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1.
Hum Mutat ; 40(4): 404-412, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30588707

RESUMO

Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n . Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT-rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Ataxinas/genética , Mutagênese Insercional , Proteínas do Tecido Nervoso/genética , Sequências Repetitivas de Ácido Nucleico , Alelos , Animais , Sequência de Bases , Estudos de Casos e Controles , Cromossomos , Sequência Conservada , Evolução Molecular , Haplótipos , Humanos , Filogenia , Portugal , Primatas
2.
Handb Clin Neurol ; 155: 143-174, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29891056

RESUMO

There are over 40 autosomal dominant spinocerebellar ataxias (SCAs) now identified. In this chapter we delineate the phenotypes of SCAs 1-44 and dentatorubral-pallidoluysian atrophy (DRPLA) and highlight the clinical and genetic features of the well characterised SCAs in detail in the main section of the chapter, along with their frequency and age at onset. We have included a section on the key phenotypic features of rare spinocerebellar ataxias and discuss rare and unusual presentations and genetic mechanisms of the ataxias and show differences between adult and paediatric presentations. We look at unusual mechanisms where knowledge is evolving in some dominant ataxias. For ease of reference we have tabulated historical aspects of the ataxias, major neurological diagnostic features, ataxias with predominant paediatric and infantile onset and list recognisable nerve conduction features. We comment on the anti-sense ataxia gene mechanisms and we discuss potential developments including exome sequencing and potential therapeutic options. A gene table listing all of the identified SCAs and DRPLA is also included with key references and gene locations and symbols with OMIM reference numbers for further reading.


Assuntos
Aberrações Cromossômicas , Epilepsias Mioclônicas Progressivas/etiologia , Ataxias Espinocerebelares/complicações , Ataxinas/genética , Genótipo , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Mutação/genética , Epilepsias Mioclônicas Progressivas/genética , Epilepsias Mioclônicas Progressivas/história , Ataxias Espinocerebelares/classificação , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/história
3.
J Neurol ; 265(7): 1618-1624, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29737427

RESUMO

Blood biomarkers in degenerative ataxias are still largely missing. Here, we aimed to provide piloting proof-of-concept that serum Neurofilament light (NfL) could offer a promising peripheral blood biomarker in degenerative ataxias. Specifically, as a marker of neuronal damage, NfL might (1) help to differentiate multiple system atrophy of cerebellar type (MSA-C) from sporadic adult-onset ataxia (SAOA), and (2) show increases in repeat-expansion spinocerebellar ataxias (SCAs) which might be amenable to treatment in the future. To explore these two hypotheses, we measured serum NfL levels by single-molecule array (Simoa) technique in 115 subjects, comprising patients with MSA-C (n = 25), SAOA (n = 25), the most frequent repeat-expansion SCAs (SCA 1, 2, 3 and 6) (n = 20), and age-matched controls (n = 45). Compared to controls, NfL was significantly increased in MSA-C, with levels significantly higher than in SAOA (AUC = 0.74 (0.59-0.89), mean and 95% confidence interval, p = .004). NfL was also significantly increased in SCA patients as compared to controls (AUC = 0.91 (0.81-1.00), p < .001), including NfL increases in SCA1 and SCA3. These findings provide first proof-of-concept that NfL might provide a promising peripheral biomarker in degenerative ataxias, e.g. supporting the differentiation of MSA-C from SAOA, and indicating neuronal damage in repeat-expansion SCAs.


