Case Report: Late-Onset Autosomal Recessive Cerebellar Ataxia Associated With SYNE1 Mutation in a Chinese Family.

Nannan Qian,Wei Dong,Wenjie Hao,Jiuxiang Wang,Taohua Wei,Wenming Yang,Ru Huang,Yue Yang,Shijie Zhang,Shan Jin

doi:10.3389/fgene.2022.795188

Abstract

Autosomal recessive cerebellar ataxia type 1 (ARCA-1), also known as autosomal recessive spinocerebellar ataxia type 8 (SCAR8), is caused by spectrin repeat containing nuclear envelope protein 1 (SYNE1) gene mutation. Nesprin-1, encoded by SYNE1, is widely expressed in various tissues, especially in the striated muscle and cerebellum. The destruction of Nesprin-1 is related to neuronal and neuromuscular lesions. It has been reported that SYNE1 gene variation is associated with Emery-Dreifuss muscular dystrophy type 4, arthrogryposis multiplex congenita, SCAR8, and dilated cardiomyopathy. The clinical manifestations of SCAR8 are mainly characterized by relatively pure cerebellar ataxia and may be accompanied by upper and/or lower motor neuron dysfunction. Some affected people may also display cerebellar cognitive affective syndrome. It is conventionally held that the age at the onset of SCAR8 is between 6 and 42 years (the median age is 17 years). Here, we report a pedigree with SCAR8 where the onset age in the proband is 48 years. This case report extends the genetic profile and clinical features of SCAR8. A new pathogenic site (c.7578del; p.S2526Sfs*8) located in SYNE1, which is the genetic cause of the patient, was identified via whole exome sequencing (WES).

Highlights

Hereditary ataxia is a group of highly heterogeneous genetic degenerative diseases characterized by chronic progressive ataxia
spinocerebellar ataxia type 8 (SCAR8) is a type of autosomal recessive ataxia, which is clinically characterized by mild cerebellar ataxia and may be accompanied by upper and/or lower motor neuron dysfunction
The pathogenicity of SYNE1 gene mutation was predicted by using the online bioinformatics software LR pred, Mutation Taster, and Ljb23_metasvm, and the results revealed it as a disease-causing mutation

Summary

Introduction

Hereditary ataxia is a group of highly heterogeneous genetic degenerative diseases characterized by chronic progressive ataxia. Its phenotype includs ataxic gait and uncoordinated eye movement, language and hand movement, and often involves pathological changes mainly affecting the spinal cord, cerebellum, and brainstem (Jayadev and Bird, 2013). Hereditary ataxia includes autosomal dominant ataxia, autosomal recessive ataxia, X-linked ataxia, and ataxia associated with mitochondrial diseases (Braga Neto et al, 2016). SCAR8 is a type of autosomal recessive ataxia, which is clinically characterized by mild cerebellar ataxia and may be accompanied by upper and/or lower motor neuron dysfunction. It is reported that the incidence of autosomal recessive ataxia is 0–7.2/100,000 (Ruano et al, 2014). Friedreich ataxia and ataxia-telangiectasia are the most common autosomal recessive ataxia, while other types such as SCAR8 are less common

Methods

Results

Conclusion