title: Analysis of a fully penetrant spinocerebellar ataxia type 8 Brazilian family.
abstract: Spinocerebellar ataxia type 8 (SCA8) is a progressive neurological disorder caused by the expanded repeat CTA/CTG of two overlapping genes, ATXN8OS and ATXN8, expressed bidirectionally. Normal alleles have 15-50 repeats, and pathogenic alleles range from 71 to 1300 repeats. The disorder is relatively rare, accounting for about 2%-5% of the autosomal dominant forms of hereditary ataxia worldwide. However, the prevalence of disease-causing ATXN8OS/ATXN8 expansions is higher than the disease because of the reduced penetrance of the expanded allele. The aim of this study was to describe the first fully penetrant SCA8 family showing mixed Brazilian African and Amerindian origin. Eight members of this family were evaluated-the mother and seven offspring-through a complete neurological examination conducted at the Neurogenetics Clinic, HCFMRP-USP in Brazil. The number of CTA/CTG repeats was obtained after polymerase chain reaction (PCR) and fragment analysis. The haplotype analysis was conducted using a microsatellite marker, D13S1296, and four single nucleotide polymorphisms (SNPs), rs1831189, rs8002227, rs11841483, and rs72284461, all spanning a 70.1 Mb region on chromosome 13q21.3. The molecular analysis showed that the expansions ranged from 104 to 109 CTA/CTG repeats in the six affected individuals and were absent in two asymptomatic daughters (aged 53 and 40 years). Three SNPs cosegregate with the expanded alleles, confirming the connection between expansion and disease in this family. As the SCA8 diagnosis demands careful interpretation, we suggest the use of linkage analysis to observe segregation of the mutation, making more accurate its genotyping.
authors.affiliation: Department of Neurosciences and Behavior Sciences, Ribeirão Preto School of Medicine, University of São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil.
authors.forename: V P
authors.identifier: http://orcid.org/0000-0002-4908-9320
authors.initials: VP
authors.lastname: Cintra
authors.affiliation: Department of Neurosciences and Behavior Sciences, Ribeirão Preto School of Medicine, University of São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil.
authors.forename: C M
authors.initials: CM
authors.lastname: Lourenço
authors.affiliation: Department of Neurosciences and Behavior Sciences, Ribeirão Preto School of Medicine, University of São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil.
authors.forename: M M V
authors.initials: MMV
authors.lastname: Rocha
authors.affiliation: Department of Neurosciences and Behavior Sciences, Ribeirão Preto School of Medicine, University of São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil.
authors.forename: P J
authors.initials: PJ
authors.lastname: Tomaselli
authors.affiliation: Department of Neurosciences and Behavior Sciences, Ribeirão Preto School of Medicine, University of São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil.
authors.forename: W
authors.initials: W
authors.lastname: Marques
mesh_terms: D000328:Adult; D000368:Aged; D001938:Brazil; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion
chemical_list: C539186:ATXN8 protein, human; D009419:Nerve Tissue Proteins
keywords: CTG repeat expansion; full penetrance; mutational frequency; spinocerebellar ataxia; spinocerebellar ataxia type 8