Assuntos
Ataxinas/genética , Cerebelo/patologia , Atrofia de Múltiplos Sistemas , Proteínas de Neurofilamentos/sangue , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/sangue , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/patologia , Projetos Piloto , Curva ROC
4.
Ann Neurol ; 83(4): 816-829, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29575033

RESUMO

OBJECTIVE: To investigate whether early neurochemical abnormalities are detectable by high-field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3, and 6, including patients without manifestation of ataxia. METHODS: A cohort of 100 subjects (N = 18-21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia [SARA] <10 for all genotypes, and 22 matched controls) was scanned at 7 Tesla to obtain neurochemical profiles of the cerebellum and brainstem. A novel multivariate approach (distance-weighted discrimination) was used to combine regional profiles into an "MRS score." RESULTS: MRS scores robustly distinguished individuals with SCA from controls, with misclassification rates of 0% (SCA2), 2% (SCA3), 5% (SCA1), and 17% (SCA6). Premanifest mutation carriers with estimated disease onset within 10 years had MRS scores in the range of early-manifest SCA subjects. Levels of neuronal and glial markers significantly correlated with SARA and an Activities of Daily Living score in subjects with SCA. Regional neurochemical alterations were different between SCAs at comparable disease severity, with SCA2 displaying the most extensive neurochemical abnormalities, followed by SCA1, SCA3, and SCA6. INTERPRETATION: Neurochemical abnormalities are detectable in individuals before manifest disease, which may allow premanifest enrollment in future SCA trials. Correlations with ataxia and quality-of-life scores show that neurochemical levels can serve as clinically meaningful endpoints in trials. Ranking of SCA types by degree of neurochemical abnormalities indicates that the neurochemistry may reflect synaptic function or density. Ann Neurol 2018;83:816-829.


Assuntos
Ácido Aspártico/análogos & derivados , Encefalopatias Metabólicas/etiologia , Encéfalo/metabolismo , Ataxias Espinocerebelares/patologia , Atividades Cotidianas , Adulto , Idoso , Ácido Aspártico/metabolismo , Ataxinas/genética , Encéfalo/diagnóstico por imagem , Encefalopatias Metabólicas/diagnóstico por imagem , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Ácido Glutâmico/metabolismo , Humanos , Inositol/metabolismo , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
5.
Sci Rep ; 8(1): 3889, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29497168

RESUMO

Multiple system atrophy (MSA) is a complex and multifactorial neurodegenerative disease, and its pathogenesis remains uncertain. Patients with MSA or spinocerebellar ataxia (SCA) show overlapping clinical phenotypes. Previous studies have reported that intermediate or long CAG expansions in SCA genes have been associated with other neurodegenerative disease. In this study, we screened for the number of CAG repeats in ATXN1, 2 and 3 in 200 patients with MSA and 314 healthy controls to evaluate possible associations between (CAG)n in these three polyQ-related genes and MSA. Our findings indicated that longer repeat lengths in ATXN2 were associated with increased risk for MSA in Chinese individuals. No relationship was observed between CAG repeat length in the three examined genes and age at onset (AO) of MSA.


Assuntos
Ataxinas/genética , Atrofia de Múltiplos Sistemas/genética , Adulto , Idade de Início , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Ataxina-1/genética , Ataxina-1/metabolismo , Ataxina-2/genética , Ataxina-2/metabolismo , Ataxina-3/genética , Ataxina-3/metabolismo , Ataxinas/metabolismo , China , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/metabolismo , Atrofia de Múltiplos Sistemas/patologia , Proteínas do Tecido Nervoso/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos , Repetições de Trinucleotídeos/genética
6.
Biophys J ; 114(2): 323-330, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29401430

RESUMO

The AXH domain of protein Ataxin 1 is thought to play a key role in the misfolding and aggregation pathway responsible for Spinocerebellar ataxia 1. For this reason, a molecular level understanding of AXH oligomerization pathway is crucial to elucidate the aggregation mechanism, which is thought to trigger the disease. This study employs classical and enhanced molecular dynamics to identify the structural and energetic basis of AXH tetramer stability. Results of this work elucidate molecular mechanisms behind the destabilizing effect of protein mutations, which consequently affect the AXH tetramer assembly. Moreover, results of the study draw attention for the first time, to our knowledge, to the R638 protein residue, which is shown to play a key role in AXH tetramer stability. Therefore, R638 might be also implicated in the AXH oligomerization pathway and stands out as a target for future experimental studies focused on self-association mechanisms and fibril formation of full-length ATX1.


