2025 American Academy of Neurology Abstract Website

Objective:

To describe rare dysferlinopathy phenotypes.

Background:

Dysferlin (DYSF) has a crucial role in sarcolemmal repair. DYSF mutations commonly manifest with limb-girdle muscular dystrophy (LGMDR2) or distal myopathy affecting posterior leg compartment muscles (Miyoshi myopathy) or less frequently, tibialis anterior. “Pseudometabolic” phenotype and asymptomatic hyperCKemia are exceedingly rare dysferlinopathy presentations with very few patients reported in the literature.

Design/Methods:

Review of clinical, serological, genetic, myopathological, and radiological studies in 3 patients with rare dysferlinopathy phenotypes.

Results:

Patient 1 is a 51-year-old female with exercise-induced myalgia predominantly affecting calf muscles for 7 years. She was known to have asymptomatic hyperCKemia (CK 812-2,223 U/L) for at least 22 years prior to symptom onset. She had normal muscle strength and mild calf enlargement. She carries two DYSF variants, c.2163-2A>G (pathogenic) and c.866C>G, p.Ser289Cys (VUS), unknown if heteroallelic. Muscle biopsy showed nuclei internalization and lack of dysferlin immunoreactivity. Patient 2 is a 20-year-old male, football player, with asymptomatic CK elevation (729-2,645 U/L). He had normal muscle strength but mild atrophy of calf muscles. He harbors two DYSF variants in trans, c.6008G>A, p.Gly2003Asp (pathogenic) and c.854C>T, p.Thr285Met (VUS). Muscle biopsy showed no myopathic changes but reduced dysferlin immunoreactivity, which was confirmed by western blot. Patient 3 is a 58-year-old female with asymptomatic hyperCKemia (CK: 249-2,096 U/L) for 2 years. She had normal strength and normal thigh muscle MRI. She has two DYSF variants in trans, c.2517del, p.Met840Trpfs*108 (pathogenic) and c.6058C>T, p.Arg2020Cys (VUS). Muscle biopsy showed minimal myopathic changes and attenuated dysferlin immunoreactivity. Needle EMG was normal in all 3 patients.

Conclusions:

These patients highlight rare manifestations of dysferlinopathy and underscore the importance of considering dysferlinopathy in the differential diagnosis of metabolic myopathies and asymptomatic hyperCKemia.