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

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

Spinocerebellar ataxia type 3: subphenotypes in a cohort of brazilian patients / Ataxia espinocerebelar do tipo 3: subfenótipos em uma coorte de pacientes brasileiros

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

A ataxia espinocerebelar do tipo 3 (AEC3) envolve os sistemas cerebelar, piramidal, extrapiramidal, do neurônio motor e oculomotor, com uma grande heterogeneidade fenotípica, o que nos levou a classificar essa desordem em diferentes subtipos clínicos de acordo com o sistema predominantemente afetado. Método Nossa série compreende 167 pacientes com AEC3, pertencentes a 68 famílias, avaliados de 1989 a 2013. Esses pacientes foram classificados em 7 diferentes subtipos. Resultados Os pacientes com AEC3 foram agrupados de acordo com as características clínicas predominantes. As três formas mais comum foram o subfenótipo 2, caracterizado por ataxia e sintomas piramidais, observado em 67,5% dos pacientes, subfenótipo 3 com ataxia e sinais periféricos, em 13,3%, e subfenótipo 6 com síndrome cerebelar pura, em 7,2%. Conclusão Nosso estudo foi o primeiro a classificar sistematicamente AEC3 em sete subtipos. Esta classificação pode ser particularmente útil para correlacionar fenótipo/genótipo com mais especificidade em futuros estudos. .

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study.

OBJECTIVE: To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits. METHODS: As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count. RESULTS: The annual increase of the SARA score was greatest in SCA1 (2.18 ± 0.17, mean ± SE) followed by SCA3 (1.61 ± 0.12) and SCA2 (1.40 ± 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 ± 0.34, second year: 1.44 ± 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females. CONCLUSIONS: Our study gives a comprehensive quantitative account of disease progression in SCA1, SCA2, SCA3, and SCA6 and identifies factors that specifically affect disease progression.

Masseter reflex in the study of spinocerebellar ataxia type 2 and type 3.

In this investigation we assess the utility of the masseter reflex for diagnostic purposes in autosomal dominant cerebellar ataxias. We studied the masseter reflex electrophysiologically in spinocerebellar ataxia type 2 (SCA2, 10 patients) and type 3 (SCA3/MJD, 13 patients). In SCA2, the masseter reflex was abnormal in 9 (90%) patients. In SCA3/MJD, the masseter reflex was normal in all 13 patients. Our findings suggest that the masseter reflex is a reliable test that provides additional data prior to molecular study in the differentiation between SCA2 and SCA3/MJD. Masseter reflex abnormalities in SCA2 patients could be better explained by dysfunction of the mesencephalic trigeminal nucleus/tract.

Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.

OBJECTIVE: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. METHODS: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. RESULTS: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.

A neurological examination score for the assessment of spinocerebellar ataxia 3 (SCA3).

Spinocerebellar ataxias (SCAs) are characterized by a heterogeneous set of clinical manifestations. Our aims were to assess the neurological features of SCA3, and to describe and test the feasibility, reliability, and validity of a comprehensive Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). The NESSCA was administered to molecularly diagnosed SCA3 patients at an outpatient neurogenetics clinic. The scale, based on the standardized neurological examination, consisted of 18 items that yielded a total score ranging from 0 to 40. The score's interrater reliability and internal consistency were investigated, and a principal components analysis and a correlation with external measures were performed. Ninety-nine individuals were evaluated. Interrater reliability ranged from 0.8 to 1 across individual items (P < 0.001); internal consistency, indicated by Cronbach's alpha, was 0.77. NESSCA scores were significantly correlated with measures of disease severity: disease stage (rho = 0.76, P < 0.001), duration (rho = 0.56, P < 0.001), and length of CAG repeat (rho = 0.30, P < 0.05). NESSCA was a reliable measure for the assessment of distinct neurological deficits in SCA3 patients. Global scores correlated with all external variables tested, showing NESSCA to be a comprehensive measure of disease severity that is both clinically useful and scientifically valid.

The Lewis family revisited: no evidence for autosomal dominant multiple system atrophy.

In 1964, Lewis reported a familial ataxia-dysautonomia syndrome reminiscent of Shy-Drager syndrome subsequently known as multiple system atrophy (MSA). Here we review this report and propose that the Lewis family may represent an unusual form of autosomal dominant cerebellar ataxia type I, which might be categorized either as SCA3 (Machado-Joseph disease) or a new SCA subtype. There remains no conclusive evidence to support the notion of hereditary MSA.

Peripheral neuropathy of Machado-Joseph disease in Taiwan: a morphometric and genetic study.

Machado-Joseph disease (MJD) is a dominantly inherited cerebellar ataxia associated with spasticity, ophthalmoplegia, dystonia and peripheral neuropathy. Presented here are 5 MJD cases. A morphometric analysis of the histopathology of their sural nerves was carried out to know the relationship between axon size and myelin thickness. MJD cases were identified by polymerase chain reaction. On the basis of the clinical symptoms, there was 1 type I, 2 type II and 2 type III patients. The sural nerves were biopsied for single-fiber, ultrastructural and morphometric analysis. Morphometric parameters such as fiber and axon sizes, myelin thickness and g ratio (axon diameter:fiber diameter) were estimated. The pathological features of the sural nerves in the 2 type III and 1 of the type II patients revealed a loss of myelinated and unmyelinated fibers, and the morphometry studies showed a decreased fiber density, the loss of large myelinated fibers, a smaller size of the axons with thinner myelin sheaths and an increased percentage of myelinated fibers with a g ratio (axon diameter:fiber diameter) above 0.7. However, only subtle pathological changes were noted in the type I patient and the remaining type II patient. Our findings suggested that there is a loss of large myelinated fibers and distal axonopathy with relative hypomyelination in the neuropathy of patients with MJD.

Doença de Machado-Joseph: atualizaçäo / Machado-Joseph disease: an update

A doença de MachadoðJoseph (DMJ) é a heredoðdegeneraçä cerebeloðmedular autossômica dominante mais comum na prática clínica. Caracterizaðse por uma ataxia cerebelar associada, em graus variáveis, a síndrome piramidal, extrapiramidal rígidoðdistônica e neuropatia periférica. Deveðse à presença de mutaçäo genética constituída de repetições trinucleotídicas instáveis (Citosina, Adenina, Guanina) no locus 14q 24.3ðp32. Neste artigo, revêemðse os principais aspectos clínicos e etiopatogênicos da doença, apresentandoðse também dois casos de uma mesma família do Rio de Janeiro

CAG repeat length and disease duration in Machado-Joseph disease: a new clinical classification.

To evaluate the clinical characteristics of Machado-Joseph disease (MJD) with reference to CAG repeat length and disease duration, we analyzed neurologic findings in 108 patients from 84 families. The majority of MJD patients presented with an ataxic gait as the initial symptom. Dysarthria and nystagmus were observed from an early stage. Bulging eyes, muscle atrophy and bradykinesia developed later. Patients with a shorter CAG repeat length or later onset had more frequent involvement of proprioceptive sensory deficit. Incidence of abnormal reflexes, tones, and proprioceptive sensation was not associated with disease duration, but with CAG repeat length. Based on these results, we propose a new clinical classification: type A (juvenile type), with hyperreflexia and dystonia, but without a proprioceptive sensory deficit; type C (adult type), with hyporeflexia and a proprioceptive sensory deficit, but without dystonia; and type B (intermediate type), the remaining patients with a mixed presentation.

Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation.

OBJECTIVE: Machado-Joseph disease (MJD) is an autosomal dominant cerebellar ataxia with extensive phenotypic variability originally described in families of Portuguese ancestry. Recently, the mutation causing the disease has been identified as an expanded CAG trinucleotide repeat. In this study relations between genotype and phenotype were investigated. METHODS: A series of 180 German patients with degenerative forms of ataxia were clinically and genetically examined. Patients bearing the MJD mutation were assigned to three phenotypes: phenotype 1 characterised by early onset and dystonia or pronounced rigidity associated with ataxia and spasticity. Main symptoms in phenotype 2 were ataxia and spasticity. In phenotype 3 onset was relatively late and peripheral neuropathy accompanied ataxia. Clinical and molecular data were correlated. RESULTS: An expanded CAG array was found in 42 patients from 22 families. Repeat length of CAG varied between 67 and 80 CAG motifs and showed an inverse correlation with the age of onset. For the development of phenotype 1 early onset (< 20 years) seemed more decisive than extensive repeat length. Phenotype 2 was present in all patients with more than 73 CAG motifs and onset between 20 and 40. Phenotype 3 developed in most patients with less than 73 CAG motifs and onset was regularly beyond the age of 40. Intrafamilial variability of both repeat length and phenotype was large reflecting meiotic instability of the expanded CAG repeat. CONCLUSIONS: The MJD mutation is the most frequent cause of dominantly inherited ataxia in Germany. Variations in repeat lengths substantially influence age of onset as well as phenotype but cannot explain why MJD characteristics of Portuguese families such as "bulging eyes", dystonia, and rigidity are essentially missing in German families. Despite the genotypic and phenotypic relations found in this study a reliable individual prognosis of the course of the disease is not possible at a presymptomatic stage.

[Molecular genetics of Machado-Joseph disease].

Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration. The CAG expansions of the MJD1 gene at chromosome 14q32.1 was identified as the cause of the disease. MJD has three factors that influence the age of the onset. The MJD1 repeat length inversely correlated with the age of onset (r = -0.87). Homozygosity of the gene exhibited an additive effect on age of onset. MJD has a gender-specific effect on the age of onset. A parent-child analysis showed the unidirectional expansion of CAG repeats. Among the three clinical subtypes, type I of MJD, with dystonia, showed a larger degree of expansion in CAG repeats of the gene and younger ages of onset than the other types.

Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease.

Machado--Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration mapped to chromosome 14q32.1. The CAG expansions of the MJD1 gene was identified as the cause of the disease. We have analyzed 90 MJD individuals from 62 independent MJD families and found that the MJD1 repeat length is inversely correlated with the age of onset (r = -0.87). The MJD chromosomes contained 61-84 repeat units, whereas normal chromosomes displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were the most common and the shortest. In association with the clinical anticipation of the disease, a parent--child analysis showed the unidirectional expansion of CAG repeats and no case of diminution in the affected family. The differences in CAG repeat length between parent and child and between siblings are greater in paternal transmission than in maternal transmission. Detailed analysis revealed that a large degree of expansion was associated with a shorter length of MJD1 gene in paternal transmission. On the other hand, the increments of increase were similar for shorter and longer expansion in maternal transmission. Among the three clinical subtypes, type I of MJD, with dystonia, showed a larger degree of expansion in CAG repeats of the gene and younger ages of onset than the other types.