological ... A-T usually have normal or above normal intelligence. View Full Definition Treatment There is no cure ...

  13. Visuomotor ataxia

    International Nuclear Information System (INIS)

    Hirose, Genjiro; Kawada, Junya; Oda, Rokuhei; Kitagawa, Yoshinobu; Kosoegawa, Hiroshi

    1985-01-01

    Three patients with visuomotor ataxia, a disorder of hand movement to grasp objects located in the periphery of the visual field, were studied clinically and neuroradiologically with conventional and reformatted CT scans. Visuomotor ataxia was noted in the hemifield contralateral to the parieto-occipital lesion with both hands regardless the side of the lesion in this study. No dominant hemisphere for visuomotor ataxia was noted. The responsible lesions for this disorder were overlapped at Broadmann's area 7, 18, 19 and their surrounded white matter including the connecting fibers to the contralateral hemisphere via the splenium of corpus callosum. No direct lesion was found in the angular gyrus (Broadmann area 39). Visuomotor ataxia was seen with both hands in our series and it can be explained by the disconnection of either or both of the direct and crossed long association fibers between visual association areas and motor association areas at the parieto-occipital junction. (author)

  14. Spinocerebellar variant of adrenoleukodystrophy with a novel ABCD1 gene mutation.

    Science.gov (United States)

    Li, Jie-Yuan; Hsu, Chia-Chi; Tsai, Chi-Ren

    2010-03-15

    X-linked adrenoleukodystrophy (X-ALD) shows a wide range of phenotypic expression, and clinical presentation as adult-onset spinocerebellar ataxia has been rarely reported. Here, we report a Taiwanese family with X-ALD. The proband, a 37-year-old man presented with dysarthria, cerebellar ataxia and mild spastic paraparesis, and had atrophy of cerebellum and upper cervical cord on MRI. One of his nephews, a 9-year-old boy had a classic childhood cerebral ALD phenotype. This family harbors a novel deletion of 1 base pair in exon 8 at nucleotide position 2245 (2245delA) in the ABCD1 gene. This is the first report of the 2245delA mutation presenting with a spinocerebellar variant of X-ALD.

  15. Desregulación del sistema endocannabionoide en las ataxias espinocerebelosas

    OpenAIRE

    Rodríguez Cueto, Carmen Aurora

    2016-01-01

    Las ataxias espinocerebelosas autosómicas dominantes SCAs son un grupo de enfermedades neurodegenerativas clínica y genéticamente heterogéneas, que se caracterizan por la pérdida de equilibrio y coordinación motora debido a la disfunción del cerebelo y de sus conexiones aferentes y eferentes. Hasta el momento se conocen 36 subtipos de SCAs siendo las más prevalentes las que se deben a la presencia de mutaciones que producen la expansión del triplete CAG en la región codificante de genes esp...

  16. 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. ...

  17. SCA13 causes dominantly inherited non-progressive myoclonus ataxia.

    Science.gov (United States)

    Montaut, Solveig; Apartis, Emmanuelle; Chanson, Jean-Baptiste; Ewenczyk, Claire; Renaud, Mathilde; Guissart, Claire; Muller, Jean; Legrand, André Pierre; Durr, Alexandra; Laugel, Vincent; Koenig, Michel; Tranchant, Christine; Anheim, Mathieu

    2017-05-01

    Spinocerebellar ataxia 13 (SCA13) is a rare autosomal dominant cerebellar ataxia. To our knowledge, its association to movement disorders has never been described. We aimed at reporting 8 new SCA13 cases with a focus on movement disorders especially myoclonus. We performed a detailed neurological examination and neurophysiological recording in 8 patients consecutively diagnosed with SCA13 between December 2013 and October 2015 and followed up in two French tertiary centers. We identified mild subcortical myoclonus in all patients, with a homogenous clinical and electrophysiological pattern. Myoclonus ataxia was very slowly progressive, like the other symptoms of the disease, whatever the age of onset. Patients with R423H mutation had an earlier age of onset than patients with R420H mutation. Myoclonus appears to be frequent in SCA13. SCA13 should be considered facing non-progressive autosomal dominant myoclonus ataxia, and polymyographic recording should be included in the diagnosis work. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Genotyping and prenatal diagnosis of a large spinocerebellar ataxia ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... Electrocardiography and chest X-ray films showed no abnormalities in heart and lungs. Pedigree. The III11, III13, III17 and III18 had similar symptoms. The pedigree has five generations and 199 members. (figure 1). There were 30 individuals affected with SCA in this pedigree, and 13 of them are alive.

  19. Genotyping and prenatal diagnosis of a large spinocerebellar ataxia ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... Amniotic fluid culture conditions and treatment. One of the fifth generation member, a 25-year-old female, was assessed during the early stages of pregnancy. She was identified as a presymptomatic carrier by previous work and this couple had received genetic counselling at our medi- cal centre, the No.

  20. Friedreich's Ataxia

    Science.gov (United States)

    ... the genetics of Friedreich's ataxia are leading to breakthroughs in treatment. Research has moved forward to the point where clinical ... be involved in the disease process, and explore new therapeutic approaches for ... disorders or research programs funded by the National Institute of Neurological ...

  1. Speech changes after coordinative training in patients with cerebellar ataxia: a pilot study

    Czech Academy of Sciences Publication Activity Database

    Tykalová, T.; Pospíšilová, M.; Čmejla, R.; Jeřábek, J.; Mareš, Pavel; Rusz, J.

    2016-01-01

    Roč. 37, č. 2 (2016), s. 293-296 ISSN 1590-1874 Institutional support: RVO:67985823 Keywords : spinocerebellar ataxia * rehabilitation * physiotherapy * ataxic dysarthria * postural alignment * acoustic analysis Subject RIV: FH - Neurology Impact factor: 1.749, year: 2016

  2. Spinocerebellar ataxia type 7 (SCA7: family princeps’ history, genealogy and geographical distribution Ataxia espinocerebelar do tipo 7 (AEC7: história, genealogia e distribuição geográfica da família princeps

    Directory of Open Access Journals (Sweden)

    Salomão da Cunha Linhares

    2006-06-01

    Full Text Available We conducted a 320 year retrospective survey of the history and genealogy of a large Brazilian family with SCA7. The ancestral couple was from the State of Ceará, Brazil, and the genealogical tree was composed of 577 individuals, including 217 males (37.6%, 255 females (44.1% and 105 individuals of unknown sex (18.1%. Based on collected information, the 118 individuals consistently affected were distributed in generations IV (n=2, V (n=28, VI (n=57, VII (n=25 and VIII (n=6 of the genealogical tree. Sixty affected members are alive, 37 of them (61.6% live in the Northeast region, 12 (20% in the Southeast, 9 (15% in the Center-West and 2 (3.3% in the North. This genealogical survey was based only on 4 of the 10 children of the ancestral couple since the destiny of the remaining 6 is unknown. We propose that other Brazilian families with SCA7 may have the same genetic origin.Avaliamos retrospectivamente 320 anos da história e da genealogia de uma família brasileira portadora de ataxia espinocerebelar do tipo 7 (AEC7. O casal ancestral é oriundo do Estado do Ceará e a árvore genealógica foi composta de 577 indivíduos, sendo 217 do sexo masculino (37,6%, 255 do sexo feminino (44,1% e 105 de sexo ignorado (18,1%. Até o presente momento, 118 indivíduos foram acometidos, distribuídos nas gerações IV (n=2, V (n=28, VI (n=57, VII (n=25 e VIII (n=6 da árvore genealógica. Entre os doentes atualmente vivos (n=60, 37 deles (61,6% encontram-se na região Nordeste, 12 (20% na região Sudeste, 9 (15% na região Centro-Oeste e 2 (3,3% na região Norte. Uma vez que a reconstituição da árvore genealógica foi baseada em apenas 4 dos 10 filhos do casal ancestral devido ao desconhecimento do destino dos outros 6, levantamos a hipótese de que outras famílias brasileiras com AEC7 possam ter a mesma origem genética.

  3. 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

  4. 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 ...

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

    Science.gov (United States)

    Saghazadeh, Amene; Hafizi, Sina; Hosseini, Firouzeh; Ashrafi, Mahmoud Reza; Rezaei, Nima

    2017-02-01

    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.

  6. [A sporadic case of episodic ataxia with nystagmus (EA-2)].

    Science.gov (United States)

    Namekawa, M; Takiyama, Y; Ueno, N; Nishizawa, M

    1998-05-01

    A 39-year-old man with episodic ataxia with nystagmus (EA-2) was reported. He showed intermittent cerebellar dysfunction, i.e., ataxia, nystagmus, dysarthria and vertigo, since he was 10 years old. Although this attack lasted for several hours, he was normal with exception of interictal nystagmus. His parents and sister showed no episodic ataxia. We ruled out the diseases, which may cause episodic ataxia, such as multiple sclerosis, vascular disorders, metabolic disorders and congenital anomalies. He was released from the attack by treatment with acetazolamide. EA-2 has been associated with mutations in the alpha 1A-voltage dependent calcium channel gene (CACNL1A4), which is also affected in familial hemiplegic migraine (FMH) and spinocerebellar ataxia type 6 (SCA6). In EA-2, frame-shift mutation leading to premature stop and splice-site mutation leading to truncated, non-functional channel protein have been reported. However, our patient did not have the mutations in the CACNL1A4 gene that were previously reported. In addition, our patient did not have an expanded CAG allele in the CACNL1A4 gene which is responsible for SCA6. Further examination is required to address whether a new mutation exists in the CACNL1A4 gene in our patient.

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

    Science.gov (United States)

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

    2012-11-13

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

  8. Autosomal recessive cerebellar ataxias

    Directory of Open Access Journals (Sweden)

    Palau Francesc

    2006-11-01

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

  9. Clinical neurogenetics: friedreich ataxia.

    Science.gov (United States)

    Collins, Abigail

    2013-11-01

    Friedreich ataxia is the most common autosomal recessive ataxia. It is a progressive neurodegenerative disorder, typically with onset before 20 years of age. Signs and symptoms include progressive ataxia, ascending weakness and ascending loss of vibration and joint position senses, pes cavus, scoliosis, cardiomyopathy, and arrhythmias. There are no disease-modifying medications to either slow or halt the progression of the disease, but research investigating therapies to increase endogenous frataxin production and decrease the downstream consequences of disrupted iron homeostasis is ongoing. Clinical trials of promising medications are underway, and the treatment era of Friedreich ataxia is beginning. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. 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 ...

  11. 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

  12. [Voluntary postural control learning with a use of visual bio-feedback in patients with spinocerebellar degenerations].

    Science.gov (United States)

    Ustinova, K I; Ioffe, M E; Chernikova, L A; Kulikov, M A; Illarioshkin, S N; Markova, E D

    2004-01-01

    The study aimed at evaluation of possibility and features of voluntary postural control learning using biofeedback from a force platform in patients with spinocerebellar ataxias. Thirty-seven patients with different forms of spinocerebellar degenerations and 13 age-matched healthy subjects were trained to shift the center of pressure (CP) during several stabilographic computer games which tested an ability to learn 2 different types of voluntary postural control: general strategy and precise coordination of CP shifting. Despite the disturbances of static posture and ability for voluntary control of CP position, patients with spinocerebellar degenerations can learn to control a vertical posture using biofeedback on stabilogram. In contrast to healthy subjects, improvement of coordination in the training process does not exert a significant influence on the static posture characteristics, in particular on lateral CP oscillations. The results obtained suggest involvement of the cerebellum in both types of postural control that distinguishes them from pathology caused by motor cortex and nigro-striatal system involved only in one type of postural control.

  13. Paraneoplastic cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma.

    Science.gov (United States)

    Fancellu, Roberto; Corsini, Elena; Bernardi, Giorgio; Buzzo, Paolo; Ferrari, Maria Luisa; Lamantea, Eleonora; Garaventa, Alberto; Truini, Mauro; Salvarani, Sandro

    2014-01-01

    We describe a case of cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma. A 28-year-old woman developed progressive ataxia with hyporeflexia at the age of 19. Brain MRI showed progressive cerebellar atrophy. Neurophysiological studies, screening of immune-mediated ataxias, oncological markers, vitamin E and genetic tests for spinocerebellar ataxia types 1,2,3, Friedreich ataxia and POLG1 were negative. Anti-Hu antibodies were positive in Western blot and indirect immunofluorescence (1:640). Total-body computed tomography revealed a mediastinum mass; the histological diagnosis was maturing ganglioneuroma. Immunohistochemistry showed a mild reaction between the tumor and the patient's serum, and no reaction between the tumor and control serum. After surgery, serum anti-Hu titer decreased, while ataxic symptoms initially worsened and then stabilized. Ganglioneuroma is a benign tumor, usually derived from the maturation of a neuroblastoma. The benign histology and the presence of anti-Hu antibodies could be related to the positive oncological prognosis and to the slow clinical course mimicking a degenerative ataxia.

  14. 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

  15. Timing Errors in Two Children with Suspected Childhood Apraxia of Speech (sCAS) during Speech and Music-Related Tasks

    Science.gov (United States)

    Peter, Beate; Stoel-Gammon, Carol

    2005-01-01

    Impaired speech prosody has been identified as a critical feature of suspected childhood apraxia of speech (sCAS). Lexical stress productions of children with sCAS have been characterized as 'excessive/equal/misplaced'. This investigation examines two potential explanations of this particular deficit, articulatory difficulty and impaired intrinsic…

  16. Retrospective Parent Report of Early Vocal Behaviours in Children with Suspected Childhood Apraxia of Speech (sCAS)

    Science.gov (United States)

    Highman, Chantelle; Hennessey, Neville; Sherwood, Mellanie; Leitao, Suze

    2008-01-01

    Parents of children with suspected Childhood Apraxia of Speech (sCAS, n = 20), Specific Language Impairment (SLI, n = 20), and typically developing speech and language skills (TD, n = 20) participated in this study, which aimed to quantify and compare reports of early vocal development. Via a questionnaire, parents reported on their child's early…

  17. Genetics Home Reference: episodic ataxia

    Science.gov (United States)

    ... 5 links) Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) GeneReview: Episodic Ataxia Type 1 GeneReview: Episodic ... MG. Episodic ataxia type 1: a neuronal potassium channelopathy. Neurotherapeutics. 2007 Apr;4(2):258-66. Review. ...

  18. 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

  19. Progressive dysarthria and ataxia

    African Journals Online (AJOL)

    Progressive dysarthria and ataxia. Lynsey McAlpinea, Fiona Cranb, Eluzai Hakimc a FY1 Stroke and Rehabilitation Medicine, St Mary's Hospital, Isle of Wight. b GPVST Stroke and Rehabilitation Medicine, St Mary's Hospital, Isle of Wight. c Consultant Physician Stroke and Rehabilitation Medicine, St Mary's Hospital, Isle of ...

  20. Principles and models of a co-operative systems of a supervision aid; SCAS: principes et modeles d`un systeme cooperatif d`assistance a la supervision

    Energy Technology Data Exchange (ETDEWEB)

    Penalva, J.M. [CEA Centre d`Etudes de la Vallee du Rhone, 30 - Marcoule (France). Dept. d`Exploitation du Retraitement et de Demantelement; Cases, E. [CEA Centre d`Etudes de la Vallee du Rhone, 30 - Marcoule (France). Dept. d`Exploitation du Retraitement et de Demantelement]|[Paris-6 Univ., 75 (France); Brezillon, P. [Paris-6 Univ., 75 (France); Minault, S.

    1994-12-31

    This paper presents the functioning principles and the necessary models for a cooperative system of supervision aid (SCAS) used for a high-automated workshop. A meta-system of supervision is made up of the operator and the SCAS. The SCAS can operate under 2 different modes: wakefulness and cooperation. On the first one the behaviours of the process and the operator is observed and analysed. On the second one, it helps to solve the problems occurred by the operator. (TEC). 3 refs.

  1. 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.

  2. 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 ...

  3. 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

    morphology in SCA2 patient fibroblasts compared to controls, and we show that treatment with CoQ10 can partially reverse these changes. Together, our results suggest that oxidative stress and mitochondrial dysfunction may be contributory factors to the pathophysiology of SCA2 and that therapeutic strategies...

  4. Spinocerebellar ataxia type 3/Machado-Joseph disease starting before adolescence

    NARCIS (Netherlands)

    Donis, Karina Carvalho; Saute, Jonas Alex Morales; Krum-Santos, Ana Carolina; Furtado, Gabriel Vasata; Mattos, Eduardo Preusser; Saraiva-Pereira, Maria Luiza; Torman, Vanessa Leotti; Jardim, Laura Bannach

    Onset of Machado-Joseph disease (SCA3/MJD) before adolescence has been rarely reported. This study aims to describe a cohort of SCA3/MJD with onset before 12 years of age, comparing their disease progression with the progression observed in patients with usual disease onset. We identified all cases

  5. Degeneration of the external cuneate nucleus in spinocerebellar ataxia type 3 (Machado-Joseph disease)

    NARCIS (Netherlands)

    Rub, U; de Vos, RAI; Brunt, ER; Schultz, C; Paulson, H; Del Tredici, K; Braak, H

    2002-01-01

    Owing to its anatomical connections, the external cuneate nucleus (ECU) plays a crucial role in processing proprioceptive input from the upper trunk and upper limbs. Here, we studied this dorsal column nucleus post-mortem in five individuals with clinically diagnosed and genetically confirmed

  6. Polyglutamine aggregation in Huntington's disease and spinocerebellar ataxia type 3 : similar mechanisms in aggregate formation

    NARCIS (Netherlands)

    Seidel, K.; Siswanto, S.; Fredrich, M.; Bouzrou, M.; Brunt, E. R.; van Leeuwen, F. W.; Kampinga, H. H.; Korf, H. -W.; Rueb, U.; den Dunnen, W. F. A.

    AimsPolyglutamine (polyQ) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease-specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (PQC) system, consisting of chaperone-mediated refolding as well

  7. Ocular-motor profile and effects of memantine in a familial form of adult cerebellar ataxia with slow saccades and square wave saccadic intrusions.

    Directory of Open Access Journals (Sweden)

    Francesca Rosini

    Full Text Available Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI and macrosaccadic oscillations (MSO. A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI. We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°-18° and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly, but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich's, in which saccadic intrusions are prominent.

