Clinical features, mutation spectrum and factors related to reaching molecular diagnosis in a cohort of patients with distal myopathies.

backgroundDistal myopathies (MPDs) are heterogeneous diseases of complex diagnosis whose prevalence and distribution in specific populations are unknown.

methodsDemographic, clinical, genetic, neurophysiological, histopathological and muscle imaging characteristics of a MPDs cohort from a neuromuscular reference center were analyzed to study their epidemiology, features, genetic distribution and factors related to diagnosis.

resultsThe series included 219 patients (61% were men, 94% Spanish and 41% sporadic cases). Mean age at onset and years of follow-up were 29 and 12.4, respectively. Patients commonly presented with gait disturbances in adulthood and did not usually exhibit a purely distal involvement, but disto-proximal involvement. HyperCKemia was detected in 56.6%, leading to consultation in 11.7%. Myopathic electromyography patterns and spontaneous activity were common; however, neurogenic features were also observed. Muscle imaging was useful for diagnosis as were certain histological features. Suspected pathogenic variants were identified in 68.7% of patients across 19 genes, but 85% concentrated in 8: MYH7, ANO5, DYSF, TTN, MYOT, HSPB1, GNE and HNRNPDL. Founder/cluster variants were found as well as overlap between myopathic and neurogenic processes. Onset before 60 years old, familial cases, very high CK levels and myopathic histopathological features were associated with a higher probability of molecular diagnosis. We found a minimum prevalence of MPDs of 3.9 per 100,000 individuals in the Valencian Community.

conclusionsThis series being the largest cohort of patients with MPDs presents their frequency and behavior. This study identifies new genes presenting as MPDs, provides data to guide diagnosis and lays the groundwork for cooperative studies.