Assuntos
Ataxinas/química , Ataxinas/genética , Mutação , Agregados Proteicos/genética , Multimerização Proteica/genética , Ataxinas/metabolismo , Simulação de Dinâmica Molecular , Estabilidade Proteica , Estrutura Quaternária de Proteína , Termodinâmica
7.
Ann Neurol ; 82(4): 615-621, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28976605

RESUMO

OBJECTIVE: Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients. METHODS: We enrolled 10 SCA38 patients, and carried out a double-blind randomized placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline and at follow-up visit, patients underwent standardized clinical assessment, brain 18-fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis. RESULTS: After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40-week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded. INTERPRETATION: DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615-621.


Assuntos
Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ataxias Espinocerebelares/tratamento farmacológico , Adulto , Ataxinas/genética , Encéfalo/diagnóstico por imagem , Método Duplo-Cego , Eletromiografia , Feminino , Fluordesoxiglucose F18/farmacocinética , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Avaliação de Resultados em Cuidados de Saúde , Tomografia por Emissão de Pósitrons , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Resultado do Tratamento
8.
Transl Psychiatry ; 7(6): e1143, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28585930

RESUMO

Depression is one of the most prevalent and debilitating psychiatric disorders worldwide. Recently, we showed that both relatively short and relatively long cytosine-adenine-guanine (CAG) repeats in the huntingtin gene (HTT) are associated with an increased risk of lifetime depression. However, to what extent the variations in CAG repeat length in the other eight polyglutamine disease-associated genes (PDAGs) are associated with depression is still unknown. We determined the CAG repeat sizes of ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1 and AR in two well-characterized Dutch cohorts-the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons-including 2165 depressed and 1058 non-depressed individuals-aged 18-93 years. The association between PDAG CAG repeat size and the risk for depression was assessed via binary logistic regression. We found that the odds ratio (OR) for lifetime depression was significantly higher for individuals with >10, compared with subjects with ≤10, CAG repeats in both ATXN7 alleles (OR=1.90, confidence interval (CI) 1.26-2.85). For TBP we found a similar association: A CAG repeat length exceeding the median in both alleles was associated with an increased risk for lifetime depression (OR=1.33, CI 1.00-1.76). In conclusion, we observed that carriers of either ATXN7 or TBP alleles with relatively large CAG repeat sizes in both alleles had a substantially increased risk of lifetime depression. Our findings provide critical evidence for the notion that repeat polymorphisms can act as complex genetic modifiers of depression.


Assuntos
Ataxina-7/genética , Predisposição Genética para Doença , Proteína de Ligação a TATA-Box/genética , Repetições de Trinucleotídeos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Ataxinas/genética , Canais de Cálcio/genética , Estudos de Casos e Controles , Transtorno Depressivo/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Receptores Androgênicos/genética , Adulto Jovem
9.
Parkinsonism Relat Disord ; 40: 69-72, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28462804

RESUMO

OBJECTIVE: We describe a Korean family in SCA2 with long-duration levodopa-responsive parkinsonism without cerebellar ataxia. METHODS: Clinical evaluation, genetic testing, and extensive imaging studies were done. RESULTS: All family members showed a typical Parkinson's disease phenotype without cerebellar ataxia for a long disease duration (up to 34 years). Genetic testing showed 40 CAG repeats and 4 CAA interruptions which is the longest repeat number among the families or patients manifesting with a parkinsonian phenotype without ataxia. Structural imaging (7T MRI and brain CT) showed a normal cerebellum and functional images showed nigrostriatal dopaminergic degeneration and normal D2 receptor binding activity, in agreement with the clinical phenotype. CONCLUSION: SCA2 should be considered as a cause of typical Parkinson's disease phenotype even in the absence of cerebellar ataxia.