  8. 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

  9. CT scanning of the brain and lumber CSF monoamine metabolites in spinocerebellar degenerative disorders

    International Nuclear Information System (INIS)

    Sasaki, Hidenao; Kanazawa, Ichiro; Nakanishi, Takao; Kuramoto, Kenmei

    1984-01-01

    Eight patients with parenchymatous cerebellar degeneration (PCD) group (3 with late cortical cerebellar atrophy and 5 with Holmes' hereditary ataxia), 14 with olivo-ponto-cerebellar atrophy (OPCA) group (4 with Shy-Drager syndrome, 6 with OPCA without family history and 4 with Menzel type SCS), 15 with Parkinson's disease and 44 control with other neurological diseases were studied. In all the spinocerebellar degenerative disorder s (SCD) cases, CVI values corresponding to the cerebellar atrophy were definitely reduced. On the other hand, PVI values corresponding to the pontine atrophy were only significantly decreased in OPCA group. However, since there were several cases showing only questionable pontine atrpphy, it seems difficult to clearly differentiate individual OPCA cases from other SCD cases on CT films alone. Concerning monoamine metabolites in CSF, it was noted that a significant reduction of HVA and total MHPG was found in the OPCA group. Among them, the patients with overt autonomic failure showed the lowest HVA level and the cases of Menzel type of SCD showed a slight reduction of HVA but an unexpected elevation of free MHPG values. The cases of Parkinson's disease showed a definite reduction of HVA. On the other hand, the cases of PCD group showed no significant difference against controls. 5-HIAA levels were not significantly different among the SCD subgroups. (J.P.N.)

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    Satya Prakash

    2008-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Fujioka Shinsuke

    2013-01-01

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

  13. 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

  14. Genetics Home Reference: Friedreich ataxia

    Science.gov (United States)

    ... Resources (9 links) Ataxia UK Brain Foundation (Australia) Christopher and Dana Reeve Paralysis Resource Center European Federation ... Institutes of Health National Library of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville Pike, ...

  15. Ataxia telangiectasia: a review

    Directory of Open Access Journals (Sweden)

    Cynthia Rothblum-Oviatt

    2016-11-01

    Full Text Available Abstract Definition of the disease Ataxia telangiectasia (A-T is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome. Epidemiology The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births. Clinical description A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations. Etiology A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress. Diagnosis The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels. Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the

  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. Neurophysiological studies and non-motor symptoms prior to ataxia in a patient with machado-joseph disease: trying to understand the natural history of brain degeneration.

    Science.gov (United States)

    Pedroso, José Luiz; Bor-Seng-Shu, Edson; Braga-Neto, Pedro; Ribeiro, Rodrigo Souza; Bezerra, Márcio Luiz Escorcio; do Prado, Lucila B F; Batista, Ilza Rosa; Alessi, Helena; Teixeira, Manoel Jacobsen; Manzano, Gilberto Mastrocola; do Prado, Gilmar Fernandes; Barsottini, Orlando Graziani Povoas

    2014-08-01

    Spinocerebellar ataxia type 3 or Machado-Joseph disease is the most common spinocerebellar ataxia. In this neurological disease, anatomical, physiological, clinical, and functional neuroimaging demonstrate a degenerative process besides the cerebellum. We performed neurophysiological and neuroimaging studies-polysomnography, transcranial sonography, vestibular-evoked myogenic potential, single-photon emission computed tomography (SPECT) with (99m)Tc-TRODAT-1, and a formal neuropsychological evaluation in a patient with sleep complaints and positive testing for Machado-Joseph disease, without cerebellar atrophy, ataxia, or cognitive complaints. Polysomnography disclosed paradoxical high amplitude of submental muscle, characterizing REM sleep without atonia phenomenon. Transcranial sonography showed hyperechogenicity of the substantia nigra. There was an absence of vestibular-evoked myogenic potentials on both sides in the patient under study, in opposite to 20 healthy subjects. Brain imaging SPECT with (99m)Tc-TRODAT-1 demonstrated a significant lower DAT density than the average observed in six healthy controls. Electroneuromyography was normal. Neuropsychological evaluation demonstrated visuospatial and memory deficits. Impairment of midbrain cholinergic and pontine noradrenergic systems, dysfunction of the pre-synaptic nigrostriatal system, changes in echogenicity of the substantia nigra, and damage to vestibulo-cervical pathways are supposed to occur previous to cerebellar involvement in Machado-Joseph disease.

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    Yubin Wang

    2016-06-01

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

  20. Properties of bilateral spinocerebellar activation of cerebellar cortical neurons

    Directory of Open Access Journals (Sweden)

    Pontus eGeborek

    2014-10-01

    Full Text Available We aimed to explore the cerebellar cortical inputs from two spinocerebellar pathways, the spinal border cell-component of the ventral spinocerebellar tract (SBC-VSCT and the dorsal spinocerebellar tract (DSCT, respectively, in the sublobule C1 of the cerebellar posterior lobe. The two pathways were activated by electrical stimulation of the contralateral lateral funiculus (coLF and the ipsilateral LF (iLF at lower thoracic levels. Most granule cells in sublobule C1 did not respond at all but part of the granule cell population displayed high-intensity responses to either coLF or iLF stimulation. As a rule, Golgi cells and Purkinje cell simple spikes responded to input from both LFs, although Golgi cells could be more selective. In addition, a small population of granule cells responded to input from both the coLF and the iLF. However, in these cases, similarities in the temporal topography and magnitude of the responses suggested that the same axons were stimulated from the two LFs, i.e. that the axons of individual spinocerebellar neurons could be present in both funiculi. This was also confirmed for a population of spinal neurons located within known locations of SBC-VSCT neurons and dorsal horn DSCT neurons. We conclude that bilateral spinocerebellar responses can occur in cerebellar granule cells, but the VSCT and DSCT systems that provide the input can also be organized bilaterally. The implications for the traditional functional separation of VSCT and DSCT systems and the issue whether granule cells primarily integrate functionally similar information or not are discussed.

  1. Effect of sulfate on the liquidus and sulfur concentration at anhydrite saturation (SCAS) of hydrous basalt at subduction zones

    Science.gov (United States)

    Chowdhury, P.; Dasgupta, R.

    2017-12-01

    Sulfur (S) as sulfide minerals, melts, and as S2- species in silicate melts is prevalent in many different tectono-magmatic settings in Earth. Yet, S as anhydrite or as SO42- species in fluids and melts is thought to be relevant for subduction zones, where the presence of sulfate over sulfide is argued to play a key role in processes such as mobility of chalcophile element [e.g., 1], oxidation of mantle and mantle-derived magmas [2], and release of excess S-rich gases [3]. However, it remains unclear what role the slab-released SO42-, dissolved in fluids or melts plays in magma genesis in sub-arc mantle. Furthermore, although oxidized arc magma is thought to transport SO42- from mantle to volcanic arc crust and atmosphere, the SO42- carrying capacity of arc basalts at mantle conditions are unknown as the existing S concentration at anhydrite saturation (SCAS) experiments are restricted to 1 GPa and mostly on felsic compositions [e.g. 4,5]. We performed piston-cylinder experiments in Au-Pd capsules at 1-3 GPa and 1000-1325 °C to investigate (a) the effect of variable dissolved SO42- (0-2 wt.% S) on the liquidus of a primary hydrous arc basalt with 4 wt.% H2O and (b) the SCAS of hydrous mafic magmas. Dissolved SO42- in the silicate melt was confirmed by S Kα X-ray peak position using electron microprobe. S-free hydrous liquidus of cpx at 2 GPa is 25 °C hotter than the liquidus with 0.1 wt.% S as SO42- and the liquidus depression with further S enrichment to anhydrite saturation ( 2 wt.% S) can be fitted by an empirical power function. Experiments on more mafic compositions show that SCAS increases with increasing temperature and CaO and decreases with SiO2. Calculations using a new SCAS model, fitted with our new data and previous experiments, and assuming 150-550 ppm S in the arc mantle [6] show that <10% melting would exhaust anhydrite, if present. The S content as SO42- of hydrous arc basalts produced by 10-20% melting [7] will be 500-4000 ppm, which is

  2. Friedreich Ataxia in Classical Galactosaemia.

    Science.gov (United States)

    Neville, Siobhán; O'Sullivan, Siobhan; Sweeney, Bronagh; Lynch, Bryan; Hanrahan, Donncha; Knerr, Ina; Lynch, Sally Ann; Crushell, Ellen

    2016-01-01

    Movement disorders such as ataxia are a recognized complication of classical galactosaemia, even in diet-compliant patients. Here, we report the coexistence of classical galactosaemia and Friedreich ataxia (FRDA) in nine children from seven Irish Traveller families. These two autosomal recessive disorders, the loci for which are located on either side of the centromere of chromosome 9, appear to be in linkage disequilibrium in this subgroup. Both conditions are known to occur with increased frequency amongst the Irish Traveller population.Each member of our cohort had been diagnosed with galactosaemia in the neonatal period, and all are homozygous for the common Q188R mutation in the GALT gene. Eight of the nine patients later presented with progressive ataxia, between the ages of 5-13 years. Another child presented in cardiac failure secondary to dilated cardiomyopathy at 7 years of age. He was not ataxic at presentation and, one year from diagnosis, his neurological examination remains normal. The diagnosis of FRDA was confirmed by detecting the common pathogenic GAA expansion in both alleles of the frataxin gene (FXN) in each patient.Neurological symptoms are easily attributed to an underlying diagnosis of galactosaemia. It is important to consider a diagnosis of Friedreich ataxia in a child from the Irish Traveller population with galactosaemia who presents with ataxia or cardiomyopathy.

  3. 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

  4. 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

  5. Falls and cerebellar ataxia

    Directory of Open Access Journals (Sweden)

    I. V. Damulin

    2015-01-01

    Full Text Available The paper considers the main causes of falls. Whatever their cause is, falls may lead to severe maladjustment in everyday life. In nearly 1 out of 10 cases, they are accompanied by severe injuries, including fractures (most commonly those of the proximal femur and humerus, hands, pelvic bones, and vertebrae, subdural hematoma, and severe soft tissue and head injuries. This process is emphasized to be multifactorial. Particular emphasis is laid on the involvement of the cerebellum and its associations, which may be accompanied by falls. This is clinically manifested mainly by gait disorders. Walking is a result of an interaction of three related functions (locomotion, maintenance of balance and adaptive reactions. In addition to synergies related to locomotion and balance maintenance, standing at rest and walking are influenced bythe following factors: postural and environmental information (proprioceptive, vestibular, and visual, the capacity to interpret and integrate this information, the ability of the musculoskeletal system to make movements, and the capability to optimally modulate these movements in view of the specific situation and the ability to choose and adapt synergy in terms of external factors and the capacities and purposes of an individual. The clinical signs of damage to the cerebellum and its associations are considered in detail. These structures are emphasized to be involved not only in movements, but also in cognitive functions. The major symptoms that permit cerebellar dysfunction to be diagnosed are given. Symptoms in cerebellar injuries are generally most pronounced when suddenly changing the direction of movements or attempting to start walking immediately after a dramatic rise. The magnitude of ataxia also increases in a patient who tries to decrease the step size. Falling tendencies or bending to one side (in other symptoms characteristic of cerebellar diseases suggest injury of the corresponding

  6. Movement disorders in hereditary ataxias.

    Science.gov (United States)

    Garcia Ruiz, Pedro J; Mayo, David; Hernandez, Jaime; Cantarero, Susana; Ayuso, Carmen

    2002-10-15

    Movement disorders are well known features of some dominant hereditary ataxias (HA), specially SCA3/Machado-Joseph disease and dentatorubropallidolusyan atrophy. However, little is known about the existence and classification of movement disorders in other dominant and recessive ataxias. We prospectively studied the presence of movement disorders in patients referred for HA over the last 3 years. Only those patients with a confirmed family history of ataxia were included. We studied 84 cases of HA, including 46 cases of recessive and 38 cases of dominant HA. Thirty out of 46 cases of recessive HA could be classified as: Friedreich ataxia (FA), 29 cases; vitamin E deficiency, 1 case. Twenty-three out of 38 cases of dominant HA could be classified as: SCA 2, 4 cases; SCA 3, 8 cases; SCA 6, 4 cases; SCA 7, 6 cases and SCA 8, 1 case. We observed movement disorders in 20/38 (52%) patients with dominant HA and 25/46 (54%) cases with recessive HA, including 16 patients (16/29) with FA. In general, postural tremor was the most frequent observed movement disorder (27 cases), followed by dystonia (22 cases). Five patients had akinetic rigid syndrome, and in 13 cases, several movement disorders coexisted. Movement disorders are frequent findings in HA, not only in dominant HA but also in recessive HA. Copyright 2002 Elsevier Science B.V.

  7. 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…

  8. 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.

  9. 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

  10. Location of the spinal cerebellar ataxia 2 locus to a 1 cM interval on chromsome 12q23-24.1

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-09-01

    Spinocerebellar ataxia 2 (SCA2) is a dominantly inherited neurodegenerative disorder characterised by progressive ataxia, dysarthria, dysmetria and dysdiadochokinesia. We have previously assigned the disease locus to chromosome 12q23-24.1 in a population from the Holguin province, Cuba, within a 31 cM interval flanked by the anonymous marker D12S53 and the phospholipase A2 gene (PLA2). Clinical as much as genealogical and geographical evidence indicate that the Cuban pedigrees are homogeneous and descend from a common ancestor. We now report fine genetic mapping of the disease locus with fourteen microsatellite loci known to span this region, which positions SCA2 in a 1 cM interval defined by the loci D12S84-AFM291xe9. Observation of a common haplotype segregating with the disease supports the existence of a founder effect in the Holguin pedigrees.

  11. [Acute benign ataxia in childhood].

    Science.gov (United States)

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

    1979-01-01

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

  12. PET Study in a Patient with Spinocerebellar Degeneration before and after Long-Term Administration of Thyrotropin Releasing Hormone

    Directory of Open Access Journals (Sweden)

    H. Tanji

    1996-01-01

    Full Text Available We studied the chronic effect of thyrotropin releasing hormone (TRH in a patient with spinocerebellar degeneration by measuring cerebral metabolic rate for glucose (CMRG1c using 2-[18F]fluoro-2-deoxy-D-glucose (18FDG and positron emission tomography (PET. A 56-year-old female, who had suffered from progressive ataxia for 2 years, was treated by intravenous administration of 2 mg TRH for 3 weeks, and CMRG1c of the brain was measured before and after treatment. CMRG1c was markedly decreased in the cerebellum and there was no significant difference before and after the treatment, i.e. mean CMRG1c values were 4.92 and 4.90 mg/100 g/min, and the ratios of the cerebellum versus the frontal cortex were 0.50 and 0.51, respectively. The degree of disequilibrium of her body examined with stabilography became better by the 19th day and further improved by the 26th day after the start of TRH treatment. Based on the present study we conclude that long-term administration of TRH did not improve CMRG1c in the cerebellum, but evidently improved the sway of gravity center by stabilography. We speculate that the chronic effect of TRH was not necessarily due to an improvement of cerebellar function, because TRH receptors are widely distributed throughout the central nervous system.

  13. Recurrent Ataxia in Children and Adolescents.

    Science.gov (United States)

    Salman, Michael S; Klassen, Samantha F; Johnston, Janine L

    2017-07-01

    Recurrent ataxia is encountered infrequently in clinical pediatric neurology practise and presents with diagnostic challenges. It is caused by several disorders. Our aims were to describe the epidemiology and clinical features in children with recurrent ataxia. A retrospective review was undertaken in 185 children with chronic ataxia, who presented during 1991 to 2008. Several databases were searched to ensure optimum ascertainment. Patients with brain tumors or isolated disorders of the peripheral nerves or vestibular system were excluded. Recurrent ataxia was reported in 21 patients. Their age range was between 6 and 32.75 years (males=12). The crude period prevalence rate for the 18-year study period was 7.44/100,000. Eight patients had episodic ataxia and seven had inflammatory and metabolic disorders. In the rest the etiology was unknown. Many patients presented with ataxia, dizziness, and vertigo. The frequency and duration of the ataxic episodes varied from several per day to one every few months. Other clinical features included developmental delay and seizures. Neuroimaging in episodic ataxia was normal and abnormal in inflammatory or metabolic disorders. Acetazolamide provided symptomatic relief in patients with episodic ataxia, while steroids were beneficial in patients with an inflammatory etiology. One child with a metabolic disorder died. Recurrent ataxia is an uncommon presentation in children and mortality is rare. Genetic, metabolic, and inflammatory disorders should be considered in these patients. Neuroimaging is essential. Acetazolamide in selected patients provides good symptomatic relief.

  14. 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 ...

  15. Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A.

    Science.gov (United States)

    García Segarra, Nuria; Gautschi, Ivan; Mittaz-Crettol, Laureane; Kallay Zetchi, Christine; Al-Qusairi, Lama; Van Bemmelen, Miguel Xavier; Maeder, Philippe; Bonafé, Luisa; Schild, Laurent; Roulet-Perez, Eliane

    2014-07-15

    Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel Ca(V)2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant Ca(V)2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. 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...

  17. 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...

  18. Radiosensitivity in ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Lavin, M.F.; Khanna, K.K.; Watters, D.

    1998-01-01

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

  19. 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.

  20. 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

  1. 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.

  2. Genes and Genetic Testing in Hereditary Ataxias

    Directory of Open Access Journals (Sweden)

    Erin Sandford

    2014-07-01

    Full Text Available 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.

  3. Levels of DNAJB family members (HSP40) correlate with disease onset in patients with spinocerebellar ataxia type 3

    NARCIS (Netherlands)

    Zijlstra, M. P.; Rujano, M. A.; Van Waarde, M. A.; Vis, E.; Brunt, E. R.; Kampinga, H. H.

    In polyglutamine disorders, the length of the expanded CAG repeat shows a strong inverse correlation with the age at disease onset, yet up to 50% of the variation in age of onset is determined by other additional factors. Here, we investigated whether variations in the expression of heat shock

  4. A Novel TTBK2 De Novo Mutation in a Danish Family with Early-Onset Spinocerebellar Ataxia

    DEFF Research Database (Denmark)

    Lindquist, Suzanne Granhøj; Møller, Lisbeth Birk; Dali, Christine I.

    2017-01-01

    examined. Exome sequencing was performed and a "movement disorders" gene panel consisting of approximately 200 genes was used for filtering, while Sanger sequencing was used for subsequent testing for the mutation in the family. Onset of symptoms in affected family members was in early childhood. A novel...

  5. Eye Position Feedback in a Model of the Vestibulo-Ocular Reflex for Spino-Cerebellar Ataxia 6

    National Research Council Canada - National Science Library

    Anderson, J

    2001-01-01

    ..., incoordination, ocular motor dysfunction, and dysarthria due to degeneration of cerebellar and brainstem neurons. Recent studies have established that there are more than 16 genetically distinct subtypes...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    , SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of genomically integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vitro and retained the disease-causing ATXN3 mutation. This iPSC line...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    -MYC, LIN28, SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vitro and retained the disease-causing ATXN3 mutation. Potentially, this i......PSC line could be a useful tool for the investigation of SCA3 disease mechanisms....

  8. 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.

  9. Aspectos moleculares das ataxias espinocerebelares autossomicas recessivas

    OpenAIRE

    Flavia Chagas Costa

    2000-01-01

    Resumo: As ataxias espinocerebelares (ABC) formam um grupo heterogêneo de doenças degenerativas que envolvem o sistema nervoso central. Esse grupo se caracteriza clinicamente por apresentar disfunção cerebelar manifestada por ataxia de marcha, incoordenação e disartria. Nos casos familiares, o padrão de herança é variável, podendo ser compatível com herança autossômica dominante (HAD) ou herança autossômica recessiva (HAR). Para as ataxias espinocerebelares com HAR existem três lócus identifi...

