SYNE1 Deficiency Manifesting Primarily With Motor Neuron Disease

Abstract

Background and objectives: SYNE1 deficiency is an autosomal recessive disorder with a broad phenotypic spectrum, most commonly presenting as adult-onset cerebellar ataxia with or without motor neuron dysfunction. We aimed to expand this spectrum by describing the clinical and genetic findings in 2 unrelated families with early-onset motor neuron disease and virtually no cerebellar signs over time.

Methods: We performed detailed clinical, neurophysiologic, and genetic studies of 2 unrelated families with juvenile amyotrophic lateral sclerosis (ALS) and biallelic variants in SYNE1.

Results: The phenotypes of both families showed onset of symptoms in childhood or adolescence, with signs of upper and lower motor neuron dysfunction in multiple territories suggestive of juvenile ALS. Patients developed progressive muscle weakness, eventually leading to respiratory distress and bulbar signs. Whole-exome sequencing identified SYNE1 biallelic truncating variants in both families: a homozygous nonsense variant, c.23131C>T (p.Gln7711*), in Family 1, and a novel homozygous splice-site variant, c.17851-1G>A, in Family 2. Notably, mild or no cerebellar manifestations were observed during the follow-up.

Discussion: This report highlights a novel phenotype of SYNE1 deficiency characterized by early-onset motor neuron disease and virtually no cerebellar manifestations, broadening the phenotypic spectrum of this complex neurodegenerative disease. These findings support investigating SYNE1 variants in juvenile ALS and including SYNE1 in motor neuron disease gene panels.

Figure 1. Schematic Representation of SYNE1 and Family Trees

(A) Schematic representation of SYNE1 domains and the location of previously reported variants in individuals with ataxia and motor neuron signs (black) and the variants identified in this report (red) based on the reference sequence SYNE1 (NM_182961.4). (B) Pedigrees of families included in this report. (C) Sanger sequencing chromatograms.

Figure 2. Clinical Features of Individuals With Motor Neuron Disease and Expansion of the Disease Phenotype

(A) Distal muscle atrophy and weakness (Family 1; individuals III:8 and III:7). (B) Marked distal atrophy (Family 2; individual III:5). (C) Proposed phenotypic spectrum of SYNE1 deficiency, modified from a previously published study. The figure shows the continuous spectrum of SYNE1 deficiency that may present with pure cerebellar manifestations (left side; previously reported) or motor neuron disease (right side; reported here) in the absence of other manifestations. Additional symptoms may be present in up to 50% of cases, increasing disease complexity and highlighting the multisystemic and neurodegenerative nature of the disease.