Assuntos
Ataxina-2/genética , Predisposição Genética para Doença , Mutação/genética , Doença de Parkinson/genética , Idoso , Ataxinas/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Ataxias Espinocerebelares/genética
10.
Hum Mol Genet ; 26(16): 3069-3080, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28525545

RESUMO

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the ATXN2 gene. The repeat resides in an encoded region of the gene resulting in polyglutamine (polyQ) expansion which has been assumed to result in gain of function, predominantly, for the ATXN2 protein. We evaluated temporal cerebellar expression profiles by RNA sequencing of ATXN2Q127 mice versus wild-type (WT) littermates. ATXN2Q127 mice are characterized by a progressive motor phenotype onset, and have progressive cerebellar molecular and neurophysiological (Purkinje cell firing frequency) phenotypes. Our analysis revealed previously uncharacterized early and progressive abnormal patterning of cerebellar gene expression. Weighted Gene Coexpression Network Analysis revealed four gene modules that were significantly correlated with disease status, composed primarily of genes associated with GTPase signaling, calcium signaling and cell death. Of these genes, few overlapped with differentially expressed cerebellar genes that we identified in Atxn2-/- knockout mice versus WT littermates, suggesting that loss-of-function is not a significant component of disease pathology. We conclude that SCA2 is a disease characterized by gain of function for ATXN2.


Assuntos
Redes Reguladoras de Genes , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Animais , Ataxina-2/genética , Ataxina-2/metabolismo , Ataxinas/genética , Sequência de Bases , Cerebelo/metabolismo , Modelos Animais de Doenças , Mutação com Ganho de Função , Expressão Gênica , Perfilação da Expressão Gênica , Camundongos , Mutação , Proteínas do Tecido Nervoso/genética , Células de Purkinje/metabolismo , Análise de Sequência de RNA , Repetições de Trinucleotídeos
11.
Parkinsonism Relat Disord ; 38: 80-84, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28216058

RESUMO

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Ataxinas/genética , Mutação/genética , Mioclonia/etiologia , Ataxias Espinocerebelares/congênito , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Eletroencefalografia , Eletromiografia , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mioclonia/genética , Exame Neurológico , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , Adulto Jovem
12.
Cerebellum ; 16(3): 615-622, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27848087

RESUMO

The aim of this study is to determine whether the initial symptom associates with motor progression in spinocerebellar ataxias (SCAs). SCAs are clinically heterogeneous and the initial presentation may represent different subtypes of SCA with different motor progression. We studied 317 participants with SCAs1, 2, 3, and 6 from the Clinical Research Consortium for SCAs (CRC-SCA) and repeatedly measured the severity of ataxia for 2 years. SCA patients were divided into gait-onset and non-gait-onset (speech, vision, and hand dexterity) groups based on the initial presentation. In addition to demographic comparison, we employed regression models to study ataxia progression in these two groups after adjusting for age, sex, and pathological CAG repeats. The majority of SCA patients had gait abnormality as an initial presentation. The pathological CAG repeat expansions were similar between the gait-onset and non-gait-onset groups. In SCA1, gait-onset group progressed slower than non-gait-onset group, while gait-onset SCA6 group progressed faster than their counterpart. In addition, the disease presented 9 years later for SCA2 gait-onset group than non-gait-onset group. Initial symptoms of SCA3 did not influence age of onset or disease progression. The initial symptom in each SCA has a different influence on age of onset and motor progression. Therefore, gait and non-gait-onset groups of SCAs might represent different subtypes of the diseases.


