Juvenile amyotrophic lateral sclerosis with complex phenotypes associated with novel SYNE1 mutations

Abstract

Mutations in SYNE1 have been originally described to cause a slowly progressive, pure cerebellar ataxia (spinocerebellar ataxia, autosomal-recessive 8; SCAR8). Notably, recent studies revealed that affected patients with SYNE1-associated ataxia can present with complex phenotypes rather than pure cerebellar ataxia, including motor neuron and brainstem dysfunctions. We herein report a Japanese patient diagnosed with juvenile amyotrophic lateral sclerosis (ALS) with a complex phenotype, who carried compound heterozygous pathogenic variants in SYNE1. Of the variants, one was a novel frameshift variant and the other was a nonsense variant previously reported as pathogenic for SCAR8. The patient showed an early age at onset with a relatively slow but progressive course of ALS, accompanied by cognitive decline. Our findings suggest that the clinical spectrum of patients carrying pathogenic SYNE1 variants is broader than expected, and SYNE1 variants should be considered in patients diagnosed with juvenile ALS, even without prominent cerebellar ataxia.

Keywords:

• Juvenile amyotrophic lateral sclerosis (ALS)
• SYNE1 mutation
• motor neuron disease
• cognitive decline

Ethics approval

Ethical approval in this research was obtained from the institutional review board of the University of Tokyo.

Declaration of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was supported by Grants-in Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan [20FC1049], and Grant Number JP20ek0109491 from the Japan Agency for Medical Research and Development (AMED) to S.T.