  10. 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.

  11. Origin, course, and laterality of spinocerebellar axons in the North American opossum, Didelphis virginiana.

    Science.gov (United States)

    Terman, J R; Wang, X M; Martin, G F

    1998-08-01

    Spinocerebellar axons have been studied extensively in placental mammals, but there have been no full reports on their origin, laterality, or spinal course in any marsupial. We have used the North American opossum (Didelphis virginiana) to obtain such information and to ask whether any spinocerebellar neurons innervate both the anterior and posterior lobes of the cerebellum through axonal collaterals. To identify spinal neurons that project to the cerebellum, we employed the retrograde transport of Fluoro-Gold (FG) from the anterior lobe, the main target of spinocerebellar axons. In some cases, cerebellar injections of FG were combined with hemisections of the rostral cervical or midthoracic spinal cord, so that laterality of spinocerebellar connections could be established. To determine whether single neurons project to both the anterior lobe and the posterior lobe, injections of Fast Blue (FB) into the anterior lobe were combined with injections of Diamidino yellow (DY) or rhodamine B dextran (RBD) into the posterior lobe, or vice versa. Following injections of FG into the anterior lobe, neurons were labeled throughout the length of the spinal cord, which differed in laminar distribution and laterality of their projections. Among other areas, neurons were labeled in the central cervical nucleus, the nucleus centrobasalis, Clarke's nucleus, the dorsal horn dorsal spinocerebellar tract area, the spinal border region, and Stilling's nucleus. When anterior lobe injections of FB were combined with injections of RBD or DY into the posterior lobe, or vice versa, some double-labeled neurons were present in all major spinocerebellar groups. Cerebellar injections of FG also retrogradely labeled spinocerebellar axons, allowing us to document their locations in the gray matter as well as within the periphery of the lateral and ventral funiculi at all spinal levels. A few spinocerebellar axons also were found in the dorsal funiculus (a dorsal column-spinocerebellar tract

  12. Cerebellar Involvement in Ataxia and Generalized Epilepsy

    NARCIS (Netherlands)

    L. Kros (Lieke)

    2015-01-01

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

  13. [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.

  14. Clinical data and characterization of the liver conditional mouse model exclude neoplasia as a non-neurological manifestation associated with Friedreich’s ataxia

    Directory of Open Access Journals (Sweden)

    Alain Martelli

    2012-11-01

    Friedreich’s ataxia (FRDA is the most common hereditary ataxia in the caucasian population and is characterized by a mixed spinocerebellar and sensory ataxia, hypertrophic cardiomyopathy and increased incidence of diabetes. FRDA is caused by impaired expression of the FXN gene coding for the mitochondrial protein frataxin. During the past ten years, the development of mouse models of FRDA has allowed better understanding of the pathophysiology of the disease. Among the mouse models of FRDA, the liver conditional mouse model pointed to a tumor suppressor activity of frataxin leading to the hypothesis that individuals with FRDA might be predisposed to cancer. In the present work, we investigated the presence and the incidence of neoplasia in the largest FRDA patient cohorts from the USA, Australia and Europe. As no predisposition to cancer could be observed in both cohorts, we revisited the phenotype of the liver conditional mouse model. Our results show that frataxin-deficient livers developed early mitochondriopathy, iron-sulfur cluster deficits and intramitochondrial dense deposits, classical hallmarks observed in frataxin-deficient tissues and cells. With age, a minority of mice developed structures similar to the ones previously associated with tumor formation. However, these peripheral structures contained dying, frataxin-deficient hepatocytes, whereas the inner liver structure was composed of a pool of frataxin-positive cells, due to inefficient Cre-mediated recombination of the Fxn gene, that contributed to regeneration of a functional liver. Together, our data demonstrate that frataxin deficiency and tumorigenesis are not associated.

  15. Impact of presymptomatic genetic testing for hereditary ataxia and neuromuscular disorders.

    Science.gov (United States)

    Smith, Corrine O; Lipe, Hillary P; Bird, Thomas D

    2004-06-01

    With the exception of Huntington disease, the psychological and psychosocial impact of DNA testing for neurogenetic disorders has not been well studied. To evaluate the psychosocial impact of genetic testing for autosomal dominant forms of hereditary ataxia and neuromuscular disorders. Patients Fifty subjects at risk for autosomal dominant forms of spinocerebellar ataxia (n = 11), muscular dystrophy (n = 28), and hereditary neuropathy (n = 12). A prospective, descriptive, observational study in a university setting of individuals who underwent genetic counseling and DNA testing. Participants completed 3 questionnaires before testing and at regular intervals after testing. The questionnaire set included the Revised Impact of Event Scale, the Hospital Anxiety and Depression Scale, demographic information, and an assessment of attitudes and feelings about genetic testing. Thirty-nine subjects (78%) completed 6 months to 5 years of posttest follow-up. Common reasons for pursuing genetic testing were to provide an explanation for symptoms, emotional relief, and information for future planning. Thirty-four (68%) had positive and 16 (32%) had negative genetic results. In those with a positive result, 26 (76%) had nonspecific signs or symptoms of the relevant disorder. Forty-two participants (84%) felt genetic testing was beneficial. Groups with positive and negative test results coped well with results. However, 13 subjects (10 with positive and 3 with negative results) reported elevated anxiety levels, and 3 (1 with positive and 2 with negative results) expressed feelings of depression during the follow-up period. The test result was not predictive of anxiety or depression. Most individuals find neurogenetic testing to be beneficial, regardless of the result. Anxiety or depression may persist in some persons with positive or negative test results. Testing can have a demonstrable impact on family planning and interpersonal relationships. Further studies are needed to

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

    Science.gov (United States)

    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 Netherlands, we sequenced the entire coding region of KCNC3 in 848 Dutch cerebellar ataxia patients with familial or sporadic origin. We evaluated the pathogenicity of the identified variants by co-segregation analysis and in silico prediction followed by biochemical and electrophysiological studies. We identified 19 variants in KCNC3 including 2 non-coding, 11 missense and 6 synonymous variants. Two missense variants did not co-segregate with the disease and were excluded as potentially disease-causing mutations. We also identified the previously reported p.R420H and p.R423H mutations in our cohort. Of the remaining 7 missense variants, functional analysis revealed that 2 missense variants shifted Kv3.3 channel activation to more negative voltages. These variations were associated with early disease onset and mild intellectual disability. Additionally, one other missense variant shifted channel activation to more positive voltages and was associated with spastic ataxic gait. Whereas, the remaining missense variants did not change any of the channel characteristics. Of these three functional variants, only one variant was in silico predicted to be damaging and segregated with disease. The other two variants were in silico predicted to be benign and co-segregation analysis was not optimal or could only be partially confirmed. Therefore, we conclude that we have identified at least one novel pathogenic mutation in KCNC3 that cause SCA13 and two additionally potential SCA13 mutations. This leads to an estimate of SCA13 prevalence in the Netherlands to be between 0.6% and 1.3%. PMID:25756792

  17. Functional analysis helps to define KCNC3 mutational spectrum in Dutch ataxia cases.

    Directory of Open Access Journals (Sweden)

    Anna Duarri

    Full Text Available 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 Netherlands, we sequenced the entire coding region of KCNC3 in 848 Dutch cerebellar ataxia patients with familial or sporadic origin. We evaluated the pathogenicity of the identified variants by co-segregation analysis and in silico prediction followed by biochemical and electrophysiological studies. We identified 19 variants in KCNC3 including 2 non-coding, 11 missense and 6 synonymous variants. Two missense variants did not co-segregate with the disease and were excluded as potentially disease-causing mutations. We also identified the previously reported p.R420H and p.R423H mutations in our cohort. Of the remaining 7 missense variants, functional analysis revealed that 2 missense variants shifted Kv3.3 channel activation to more negative voltages. These variations were associated with early disease onset and mild intellectual disability. Additionally, one other missense variant shifted channel activation to more positive voltages and was associated with spastic ataxic gait. Whereas, the remaining missense variants did not change any of the channel characteristics. Of these three functional variants, only one variant was in silico predicted to be damaging and segregated with disease. The other two variants were in silico predicted to be benign and co-segregation analysis was not optimal or could only be partially confirmed. Therefore, we conclude that we have identified at least one novel pathogenic mutation in KCNC3 that cause SCA13 and two additionally potential SCA13 mutations. This leads to an estimate of SCA13 prevalence in the Netherlands to be between 0.6% and 1.3%.

  18. 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

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

    NARCIS (Netherlands)

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

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

  20. Current concepts in the treatment of hereditary ataxias

    Directory of Open Access Journals (Sweden)

    Pedro Braga Neto

    2016-03-01

    Full Text Available ABSTRACT Hereditary ataxias (HA represents an extensive group of clinically and genetically heterogeneous neurodegenerative diseases, characterized by progressive ataxia combined with extra-cerebellar and multi-systemic involvements, including peripheral neuropathy, pyramidal signs, movement disorders, seizures, and cognitive dysfunction. There is no effective treatment for HA, and management remains supportive and symptomatic. In this review, we will focus on the symptomatic treatment of the main autosomal recessive ataxias, autosomal dominant ataxias, X-linked cerebellar ataxias and mitochondrial ataxias. We describe management for different clinical symptoms, mechanism-based approaches, rehabilitation therapy, disease modifying therapy, future clinical trials and perspectives, genetic counseling and preimplantation genetic diagnosis.

  1. 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.

  2. 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....

  3. 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.

  4. 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.

  5. Genetics Home Reference: ataxia with oculomotor apraxia

    Science.gov (United States)

    ... a common form of ataxia in Portugal and Japan. Type 2 is estimated to occur in 1 ... Reviewed : April 2015 Published : March 6, 2018 The resources on this site should not be used as a ... Department of Health & Human Services National Institutes of Health National Library of ...

  6. 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...

  7. 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.

  8. 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.

  9. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia

    Science.gov (United States)

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

    2017-01-01

    Adrenoleukodystrophy (ALD) is a rare and progressive neurogenetic disease that may manifest disparate symptoms. The present study aims at investigating the role of ataxic variant of ALD (AVALD) in patients with adult-onset cerebellar ataxia, as well as characterizing their clinical features that distinguish AVALD from other cerebellar ataxias. Mutations in the ATP binding cassette subfamily D member 1 gene (ABCD1) were ascertained in 516 unrelated patients with ataxia. The patients were categorized into three groups: molecularly unassigned hereditary ataxia (n = 118), sporadic ataxia with autonomic dysfunctions (n = 296), and sporadic ataxia without autonomic dysfunctions (n = 102). Brain MRIs were scrutinized for white matter hyperintensity (WMH) in the parieto-occipital lobes, frontal lobes, corticospinal tracts, pons, middle cerebellar peduncles and cerebellar hemispheres. Two ABCD1 mutations (p.S108L and p.P623fs) previously linked to cerebral ALD and adrenomyeloneuropathy but not AVALD were identified. ALD accounts for 0.85% (1/118) of the patients with molecularly unassigned hereditary ataxia and 0.34% (1/296) of the patients with sporadic ataxia with autonomic dysfunctions. WMH in the corticospinal tracts and WMH in the cerebellar hemispheres were strongly associated with AVALD rather than other ataxias. To conclude, ALD accounts for approximately 0.39% (2/516) of adult-onset cerebellar ataxias. This study expands the mutational spectrum of AVALD and underscores the importance of considering ALD as a potential etiology of cerebellar ataxia. PMID:28481932

  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. Direct and indirect spino-cerebellar pathways: shared ideas but different functions in motor control

    Directory of Open Access Journals (Sweden)

    Juan eJiang

    2015-07-01

    Full Text Available The impressive precision of mammalian limb movements relies on internal feedback pathways that convey information about ongoing motor output to cerebellar circuits. The spino-cerebellar tracts (SCT in the cervical, thoracic and lumbar spinal cord have long been considered canonical neural substrates for the conveyance of internal feedback signals. Here we consider the distinct features of an indirect spino-cerebellar route, via the brainstem lateral reticular nucleus (LRN, and the implications of this pre-cerebellar ‘detour’ for the execution and evolution of limb motor control. Both direct and indirect spino-cerebellar pathways signal spinal interneuronal activity to the cerebellum during movements, but evidence suggests that direct SCT neurons are mainly modulated by rhythmic activity, whereas the LRN also receives information from systems active during postural adjustment, reaching and grasping. Thus, while direct and indirect spino-cerebellar circuits can both be regarded as internal copy pathways, it seems likely that the direct system is principally dedicated to rhythmic motor acts like locomotion, while the indirect system also provides a means of pre-cerebellar integration relevant to the execution and coordination of de

  12. Rhythmic activity of feline dorsal and ventral spinocerebellar tract neurons during fictive motor actions

    DEFF Research Database (Denmark)

    Fedirchuk, Brent; Stecina, Katinka; Kristensen, Kasper Kyhl

    2013-01-01

    nerves. Spinocerebellar tract cells with cell bodies located in the lumbar segments were identified by electrophysiological techniques and examined by extra- and intracellular microelectrode recordings. During fictive locomotion, 57/81 DSCT and 30/30 VSCT neurons showed phasic, cycle-related activity...

  13. 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.

  14. Hereditary spastic paraplegia with cerebellar ataxia

    DEFF Research Database (Denmark)

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

    2004-01-01

    Complex forms of hereditary spastic paraplegia (HSP) are rare and usually transmitted in an autosomal recessive pattern. A family of four generations with autosomal dominant hereditary spastic paraplegia (AD-HSP) and a complex phenotype with variably expressed co-existing ataxia, dysarthria......, unipolar depression, epilepsy, migraine, and cognitive impairment was investigated. Genetic linkage analysis and sequencing of the SPG4 gene was performed and electrophysiologic investigations were carried out in six individuals and positron emission tomography (PET) in one patient. The disease was linked...... 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...

  15. 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

  16. Pharmacometabolomic signature of ataxia SCA1 mouse model and lithium effects.

    Directory of Open Access Journals (Sweden)

    Bertrand Perroud

    Full Text Available We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1 disease mouse model (Sca1(154Q/+. To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1(154Q/+ mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1(154Q/+ mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1(154Q/+ cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1(154Q/+ mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002, with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1(154Q/+ mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1(154Q/+ mice and restored upon lithium treatment, might relate to lithium neuroprotective properties.

  17. Chronic GM2 gangliosidosis masquerading as atypical Friedreich ataxia: clinical, morphologic, and biochemical studies of nine cases.

    Science.gov (United States)

    Willner, J P; Grabowski, G A; Gordon, R E; Bender, A N; Desnick, R J

    1981-07-01

    A progressive spinocerebellar degenerative disorder was characterized in nine patients, aged 11 to 37 years, from four unrelated Ashkenazi Jewish families; affected individuals had markedly deficient beta-hexosaminidase A activity. Symptoms included early onset of cerebellar signs (tremor, incoordination, and dysarthia) and, with maturity, the development of upper and lower motor neuron disorders, marked dysarthia, and ataxia. Three older patients, aged 26, 32, and 37 years, had dementia or recurrent psychotic episodes. Membrane-bound lamellar cytoplasmic inclusions, consistent with lysosomal ganglioside accumulation, were observed in rectal ganglia. The activity of beta-hexosaminidase A was markedly deficient in all sources analyzed. Parents had activities consistent with heterozygosity, confirming autosomal-recessive transmission of the beta-hexosaminidase A-deficient gene and the adult variant disorder. Residual beta-hexosaminidase A activity, partially purified by anion-exchange chromatography from cultured skin fibroblasts of the affected individuals, was heat-labile and co-electrophoresed with normal beta-hexosaminidase A. These findings suggest that these patients were allelic for a new beta-hexosaminidase A mutation and may represent a genetic compound of this allele and the allele causing Tay-Sachs disease.

  18. 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 ...

  19. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.

    Directory of Open Access Journals (Sweden)

    Tyler Mark Pierson

    2011-10-01

    Full Text Available We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7. Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28, a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2(Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2(Y616C complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other "mitochondrial" features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.

  20. Spinocerebellar degeneration and slow saccades in three generations of a kinship: clinical and electrophysiologic findings

    Directory of Open Access Journals (Sweden)

    Enaytolah Niakan

    1984-09-01

    Full Text Available Four members of a family with spinocerebellar degeneration and slow saccadic eye movements are described. Detailed electrophysiological studies revealed abnormalities of neurological pathways not apparent clinically. The patients had slow saccades as mesasured electrophysiologically, as well as absence of rapid eye movements (REM despite REM stages of sleep. These studies suggest that although saccadic eye movement and REM are mediated through the pontine paramedian reticular formation, other characteristics of REM sleep are not necessarily mediated through the same neurons.

  1. Ataxia caused by amiodarone in older people.

    Science.gov (United States)

    Hindle, J V; Ibrahim, Amin; Ramaraj, Radhakrishnan

    2008-05-01

    Amiodarone is recommended for the cardioversion of atrial fibrillation and prevention of paroxysmal atrial fibrillation in patients with structural heart disease, coronary artery disease or left ventricular dysfunction. It has well-recognised side-effects on the skin, lungs, liver, thyroid and eyes. Neurological side-effects, including ataxia and neuropathy, also occur, and may be more prevalent in older patients. These side-effects are reversible after cessation of amiodarone. Monitoring of amiodarone therapy should include assessment of the central and peripheral nervous system especially in older patients.

  2. 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.

  3. 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

  4. 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…

  5. 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

  6. 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…

  7. Spino-Cerebellar Degeneration, Hormonal Disorder, Hypogonadism, Deaf Mutism and Mental Deficiency

    Science.gov (United States)

    Sylvester, P. E.

    1972-01-01

    Post mortem examinations were done on two adult siblings (one female and one male) who had been clinically described as suffering from mental handicap, deaf mutism, ataxia, hypogonadism, and hormonal disorders. (DB)

  8. Auditory perception in individuals with Friedreich's ataxia.

    Science.gov (United States)

    Rance, Gary; Corben, Louise; Barker, Elizabeth; Carew, Peter; Chisari, Donella; Rogers, Meghan; Dowell, Richard; Jamaluddin, Saiful; Bryson, Rochelle; Delatycki, Martin B

    2010-01-01

    Friedreich's ataxia (FRDA) is an inherited ataxia with a range of progressive features including axonal degeneration of sensory nerves. The aim of this study was to investigate auditory perception in affected individuals. Fourteen subjects with genetically defined FRDA participated. Two control groups, one consisting of healthy, normally hearing individuals and another comprised of subjects with sensorineural hearing loss, were also assessed. Auditory processing was evaluated using structured tasks designed to reveal the listeners' ability to perceive temporal and spectral cues. Findings were then correlated with open-set speech understanding. Nine of 14 individuals with FRDA showed evidence of auditory processing disorder. Gap and amplitude modulation detection levels in these subjects were significantly elevated, indicating impaired encoding of rapid signal changes. Electrophysiologic findings (auditory brainstem response, ABR) also reflected disrupted neural activity. Speech understanding was significantly affected in these listeners and the degree of disruption was related to temporal processing ability. Speech analyses indicated that timing cues (notably consonant voice onset time and vowel duration) were most affected. The results suggest that auditory pathway abnormality is a relatively common consequence of FRDA. Regular auditory evaluation should therefore be part of the management regime for all affected individuals. This assessment should include both ABR testing, which can provide insights into the degree to which auditory neural activity is disrupted, and some functional measure of hearing capacity such as speech perception assessment, which can quantify the disorder and provide a basis for intervention. Copyright 2009 S. Karger AG, Basel.

