SYNE1 – Autosomal Recessive Ataxia of Beauce Type

Autosomal recessive cerebellar ataxia type 1 (ARCA1), also known as Beauce ataxia, is caused by biallelic variants in SYNE1, encoding the nuclear envelope spectrin‐repeat protein nesprin-1. The gene–disease link was first established in a cluster of French-Canadian families with 64 probands across 30 unrelated families, all presenting with adult-onset pure cerebellar degeneration and dysarthria (PMID:17503513).

Clinically, patients manifest slowly progressive cerebellar ataxia and dysarthria, with occasional brisk reflexes and oculomotor abnormalities. Two Saudi Arabian siblings were initially misdiagnosed with multiple sclerosis before identification of compound SYNE1 missense variants c.17483C>G (p.Thr5828Arg) and c.14091G>T (p.Met4697Ile) (PMID:28017257). A late-onset Chinese case harbored a novel frameshift c.7578del (p.Lys2526AsnfsTer2) expanding onset beyond the typical 6–42 years range (PMID:35281832).

Multi-patient sequencing in China (158 ataxia patients) identified 10 pathogenic SYNE1 variants (eight truncating, two missense) in six unrelated families, correlating C-terminal variants with motor neuron and cognitive involvement (PMID:32889669). Across all cohorts, over 35 distinct truncating and missense variants have been reported in ~73 probands. A founder effect of truncating alleles in Quebec underscores recurrent alleles in specific populations.

Segregation analyses demonstrate recessive transmission in 39 families with multiple affected relatives and full cosegregation of biallelic loss-of-function or missense variants, consistent with AR inheritance. The phenotypic spectrum ranges from pure cerebellar ataxia to additional motor neuron signs, cognitive impairment, and dysarthria.

Functional assessment of nesprin-1 in mouse knockout models revealed critical roles in nuclear positioning and anchorage but did not recapitulate cerebellar degeneration, suggesting species-specific or isoform-dependent effects (PMID:19864491). Drosophila studies implicate nesprin-1 isoforms in muscle and nuclear organization but further cerebellar‐focused models are needed.

In summary, strong clinical and genetic evidence supports a definitive association of SYNE1 with autosomal recessive ataxia of Beauce type. SYNE1 testing should be integrated into diagnostic panels for adult-onset cerebellar ataxia and atypical multiple sclerosis, enabling accurate genetic counseling and guiding future therapeutic development.

References

• Annals of neurology • 2007 • Clinical and genetic study of autosomal recessive cerebellar ataxia type 1 PMID:17503513
• Journal of the neurological sciences • 2017 • Autosomal Recessive Cerebellar Ataxia type 1 mimicking multiple sclerosis: A report of two siblings with a novel mutation in SYNE1 gene in a Saudi family PMID:28017257
• Frontiers in genetics • 2022 • Case Report: Late-Onset Autosomal Recessive Cerebellar Ataxia Associated With SYNE1 Mutation in a Chinese Family PMID:35281832
• Cerebellum (London, England) • 2021 • Autosomal Recessive Cerebellar Ataxia Type 1: Phenotypic and Genetic Correlation in a Cohort of Chinese Patients with SYNE1 Variants PMID:32889669
• Human molecular genetics • 2010 • Nesprin 1 is critical for nuclear positioning and anchorage PMID:19864491

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