Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia

The AFG3L2 gene encodes AFG3-like protein 2, which is a subunit of human mitochondrial ATPases associated with various cellular protease activities (m-AAA). The clinical spectrum of AFG3L2 mutations is broad. Dominant AFG3L2 mutations can cause autosomal dominant spinocerebellar ataxia type 28 (SCA28), whereas biallelic AFG3L2 mutations may lead to spastic ataxia 5 (SPAX5). However, the role of AFG3L2 mutations in autosomal recessive spinocerebellar ataxia (SCAR) remains elusive. The aim of this study is to delineate the clinical features and spectrum of AFG3L2 mutations in a Taiwanese cohort with cerebellar ataxia. Mutational analyses of AFG3L2 were carried out by targeted resequencing in a cohort of 133 unrelated patients with molecularly undetermined cerebellar ataxia. We identified one single patient carrying compound heterozygous mutations in AFG3L2, p. [R632*];[V723M] (c.[1894C > T];[2167G > A]). The patient has suffered from apparently sporadic and slowly progressive cerebellar ataxia, ptosis, and ophthalmoparesis since age 55 years. These findings expand the clinical spectrum of AFG3L2 mutations and suggest a new subtype of late-onset SCAR caused by biallelic AFG3L2 mutations.