  9. Ataxia telangiectasia: presentation and diagnostic delay.

    Science.gov (United States)

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

    2017-04-01

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

  10. 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.

  11. 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

    2018-04-01

    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.

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

    Directory of Open Access Journals (Sweden)

    Valeriana Moura Ribeiro

    1968-03-01

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

  13. 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,

  14. 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.

  15. 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 prating 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.

  16. 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

  17. 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 ...

  18. [Hereditary ataxia and sensory-motor neuropathy].

    Science.gov (United States)

    Miladinović, Ksenija; Hodzić, Samiha; Zjuzin, Nadezda; Lokmic, Eldan

    2003-01-01

    The authors presented this case because of the determined characteristics in the clinical picture and electrophysiologic finding which refer to spinocerebral degeneration and neuropathia of the hereditary type, and give the possibility of the classification into two nosologic entities. One is Roussey Levy's syndrome, what is the advisable diagnosis of our patient, and another Freidreich's ataxia. Regardless to the impossibility of the establishing of diagnosis by means the specific enzimatic and genetic tests, the authors on the basis of the clinical picture, electromioncurographic findings and data from the literature of the diagnostic ally decided for Freidreich's ataxya. The neuropathy have classified into the hereditary motor sensor neuropathy--HMSN type II and presented its characteristics.

  19. 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.

  20. The effect of piracetam on ataxia: clinical observations in a group of autosomal dominant cerebellar ataxia patients.

    Science.gov (United States)

    Ince Gunal, D; Agan, K; Afsar, N; Borucu, D; Us, O

    2008-04-01

    Autosomal dominant cerebellar ataxias are clinically and genetically heterogeneous neurodegenerative disorders. There is no known treatment to prevent neuronal cell death in these disorders. Current treatment is purely symptomatic; ataxia is one of the most disabling symptoms and represents the main therapeutic challenge. A previous case report suggesting benefit from administration of high dose piracetam inspired the present study of the efficacy of this agent in patients with cerebellar ataxia. Piracetam is a low molecular weight derivative of gamma-aminobutyric acid. Although little is known of its mode of action, its efficacy has been documented in a wide range of clinical indications, such as cognitive disorders, dementia, vertigo and dyslexia, as well as cortical myoclonus. The present report investigated the role of high dose piracetam in patients with cerebellar ataxia. Eight patients with autosomal dominant cerebellar ataxia were given intravenous piracetam 60 g/day by a structured protocol for 14 days. The baseline and end-of-the study evaluations were based on the International Cooperative Ataxia Rating Scale. Statistical analysis demonstrated a significant improvement in the patients' total score (P = 0.018) and a subscale analysis showed statistical significance for only the posture and gait disturbances item (P = 0.018). This study is providing good clinical observation in favour of high dose piracetam infusion to reduce the disability of the patients by improving their gait ataxia.

  1. Guidelines for the pathoanatomical examination of the lower brain stem in ingestive and swallowing disorders and its application to a dysphagic spinocerebellar ataxia type 3 patient

    NARCIS (Netherlands)

    Rub, U; Brunt, ER; Del Turco, D; de Vos, RAI; Gierga, K; Paulson, H; Braak, H

    Despite the fact that considerable progress has been made in the last 20 years regarding the three-phase process of ingestion and the lower brain stem nuclei involved in it, no comprehensive descriptions of the ingestion-related lower brain stem nuclei are available for neuropathologists confronted

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H266 clone 10 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H196 clone 7 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    (iPSC) lines of SCA2 patients in order to study a disease-specific phenotype. Here, we demonstrate the gene correction of the iPSC line H271 clone 1 where we have exchanged the expanded CAG repeat of the ATXN2 gene with the normal length found in healthy alleles. This gene corrected cell line...

  5. Validity and reliability of the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and Rating of Ataxia (SARA) in multiple sclerosis patients with ataxia.

    Science.gov (United States)

    Salcı, Yeliz; Fil, Ayla; Keklicek, Hilal; Çetin, Barış; Armutlu, Kadriye; Dolgun, Anıl; Tuncer, Aslı; Karabudak, Rana

    2017-11-01

    Ataxia is an extremely common problem in multiple sclerosis (MS) patients. Thus, appropriate scales are required for detailed assessment of this issue. The aim of our study was to investigate the reliability and validity of the Turkish version of the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxia (SARA), which are widely used in ataxia evaluation in the context of other cerebellar diseases. This cross-sectional study included 80 MS patients with Kurtzke cerebellar functional system score (C-FSS) greater than zero and slight pyramidal involvement. The Expanded Disability Status Scale (EDSS), C-FSS, and Berg Balance Scale (BBS) were administered. SARA and ICARS were assessed on first admission by two physical therapists. Seven days later, second assessments were repeated in same way for reliability. Intra-rater and inter-rater reliability were found to be high for both ICARS and SARA (prating results were determined by five different factors that did not coincide with the ICARS sub-scales. Our study demonstrated that ICARS and SARA are both reliable in MS patients with ataxia. Although ICARS has some structural problems, it seems to be more valid given its high correlations with EDSS and C-FSS. SARA also can be preferred as a brief assessment. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Predominance of null mutations in ataxia-telangiectasia

    NARCIS (Netherlands)

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

    1996-01-01

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

  7. 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.

  8. Visuomotor ataxia. Clinical and CT scan studies in three cases

    Energy Technology Data Exchange (ETDEWEB)

    Hirose, Genjiro; Kawada, Junya; Oda, Rokuhei; Kitagawa, Yoshinobu; Kosoegawa, Hiroshi

    1985-03-01

    Three patients with visuomotor ataxia, a disorder of hand movement to grasp objects located in the periphery of the visual field, were studied clinically and neuroradiologically with conventional and reformatted CT scans. Visuomotor ataxia was noted in the hemifield contralateral to the parieto-occipital lesion with both hands regardless the side of the lesion in this study. No dominant hemisphere for visuomotor ataxia was noted. The responsible lesions for this disorder were overlapped at Broadmann's area 7, 18, 19 and their surrounded white matter including the connecting fibers to the contralateral hemisphere via the splenium of corpus callosum. No direct lesion was found in the angular gyrus (Broadmann area 39). Visuomotor ataxia was seen with both hands in our series and it can be explained by the disconnection of either or both of the direct and crossed long association fibers between visual association areas and motor association areas at the parieto-occipital junction. (author).

  9. 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...

  10. 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. 

  11. 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.

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

    Science.gov (United States)

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

    2016-11-01

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

  13. 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.

  14. An ontology-aware integration of clinical models, terminologies and guidelines: an exploratory study of the Scale for the Assessment and Rating of Ataxia (SARA).

    Science.gov (United States)

    Maarouf, Haitham; Taboada, María; Rodriguez, Hadriana; Arias, Manuel; Sesar, Ángel; Sobrido, María Jesús

    2017-12-06

    Electronic rating scales represent an important resource for standardized data collection. However, the ability to exploit reasoning on rating scale data is still limited. The objective of this work is to facilitate the integration of the semantics required to automatically interpret collections of standardized clinical data. We developed an electronic prototype for the Scale of the Assessment and Rating of Ataxia (SARA), broadly used in neurology. In order to address the modeling challenges of the SARA, we propose to combine the best performances from OpenEHR clinical archetypes, guidelines and ontologies. A scaled-down version of the Human Phenotype Ontology (HPO) was built, extracting the terms that describe the SARA tests from free-text sources. This version of the HPO was then used as backbone to normalize the content of the SARA through clinical archetypes. The knowledge required to exploit reasoning on the SARA data was modeled as separate information-processing units interconnected via the defined archetypes. Each unit used the most appropriate technology to formally represent the required knowledge. Based on this approach, we implemented a prototype named SARA Management System, to be used for both the assessment of cerebellar syndrome and the production of a clinical synopsis. For validation purposes, we used recorded SARA data from 28 anonymous subjects affected by Spinocerebellar Ataxia Type 36 (SCA36). When comparing the performance of our prototype with that of two independent experts, weighted kappa scores ranged from 0.62 to 0.86. The combination of archetypes, phenotype ontologies and electronic information-processing rules can be used to automate the extraction of relevant clinical knowledge from plain scores of rating scales. Our results reveal a substantial degree of agreement between the results achieved by an ontology-aware system and the human experts.

  15. Diffusion tensor imaging for nerve fiber bundles in the brain stem and spinocerebellar degeneration

    International Nuclear Information System (INIS)

    Honma, Tsuguo

    2009-01-01

    Diffusion tensor imaging (DTI) can create an image of the anisotropic nature of diffusion and express it quantitatively. Nerve fibers have a large anisotropic diffusion, and it is possible to obtain images of the nerve fiber bundle. The purpose of this study is to observe the nerve fiber bundles in the brain stem using DTI and study its potential for diagnosing the type of spinocerebellar degeneration (SCD). Fractional anisotropy (FA) maps and 3D-tractography images were obtained for 41 subjects with no brain stem abnormalities. We created an apparent diffusion coefficient (ADC) map and an FA map using DTI for 16 subjects in the disease group (11 with hereditary SCD and 5 with non-hereditary SCD) and 25 in the control group. The diffusion value of the pons and middle cerebellar peduncle was measured using ADC, and the degree of anisotropic diffusion was measured using FA. The pyramidal tract, superior cerebellar peduncle, and inferior cerebellar peduncle were clearly demonstrated for all cases. ADC for the middle cerebellar peduncle in spinocerebellar ataxin (SCA)1 was significantly higher, similar to that for the pons in dentatorubro-pallidoluysian atrophy (DRPLA). In MSA-C, ADC for both the pons and middle cerebellar peduncle was significantly elevated and FA was significantly decreased. There were no significant changes in SCA3. We could observe the nerve fiber bundles in the brain stem using DTI. FA and ADC measurements with DTI can aid in diagnosing the type of SCD. (author)

  16. Ataxia telangiectasia: LET dependence of cellular inactivation

    International Nuclear Information System (INIS)

    Blakely, E.A.; Tobias, C.A.

    1984-01-01

    Human Ataxia telangiectasia cells (AT 2SF line) have been irradiated in vitro under aerobic and hypoxic conditions with heavy-ion beams accelerated at the Berkeley Bevalac as a part of a study to characterize the radiation responses of genetically sensitive and resistant cell lines to high LET radiations. Results from track-segment exposures to neon, silicon, argon and iron ion beams accelerated to initial energies of from 225 to 670 MeV/amu provided an LET range between 30 to 1,000 KeV/μm. The data indicate: (1) The sensitivity of AT cells increases with increasing LET, similar to resistant human lines (e.g., T-1 cells). However, due to efficient repair, T-1 cells are more resistant than AT cells at LET values below 200 keV/μm; (2) Maximum cell kill occurs for both lines at 100-200 keV/μm; at higher LET the sensitivity of the two lines approach each other; (3) There is only small variation in the sensitivity of AT cells to particles of various atomic numbers at the same LET; differences are more pronounced in the LET domain between 50 and 200 keV/μm; and (4) AT cells have slightly lower OER values than T-1 cells in the range of LET studied below 200 keV/μm

  17. 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.

  18. 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.

  19. 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.

  20. 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.

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

    NARCIS (Netherlands)

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

    2003-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Meenal Garg

    2017-01-01

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

  3. 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.

  4. 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

  5. Clinical neurogenetics: fragile x-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Hall, Deborah A; O'Keefe, Joan A

    2013-11-01

    This article summarizes the clinical findings, genetics, pathophysiology, and treatment of fragile X-associated tremor ataxia syndrome. The disorder occurs from a CGG repeat (55-200) expansion in the fragile X mental retardation 1 gene. It manifests clinically in kinetic tremor, gait ataxia, and executive dysfunction, usually in older men who carry the genetic abnormality. The disorder has distinct radiographic and pathologic findings. Symptomatic treatment is beneficial in some patients. The inheritance is X-linked and family members may be at risk for other fragile X-associated disorders. This information is useful to neurologists, general practitioners, and geneticists. Copyright © 2013. Published by Elsevier Inc.

  6. 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

  7. Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

    Science.gov (United States)

    2017-09-28

    -Hirschhorn Syndrome; 4p16.3 Microduplication Syndrome; 4p Deletion Syndrome, Non-Wolf-Hirschhorn Syndrome; Autosomal Recessive Stickler Syndrome; Stickler Syndrome Type 2; Stickler Syndrome Type 1; Stickler Syndrome; Mucolipidosis Type 4; X-linked Spinocerebellar Ataxia Type 4; X-linked Spinocerebellar Ataxia Type 3; X-linked Intellectual Disability - Ataxia - Apraxia; X-linked Progressive Cerebellar Ataxia; X-linked Non Progressive Cerebellar Ataxia; X-linked Cerebellar Ataxia; Vitamin B12 Deficiency Ataxia; Toxic Exposure Ataxia; Unclassified Autosomal Dominant Spinocerebellar Ataxia; Thyroid Antibody Ataxia; Sporadic Adult-onset Ataxia of Unknown Etiology; Spinocerebellar Ataxia With Oculomotor Anomaly; Spinocerebellar Ataxia With Epilepsy; Spinocerebellar Ataxia With Axonal Neuropathy Type 2; Spinocerebellar Ataxia Type 8; Spinocerebellar Ataxia Type 7; Spinocerebellar Ataxia Type 6; Spinocerebellar Ataxia Type 5; Spinocerebellar Ataxia Type 4; Spinocerebellar Ataxia Type 37; Spinocerebellar Ataxia Type 36; Spinocerebellar Ataxia Type 35; Spinocerebellar Ataxia Type 34; Spinocerebellar Ataxia Type 32; Spinocerebellar Ataxia Type 31; Spinocerebellar Ataxia Type 30; Spinocerebellar Ataxia Type 3; Spinocerebellar Ataxia Type 29; Spinocerebellar Ataxia Type 28; Spinocerebellar Ataxia Type 27; Spinocerebellar Ataxia Type 26; Spinocerebellar Ataxia Type 25; Spinocerebellar Ataxia Type 23; Spinocerebellar Ataxia Type 22; Spinocerebellar Ataxia Type 21; Spinocerebellar Ataxia Type 20; Spinocerebellar Ataxia Type 2; Spinocerebellar Ataxia Type 19/22; Spinocerebellar Ataxia Type 18; Spinocerebellar Ataxia Type 17; Spinocerebellar Ataxia Type 16; Spinocerebellar Ataxia Type 15/16; Spinocerebellar Ataxia Type 14; Spinocerebellar Ataxia Type 13; Spinocerebellar Ataxia Type 12; Spinocerebellar Ataxia Type 11; Spinocerebellar Ataxia Type 10; Spinocerebellar Ataxia Type 1 With Axonal Neuropathy; Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia - Unknown; Spinocerebellar Ataxia - Dysmorphism

  8. Excitatory inputs to four types of spinocerebellar tract neurons in the cat and the rat thoraco-lumbar spinal cord

    Science.gov (United States)

    Shrestha, Sony Shakya; Bannatyne, B Anne; Jankowska, Elzbieta; Hammar, Ingela; Nilsson, Elin; Maxwell, David J

    2012-01-01

    The cerebellum receives information from the hindlimbs through several populations of spinocerebellar tract neurons. Although the role of these neurons has been established in electrophysiological experiments, the relative contribution of afferent fibres and central neurons to their excitatory input has only been estimated approximately so far. Taking advantage of differences in the immunohistochemistry of glutamatergic terminals of peripheral afferents and of central neurons (with vesicular glutamate transporters VGLUT1 or VGLUT2, respectively), we compared sources of excitatory input to four populations of spinocerebellar neurons in the thoraco-lumbar spinal cord: dorsal spinocerebellar tract neurons located in Clarke's column (ccDSCT) and in the dorsal horn (dhDSCT) and ventral spinocerebellar tract (VSCT) neurons including spinal border (SB) neurons. This was done on 22 electrophysiologically identified intracellularly labelled neurons in cats and on 80 neurons labelled by retrograde transport of cholera toxin b subunit injected into the cerebellum of rats. In both species distribution of antibodies against VGLUT1 and VGLUT2 on SB neurons (which have dominating inhibitory input from limb muscles), revealed very few VGLUT1 contacts and remarkably high numbers of VGLUT2 contacts. In VSCT neurons with excitatory afferent input, the number of VGLUT1 contacts was relatively high although VGLUT2 contacts likewise dominated, while the proportions of VGLUT1 and VGLUT2 immunoreactive terminals were the reverse on the two populations of DSCT neurons. These findings provide morphological evidence that SB neurons principally receive excitatory inputs from central neurons and provide the cerebellum with information regarding central neuronal activity. PMID:22371473

  9. 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.

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  11. 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 ...

  12. 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.…

  13. 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 me...

  14. Treatment for dysphagia (swallowing difficulties) in hereditary ataxia.

    Science.gov (United States)

    Vogel, Adam P; Keage, Megan J; Johansson, Kerstin; Schalling, Ellika

    2015-11-13

    Hereditary ataxias are a heterogeneous group of disorders resulting in progressive inco-ordination. Swallowing impairment, also known as dysphagia, is a common and potentially life threatening sequel of disease progression. The incidence and nature of dysphagia in these conditions is largely unknown. The loss of an effective and safe swallow can dramatically affect the health and well-being of an individual. Remediation of difficulties of eating and drinking is an important goal in the clinical care of people with hereditary ataxia. To assess the effects of interventions for swallowing impairment (dysphagia) in people with hereditary ataxias. We searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL Plus, PsycINFO, and the Education Resources Information Center (ERIC) on 14 September 2015. We also searched Linguistics and Language Behavior Abstracts (LLBA), Dissertation Abstracts, and Trials Registries on 24 September 2015. We considered all randomised controlled trials (RCTs) and quasi-RCTs that compared treatments for hereditary ataxia with placebo or no treatment. We only included studies measuring dysphagia. Three review authors (ES, KJ, MK) independently screened all titles and abstracts. In the event of any disagreement or uncertainty over the inclusion of a particular paper, the review authors planned to meet and reach consensus. We identified no RCTs from the 519 titles and abstracts screened. We excluded papers primarily for not including participants with a hereditary ataxia (that is, being focused on other neurological conditions), being theoretical reviews rather than intervention studies, or being neither randomised nor quasi-randomised trials.We identified five papers of various design that described treatment for dysphagia, or improvement to swallow as a by-product of treatment, in people with hereditary ataxia. None of these studies were RCTs or

  15. 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,

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  17. 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.

