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.

Identification of Abnormal 51 CTA/CTG Expansion as Probably the Shortest Pathogenic Allele for Spinocerebellar Ataxia-8 in China

“…In addition, all the patients in this study suffered from cognitive decline during the course of the disease, but none experienced dysphagia and abnormal muscular tension, suggesting that dysphagia and muscular tension are rare signs of SCA8. These clinical signs differ to some degree compared with the previous reports of SCA8 patients from Japan, Brazil, and Finland [9][10][11].…”

“…SCA8 is a relatively uncommon, slowly progressive ataxia with an estimated worldwide prevalence of 1:100 000 and only a few SCA8 pedigrees have been specifically documented. In addition to several Japanese cases on account of a founder effect [2,9], SCA8 cases have only been detected in 2 Brazilian [10,11], 15 Finnish [8], and 8 Czech pedigrees [5]. Our study is the first report of SCA8 in the Han Chinese population, presenting clinical and genetic analysis of 3 Chinese SCA8 pedigrees.…”

CCG•CGG interruptions in high penetrance SCA8 families increase RAN translation and protein toxicity

“…Taken together, these data indicate that the inclusion of sequence information during genetic testing, specifically the presence or absence of CCG•CGG interruptions, will provide patients and families with additional information relevant to disease penetrance. Sequence analyses will also further our understanding of the role of additional types of interruptions on disease penetrance in SCA8 and help identify the causes of high penetrance in other large SCA8 families in the literature for which the expansion sequences are unknown (Cintra et al, 2017). Additionally, we identify SCA8 patients with shorter repeat expansions than have been previously reported, expanding the range of repeats found in individuals affected with ataxia to 54-1455 repeats.…”

CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity

“…However, SCA8 ataxia patients may or may not have a family history of disease or sequence interruptions (Table 3). Sequence analyses will also further our understanding of the role of additional types of interruptions on disease penetrance in SCA8 and help identify the causes of high penetrance in other large SCA8 families in the literature for which the expansion sequences are unknown (Cintra et al , 2017). Additionally, we have identified SCA8 patients with shorter repeat expansions than have been previously reported, expanding the range of repeats found in individuals affected with ataxia to 54–1,455 repeats.…”