SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report

BACKGROUND: SYNE1 encodes nesprin-1, a nuclear envelope protein involved in cytoskeletal linkage, nuclear positioning, and neuromuscular integrity. Biallelic SYNE1 variants cause a broad spectrum ranging from cerebellar ataxia to arthrogryposis multiplex congenita and motor neuron disease-like phenotypes. Distinguishing these entities can be difficult when subtle distal contractures coexist with neurogenic electrophysiological findings. CASE PRESENTATION: A 22-year-old woman born to consanguineous parents presented with bilateral intrinsic hand muscle wasting, impaired fine motor performance, and mild gait difficulty. Examination showed distal hand atrophy, mild weakness of the abductor pollicis brevis and first dorsal interosseous muscles, brisk deep tendon reflexes, preserved sensation, and mild distal finger contractures. Sensory nerve conduction studies were normal. Motor studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude on the left. Needle electromyography showed widespread chronic neurogenic motor unit changes affecting the upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal. SMN1 deletion testing and selected familial amyotrophic lateral sclerosis gene testing were negative. Whole exome sequencing identified a homozygous truncating SYNE1 variant, NM_182961.4:c.21009G > A; p.(Trp7003Ter). Segregation analysis confirmed heterozygous carrier status in both parents and two unaffected siblings. At 24-month follow-up, weakness, atrophy, contractures, reflex pattern, and functional status remained clinically stable, without bulbar, cerebellar, sensory, or clinically evident respiratory involvement. CONCLUSIONS: This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype. The case also supports including SYNE1 in genetic testing panels for young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist.