Spinal Cord Damage in Spinocerebellar Ataxia Type 1
Carlos Roberto MartinsAlberto MartínezThiago Junqueira Ribeiro de RezendeLucas BrancoJosé Luiz PedrosoOrlando Graziani Póvoas BarsottiniÍscia Lopes‐CendesMarcondes C. França
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Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.
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Diseases classified as spinocerebellar ataxias typically feature ataxia as a prominent feature, but many also are associated with various other neurological deficits. The term spinocerebellar ataxia usually implies inheritance with an autosomal dominant pattern, but sporadic forms exist. Because of significant clinical and pathological variability, even within single entities, spinocerebellar ataxias have been difficult to characterize and diagnose. Recent advances in genetic characterization have provided insight into better classification and understanding of the pathogenetic mechanisms of these diseases. A number of the spinocerebellar ataxias have been shown to have trinucleotide repeat expansions which can result in the expression of elongated polyglutamine residues in the protein encoded by the affected gene. In other spinocerebellar ataxias, nucleotide repeat expansions occur in non-translated regions of the gene and may alter gene expression in other ways. In yet other spinocerebellar ataxias structural proteins or functional proteins are mutated, but many of the spinocerebellar ataxias remain uncharacterized genetically.
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OBJECTIVE: Spinocerebellar ataxias are neurodegenerative disorders involving the cerebellum and its connections.There are more than 30 distinct subtypes, 16 of which are associated with an identified gene.The aim of the current study was to evaluate a large group of patients from 104 Brazilian families with spinocerebellar ataxias. METHODS:We studied 150 patients from 104 families with spinocerebellar ataxias who had received molecular genetic testing for spinocerebellar ataxia types 1,2,3,6,7,8,10,12,17, and dentatorubral-pallidoluysian atrophy.A statistical analysis of the results was performed using basic descriptive statistics and the correlation coefficient (r), Student's t-test, chi-square test, and Yates' correction.The statistical significance level was established for p-values ,0.05. RESULTS:The results show that the most common subtype was spinocerebellar ataxia 3, which was followed by spinocerebellar ataxia 10.Moreover, the comparison between patients with spinocerebellar ataxia 3, spinocerebellar ataxia 10, and other types of spinocerebellar ataxia revealed distinct clinical features for each type.In patients with spinocerebellar ataxia 3, the phenotype was highly pleomorphic, although the most common signs of disease included cerebellar ataxia (CA), ophthalmoplegia, diplopia, eyelid retraction, facial fasciculation, pyramidal signs, and peripheral neuropathy.In patients with spinocerebellar ataxia 10, the phenotype was also rather distinct and consisted of pure cerebellar ataxia and abnormal saccadic eye movement as well as ocular dysmetria.Patients with spinocerebellar ataxias 2 and 7 presented highly suggestive features of cerebellar ataxia, including slow saccadic ocular movements and areflexia in spinocerebellar ataxia 2 and visual loss in spinocerebellar ataxia 7.CONCLUSIONS: Spinocerebellar ataxia 3 was the most common subtype examined, followed by spinocerebellar ataxia 10.Patients with spinocerebellar ataxia 2 and 7 demonstrated highly suggestive features, whereas the phenotype of spinocerebellar ataxia 3 patients was highly pleomorphic and spinocerebellar ataxia 10 patients exhibited pure cerebellar ataxia.Epilepsy was absent in all of the patients with spinocerebellar ataxia 10 in this series.
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The clinical diagnosis of inherited spinocerebellar ataxias is difficult, because phenotypes frequently overlap. The authors attempt to review the different inherited ataxia syndromes, discussing the most frequent one, Friedreich-ataxia in detail. The case of a patient with Friedreich-ataxia is presented, where the genetically supported diagnosis has been made more than ten years following the onset of the symptoms, after several hospitalizations and misdiagnosis. The correct diagnosis can be established based on the Geoffroy-Harding criteria and gene mutation analysis.
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