  18. Tremor in neurodegenerative ataxias, Huntington disease and tic disorder.

    Science.gov (United States)

    Rudzińska, M; Krawczyk, M; Wójcik-Pędziwiatr, M; Szczudlik, A; Tomaszewski, T

    2013-01-01

    Tremor is the most prevalent movement disorder, defined as rhythmic oscillations of a body part, caused by alternating or synchronic contractions of agonistic or antagonistic muscles. The aim of the study was to assess prevalence and to characterize parameters of tremor accompanying de-generative ataxias, Huntington disease (HD) and tic disorders in comparison with a control group. Forty-three patients with degenerative ataxias, 28 with HD and 26 with tic disorders together with 51 healthy controls were included in the study. For each participant, clinical and instrumental assessment (accelerometer, electromyography [EMG], graphic tablet) of hand tremor was performed. Frequency and severity of tremor were assessed in three positions: at rest (rest tremor), with hands extended (postural tremor), during the 'finger-to-nose' test and during Archimedes spiral drawing (kinetic tremor). Based on the mass load test, the type of tremor was determined as essential tremor type or enhanced physiological tremor type. The incidence of tremor in the accelerometry in patients with degenerative ataxia (50%) significantly differs from controls (10%) (p = 0.001). The dominant tremor was postural, low-intense, with 7-Hz frequency, essential tremor (23%) or other tremor type (23%), while enhanced physiological tremor was the least frequent (2%). Tremor in patients with HD and tic disorders was found in 10% and 20% of patients, respectively, similarly to the control group. Tremor was mild, postural and of essential tremor type, less frequently of enhanced physiological tremor type. No correlation between severity of tremor and severity of disease was found. The prevalence of tremor is considerably higher among patients with degenerative ataxias compared with HD, tic disorder and the control group. The most common type of tremor accompanying ataxias, HD and tic disorders is essential tremor type.

  19. 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.

  20. 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.

  1. [Cutting-edge MRI techniques for studying neurological diseases focusing on spinocerebellar degeneration].

    Science.gov (United States)

    Watanabe, Hirohisa; Senda, Joe; Ito, Mizuki; Atsuta, Naoki; Haram, Kazuhiro; Watanabe, Hazuki; Nakamura, Ryoichi; Tsuboi, Takashi; Yoshida, Mari; Naganawa, Shinji; Sobue, Gen

    2013-01-01

    This symposium discusses the utility of the different MR techniques in the diagnosis and management of spinocerebellar degeneration (SCD). Conventional MRI is widely used and can show characteristic signal abnormalities such as putaminal hyperintensity, hyperintense putaminal rim, putaminal hypointensity, hot cross bun sign in the pontine base, and hyperintensity in the middle cerebellar peduncles strengthening a diagnosis of multiple system atrophy (MSA). However, the diagnostic utility of these signal abnormalities in early MSA remains restricted. In addition, it should be considered that different magnetic field strengths and sequences could be influenced on the findings resulting false negative. On the other hand, proton magnetic resonance spectroscopy, diffusion weighted imaging (DWI), diffusion tensor imaging (DTI) and voxel based morphometry (VBM) in the pontine base, cerebellum, and putamen will be informative in the early diagnosis of MSA and other SCD prior to conventional MRI changes and even before any clinical manifestation of symptoms. Particularly, DWI, DTI, and VBM are expected to have potential as surrogate markers of disease progression. Further prospective and large studies including earlier disease stages will be needed to clarify whether these novel MR techniques will aid in the future sets of diagnostic criteria and therapeutic trials.

  2. A 70-year-old male with peripheral neuropathy, ataxia and antigliadin antibodies shows improvement in neuropathy, but not ataxia, after intravenous immunoglobulin and gluten-free diet

    Directory of Open Access Journals (Sweden)

    Dharshan Anandacoomaraswamy

    2008-10-01

    Full Text Available Dharshan Anandacoomaraswamy1, Jagdeesh Ullal2, Aaron I Vinik21Department of Internal Medicine, Coney Island Hospital, Brooklyn, NY, USA; 2Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USAAbstract: This is a case of a 70-year-old man with severe peripheral neuropathy, type 2 diabetes and progressively worsening cerebellar ataxia. He was found to have circulating antigliadin and antireticulin antibodies compatible with celiac disease in the absence of intestinal pathology. The peripheral neuropathy improved with a gluten-free diet, antioxidants and intravenous immunoglobulin, whereas the ataxia did not. This case illustrates the need to test for celiac disease in patients with idiopathic ataxia and peripheral neuropathy and the need for alternative therapies for ataxia. Keywords: celiac disease, peripheral neuropathy, autoimmune disease, cerebellar ataxia, type 2 diabetes

  3. Ataxias and cerebellar dysfunction: involvement of synaptic plasticity deficits?

    Science.gov (United States)

    Rinaldo, Lorenzo; Hansel, Christian

    2011-01-01

    Summary Adaptive processes within cerebellar circuits, such as long-term depression and long-term potentiation at parallel fiber-Purkinje cell synapses, have long been seen as important to cerebellar motor learning, and yet little attention has been given to any possible significance of these processes for cerebellar dysfunction and disease. Several forms of ataxia are caused by mutations in genes encoding for ion channels located at key junctures in pathways that lead to the induction of synaptic plasticity, suggesting that there might be an association between deficits in plasticity and the ataxic phenotype. Herein we explore this possibility and examine the available evidence linking the two together, highlighting specifically the role of P/Q-type calcium channels and their downstream effector small-conductance calcium-sensitive (SK2) potassium channels in the regulation of synaptic gain and intrinsic excitability, and reviewing their connections to ataxia. PMID:21232209

  4. 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.

  5. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS).

    Science.gov (United States)

    Taki, Masakatsu; Nakamura, Takashi; Matsuura, Hiraku; Hasegawa, Tatsuhisa; Sakaguchi, Hirofumi; Morita, Kanako; Ishii, Ryotaro; Mizuta, Ikuko; Kasai, Takashi; Mizuno, Toshiki; Hirano, Shigeru

    2017-10-28

    Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a novel ataxic disorder consisting of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a somatosensory deficit. We report the first Japanese case of CANVAS. The patient is a 68-year-old Japanese male. He was referred to our university for further evaluation of progressive gait disturbance and ataxia. He exhibited horizontal gaze-evoked nystagmus and sensory deficit. Nerve conduction studies showed sensory neuronopathy. Magnetic resonance imaging showed the atrophy of vermis but not of the brainstem. The caloric stimulation and video head impulse test (vHIT) showed bilateral vestibulopathy. The visually enhanced vestibulo-ocular reflex (VVOR) was also impaired. In addition to neurological and electrophysiological examinations, simple neuro-otological examinations (i.e., caloric stimulation, vHIT, and VVOR) may reveal more non-Caucasian cases. Copyright © 2017. Published by Elsevier B.V.

  6. Case Report: Neuro-Imaging Findings in Ataxia Telangiectasia

    Directory of Open Access Journals (Sweden)

    Farhad Mahvelati

    2004-06-01

    Full Text Available Ataxia Telangiectasia (AT is an autosomal recessive inherited disorder in which cutaneous and scleral Telangiectasia, cerebellar ataxia and immunodeficiency occur. There is a high incidence of development of malignant tumors, mainly lymphomas. Cerebellar atrophy is the most prominent abnormality and is shown better by magnetic resonance imaging (MRI than CT-Scan. Intracranial hemorrhage occurs rarely. We report a 7 years old boy who admitted for recurrent pulmonary infections. His examination showed ataxic gait with decreased deep tendon reflexes in lower extremities. He had telangiectasia in the eyes and his speech was slurred and difficult. Brain MRI showed cerebellar atrophy with diffuse hyperintensity in white matter, most prominent in occipital region, which was suggestive of leukodystrophy. This white matter change was not reported before in AT.

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

    OpenAIRE

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

    2015-01-01

    Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial...

  8. Transient cerebellopontine demyelinisation revealed by MRI in acute cerebellar ataxia

    International Nuclear Information System (INIS)

    Aufricht, C.A.; Tenner, W.; Rosenmayr, F.; Stiglbauer, R.

    1990-01-01

    An eight year old boy was admitted to our ward with a history of abrupt onset of rapidly progressive gait disorder, nausea, vertigo and vomiting. The clinical as well as the laboratory findings suggested the diagnosis of acute cerebellar ataxia. Magnetic resonance imaging (MRI), however, showed marked demyelinisation in the cerebellar region and visual evoked potentials were pathologic. After immunosuppression the patient promptly improved clinically and the lesions depicted by MRI disappeared almost completely. (orig.)

  9. The Development of Ataxia Telangiectasia Mutated Kinase Inhibitors

    Czech Academy of Sciences Publication Activity Database

    Andrs, M.; Kobarecny, J.; Nepovimova, E.; Jun, D.; Hodný, Zdeněk; Moravcová, Simona; Hanzlíková, Hana; Kuca, K.

    2014-01-01

    Roč. 14, č. 10 (2014), s. 805-811 ISSN 1389-5575 R&D Projects: GA MŠk(CZ) CZ.1.07/2.3.00/30.0044 Grant - others:MH CZ - DRO (University Hospital Hradec Kralove(CZ) 00179906 Institutional support: RVO:68378050 Keywords : Ataxia telangiectasia mutated * cancer * chemosensitization * DNA damage response Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.903, year: 2014

  10. 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.

  11. 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.

  12. 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

  13. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia

    Directory of Open Access Journals (Sweden)

    Arvind Chaturvedi

    2011-01-01

    Full Text Available Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and vomiting along with severe vertigo, ataxia and hypertension. Neurological evaluation was normal except for the presence of vertigo and ataxia. Computerised tomography scan brain was also normal. Patient was admitted for observation and symptomatic treatment was given. Vertigo and ataxia gradually improved over 24 hours.

  14. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia.

    Science.gov (United States)

    Chaturvedi, Arvind; Dash, Hh

    2011-07-01

    Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and vomiting along with severe vertigo, ataxia and hypertension. Neurological evaluation was normal except for the presence of vertigo and ataxia. Computerised tomography scan brain was also normal. Patient was admitted for observation and symptomatic treatment was given. Vertigo and ataxia gradually improved over 24 hours.

  15. 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.

  16. Abnormal brain MRI in a case of acute ataxia as the only sign of abdominal neuroblastoma

    International Nuclear Information System (INIS)

    Molla Mohammadi, M.; Karimzadeh, P.; Khatami, A.; Jadali, F.

    2010-01-01

    Ataxia is a movement disorder that may manifest an acute, intermittent, non progressive or chronic progressive course. Ataxia alone is rare as a para neoplastic sign, especially if it is due to neuroblastoma (abdominal or chest). We report an abdominal neuroblastoma in a two-year-old girl presenting with only acute ataxia and abnormal neuroimaging. Brain MRI showed abnormal signal finding in the medulla, pons, cortico spinal tract and the periventricular space. In the abdominal CT, a mass was detected in the right adrenal gland with calcification and the histopathologic examination re-vealed neuroblastoma. We suggest in children with acute ataxia, with or without opalescence-myoclonus, neuroblastoma should be considered.

  17. Acoustic characteristics of ataxic speech in Japanese patients with spinocerebellar degeneration (SCD).

    Science.gov (United States)

    Ikui, Yukiko; Tsukuda, Mamoru; Kuroiwa, Yoshiyuki; Koyano, Shigeru; Hirose, Hajime; Taguchi, Takahide

    2012-01-01

    In English- and German-speaking countries, ataxic speech is often described as showing scanning based on acoustic impressions. Although the term 'scanning' is generally considered to represent abnormal speech features including prosodic excess or insufficiency, any precise acoustic analysis of ataxic speech has not been performed in Japanese-speaking patients. This raises the question of what is the most dominant acoustic characteristic of ataxic speech in Japanese subjects, particularly related to the perceptual impression of 'scanning'. The study was designed to investigate the nature of speech characteristics of Japanese ataxic subjects, particularly 'scanning', by means of acoustic analysis. The study comprised 20 Japanese cases with spinocerebellar degeneration diagnosed to have a perceptual impression of scanning by neurologists (ataxic group) and 20 age-matched normal healthy subjects (control group). Recordings of speech samples of Japanese test sentences were obtained from each subject. The recorded and digitized acoustic samples were analysed using 'Acoustic Core-8' (Arcadia Inc.). Sentence duration was significantly longer in the ataxic group as compared with the control group, indicating that the speaking rate was slower in the ataxic subjects. Segment duration remained consistent in both vowels and consonants in the control group as compared with the ataxic group. In particular, the duration of vowel segments, i.e. the nucleus of Japanese mora, was significantly invariable in the control group regardless of differences between subjects as well as in segments compared with the ataxic group. In addition, the duration of phonemically long Japanese vowels was significantly shorter in the ataxic group. The results indicate that the perceptual impression of 'scanning' in Japanese ataxic cases derives mainly from the breakdown of isochrony in terms of difficulty in keeping the length of vowel segments of Japanese invariable during speech production. In

  18. 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.

  19. A cast-iron guarantee of ataxia and deafness.

    Science.gov (United States)

    Shingde, Meena; Ell, Jonathan; Pamphlett, Roger

    2005-09-01

    Superficial siderosis of the central nervous system (CNS) is a rare condition that is thought to be caused by repeated subarachnoid haemorrhages. The major clinical features are progressive bilateral hearing loss, cerebellar ataxia and pyramidal dysfunction. Ante-mortem diagnosis is now possible due to MRI and post mortem reports of this condition are becoming rare. Despite the occurrence of typical clinical features the diagnosis is often missed during life if CT scanning alone is performed. We describe a case of superficial siderosis of the CNS with clinical and post mortem findings as a reminder of this unusual condition.

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model. RESULTS Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase...... in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed...

  1. Ataxia cerebelar aguda na criança

    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.

  2. [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.

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

    NARCIS (Netherlands)

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

    2014-01-01

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

  4. [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.

  5. 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…

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

    Science.gov (United States)

    ... Share: Email Facebook Twitter Home Health Conditions FXTAS Fragile X-associated tremor/ataxia syndrome Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description Fragile X-associated tremor/ataxia syndrome ( FXTAS ) is characterized by ...

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

    NARCIS (Netherlands)

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

    1992-01-01

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

  8. 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

  9. 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

  10. 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.

  11. 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).

  12. 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.

  13. Clinical and genetic features of ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Bundey, S.

    1994-01-01

    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)

  14. 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.

  15. 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

  16. 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

  17. SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases.

    Science.gov (United States)

    Choquet, Karine; Tétreault, Martine; Yang, Sharon; La Piana, Roberta; Dicaire, Marie-Josée; Vanstone, Megan R; Mathieu, Jean; Bouchard, Jean-Pierre; Rioux, Marie-France; Rouleau, Guy A; Boycott, Kym M; Majewski, Jacek; Brais, Bernard

    2016-07-01

    Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed whole-exome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients.

  18. [Clinical and diagnostic considerations on degenerative spino-cerebellar diseases. A clinical and instrumental description of 2 cases].

    Science.gov (United States)

    Trebini, F; Appiotti, A; Scarzella, G

    1990-11-01

    Two cases of spino-cerebellar heredoataxia are reported. The first patient, aged 18, presented the clinical peculiarities of Friedreich's disease; subjected to encephalic CT and encephalomedullary NMR the proved normal; EMG study and visual, acoustic and somatosensorial evoked potentials were not normal but there was nothing specifically wrong. The second patient, aged 30, followed up for more than 10 years, presented the clinical aspects of Pierre Marie disease; stress is laid on encephalic CT examinations carried out at the age of 20 and 30. These were pathological due to the marked dilatation of the IVth ventricle and the basal cisternae; evoked potential changes were aspecific. The nosography is discussed, especially as regards clinical diagnosis, in the absence of typical neuroradiological or other instrumental aspects and, obviously, in the absence of anatomopathological signs.

  19. Yeast Sgf73/Ataxin-7 serves to anchor the deubiquitination module into both SAGA and Slik(SALSA HAT complexes

    Directory of Open Access Journals (Sweden)

    Lee Kenneth K

    2009-02-01

    Full Text Available Abstract Spinocerebellar ataxia (SCA is a physically devastating, genetically inherited disorder characterized by abnormal brain function that results in the progressive loss of the ability to coordinate movements. There are many types of SCAs as there are various gene mutations that can cause this disease. SCA types 1–3, 6–10, 12, and 17 result from a trinucleotide repeat expansion in the DNA-coding sequence. Intriguingly, recent work has demonstrated that increased trinucleotde expansions in the SCA7 gene result in defect in the function of the SAGA histone acetyltransferase complex. The SCA7 gene encodes a subunit of the SAGA complex. This subunit is conserved in yeast as the SGF73 gene. We demonstrate that Sgf73 is required to recruit the histone deubiquitination module into both SAGA and the related SliK(SALSA complex, and to maintain levels of histone ubiquitination, which is necessary for regulation of transcription at a number of genes.

  20. 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. 

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

    Science.gov (United States)

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

    2015-12-01

    Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document. Copyright ©ERS 2015.

