Prevalence of spinocerebellar ataxia 36 in a US population

摘要

Objective: To assess the prevalence and clinical features of individuals affected by spinocerebellar ataxia 36 (SCA36) at a large tertiary referral center in the United States. Methods: A total of 577 patients with undiagnosed sporadic or familial cerebellar ataxia comprehensively evaluated at a tertiary referral ataxia center were molecularly evaluated for SCA36. Repeat primed PCR and fragment analysis were used to screen for the presence of a repeat expansion in the NOP56 gene. Results: Fragment analysis of triplet repeat primed PCR products identified a GGCCTG hexanucleotide repeat expansion in intron 1 of NOP56 in 4 index cases. These 4 SCA36-positive families comprised 2 distinct ethnic groups: white (European) (2) and Asian (Japanese [1] and Vietnamese [1]). Individuals affected by SCA36 exhibited typical clinical features with gait ataxia and age at onset ranging between 35 and 50 years. Patients also suffered from ataxic or spastic limbs, altered reflexes, abnormal ocular movement, and cognitive impairment. Conclusions: In a US population, SCA36 was observed to be a rare disorder, accounting for 0.7% (4/577 index cases) of disease in a large undiagnosed ataxia cohort. Genetic cerebellar ataxia is a clinically heterogeneous disease that progressively destroys the cerebellum and consequently impairs balance and coordination in the affected individual. 1 The diagnosis of cerebellar ataxia can be challenging because there are more than 500 genes associated with either primary or secondary ataxia, and many affected families remain undiagnosed for decades. The introduction of unbiased genomic diagnostic testing methods, such as clinical exome sequencing, into the diagnostic evaluation has greatly improved time to diagnosis, 2 , 3 but is limited in its ability to detect certain forms of genetic mutation such as repeat expansion disorders. 4 , 5 The spinocerebellar ataxias (SCAs) are a diverse group of neurodegenerative disorders characterized by an autosomal dominant pattern of inheritance and cerebellar symptoms, currently consisting of at least 43 distinct clinical entities, of which 11 are repeat expansion disorders. 6 One of these conditions, spinocerebellar ataxia 36 (SCA36), is caused by a GGCCTG hexanucleotide repeat expansion in the first intron of the pre-mRNA processing gene, nucleolar protein 56 (NOP56). 7 Individuals with this disorder show progressive, late-onset, ataxic symptoms affecting limb, trunk, and/or gait stability. 7 To date, SCA36 prevalence has been reported in regions of Japan, 7 , 8 Spain, 9 France, 8 Germany, 8 and most recently, in China, 10 but its prevalence in the United States is undetermined. Through combined methods of exome sequencing, linkage analysis, and fluorescent repeat primed PCR (RP-PCR), we molecularly identified SCA36 in 4 index cases, representing less than 1% of the undiagnosed population at a tertiary referral ataxia center.