Assuntos
Ataxinas/genética , Ataxia Cerebelar/genética , Ataxias Espinocerebelares/genética , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Ataxias Espinocerebelares/diagnóstico , Repetições de Trinucleotídeos/genética
13.
Clin Genet ; 90(4): 305-14, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27220866

RESUMO

Spinocerebellar ataxia (SCA) comprises a large group of heterogeneous neurodegenerative disorders inherited in an autosomal dominant fashion. It is characterized by progressive cerebellar ataxia with oculomotor dysfunction, dysarthria, pyramidal signs, extrapyramidal signs, pigmentary retinopathy, peripheral neuropathy, cognitive impairment and other symptoms. It is classified according to the clinical manifestations or genetic nosology. To date, 40 SCAs have been characterized, and include SCA1-40. The pathogenic genes of 28 SCAs were identified. In recent years, with the widespread clinical use of next-generation sequencing, the genes underlying SCAs, and the mutants as well as the affected phenotypes were identified. These advances elucidated the phenotype-genotype relationship in SCAs. We reviewed the recent clinical advances, genetic features and phenotype-genotype correlations involving each SCA and its differentiation. The heterogeneity of the disease and the genetic diagnosis might be attributed to the regional distribution and clinical characteristics. Therefore, recognition of the phenotype-genotype relationship facilitates genetic testing, prognosis and monitoring of symptoms.


Assuntos
Estudos de Associação Genética , Ataxias Espinocerebelares/genética , Ataxinas/química , Ataxinas/genética , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética , Mutação , Análise de Sequência de DNA , Ataxias Espinocerebelares/patologia
14.
J Mol Neurosci ; 58(1): 83-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26454745

RESUMO

The polyglutamine spinocerebellar ataxias (SCAs) constitute a clinically and genetically heterogeneous group of rare late-onset neurodegenerative disorders, caused by CAG expansions in the coding region of the respective genes. Given their considerable clinical overlapping, differential diagnosis relies on molecular testing. Laboratory best practice guidelines for molecular genetic testing of the SCAs were released in 2010 by the European Molecular Genetics Quality Network, following the recognition of gross genotyping errors by some diagnostic laboratories. The main goal of this study was to verify the existence of inter-laboratorial consistency comparing genotypes for SCA1, SCA2, SCA3, SCA6 and SCA7 obtained by independent diagnostic laboratories. The individual impact of different methodological issues on the genotype for the several SCAs was also analysed. Four international collaborative diagnostic laboratories provided 79 samples and the respective SCA genotypes. Samples were genotyped in-house for all SCAs using an independent methodology; comparison of the allele size obtained with the one provided by the collaborative laboratories was performed. Globally, no significant differences were identified, a result which could be reflecting the fulfilment of recommendations for the molecular testing of SCAs and demonstrating an improvement in genotyping accuracy.


Assuntos
Ataxinas/genética , Testes Genéticos/normas , Técnicas de Genotipagem/normas , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos/genética , Genótipo , Humanos , Variações Dependentes do Observador , Peptídeos/genética
15.
Neurology ; 85(15): 1283-92, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26354989

RESUMO

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. RESULTS: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. CONCLUSIONS: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.


Assuntos
Frequência do Gene/genética , Predisposição Genética para Doença , Doença de Parkinson/genética , Peptídeos/genética , Expansão das Repetições de Trinucleotídeos/genética , Idoso , Ataxinas/genética , Ataxinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Doença de Parkinson/epidemiologia , Fenótipo , Risco
16.
J Neurosci ; 35(32): 11292-307, 2015 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-26269637

RESUMO

UNLABELLED: Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT: In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensatory role for neuronal shrinkage. Purkinje neuron firing in these mice is initially normal, but is followed by abnormal membrane depolarization resulting from a reduction in potassium channels. Subsequently, these electrophysiological effects are counteracted by cell atrophy, which by restoring normal potassium channel membrane density, re-establishes pacemaker firing. Reversing the initial membrane depolarization improved motor function and Purkinje neuron morphology in the SCA1 mice. These results suggest that Purkinje neuron remodeling in ataxia is an active compensatory response that serves to normalize intrinsic membrane excitability.


