A case of childhood-onset oculopharyngeal myopathy with a novel HNRNPA2B1 duplication

Objectives. To describe the clinical, histological, genetic, and long-term clinical features of an early-onset oculopharyngeal muscular dystrophy (OPMD)-like myopathy associated with a novel HNRNPA2B1 variant, and to highlight the importance of re-evaluating unresolved myopathies.

Methods. We report a 41-year-old Italian woman with childhood-onset ptosis, ophthalmoparesis, proximal and axial weakness, and dysphagia. Clinical, radiological, histological, and genetic data collected over more than two decades were reviewed. Muscle biopsies underwent routine histochemical, immunohistochemical, and ultrastructural assessment. Previous testing included PABPN1 GCN repeat expansion analysis and mitochondrial DNA analyses - including mtDNA rearrangements and mtDNA NGS sequencing. Extended next-generation sequencing using a myopathy panel was subsequently performed, followed by parental segregation analysis.

Results. Symptoms began at age 6 with bilateral ptosis and progressed slowly to severe ophthalmoparesis, facial, axial, and proximal limb weakness, dysphagia, and respiratory impairment. Muscle biopsies showed rimmed and autophagic vacuoles, centralized nuclei, and minor mitochondrial changes. Long-term follow-up documented ineffective cough, mild restrictive respiratory involvement with recurrent pneumonias, early-onset osteoporosis with multiple fractures, and severe jaw contracture, without cardiac or central nervous system involvement. Extended genetic testing identified a novel heterozygous likely pathogenic HNRNPA2B1 duplication, c.1036_1037dup, p.(Tyr347ValfsTer25), not detected in the segregation analysis in both parents.

Conclusions. This case expands the phenotypic spectrum of rare HNRNPA2B1-related early-onset OPMD-like myopathy and provides longitudinal evidence and degree of multisystem involvement. Periodic diagnostic re-evaluation of unsolved myopathies in the genomic era may improve diagnosis, multidisciplinary management, and genetic counselling.