Noncoding repeat expansions for ALS in Japan are associated with the <i>ATXN8OS</i> gene

Abstract

<h3>Objective</h3> To assess the contribution of noncoding repeat expansions in Japanese patients with amyotrophic lateral sclerosis (ALS). <h3>Methods</h3> Sporadic ALS in Western countries is frequently associated with noncoding repeat expansions in the <i>C9ORF72</i> gene. Spinocerebellar ataxia type 8 (SCA8) is another noncoding repeat disease caused by expanded CTA/CTG repeats in the <i>ATXN8OS</i> gene. Although the involvement of upper and lower motor neurons in SCA8 has been reported, a positive association between SCA8 and ALS remains unestablished. Spinocerebellar ataxia type 36 is a recently identified disease caused by noncoding repeat expansions in the <i>NOP56</i> gene and is characterized by motor neuron involvement. We collected blood samples from 102 Japanese patients with sporadic ALS and analyzed the <i>ATXN8OS</i> gene by the PCR–Sanger sequencing method and the <i>C9ORF72</i> and <i>NOP56</i> genes by repeat-primed PCR assay. <h3>Results</h3> Three patients with ALS (3%) had mutations in the <i>ATXN8OS</i> gene, whereas no patient had a mutation in the <i>C9ORF72</i> or <i>NOP56</i> gene. The mutation-positive patients were clinically characterized by neck weakness or bulbar-predominant symptoms. None of our patients had apparent cerebellar atrophy on MRI, but 2 had nonsymptomatic abnormalities in the white matter or putamen. <h3>Conclusions</h3> Our finding reveals the importance of noncoding repeat expansions in Japanese patients with ALS and extends the clinical phenotype of SCA8. Three percent seems small but is still relatively large for Japan, considering that the most commonly mutated genes, including the <i>SOD1</i> and <i>SQSTM1</i> genes, only account for 2%–3% of sporadic patients each.