Analysis of diagnostic pitfalls in 125 genetically confirmed cases of distal myopathies

Background Distal myopathies (DMs) comprise a heterogeneous group of hereditary muscle diseases characterized by predominant distal muscle weakness and atrophy overlapping with hereditary neuropathies, leading to diagnostic delays or misclassification. Results We conducted a retrospective analysis of 125 patients from 103 families with DMs revealed at a federal genetics referral center in Russia from 2010 to 2025, representing the largest Russian DM cohort. Causative variants were identified in 20 genes, most commonly in the GNE (30.1%), DYSF (13.6%), and TTN (9.7%) genes. Although distal muscle involvement predominated, lower limb muscle magnetic resonance imaging (MRI) showed proximal involvement in 93.4% (71/76) of cases regardless of disease stage. Across the cohort, gracilis, rectus femoris, and tibialis posterior were relatively spared. Referral misdiagnosis as hereditary neuropathy occurred in 32.8% (41/125) of cases. To characterize diagnostic pitfalls, we compared patients initially referred with neuropathy to those referred with DM. We demonstrated that group differences were evident solely in the needle electromyography (EMG) reports, while clinical features and lower limb muscle MRI data were broadly comparable. We analyzed the probable causes of EMG misinterpretations, which most commonly included severe spontaneous activity being mistaken for active denervation, high-amplitude motor unit potentials being misclassified as neurogenic, and, in some cases, the wrong choice of muscle for the study. Conclusion According to our data, one-third of patients with DM were initially referred for suspected neuropathy. In many cases, misclassification was likely due to pitfalls in EMG interpretation, highlighting the need for careful EMG analysis in patients with myopathies.