Oculopharyngeal Muscular Dystrophy: From Molecular Pathogenesis to Gene Therapy

Oculopharyngeal muscular dystrophy (OPMD) is a rare, late-onset, autosomal dominant muscular dystrophy caused by a trinucleotide GCN repeat expansion in the PABPN1 gene on chromosome 14q11.2. The disease is clinically characterised by progressive ptosis, dysphagia, and proximal limb weakness, with onset typically between the fifth and sixth decades. OPMD affects approximately 1:100,000 individuals in Europe, with substantially higher prevalence in specific founder populations, reaching 1:600 among Bukharan Jews and 1:1,000 in French Canadians. The expanded polyalanine tract in PABPN1 promotes protein misfolding and formation of tubulofilamentous intranuclear inclusions, the histopathological hallmark of the disease. Pathogenic mechanisms involve a complex interplay of gain-of-function toxicity from aggregated mutant PABPN1, loss-of-function effects due to reduced polyadenylation efficiency, and dominant-negative impairment of poly(A) tail elongation, mRNA processing and nuclear mRNA export. Recent advances in proximity proteomics have refined the understanding of how the alanine expansion destabilises PABPN1 and alters its interactome. Diagnosis relies on molecular genetic testing of the PABPN1 GCN repeat expansion, while PABPN1 immunofluorescence on muscle biopsy provides a highly sensitive and specific ancillary tool. Current management remains symptomatic, including cricopharyngeal myotomy for dysphagia and surgical correction of ptosis. The therapeutic landscape is evolving, with BB-301, an adeno-associated virus-based gene therapy employing a DNA-directed RNA interference (ddRNAi) silence-and-replace strategy, currently in a Phase 1b/2a clinical trial. This review provides a comprehensive synthesis of OPMD, spanning historical background, molecular genetics, pathophysiology, clinical presentation, diagnostic approach, and the emerging therapeutic pipeline.