Spinocerebellar Ataxia 36 is a Frequent Cause of Hereditary Ataxia in Eastern Spain

Abstract

BackgroundBackground: Autosomal dominant spinocerebellar ataxia 36 (SCA36) is caused by hexanucleotide repeat expansion in the NOP56 gene. Objectives Objectives: To assess frequency, clinical and genetic features of SCA36 in Eastern Spain. Methods Methods: NOP56 expansion was tested in a cohort of undiagnosed cerebellar ataxia families (n = 84). Clinical characterization and haplotype studies were performed. ResultsResults: SCA36 was identified in 37 individuals from 16 unrelated families. It represented 5.4% of hereditary ataxia patients. The majority were originally from the same region and displayed a shared haplotype. Mean age at onset was 52.5 years. Non-ataxic features included: hypoacusis (67.9%), pyramidal signs (46.4%), lingual fasciculations/atrophy (25%), dystonia (17.8%), and parkinsonism with evidence of dopaminergic denervation (10.7%). Conclusions Conclusions: SCA36 is a frequent cause of hereditary ataxia in Eastern Spain, and is associated with a strong founder effect. SCA36 analysis should be considered prior to other studies, especially in AD presentations. Parkinsonism reported here broadens SCA36 clinical spectrum.SCA36 is caused by a large GGCCTG hexanucleotide noncoding repeat in the nucleolar protein 56 (NOP56) gene. It was initially described in Western Japan (3.6% of all SCA) 1 and in the Costa da Morte region of Spain (6.3%). 2 Patients usually exhibit late-onset progressive cerebellar ataxia, characteristically associated with upper and lower motor neuron involvement in the form of lingual and/or skeletal muscle atrophy and fasciculations, and sensorineural hearing loss. 2,3 In recent years, additional features were added to SCA36 phenotypes such as dystonia 4-6 and cognitive-affective cerebellar syndrome (CCAS). 7 In this study, we investigated the frequency and clinical characteristics of SCA36 in Eastern Spain. Haplotype analysis was conducted to ascertain a founder effect in our population. MethodsPatients were enrolled from the Ataxia Clinic at Hospital Universitari i Politècnic La Fe, a national referral center for Hereditary Cerebellar Ataxia and Spastic Paraplegia. The inclusion criteria were: (1) patients with a progressive cerebellar ataxia with negative studies for acquired etiologies; (2) sporadic or AD presentation; and (3) negative genetic studies including analysis of trinucleotide repeat expansion ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, DRPLA and Friedreich ataxia) and/or clinical exome sequencing. 8 Ultimately, SCA36 was screened in 84 index patients from 297 pedigrees. Written informed consent was obtained before the genetic analysis.