Dystrophinopathies

This article provides an overview of the dystrophinopathies, which are primary muscle disorders inherited in an X-linked recessive fashion due to pathogenic variants in DMD on chromosome Xp21 encoding the protein dystrophin. These include Duchenne and Becker muscular dystrophies, as well as an intermediate phenotype, dilated cardiomyopathy, and manifesting female carriers. Clinical examples illustrate the workup and management of patients with suspected dystrophinopathy.

Historically, the management of the dystrophinopathies was largely supportive, with corticosteroids as the only pharmacologic option to delay loss of ambulation and respiratory and cardiac complications. Newer formulations of corticosteroids aim to improve their side effect profile while preserving efficacy. The US Food and Drug Administration (FDA) recently approved treatments directed at the underlying genetic defect in Duchenne muscular dystrophy, including exon-skipping and microdystrophin-based gene therapies and a new class of histone deacetylase inhibitors. The impact of these newer therapies on the natural history of the disease is unknown. Two patient deaths in the spring of 2025 were deemed related to delandistrogene moxeparvovec use in nonambulatory patients, and dosing in these patients has been paused.

Dystrophinopathies may present with motor delay, progressive proximal and axial weakness, calf hypertrophy, and elevated creatine kinase greater than 1000 U/L. Elevated transaminases in the setting of elevated creatine kinase with normal γ-glutamyl transferase and speech delay or autism in boys are less common initial presentations. Genetic testing is typically the next step in diagnosis and, depending on the nature of the variation and predicted severity of the phenotype, can guide the choice of treatment.