  2. Exonic deletions of FXN and early-onset Friedreich ataxia.

    Science.gov (United States)

    Anheim, Mathieu; Mariani, Louise-Laure; Calvas, Patrick; Cheuret, Emmanuel; Zagnoli, Fabien; Odent, Sylvie; Seguela, Claire; Marelli, Cecilia; Fritsch, Marlène; Delaunoy, Jean-Pierre; Brice, Alexis; Dürr, Alexandra; Koenig, Michel

    2012-07-01

    Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene. The remaining patients are compound heterozygous for an expansion and a point mutation. Patients who are compound heterozygous for an exonic deletion and an expansion are exquisitely rare. To describe 6 patients affected with FA due to an exonic deletion mutation (FAexdel) and to compare these 6 patients with FAexdel with 46 patients consecutively diagnosed with typical FA due to homozygous GAA expansion and whose small expansions were within the same range as that of the expansions of the patients with FAexdel. Description of a series. Academic research. Six patients with FAexdel and 46 patients with typical FA. FXN gene analysis, including assessments of GAA expansion and exon sequencing and determination of exonic copy numbers using multiplex ligation-dependent probe amplification. We identified 6 patients with FA who presented with the combination of 1 GAA expansion and 1 FXN exonic deletion. The mean (SD) age at onset of the disease was earlier for patients with FAexdel (7 [4] years [range, 3-12 years]) than for patients with typical FA (15 [5] years [range, 6-30 years]) (P = .001), and the median time to confinement to wheelchair was shorter for patients with FAexdel (20 years) than for patients with typical FA (28 years) (P = .002). There was no difference between the mean (SD) size of the expansion for the patients with FAexdel (780 [256] GAA triplet repeat sequences [range, 340-1070 GAA triplet repeat sequences]) and the mean (SD) size of the short expansion for the patients with typical FA (634 [163] GAA triplet repeat sequences [range, 367-1000 GAA triplet repeat sequences]) (P = .10). The mean disease duration before becoming wheelchair bound was shorter for patients with FAexdel (9 years) than for patients with typical FA (13 years), and the

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

    Directory of Open Access Journals (Sweden)

    Jayesh M. Bhatt

    2015-12-01

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

  4. G2 chromosomal radiosensitivity of ataxia-telangiectasia heterozygotes

    International Nuclear Information System (INIS)

    Parshad, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

    1985-01-01

    Five lines of skin fibroblasts from individuals heterozygous for ataxia-telangiectasia (A-T), compared with six cell lines from age-matched normal controls, show a much higher frequency of chromatid breaks and gaps following x-irradiation during the G2 phase of the cell cycle. The magnitude of this difference suggests that G2 chromatid radiosensitivity could provide the basis for an assay to detect A-T heterozygotes. Though clinically normal, A-T heterozygotes share a high risk of cancer with A-T homozygotes and constitute approximately 1% of the human population. Further, we propose that G2 chromosomal radiosensitivity, which appears to result from a DNA repair deficiency, may be associated with a genetic predisposition to cancer

  5. Impact of Mobility Device Use on Quality of Life in Children With Friedreich Ataxia.

    Science.gov (United States)

    Ejaz, Resham; Chen, Shiyi; Isaacs, Charles J; Carnevale, Amanda; Wilson, Judith; George, Kristen; Delatycki, Martin B; Perlman, Susan L; Mathews, Katherine D; Wilmot, George R; Hoyle, J Chad; Subramony, Sub H; Zesiewicz, Theresa; Farmer, Jennifer M; Lynch, David R; Yoon, Grace

    2018-01-01

    To determine how mobility device use impacts quality of life in children with Friedreich ataxia. Data from 111 pediatric patients with genetically confirmed Friedreich ataxia were collected from a prospective natural history study utilizing standardized clinical evaluations, including health-related quality of life using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Module. Mobility device use was associated with worse mean PedsQL total, physical, emotional, social, and academic subscores, after adjusting for gender, age of disease onset, and Friedreich Ataxia Rating Scale score. The magnitude of the difference was greatest for the physical subscore (-19.5 points, 95% CI = -30.00, -8.99, P mobility devices trended toward worse physical subscore (-16.20 points, 95% CI = -32.07, -0.33, P = .05). Mobility device use is associated with significant worsening of all domains of quality of life in children with Friedreich ataxia.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

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

    OpenAIRE

    Vaidya Sachin; Desai Shrinivas; Khadilkar Satish; Mehta Neeta

    2004-01-01

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

  13. 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

  14. 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.

  15. 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.

  16. A Survey on 100 Children with Acute Ataxia in Mofid Children Hospital Tehran, Iran

    Directory of Open Access Journals (Sweden)

    Parvaneh Karim-Zadeh

    2003-04-01

    Full Text Available Objective: The term “Ataxia” is used to denote disturbances of the body posture and its movement that are normally controlled by the cerebellum. frontal lobes and the posterior columns of the spinal cord. The initial symptom and the most prominent feature of ataxia is abnormal gait which is characterized by lurching and wide base walking. Knowing that, the acute ataxia is among those problems that brings very soon the child to pediatrics neurology department and in view of lack of any survey in this neid in our country, we decided to investigate the etiology of acute ataxia in Islamic Republic of Iran. Materials & Methods: Our patients were recruited from 100 children who were brought to neurology service of Mofid children hospital with the chief complaint of acute ataxia over 2 years period. (sep 2001 to sep 2003. All of those 100 patients were admitted and required investigations were performed. Results: Results of our workup revealed that the most common cause of acute ataxia is acute cerebellar one, which all of them preceded by viral febrile illness. The second frequent cause of acute. Ataxia is due to drug intoxication, which commonly was observed between 2 – 4 years period. Conclusion: The remaining etiologies in descending frequency were as follow, Infectious polyneuropathy, Migraine, Opsoclonus – Myoclonus, Brain tumor, ADEM,MS and Epilepsy.

  17. Ataxia Oculomotor Apraxia Type 1 in the Siblings of a Family: A Novel Mutation.

    Science.gov (United States)

    Karimzadeh, Parvaneh; Khayatzadeh Kakhki, Simin; Esmail Nejad, Shaghayegh Sadat; Houshmand, Masood; Ghofrani, Mohammad

    2017-01-01

    Although AOA1 (ataxia oculomotor apraxia1) is one of the most common causes of autosomal recessive cerebellar ataxias in Japanese population, it is reported from all over the world. The clinical manifestations are similar to ataxia telangiectasia in which non-neurological manifestations are absent and include almost 10% of autosomal recessive cerebellar ataxias. Dysarthria and gait disorder are the most two common and typical manifestations. Oculomotor apraxia is usually seen a few years after the manifestations start. APTX gene on 9p13.3 chromosome is expressed in the cells of all human body tissues and different mutations had been discovered. Here we report two siblings (a girl and a boy) of consanguineous parents visited at Mofid Pediatrics Hospital in 2015, with history of gait ataxia, titubation, tremor, and oculomotor apraxia around five yr old and after that. The brother showed symptoms of disease earlier and more severe than his sister did. After ruling out the common etiologies of progressive ataxia, we did genetic study for AOA1 that showed a homozygous frameshift mutation as c.418_418 del was found. This mutation was not reported before so this was a new mutation in APTX gene.

  18. 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.

  19. Epigenetics in Friedreich's Ataxia: Challenges and Opportunities for Therapy

    Directory of Open Access Journals (Sweden)

    Chiranjeevi Sandi

    2013-01-01

    Full Text Available Friedreich's ataxia (FRDA is an autosomal recessive neurodegenerative disorder caused by homozygous expansion of a GAA·TTC trinucleotide repeat within the first intron of the FXN gene, leading to reduced FXN transcription and decreased levels of frataxin protein. Recent advances in FRDA research have revealed the presence of several epigenetic modifications that are either directly or indirectly involved in this FXN gene silencing. Although epigenetic marks may be inherited from one generation to the next, modifications of DNA and histones can be reversed, indicating that they are suitable targets for epigenetic-based therapy. Unlike other trinucleotide repeat disorders, such as Huntington disease, the large expansions of GAA·TTC repeats in FRDA do not produce a change in the frataxin amino acid sequence, but they produce reduced levels of normal frataxin. Therefore, transcriptional reactivation of the FXN gene provides a good therapeutic option. The present paper will initially focus on the epigenetic changes seen in FRDA patients and their role in the silencing of FXN gene and will be concluded by considering the potential epigenetic therapies.

  20. Cognitive functions in ataxia with oculomotor apraxia type 2.

    Science.gov (United States)

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

    2012-01-01

    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 AOA2. A broad range of neuropsychological examination protocol was administered including the following domains: short-term, working- and episodic-memories, executive functions, implicit sequence learning, and the temporal parameters of speech. The performance on the Listening Span, Letter Fluency, Serial Reaction Time Task, and pause ratio in speech was 2 or more standard deviations (SD) lower compared to controls, and 1 SD lower on Backward Digit Span, Semantic Fluency, articulation rate, and speech tempo. These findings indicate that the pathogenesis of the cerebrocerebellar circuit in AOA2 is responsible for the weaker coordination of complex cognitive functions such as working memory, executive functions, speech, and sequence learning.

  1. 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.

  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. Cognitive Functions in Ataxia with Oculomotor Apraxia Type 2

    Directory of Open Access Journals (Sweden)

    Péter eKlivényi

    2012-08-01

    Full Text Available 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. Methods: A broad range of neuropsychological examination protocol was administered including the following domains: short-term, working- and episodic- memories, executive functions, implicit sequence learning, and the temporal parameters of speech. Results: The performance on the Listening Span, Letter Fluency, Serial Reaction Time Task and pause ratio in speech was 2 or more standard deviations (SD lower compared to controls, and 1 SD lower on Backward Digit Span, Semantic Fluency, articulation rate and speech tempo. Conclusions: These findings indicate that the pathogenesis of the cerebrocerebellar circuit in AOA2 is responsible for the weaker coordination of complex cognitive functions such as working memory, executive functions, speech and sequence learning.

  5. 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).

  6. 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.

  7. Neurophysiological evidence for generalized sensory neuronopathy in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome.

    Science.gov (United States)

    Szmulewicz, David J; Seiderer, Linda; Halmagyi, G Michael; Storey, Elsdon; Roberts, Leslie

    2015-04-01

    Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently described multisystem ataxia defined by the presence of cerebellar ataxia, bilateral vestibulopathy, and a somatosensory deficit. The characteristic clinical sign is an abnormal visually enhanced vestibuloocular reflex. The somatosensory deficit contributes to a significant level of disability in CANVAS. This study was a neurophysiological investigation of 14 patients with CANVAS. Findings revealed uniformly absent sensory nerve action potentials in all limbs, abnormal blink reflexes in 13 of 14 patients, and abnormal masseter reflexes in 6 of 11 patients. Tibial H-reflexes were absent in 11 of 14 patients. Somatosensory evoked potentials were abnormal in 10 of the 11 patients tested, and brainstem auditory evoked responses were abnormal in 3 of 8. Cutaneous silent period responses were abnormal in 7 of 14 patients. We suggest that a sensory neuronopathy should be sought in cerebellar and/or vestibular ataxias, particularly where the degree of ataxia is out of proportion to the clinically identified cerebellar and/or vestibular dysfunction. © 2014 Wiley Periodicals, Inc.

  8. 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.

  9. 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.

  10. Childhood hereditary ataxias: experience from a tertiary referral university hospital in Turkey.

    Science.gov (United States)

    Arslan, Elif Acar; Göçmen, Rahşan; Oğuz, Kader Karlı; Konuşkan, Gökçen Düzgün; Serdaroğlu, Esra; Topaloğlu, Haluk; Topçu, Meral

    2017-12-01

    Hereditary ataxias are a group of genetic disorders that are progressive and heterogeneous. The purpose of this study was to develop a practical and time-efficient approach to diagnosing childhood hereditary ataxias by analyzing characteristics and final diagnosis at a tertiary referral clinic for pediatric neurology. 196 patients admitted to the pediatric neurology department were included. The medical records were examined for demographic features, neurological, laboratory, electrophysiological, cranial imaging, and pathological findings, and for genetic studies. Patients were divided into two groups based on whether a final diagnosis was made. The undiagnosed and diagnosed groups consisted of 157 (81.1%) and 39 (19.9%) patients, respectively. The two groups differed in terms of levels of history of consanguineous marriage and mental and motor development before diagnosis, absence of deep tendon reflexes, and the presence of polyneuropathic changes detected by electromyelography (EMG), abnormal visual evoked potentials (VEPs), electroretinography (ERG), and muscle biopsy. To the best of our knowledge, this is the first study involving a large spectrum of diseases related to autosomal recessive ataxias in childhood in Turkey. One out of five patients with hereditary childhood ataxias can be diagnosed with clinical and laboratory and electrodiagnostic examination, especially with the help of imaging facilities, while genetic analysis is not possible for every child. Cranial magnetic resonance imaging followed by EMG provides the most important clues for the diagnosis of hereditary childhood ataxias.

  11. 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.

  12. Cellular responses to ionizing and ultraviolet radiation in ataxia telangiectasia

    International Nuclear Information System (INIS)

    Loberg, L.I.; McGrath, S.J.; Dixon, K.

    1995-01-01

    Ataxia telangiectasia (AT) is a genetic disease characterized by a wide variety of symptoms including a marked increase of cancer incidence and hypersensitivity to ionizing radiation (IR). Hypersensitivity is expressed as decreased cell survival, increased induction of chromosomal damage, radioresistant DNA synthesis and absence of G1 arrest following exposure of cells to IR. The defect in AT may lie in the regulation of DNA replication and control of the cell cycle. Fluorescence-activated cell sorting (FACS) analysis confirms the alterations of cell cycle control in AT cells following exposure to 1Gy ionizing radiation. Replication activity in the in vitro system parallels in vivo DNA synthesis in that: (a) extracts from normal cells exposed to 1Gy IR show a dramatic decrease in replication activity, and (b) extracts from AT cells exposed 1Gy IR do not show such a decrease in replication activity. The inability of AT cells to inhibit DNA replication following exposure to IR is a response which is seen after exposure to other types of DNA damaging agents. AT and normal cells were treated with 254nm UV radiation. Following exposure to 10J UV radiation, normal cells show dramatic DNA replication arrest while AT cells do not demonstrate DNA replication arrest. It appears that failure to halt DNA synthesis is a global feature of AT cells exposed to radiation. Phosphorylation changes of the essential replication protein, single strand binding protein (hSSB), have been investigated after both UV and ionizing radiation exposure. Previous work in the lab has shown, via immunoblotting techniques, that hSSB is hyperphosphorylated in HeLa cells following exposure to 10J UV radiation. In AT cells, hyperphosphorylation of hSSB also occurs following 10J UV radiation, but not 1Gy Ir. Further research is being conducted to examine the apparent uncoupling of DNA synthesis control and hyperphosphorylation of hSSB in UV-exposed AT cells

  13. 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/.

  14. Mouse Models of Fragile X-Associated Tremor Ataxia

    Science.gov (United States)

    Berman, Robert F.; Willemsen, Rob

    2009-01-01

    Objective To describe the development of mouse models of Fragile X-associated Tremor/Ataxia (FXTAS) and the behavioral, histological and molecular characteristics of these mice. Method This paper compares the pathophysiology and neuropsychological features of FXTAS in humans to the major mouse models of FXTAS. Specifically, the development of a transgenic mouse line carrying an expanded CGG trinucleotide repeat in the 5′untranslated regions of the Fmr1 gene is described along with a description of the characteristic intranuclear ubiquitin positive inclusions and the behavioral sequella observed in these mice. Results CGG KI mice model many of the important features of FXTAS, although some aspects are not well modeled in mice. Aspects of FXTAS that are modeled well include elevated levels of Fmr1 mRNA, reduced levels of Fmrp, the presence of intranuclear inclusions that develop with age and show similar distributions within neurons, and neuropsychological and cognitive deficits, including poor motor function, impaired memory and evidence of increased anxiety. Features of FXTAS that are not well modeled in these mice include intentional tremors that are observed in some FXTAS patients but have not been reported in CGG KI mice. In addition, while intranuclear inclusions in astrocytes are very prominent in FXTAS, there are relatively few observed in CGG KI mice. A number of additional features of FXTAS have not been systematically examined in mouse models yet, including white matter disease, hyperintensities in T2-weighted MRI, and brain atrophy, although these are currently under investigation in our laboratories. Conclusion The available mouse model has provided valuable insights into the molecular biology and pathophysiology of FXTAS, and will be particularly useful for developing and testing new therapeutic treatments in the future. PMID:19574928

  15. Targeted next-generation sequencing of a 12.5 Mb homozygous region reveals ANO10 mutations in patients with autosomal-recessive cerebellar ataxia.

    NARCIS (Netherlands)

    Vermeer, S.; Hoischen, A.; Meijer, R.P.; Gilissen, C.F.H.A.; Neveling, K.; Wieskamp, N.A.W.; Brouwer, A.; Koenig, M.; Anheim, M.; Assoum, M.; Drouot, N.; Todorovic, S.; Milic-Rasic, V.; Lochmuller, H.; Stevanin, G.; Goizet, C.; David, A.; Durr, A.; Brice, A.; Kremer, B.; Warrenburg, B.P.C. van de; Schijvenaars, M.M.V.A.P.; Heister, A.; Kwint, M.P.; Arts, P.J.W.; Wijst, J.A.J. van der; Veltman, J.; Kamsteeg, E.J.; Scheffer, H.; Knoers, N.V.A.M.

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations

  16. Targeted Next-Generation Sequencing of a 12.5 Mb Homozygous Region Reveals ANO10 Mutations in Patients with Autosomal-Recessive Cerebellar Ataxia

    NARCIS (Netherlands)

    Vermeer, Sascha; Hoischen, Alexander; Meijer, Rowdy P. P.; Gilissen, Christian; Neveling, Kornelia; Wieskamp, Nienke; de Brouwer, Arjan; Koenig, Michel; Anheim, Mathieu; Assoum, Mirna; Drouot, Nathalie; Todorovic, Slobodanka; Milic-Rasic, Vedrana; Lochmueller, Hanns; Stevanin, Giovanni; Goizet, Cyril; David, Albert; Durr, Alexandra; Brice, Alexis; Kremer, Berry; van de Warrenburg, Bart P. C.; Schijvenaars, Mascha M. V. A. P.; Heister, Angelien; Kwint, Michael; Arts, Peer; van der Wijst, Jenny; Veltman, Joris; Kamsteeg, Erik-Jan; Scheffer, Hans; Knoers, Nine

    2010-01-01

    Autosomal-recessive cerebellar ataxias comprise a clinically and genetically heterogeneous group of neurodegenerative disorders. In contrast to their dominant counterparts, unraveling the molecular background of these ataxias has proven to be more complicated and the currently known mutations

  17. 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.

  18. Nuclear Magnetic Resonance skull in Cuban families first diagnosed with Friedreich's ataxia

    International Nuclear Information System (INIS)

    Cruz Marinno, Tania; Alvarez Cuesta, Jose Alberto; Aguilera Rodriguez, Raul; Velazquez Perez, Luis

    2011-01-01

    Friedreich's ataxia is characterized by age of onset before 25 years, progressive ataxia, dysarthria, absent deep tendon reflexes and impaired vibration sense. This research was conducted in order to describe the imaging features of central nervous system structures in the early Cuban families diagnosed with the disease. A team of 0.23 Tesla-PANORAMA-Phylips Medical Systems, with a standard head coil, axial slices were obtained using 5mm thick FLAIR sequences, T1 and T2, and sagittal T1 and T2 in three individuals with confirmatory molecular diagnosis of Friedreich's ataxia and six healthy controls matched by age and sex. The morphological structures most affected are the cervical spinal cord, cerebellum and pons, which provides in vivo evidence that the disease leads to atrophy of these structures

  19. 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

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

    NARCIS (Netherlands)

    van Os, N J H; Roeleveld, N; Weemaes, C M R; Jongmans, M C J; Janssens, G O; Taylor, A M R; Hoogerbrugge, N; Willemsen, Michel A A P

    Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers

  1. Intra-Erythrocyte Infusion of Dexamethasone Reduces Neurological Symptoms in Ataxia Teleangiectasia Patients: Results of a Phase 2 Trial

    OpenAIRE

    Chessa, Luciana; Leuzzi, Vincenzo; Plebani, Alessandro; Soresina, Annarosa; Micheli, Roberto; D’Agnano, Daniela; Venturi, Tullia; Molinaro, Anna; Fazzi, Elisa; Marini, Mirella; Ferremi Leali, Pierino; Quinti, Isabella; Cavaliere, Filomena Monica; Girelli, Gabriella; Pietrogrande, Maria Cristina

    2014-01-01

    Background Ataxia Teleangiectasia [AT] is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer. No therapies are available for this devastating disease. Recent observational studies in few patients showed beneficial effects of short term treatment with betamethasone. To avoid the characteristic side effects of long-term administration of steroids we developed a me...