Assuntos
Cerebelo/patologia , Potenciais da Membrana/fisiologia , Células de Purkinje/patologia , Ataxias Espinocerebelares/patologia , Potenciais de Ação/fisiologia , Animais , Ataxina-1 , Ataxinas , Atrofia/patologia , Atrofia/fisiopatologia , Cerebelo/fisiopatologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Células de Purkinje/fisiologia , Ataxias Espinocerebelares/fisiopatologia
17.
J Neurosci ; 35(27): 9799-810, 2015 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-26156983

RESUMO

Many neural circuits show fast reconfiguration following altered sensory or modulatory inputs to generate stereotyped outputs. In the motor circuit of Xenopus tadpoles, I study how certain voltage-dependent ionic currents affect firing thresholds and contribute to circuit reconfiguration to generate two distinct motor patterns, swimming and struggling. Firing thresholds of excitatory interneurons [i.e., descending interneurons (dINs)] in the swimming central pattern generator are raised by depolarization due to the inactivation of Na(+) currents. In contrast, the thresholds of other types of neurons active in swimming or struggling are raised by hyperpolarization from the activation of fast transient K(+) currents. The firing thresholds are then compared with the excitatory synaptic drives, which are revealed by blocking action potentials intracellularly using QX314 during swimming and struggling. During swimming, transient K(+) currents lower neuronal excitability and gate out neurons with weak excitation, whereas their inactivation by strong excitation in other neurons increases excitability and enables fast synaptic potentials to drive reliable firing. During struggling, continuous sensory inputs lead to high levels of network excitation. This allows the inactivation of Na(+) currents and suppression of dIN activity while inactivating transient K(+) currents, recruiting neurons that are not active in swimming. Therefore, differential expression of these currents between neuron types can explain why synaptic strength does not predict firing reliability/intensity during swimming and struggling. These data show that intrinsic properties can override fast synaptic potentials, mediate circuit reconfiguration, and contribute to motor-pattern switching.


Assuntos
Geradores de Padrão Central/fisiologia , Locomoção/fisiologia , Inibição Neural/fisiologia , Periodicidade , Filtro Sensorial/efeitos dos fármacos , 4-Aminopiridina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Anestésicos Locais/farmacologia , Animais , Ataxinas , Geradores de Padrão Central/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Gonadotropinas/farmacologia , Humanos , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Locomoção/efeitos dos fármacos , Masculino , Proteínas do Tecido Nervoso/farmacologia , Inibição Neural/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Natação/fisiologia , Xenopus
18.
Parkinsonism Relat Disord ; 21(8): 943-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26077168

RESUMO

BACKGROUND: To investigate the association of repeat expansion size in 10 common degenerative hereditary ataxia genes with essential tremor. These genes were spinocerebellar ataxia (SCA)-1 (ATXN1), SCA-2 (ATXN2), SCA-3 (ATXN3), SCA-6 (CACNA1A), SCA-7 (ATXN7), SCA-8 (ATXN8OS), SCA-10 (ATXN10), SCA-12 (PPP2R2B), SCA-17 (TBP) and dentatorubral-pallidolysian atrophy (DRPLA) (ATN1). METHODS: Genetic analysis of repeat size in 10 degenerative hereditary ataxia loci was performed in 323 essential tremor patients and 299 controls enrolled at Columbia University. To test for differences in the allele distribution between patients and controls, a CLUMP analysis was performed. RESULTS: None of the essential tremor patients had a repeat expansion in the intermediate or pathogenic range. Significant differences in the distribution of repeats in the 'normal' range for SCA2 and SCA8 (both p ≤ 0.02) were observed between essential tremor patients and controls. CONCLUSIONS: Our study suggests that pathogenic repeat expansions in SCA loci are not associated with essential tremor.


