Clinicopathological, imaging and genetic spectrum of inherited rimmed vacuolar myopathies in a Chinese cohort

Background Inherited rimmed vacuolar myopathies (RVMs) are genetically and clinically heterogeneous neuromuscular disorders characterised by rimmed vacuoles on muscle biopsy and associated with autophagic impairment. Their expanding genetic spectrum and overlapping phenotypes pose substantial diagnostic challenges. Methods We conducted an integrated multimodal study of 48 patients from 47 unrelated families with rimmed vacuolar pathology. Evaluation included comprehensive clinical phenotyping, muscle MRI, electromyography, histopathology, immunofluorescence for aggrephagy markers (p62, NBR1, ubiquitin and LAMP-2) and electron microscopy. Genetic investigations comprised targeted sequencing panels and whole-exome sequencing, supplemented by screening for repeat expansions and copy-number variations. Results A definitive molecular diagnosis was established in 42 patients (87.5%), involving 16 distinct disease-causing genes. The most frequent diagnoses were GNE myopathy (n=12), oculopharyngeal muscular dystrophy (n=5), myotonic dystrophy type 1 (n=5), facioscapulohumeral muscular dystrophy (n=3), Pompe disease (n=3) and limb-girdle muscular dystrophy caused by variants in DYSF, TCAP, TTN or HNRNPDL. Additional diagnoses included oculopharyngodistal myopathy, PLIN4-related myopathy, Becker muscular dystrophy, and SMPX, ADSS1 and PNPLA2-related myopathies. Clinical presentations included distal-predominant, proximal-predominant, combined proximal-distal and oculopharyngeal involvement. RV burden varied among genetic subtypes and was accompanied by variable accumulation of aggrephagy markers. Conclusion Rimmed vacuolar pathology represents a common morphological endpoint of diverse molecular mechanisms, including defects in sialic acid biosynthesis, membrane repair, RNA metabolism, lipid handling and lysosomal function. The extensive genotypic heterogeneity underlying RVMs underscores the need to integrate detailed clinical phenotyping with a comprehensive multimodal diagnostic approach.