Dysferlinopathy as cause of long-term hyperCKemia with preserved strength

Dysferlin (DYSF) has a crucial role in sarcolemmal repair. While DYSF mutations commonly manifest as limb-girdle muscular dystrophy (LGMDR2) or distal Miyoshi myopathy, atypical manifestations, such as asymptomatic hyperCKemia and pseudometabolic myopathy, are rarely reported. We describe clinical, serologic, radiologic, genetic, and muscle pathology findings of three patients with rare dysferlinopathy phenotypes and long-term follow up in one of them. We also review the literature pertinent to uncommon forms of dysferlinopathy presenting with hyperCKemia and pseudometabolic phenotype.

Patient 1 is a 51-year-old female with exercise-induced myalgia predominantly affecting calf muscles for 7 years. She had a 22-year history of asymptomatic hyperCKemia (CK 812-2,223 U/L). Neurologic exam showed mild calf enlargement without weakness. CT of the lower limb revealed fatty infiltration of distal peroneal and calf muscles. Genetic testing showed two DYSF variants, c.2163-2A > G (pathogenic) and c.866C > G, p.Ser289Cys (VUS), unknown if heteroallelic. Muscle biopsy demonstrated nuclei internalization and absent dysferlin immunoreactivity. Patient 2 is a 20-year-old male, football player, with an episode of exercise-induced myalgia followed by asymptomatic persistent hyperCKemia (729-2,645 U/L). He had normal strength but mild calf muscle atrophy. Muscle MRI demonstrated subtle T2 hyperintensity in the posterior leg compartment musculature. He has two heteroallelic DYSF variants, c.6008G > A, p.Gly2003Asp (pathogenic) and c.854C > T, p.Thr285Met (VUS). Muscle biopsy showed no myopathic changes but reduced dysferlin immunoreactivity. Patient 3 is a 58-year-old female with incidentally detected asymptomatic hyperCKemia (CK: 249-2,096 U/L) for 2 years. She had normal strength and normal lower limb muscle MRI. She carries two heteroallelic DYSF variants, c.2517del, p.Met840Trpfs*108 (pathogenic) and c.6058C > T, p.Arg2020Cys (VUS). Muscle biopsy showed minimal myopathic changes and attenuated dysferlin immunoreactivity. Reduced dysferlin expression was confirmed by western blot in patients 2 and 3. Needle EMG was normal in all patients.

Dysferlinopathy should be considered in the differential diagnosis of metabolic myopathies and asymptomatic hyperCKemia. Patient 1's long history of hyperCKemia without weakness over two decades suggests that CK elevation in dysferlinopathy does not necessarily predict development of weakness. Additionally, the lack of dystrophic changes on muscle biopsy of patients with asymptomatic or minimally symptomatic hyperCKemia should not discourage the search for dysferlin deficiency in muscle, particularly in the setting of DYSF variants.