Assuntos
Ataxinas/genética , Tremor Essencial/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Feminino , Loci Gênicos , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA
19.
Psychogeriatrics ; 15(3): 212-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25920043

RESUMO

A 50-year-old Japanese man showed slowly progressive gait disturbance and dysarthria. Neurological examination 5 years after onset revealed slow eye movement with nystagmus as well as limb and truncal ataxia. Magnetic resonance imaging showed atrophy of the cerebellum and brainstem. Because genetic examination revealed CAG repeat expansion of the ataxin-1 gene, the patient was diagnosed with spinocerebellar ataxia type 1. Ten years after onset, he showed psychiatric symptoms with cognitive impairment, and antipsychotic drugs were administered. As psychiatric symptoms gradually worsened, particularly with regard to resisting nursing care and shouting, the doses of the drugs were increased. Although the clinicopathologic findings were generally identical to previously reported spinocerebellar ataxia type 1 cases with the exception of the conspicuous psychiatric symptoms, there are two notable immunohistochemical findings. Firstly, numerous anti-expanded polyglutamine antibody-immunopositive neuronal inclusions were extensively observed, including in the cerebral cortex and limbic system, but not in the Purkinje cells. Secondly, anti-fused in sarcoma antibody-immunopositive intranuclear inclusions were extensively observed. We posit that the anti-expanded polyglutamine antibody-immunopositive neuronal inclusions and possibly the anti-fused in sarcoma antibody-immunopositive inclusions, particularly those in the neocortex and limbic system, may correspond to the psychiatric symptoms and cognitive impairment that were observed in the patient.


Assuntos
Encéfalo/patologia , Peptídeos/metabolismo , Sarcoma/patologia , Ataxias Espinocerebelares/patologia , Expansão das Repetições de Trinucleotídeos , Ataxinas , Atrofia , Humanos , Imuno-Histoquímica , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia , Neurônios/patologia
20.
Mymensingh Med J ; 24(1): 44-51, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25725667

RESUMO

This study was conducted to find out Spinocerebellar Ataxias (SCA) by genetic analysis from those patients presenting with Parkinsonism in the Neurology department of Mymensingh Medical College Hospital, Bangladesh. A sample of about 5ml blood was collected by venipuncture in EDTA tube after having informed consent from each patients and healthy individual, with due Institutional Ethical committee approval for genetic study of 7 healthy people and 9 patients. The neurological disorder along with a complete physical and/or psychological, as well as family history and demographic data was recorded with a prescribed questionnaire by the neurologists of Mymensingh Medical College Hospital. Extraction of genomic DNA from the venous blood using Flexi Gene DNA kit (Qiagen, Japan) was performed in Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh. The extracted DNA was stored, accumulated and then were sent to Division of Clinical Genetics, Department of Medical Genetics, Osaka University Medical School, Suita, Osaka 565 0871, Japan for PCR and further analysis. PCR amplification of the CAG repeat was performed for the SCA1, SCA2, SCA3, SCA6 loci using primers SCA1N-F1 and SCA1N-R1, SCA2-F1 and SCA2-R1, MJDF1 and MJDR1, SCA6-F1 and SCA6-R1, respectively. SCA1 PCR of both healthy individual and suspected Parkinsons Disease (PD) patients DNA was found 250 bp (no. of CAG repeats=36). SCA2 PCR products reveal the DNA products of about 150 bp (no. of CAG repeats=23) except one patient that was suspected and it was sequenced and revealed 175bp (no. of CAG repeats=30). SCA3 PCR product size of both healthy individual and patient DNA was within 250 (no. of CAG repeats=11) to 300 bp (no. of CAG repeats=28) except one patient which was about 320 bp and its CAG repeats was about 34. SCA6 PCR product size of both healthy individual and patient DNA was about 150 bp (no. of CAG repeats=16).


Assuntos
Testes Genéticos , Doença de Parkinson/genética , Ataxias Espinocerebelares/genética , Ataxina-3 , Ataxinas , Canais de Cálcio/genética , Diagnóstico Diferencial , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Repetições de Trinucleotídeos
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