  2. Clinical comparison between AVED patients with 744 del A mutation and Friedreich ataxia with GAA expansion in 15 Moroccan families

    NARCIS (Netherlands)

    Benomar, Ali; Yahyaoui, Mohammed; Meggouh, Farid; Bouhouche, Ahmed; Boutchich, Mohammed; Bouslam, Naima; Zaim, Abdelhaq; Schmitt, Michèle; Belaidi, Halima; Ouazzani, Reda; Chkili, Taïb; Koenig, Michel

    2002-01-01

    Fifteen Moroccan families with a phenotype resembling Friedreich Ataxia (FA) were studied. Seven families (13 patients) had the 744 del A mutation in the alpha-tocopherol transfer protein (alpha-TTP) gene, characteristic of ataxia with vitamin E deficiency (AVED). The other eight families (16

  3. 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

  4. Pediatric Opsoclonus-Myoclonus-Ataxia Syndrome Associated With Anti-N-methyl-D-aspartate Receptor Encephalitis.

    Science.gov (United States)

    Player, Brittany; Harmelink, Matthew; Bordini, Brett; Weisgerber, Michael; Girolami, Michael; Croix, Michael

    2015-11-01

    The full clinical spectrum of anti-N-methyl-D-aspartate receptor encephalitis is unknown in the pediatric population. We describe a previously healthy 4-year-old girl presenting with opsoclonus-myoclonus together with ataxia who had NR1-specific, anti-N-methyl-D-aspartate receptor antibodies in the cerebral spinal fluid. The presence of NR1-specific, anti-N-methyl-D-aspartate receptor antibodies in the setting of opsoclonus-myoclonus and ataxia syndrome may represent an expansion of the clinical presentations of anti-N-methyl-D-aspartate receptor encephalitis. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    OpenAIRE

    Folgori, Laura; Scarselli, Alessia; Angelino, Giulia; Ferrari, Francesca; Antoccia, Antonio; Chessa, Luciana; Finocchi, Andrea

    2010-01-01

    Abstract Ataxia-telangiectasia (A-T) is a complex multisystem disorder characterized by progressive neurological impairment, variable immunodeficiency and oculo-cutaneous telangiectasia. A-T is a member of chromosomal breakage syndromes and it is caused by a mutation in the ataxia-telangiectasia mutated (ATM) gene. Because of a wide clinical heterogeneity, A-T is often difficult to diagnose in children. We report an unusual case of a 3-year-old boy affected by A-T who presented exclusively wi...

  6. 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.

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    Abdul Qayyum Rana

    2013-01-01

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

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

    OpenAIRE

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

    2015-01-01

    Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the l...

  11. GAD Antibody-Associated Late-Onset Cerebellar Ataxia in Two Female Siblings

    Directory of Open Access Journals (Sweden)

    Joseph Kuchling

    2014-11-01

    Full Text Available Background: Anti-glutamic acid decarboxylase antibody (GAD-ab-associated cerebellar ataxia is a rare neurological disorder characterized by cerebellar symptoms concomitant with high GAD-ab levels in serum and cerebrospinal fluid (CSF. Case Report: We report on 2 female siblings (aged 74 and 76 years presenting with gradual progression of rotational vertigo, gait ataxia and vertical diplopia, continuously progressing for 6 months and 6 years, respectively. Autoimmune laboratory examinations showed remarkably increased serum and CSF GAD-ab levels. Their medical histories revealed late-onset type 1 diabetes mellitus (T1DM and other concomitant autoimmune disorders (Grave's disease, Hashimoto's thyroiditis. Cerebral MRI and laboratory examinations were unremarkable. The diagnosis of GAD-ab-associated cerebellar ataxia with particular brainstem involvement was established in both women. After the exclusion of an underlying malignancy, immunosuppressive therapy has been initiated in both patients, which resulted in stabilization in one and in clinical improvement in the other patient. Discussion: The unique association of autoantibody-mediated cerebellar ataxia and late-onset T1DM in 2 siblings with similar clinical and paraclinical phenotypes strengthens the concept that hereditary factors might play a relevant role also in autoimmune diseases so far considered to be sporadic. Moreover, the occurrence of continuous vertical diplopia broadens the clinical spectrum of GAD-ab-associated neurological syndromes.

  12. 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

  13. 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

  14. 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.

  15. [Progressive ataxia and cognitive deficits caused by premutation in the fragile-X-mental retardation gene

    NARCIS (Netherlands)

    Roks, G.; Sistermans, E.A.; Vries, L.B.A. de; Nijssen, P.C.

    2005-01-01

    A 75-year-old man had progressive difficulty with walking, intention tremor, ataxia, and mild cognitive deficits. MRI scan ofthe brain showed symmetrical hyperintensities in the middle cerebellar peduncles. DNA analysis ofthe fragile-X gene revealed an expansion of 150-200 repetitions in the

  16. 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.

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

    African Journals Online (AJOL)

    She also had human immunoglobulin therapy and was immunised with pneumococcal and influenza vaccines with some clinical response but subsequently died. Conclusion: Ataxia telangiectasia is a rare multisystemic disorder with high morbidity and mortality in children. Delay in diagnosis and pulmonary complications ...

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

    International Nuclear Information System (INIS)

    Schneider, Tanja; Thomalla, Goetz; Goebell, Einar; Piotrowski, Anna; Yousem, David Mark

    2015-01-01

    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.)

  19. 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.

  20. 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…

  1. Exome Sequencing as a Diagnostic Tool for Pediatric-Onset Ataxia

    Science.gov (United States)

    Sawyer, Sarah L; Schwartzentruber, Jeremy; Beaulieu, Chandree L; Dyment, David; Smith, Amanda; Chardon, Jodi Warman; Yoon, Grace; Rouleau, Guy A; Suchowersky, Oksana; Siu, Victoria; Murphy, Lisa; Hegele, Robert A; Marshall, Christian R; Bulman, Dennis E; Majewski, Jacek; Tarnopolsky, Mark; Boycott, Kym M

    2014-01-01

    Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative. PMID:24108619

  2. 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.

  3. 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

  4. 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

  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. 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

  7. 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.

  8. 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.

  9. 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...

  10. 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.

  11. 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.

  12. 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.

  13. Huntington's disease-like and ataxia syndromes: identification of a family with a de novo SCA17/TBP mutation

    DEFF Research Database (Denmark)

    Bech, Sara; Petersen, Thor; Nørremølle, Anne

    2010-01-01

    with a Huntington's disease-like phenotype without the HD-gene mutation and 178 patients with genetically unclassified cerebellar ataxia for the mutation in TBP. A 33-year old woman presenting with an HD like phenotype with a de novo 54 CAG/CAA repeat expansion was identified. Her normal allele included 38 repeats......-like phenotypes and ataxia syndromes, also in isolated cases....

  14. [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.

  15. 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.

  16. Oculomotor apraxia and dilated cardiomyopathy with ataxia syndrome: A case report.

    Science.gov (United States)

    Benson, Matthew D; Ferreira, Patrick; MacDonald, Ian M

    2017-01-01

    Dilated cardiomyopathy with ataxia syndrome (DCMA) is a rare mitochondrial condition associated with early onset cardiomyopathy and non-progressive ataxia. The cardiac manifestations may be progressive and often severe, resulting in significant morbidity and mortality. While optic nerve atrophy has been described in patients with DCMA, to our knowledge, there have been no reports of additional ocular phenotypes. We present two related Dariusleut Hutterite patients with documented DCMA syndrome and disorders of ocular motility: poor smooth pursuit and difficulty initiating saccadic eye movements and maintaining target fixation. We thus report the first cases of oculomotor apraxia in DCMA syndrome. By identifying these associated findings early in life, we hope to improve both the clinical diagnostic accuracy and timeliness of intervention in cases of DCMA.

  17. New observations in the fragile X-associated tremor/ataxia syndrome (FXTAS phenotype

    Directory of Open Access Journals (Sweden)

    Avram eFraint

    2014-10-01

    Full Text Available Purpose: Fragile X-associated tremor/ataxia syndrome (FXTAS was originally defined as tremor, ataxia, cognitive decline and parkinsonism in individuals who carry between 55-200 CGG repeats in the promoter region of the fragile X mental retardation 1 (FMR1 gene. This paper describes a series of patients who meet the definition of FXTAS who presented for care between 2009-2014. Methods/Results: Retrospective chart review of patients seen in the FXTAS clinic at Rush University in Chicago. Conclusions: Patients with FXTAS may present with a progressive supranuclear palsy-like phenotype and eye movement abnormalities are common in these patients. Rapid worsening of gait abnormalities in FXTAS may be due to a secondary spinal issue and should be aggressively treated to regain function. Finally, the FXTAS Rating Scale score does not reliably inform the certainty of diagnosis or CGG repeat size in these patients.

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

    Science.gov (United States)

    Hagerman, Randi J; Hall, Deborah A; Coffey, Sarah; Leehey, Maureen; Bourgeois, James; Gould, John; Zhang, Lin; Seritan, Andreea; Berry-Kravis, Elizabeth; Olichney, John; Miller, Joshua W; Fong, Amy L; Carpenter, Randall; Bodine, Cathy; Gane, Louise W; Rainin, Edgar; Hagerman, Hillary; Hagerman, Paul J

    2008-01-01

    Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS. PMID:18686748

  19. Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome: a slowly progressive disorder with stereotypical presentation.

    Science.gov (United States)

    Cazzato, Daniele; Bella, Eleonora Dalla; Dacci, Patrizia; Mariotti, Caterina; Lauria, Giuseppe

    2016-02-01

    Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a newly described condition with onset in adulthood, characterized by progressive balance impairment and sensory disturbances in the lower limbs, which can severely affect patients' quality of life. Its pathogenesis remains obscure and the diagnosis challenging. We described four patients complaining of slowly progressive gait unbalance and sensory disturbances at the feet followed, after a period ranging 2-6 years, by cerebellar dysfunction. All patients showed gait and limb ataxia, positive Romberg sign, cerebellar dysarthria, gaze-evoked nystagmus, absent deep tendon reflexes, and impaired vibratory sensation. Nerve conduction studies revealed axonal sensory neuropathy, brain magnetic resonance imaging showed cerebellar atrophy, and otoneurological investigation demonstrated bilateral vestibular areflexia with impaired vestibulo-ocular reflexes. The diagnosis of CANVAS should be suspected on clinical ground based on homogeneous course of symptoms and signs, and addressed by video-oculography eye movement recording.

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

    Science.gov (United States)

    Alqwaifly, Mohammed; Bohlega, Saeed

    2016-06-15

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

  1. Ataxia and hypogonadotropic hypogonadism with intrafamilial variability caused by RNF216 mutation

    Directory of Open Access Journals (Sweden)

    Mohammed Alqwaifly

    2016-06-01

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

  2. Proposed diagnostic criteria for cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS).

    Science.gov (United States)

    Szmulewicz, David J; Roberts, Leslie; McLean, Catriona A; MacDougall, Hamish G; Halmagyi, G Michael; Storey, Elsdon

    2016-02-01

    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. 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. 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.

  3. A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia.

    Science.gov (United States)

    Mestre, Tiago A; Manole, Andreea; MacDonald, Heather; Riazi, Sheila; Kraeva, Natalia; Hanna, Michael G; Lang, Anthony E; Männikkö, Roope; Yoon, Grace

    2016-10-01

    Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.

  4. [Advances in Neurological Therapeutics for Friedreich Ataxia and Machado-Joseph Disease].

    Science.gov (United States)

    Yabe, Ichiro; Sasaki, Hidenao

    2017-08-01

    We reviewed advances in therapeutics for both Friedreich ataxia and Machado-Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported. We expect that these results will translate to therapeutic strategies for patients with these disorders. In addition, biomarkers play an important role when novel treatments are discovered and clinical trials are performed: hence at present, a number of biomarkers such as gait analysis by triaxial accelerometers and prism adaptation of hand-reaching movements, are being examined.

  5. 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.

  6. Xeroderma Pigmentosum/De Sanctis-Cacchione Syndrome: Unusual Cause of Ataxia

    Directory of Open Access Journals (Sweden)

    Robert Fekete

    2014-03-01

    Full Text Available Introduction: Xeroderma pigmentosum (XP is a rare autosomal recessive disorder of DNA repair, with a prevalence of 1 in 1 million. It may also be a cause of neurological symptoms including sensorineural hearing loss, peripheral neuropathy, ataxia, and chorea. Severe neurological symptoms including mental retardation, short stature, and hypogonadism invoke De Sanctis-Cacchione syndrome (DCS. Case Report: The patient was a 55-year-old woman with a history of mental retardation who developed chorea at age 32 and ataxia at age 37. She had numerous facial scars from 10 prior basal cell carcinoma excisions as well as diminished deep tendon reflexes, bilateral hearing loss, dysphagia, and skin freckling. Brain MRI revealed severe cortical, cerebellar, and brainstem atrophy. Supportive treatment and prevention of further damage from UV light is the mainstay of treatment in XP and DCS. Conclusion: XP and related disorders should be considered in the setting of neurological disorder and multiple cutaneous cancers.

  7. 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......-pulse transcranial magnetic stimulation at an interstimulus interval of 2 and 10 ms to assess intracortical inhibition and facilitation, respectively. The time course of burst-induced excitability changes differed between groups. Healthy controls showed a short-lived increase in excitability that was only present 50...... ms after the burst. In contrast, patients with episodic ataxia type 2 showed an abnormally prolonged increase in corticospinal excitability that was still present 250 ms after the transcranial magnetic stimulation burst. Furthermore, while controls showed a decrease in intracortical facilitation...

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

    Directory of Open Access Journals (Sweden)

    Antoccia Antonio

    2010-04-01

    Full Text Available Abstract Ataxia-telangiectasia (A-T is a complex multisystem disorder characterized by progressive neurological impairment, variable immunodeficiency and oculo-cutaneous telangiectasia. A-T is a member of chromosomal breakage syndromes and it is caused by a mutation in the ataxia-telangiectasia mutated (ATM gene. Because of a wide clinical heterogeneity, A-T is often difficult to diagnose in children. We report an unusual case of a 3-year-old boy affected by A-T who presented exclusively with extensive cutaneous granulomatosis and severe combined immunodeficiency, without neurological abnormalities, at the time of diagnosis. This case clearly emphasizes the variable presentation of A-T syndrome and highlights the difficulties in the early diagnosis of A-T. A-T should be considered in children with evidence of combined humoral and cellular immunodeficiency associated with unexplained skin granulomatous lesions, even in the absence of the classic features of this syndrome.

  9. Progressive Supranuclear Gaze Palsy with Predominant Cerebellar Ataxia: A Case Series with Videos

    Directory of Open Access Journals (Sweden)

    Zheyu Xu

    2017-05-01

    Full Text Available Progressive supranuclear palsy (PSP with predominant cerebellar ataxia (PSP-C is a rare phenotype of PSP. The clinical and radiological features of this disorder remain poorly characterized. Through a retrospective case series, we aim to characterize the clinical and radiological features of PSP-C. Four patients with PSP-C were identified: patients who presented with prominent cerebellar dysfunction that disappeared with the progression of the disease. Supranuclear gaze palsy occurred at a mean of 2.0 ± 2.3 years after the onset of ataxia. Mild cerebellar volume loss and midbrain atrophy were detected on brain imaging, which are supportive of a diagnosis of PSP. Videos are presented illustrating the co-existence of cerebellar signs and supranuclear gaze palsy and the disappearance of cerebellar signs with disease progression. Better recognition and the development of validated diagnostic criteria would aid in the antemortem recognition of this rare condition.

  10. hiPSC Disease Modeling of Rare Hereditary Cerebellar Ataxias: Opportunities and Future Challenges

    Czech Academy of Sciences Publication Activity Database

    Lukovic, D.; Moreno-Manzano, V.; Rodriquez; Jimenez, F.J.; Vilches, A.; Syková, Eva; Jendelová, Pavla; Stojkovic, M.; Erceg, Slaven

    2017-01-01

    Roč. 23, č. 5 (2017), s. 554-566 ISSN 1073-8584 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) LO1309; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:68378041 Keywords : 3D organoids * ataxia * disease modelling Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Developmental biology Impact factor: 7.391, year: 2016

  11. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia

    OpenAIRE

    Arvind Chaturvedi; H H Dash

    2011-01-01

    Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and...

  12. 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.

  13. 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.

  14. Automated quantitative analysis to assess motor function in different rat models of impaired coordination and ataxia.

    Science.gov (United States)

    Kyriakou, Elisavet I; van der Kieft, Jan G; de Heer, Raymond C; Spink, Andrew; Nguyen, Huu Phuc; Homberg, Judith R; van der Harst, Johanneke E

    2016-08-01

    An objective and automated method for assessing alterations in gait and motor coordination in different animal models is important for proper gait analysis. The CatWalk system has been used in pain research, ischemia, arthritis, spinal cord injury and some animal models for neurodegenerative diseases. Our goals were to obtain a comprehensive gait analysis of three different rat models and to identify which motor coordination parameters are affected and are the most suitable and sensitive to describe and detect ataxia with a secondary focus on possible training effects. Both static and dynamic parameters showed significant differences in all three models: enriched housed rats show higher walking and swing speed and longer stride length, ethanol-induced ataxia affects mainly the hind part of the body, and the SCA17 rats show coordination disturbances. Coordination changes were revealed only in the case of the ethanol-induced ataxia and the SCA17 rat model. Although training affected some gait parameters, it did not obscure group differences when those were present. To our knowledge, a comparative gait assessment in rats with enriched housing conditions, ethanol-induced ataxia and SCA17 has not been presented before. There is no gold standard for the use of CatWalk. Dependent on the specific effects expected, the protocol can be adjusted. By including all sessions in the analysis, any training effect should be detectable and the development of the performance over the sessions can provide insight in effects attributed to intervention, treatment or injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. 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.

  16. Progress in the research of Ataxia Telangiectasia as a radiation sensitive syndrome

    International Nuclear Information System (INIS)

    Wang Mingming; Zheng Siying; Cao Jianping

    2003-01-01

    Ataxia Telangiectasia (AT) as a genetic disorder results from single gene mutation, characterized by radiosensitivity, progressive nerve degeneration, immunodeficiency, premature aging and cancer predisposition. Progress in the research of AT is reviewed in this paper, including the clinical symptoms of this disorder, as well as the localization, structure and function of ATM (AT mutated) gene, the effects of ionizing radiation on the signal transduction of AT cells, AT genomic instability and AT gene therapy

  17. Friedreich's Ataxia: Cardiac Evaluation of 25 Patients with Clinical Diagnosis and Literature Review

    Directory of Open Access Journals (Sweden)

    Albano Lilian Maria José

    2002-01-01

    Full Text Available OBJECTIVE - Cardiac evaluation (clinical, electrocardiographic and echocardiographic of 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia (FA related to the frequency and the size of GAA repeats (unstable expansion of trinucleotide repeats that results in the disease. METHODS - Clinical and cardiac study including electrocardiogram and echocardiogram of all patients and molecular analysis to detect the frequency and the size of GAA expansion, by polymerase chain reaction analysis. RESULTS - Homozygous GAA expansion was detected in 17 patients (68% -- all typical cases. In 8 (32% cases (6 atypical and 2 typical, no GAA expansion was observed, therefore it was not considered Friedreich's ataxia. All patients with GAA expansion (100% had electrocardiographic abnormalities, and only 25% of the cases without GAA expansion had some abnormality on this exam. However, only 6% of all patients revealed some signals/symptoms suggestive of cardiac involvement. CONCLUSION - A molecular analysis is essential to confirm the diagnosis of Friedreich's ataxia; however, an adequate cardiac evaluation, including an electrocardiogram, was extremely useful to better screening the patients which should perform these molecular analysis.

  18. Novel Mitochondrial Homoplasmic T4216C Mutation in Iranian Patients with Friedreich Ataxia

    Directory of Open Access Journals (Sweden)

    M Heidari

    2010-06-01

    Full Text Available Introduction: The mitochondrial defects in Friedreich ataxia (FRDA have been reported in many researches. Friedreich ataxia is an autosomal recessive neurodegenerative disorder caused by decreased expression of the Frataxin protein. Frataxin deficiency leads to excessive free radical production and dysfunction of respiratory chain complexes. Mitochondrial DNA (mtDNA could be considered as a candidate modifier factor for FRDA disease. It prompted us to focus on the mtDNA and monitor the nucleotide changes of genome which are probably the cause of respiratory chain defects and reduced ATP generation. Methods: We searched the mitochondrial NADH dehydroganase I (ND1 gene by PCR-TTGE and DNA fragments showing abnormal banding patterns were sequenced for the identification of exact mutations. Results: In 20 patients, we detected 3 mtDNA mutations which is novel in Friedreich ataxia. T4216C mutation results in conversion of Tyrosine to Histidine in 313 amino acid locations in ND1 and bioinformatics studies show that ND1 protein loses sixth intramembrane α chain. Conclusion: Our results showed that ND1 gene mutations in FRDA samples are higher than normal controls (P<0.001. It is possible that mutations in mtDNA could constitute a predisposing factor in combination with environmental risk factors that could affect the age of onset and rate of disease progression.

  19. 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

  20. 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

  1. 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.

  2. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) - a case report and review of literature.

    Science.gov (United States)

    Figura, Monika; Gaweł, Małgorzata; Kolasa, Anna; Janik, Piotr

    2014-01-01

    CANVAS (cerebellar ataxia with neuropathy and vestibular areflexia syndrome) is a rare neurological syndrome of unknown etiology. The main clinical features include bilateral vestibulopathy, cerebellar ataxia and sensory neuropathy. An abnormal visually enhanced vestibulo-ocular reflex is the hallmark of the disease. We present a case of 58-year-old male patient who has demonstrated gait disturbance, imbalance and paresthesia of feet for 2 years. On examination ataxia of gait, diminished knee and ankle reflexes, absence of plantar reflexes, fasciculations of thigh muscles, gaze-evoked downbeat nystagmus and abnormal visually enhanced vestibulo-ocular reflex were found. Brain magnetic resonance imaging revealed cerebellar atrophy. Vestibular function testing showed severely reduced horizontal nystagmus in response to bithermal caloric stimulation. Nerve conduction study revealed loss of upper and lower limb sensory nerve action potentials. The course of illness was progressive with ataxic gait and unsteadiness as the most disabling symptoms. We report 4-year follow-up of the patient since the beginning of the disease. Copyright © 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  3. 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.

  4. Imaging study of lymphoreticular tumor development in ataxia-telangiectasia and Nijmegen breakage syndrome

    International Nuclear Information System (INIS)

    Martinez-Leon, M. I.; Ceres-Ruiz, L.; Cuesta, M. A.; Garcia-Martin, F. J.

    2003-01-01

    Ataxia-telangiectasia (AT), or Louis-Bar syndrome, is an autosomal recessive illness characterized by progressive cerebellar ataxia, oculo-cutaneous telangiectasia, immunodeficiency combined with susceptibility to sinopulmonary infections and high incidence of neoplastic development. Nijmegen breakage syndrome (NBS) is a variant of AT, is also an autosomal recessive illness that presents cerebellar ataxia, as well as combined immunodeficiency and a tendency toward tumor development. Contrary to Louis-Bar syndrome, it doesn't present telangiectasia and exhibits a characteristics phenotype (short stature, bird-like face and microcephaly). Both entities are classified as syndrome of chromosomal instability or chromosomal fragility, a group which also includes Bloom syndrome and Fanconi anemia. All of these show an increase in the frequency of neoplastic pathologies, mainly lymphoid tumors. We present three patients,two with AT and one with NBS, who developed different lymphoma types in the course of the illness. We highlight the most outstanding aspects from a clinical-radiological point of view. (Author) 17 refs

  5. NCBI nr-aa BLAST: CBRC-TNIG-21-0002 [SEVENS

    Lifescience Database Archive (English)

    Full Text Available CBRC-TNIG-21-0002 ref|NP_036858.1| spinocerebellar ataxia 1 [Rattus norvegicus] sp|...Q63540|ATX1_RAT Ataxin-1 (Spinocerebellar ataxia type 1 protein homolog) emb|CAA62822.1| sca1 [Rattus norveg

  6. 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.

  7. 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.

  8. Insights into the role of oxidative stress in the pathology of Friedreich ataxia using peroxidation resistant polyunsaturated fatty acids

    Directory of Open Access Journals (Sweden)

    M. Grazia Cotticelli

    2013-01-01

    Full Text Available Friedreich ataxia is an autosomal recessive, inherited neuro- and cardio-degenerative disorder characterized by progressive ataxia of all four limbs, dysarthria, areflexia, sensory loss, skeletal deformities, and hypertrophic cardiomyopathy. Most disease alleles have a trinucleotide repeat expansion in the first intron of the FXN gene, which decreases expression of the encoded protein frataxin. Frataxin is involved in iron–sulfur-cluster (ISC assembly in the mitochondrial matrix, and decreased frataxin is associated with ISC-enzyme and mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. To assess the role of oxidative stress in lipid peroxidation in Friedreich ataxia we used the novel approach of treating Friedreich ataxia cell models with polyunsaturated fatty acids (PUFAs deuterated at bis-allylic sites. In ROS-driven oxidation of PUFAs, the rate-limiting step is hydrogen abstraction from a bis-allylic site; isotopic reinforcement (deuteration of bis-allylic sites slows down their peroxidation. We show that linoleic and α-linolenic acids deuterated at the peroxidation-prone bis-allylic positions actively rescue oxidative-stress-challenged Friedreich ataxia cells. The protective effect of the deuterated PUFAs is additive in our models with the protective effect of the CoQ10 analog idebenone, which is thought to decrease the production of free radicals. Moreover, the administration of deuterated PUFAs resulted in decreased lipid peroxidation as measured by the fluorescence of the fatty acid analog C11-BODIPY (581/591 probe. Our results are consistent with a role for lipid peroxidation in Friedreich ataxia pathology, and suggest that the novel approach of oral delivery of isotope-reinforced PUFAs may have therapeutic potential in Friedreich ataxia and other disorders involving oxidative stress and lipid peroxidation.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. Recurrent major depression, ataxia, and cardiomyopathy: association with a novel POLG mutation?

    Directory of Open Access Journals (Sweden)

    Verhoeven WMA

    2011-05-01

    Full Text Available Willem MA Verhoeven1,2, Jos IM Egger1,3,4, Berry PH Kremer5, Boudewijn JHB de Pont1, Carlo LM Marcelis61Vincent van Gogh Institute for Psychiatry, Centre of Excellence for Neuropsychiatry, Venray, The Netherlands; 2Erasmus University Medical Centre, Department of Psychiatry, Rotterdam, The Netherlands; 3Behavioural Science Institute, Radboud University Nijmegen, Nijmegen, The Netherlands; 4Donders Institute for Brain, Cognition and Behaviour, Centre for Cognition, Radboud University Nijmegen, Nijmegen, The Netherlands; 5Department of Neurology, University Medical Centre Groningen, The Netherlands; 6Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsAbstract: At present, more than 100 disease mutations in mitochondrial DNA polymerase γ (POLG have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter being associated with Parkinsonism and depressive or psychotic syndromes. In this report, a middle-aged female patient with recurrent major depression with melancholic features, slowly progressive gait instability, and dilated cardiomyopathy is described. Detailed diagnostic evaluation was performed to elucidate the supposed relationship between ataxia, cardiomyopathy, and major depression with melancholia. After extensive genetic and metabolic investigation, a nucleotide substitution c.2207 A→G in the POLG gene resulting in amino acid change Asn 736Ser in exon 13 was demonstrated. This mutation was considered to be compatible with a mitochondrial disorder and implicated in the pathophysiology of the neuropsychiatric syndrome. It is concluded that this novel POLG mutation forms the most parsimonious etiological explanation for the here-described combination of ataxia, major depression, and cardiomyopathy. Therefore, in patients with a complex neuropsychiatric

  16. 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.

  17. 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.

  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. Mutations in GALC cause late-onset Krabbe disease with predominant cerebellar ataxia.

    Science.gov (United States)

    Shao, Yi-Hong; Choquet, Karine; La Piana, Roberta; Tétreault, Martine; Dicaire, Marie-Josée; Boycott, Kym M; Majewski, Jacek; Brais, Bernard

    2016-04-01

    Mutations in GALC cause Krabbe disease. This autosomal recessive leukodystrophy generally presents in early infancy as a severe disorder, but sometimes manifests as a milder adult-onset disease with spastic paraplegia as the main symptom. We recruited a family with five affected individuals presenting with adult-onset predominant cerebellar ataxia with mild spasticity. Whole exome sequencing (WES) revealed one novel and one previously reported compound heterozygous variants in GALC. Magnetic resonance imaging (MRI) confirmed the presence of typical Krabbe features. Our findings expand the phenotypic spectrum of adult-onset Krabbe disease and demonstrate the usefulness of combining WES and pattern-specific MRI for the diagnosis of neurodegenerative diseases.

  20. 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.

  1. 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.

  2. 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.

  3. Establishment and Maintenance of Primary Fibroblast Repositories for Rare Diseases-Friedreich's Ataxia Example.

    Science.gov (United States)

    Li, Yanjie; Polak, Urszula; Clark, Amanda D; Bhalla, Angela D; Chen, Yu-Yun; Li, Jixue; Farmer, Jennifer; Seyer, Lauren; Lynch, David; Butler, Jill S; Napierala, Marek

    2016-08-01

    Friedreich's ataxia (FRDA) represents a rare neurodegenerative disease caused by expansion of GAA trinucleotide repeats in the first intron of the FXN gene. The number of GAA repeats in FRDA patients varies from approximately 60 to repositories, especially in the context of rare and heterogeneous disorders, are presented. Although the economic aspect of creating and maintaining such repositories is important, the benefits of easy access to a collection of well-characterized cell lines for the purpose of drug discovery or disease mechanism studies overshadow the associated costs. Importantly, all FRDA fibroblast cell lines collected in our repository are available to the scientific community.

  4. Establishment and Maintenance of Primary Fibroblast Repositories for Rare Diseases—Friedreich's Ataxia Example

    Science.gov (United States)

    Li, Yanjie; Polak, Urszula; Clark, Amanda D.; Bhalla, Angela D.; Chen, Yu-Yun; Li, Jixue; Farmer, Jennifer; Seyer, Lauren; Lynch, David

    2016-01-01

    Friedreich's ataxia (FRDA) represents a rare neurodegenerative disease caused by expansion of GAA trinucleotide repeats in the first intron of the FXN gene. The number of GAA repeats in FRDA patients varies from approximately 60 to repositories, especially in the context of rare and heterogeneous disorders, are presented. Although the economic aspect of creating and maintaining such repositories is important, the benefits of easy access to a collection of well-characterized cell lines for the purpose of drug discovery or disease mechanism studies overshadow the associated costs. Importantly, all FRDA fibroblast cell lines collected in our repository are available to the scientific community. PMID:27002638

  5. 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.

  6. 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.

  7. 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...

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

    Directory of Open Access Journals (Sweden)

    Vahid Ezzatizadeh

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

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

    Directory of Open Access Journals (Sweden)

    Godani M

    2015-05-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  11. Sugammadex reversal of rocuronium-induced neuromuscular block in a patient with ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Kang, E.; Jung, J.W.

    2015-01-01

    A 17-year-old adolescent with ataxia-telangiectasia was scheduled to have laparoscopic colectomy for a resection of colon cancer. He had symptoms and signs of dyspnea, generalized dystonia, dysmetria, ataxia, and telangiectasia on the orbit. General anesthesia was performed, and rocuronium 30 mg was administered for muscle relaxation. Deep neuromuscular block (post-tetanic count: 0-8) was maintained for 95 minutes without additional rocuronium. On completion of surgery, sugammadex 80 mg was injected and train-of-four ratio was 0.93 at 210 seconds after administration. The tracheal tube was removed 5 min after the end of surgery. He recovered full spontaneous respiration and voluntary movements within 1 minute after extubation. After the surgery, he transferred to the intensive care unit and discharged 14 days after the surgery without any concrete problem. The reversal of rocuronium induced neuromuscular block by sugammadex was fast, complete, and recovered to the initial preoperative level of neuromuscular function in this patient. (author)

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

    Directory of Open Access Journals (Sweden)

    Teresa Anglada

    2016-01-01

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

  13. Generation and validation of a zebrafish model of EAST (epilepsy, ataxia, sensorineural deafness and tubulopathy syndrome

    Directory of Open Access Journals (Sweden)

    Fahad Mahmood

    2013-05-01

    Recessive mutations in KCNJ10, which encodes an inwardly rectifying potassium channel, were recently identified as the cause of EAST syndrome, a severe and disabling multi-organ disorder consisting of epilepsy, ataxia, sensorineural deafness and tubulopathy that becomes clinically apparent with seizures in infancy. A Kcnj10 knockout mouse shows postnatal mortality and is therefore not suitable for drug discovery. Because zebrafish are ideal for in vivo screening for potential therapeutics, we tested whether kcnj10 knockdown in zebrafish would fill this need. We cloned zebrafish kcnj10 and demonstrated that its function is equivalent to that of human KCNJ10. We next injected splice- and translation-blocking kcnj10 antisense morpholino oligonucleotides and reproduced the cardinal symptoms of EAST syndrome – ataxia, epilepsy and renal tubular defects. Several of these phenotypes could be assayed in an automated manner. We could rescue the morphant phenotype with complementary RNA (cRNA encoding human wild-type KCNJ10, but not with cRNA encoding a KCNJ10 mutation identified in individuals with EAST syndrome. Our results suggest that zebrafish will be a valuable tool to screen for compounds that are potentially therapeutic for EAST syndrome or its individual symptoms. Knockdown of kcnj10 represents the first zebrafish model of a salt-losing tubulopathy, which has relevance for blood pressure control.

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

    Directory of Open Access Journals (Sweden)

    Madjdinasab Nastaran

    2009-10-01

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

  15. Autonomic dysfunction is a major feature of cerebellar ataxia, neuropathy, vestibular areflexia 'CANVAS' syndrome.

    Science.gov (United States)

    Wu, Teddy Y; Taylor, Jennifer M; Kilfoyle, Dean H; Smith, Andrew D; McGuinness, Ben J; Simpson, Mark P; Walker, Elizabeth B; Bergin, Peter S; Cleland, James C; Hutchinson, David O; Anderson, Neil E; Snow, Barry J; Anderson, Tim J; Paermentier, Laura A F; Cutfield, Nick J; Chancellor, Andrew M; Mossman, Stuart S; Roxburgh, Richard H

    2014-10-01

    Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative ganglionopathy. Prompted by the presence of symptomatic postural hypotension in two patients with CANVAS, we hypothesized that autonomic dysfunction may be an associated feature of the syndrome. We assessed symptoms of autonomic dysfunction and performed autonomic nervous system testing among 26 patients from New Zealand. After excluding three patients with diabetes mellitus, 83% had evidence of autonomic dysfunction; all patients had at least one autonomic symptom and 91% had more than two symptoms. We also found a higher rate of downbeat nystagmus (65%) than previously described in CANVAS. We confirmed that sensory findings on nerve conduction tests were consistent with a sensory ganglionopathy and describe two patients with loss of trigeminal sensation consistent with previous pathological descriptions of trigeminal sensory ganglionopathy. Our results suggest that autonomic dysfunction is a major feature of CANVAS. This has implications for the management of patients with CANVAS as the autonomic symptoms may be amenable to treatment. The findings also provide an important differential diagnosis from multiple system atrophy for patients who present with ataxia and autonomic failure. © 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.

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

    Directory of Open Access Journals (Sweden)

    Maryam Rahimi Balaei

    2016-01-01

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

  17. Neuroprotective Role of Liver Growth Factor “LGF” in an Experimental Model of Cerebellar Ataxia

    Directory of Open Access Journals (Sweden)

    Lucía Calatrava-Ferreras

    2014-10-01

    Full Text Available Cerebellar ataxias (CA comprise a heterogeneous group of neurodegenerative diseases characterized by a lack of motor coordination. They are caused by disturbances in the cerebellum and its associated circuitries, so the major therapeutic goal is to correct cerebellar dysfunction. Neurotrophic factors enhance the survival and differentiation of selected types of neurons. Liver growth factor (LGF is a hepatic mitogen that shows biological activity in neuroregenerative therapies. We investigate the potential therapeutic activity of LGF in the 3-acetylpiridine (3-AP rat model of CA. This model of CA consists in the lesion of the inferior olive-induced by 3-AP (40 mg/kg. Ataxic rats were treated with 5 µg/rat LGF or vehicle during 3 weeks, analyzing: (a motor coordination by using the rota-rod test; and (b the immunohistochemical and biochemical evolution of several parameters related with the olivo-cerebellar function. Motor coordination improved in 3-AP-lesioned rats that received LGF treatment. LGF up-regulated NeuN and Bcl-2 protein levels in the brainstem, and increased calbindin expression and the number of neurons receiving calbindin-positive projections in the cerebellum. LGF also reduced extracellular glutamate and GABA concentrations and microglia activation in the cerebellum. In view of these results, we propose LGF as a potential therapeutic agent in cerebellar ataxias.

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

    Science.gov (United States)

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

    2016-10-01

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

  19. Ataxia Telangiectasia

    Science.gov (United States)

    ... A-T families in collaboration with registries in Norway, Sweden, Denmark, and Finland. Another large, multi-site ... Publications Site Map Digital Standards for NCI Websites POLICIES Accessibility Comment Policy Disclaimer FOIA Privacy & Security Reuse & ...

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

    Czech Academy of Sciences Publication Activity Database

    Andrs, M.; Korábečný, J.; Nepovimova, E.; Jun, D.; Hodný, Zdeněk; Kuca, K.

    2016-01-01

    Roč. 16, č. 3 (2016), s. 200-208 ISSN 1568-0096 Institutional support: RVO:68378050 Keywords : Ataxia telangiectasia and Rad3-related kinase (ATR) * cancer * chemosensitization * DNA damage response * phosphatidylinositol 3-kinase-related protein kinases (PIKK) * radiosensitization * synthetic lethality Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.992, year: 2016