Duchenne Muscular Dystrophy · DMD

Description

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by pathogenic variants in DMD, the largest gene in the human genome, which encodes the cytoskeletal protein dystrophin. Out-of-frame deletions, duplications, and point mutations abolish dystrophin production. Without dystrophin the link between the muscle fiber cytoskeleton and the extracellular matrix fails, and repeated contraction injury drives progressive muscle fiber necrosis and replacement of muscle by fat and fibrosis. Affected boys typically present between ages two and five with delayed motor milestones, calf pseudohypertrophy, Gowers sign on rising from the floor, and elevated serum creatine kinase often in the tens of thousands. Loss of independent ambulation historically occurred between ages 8 and 14, with cardiomyopathy and respiratory failure determining survival into the late twenties or thirties under modern care.

Becker muscular dystrophy reflects in-frame variants in the same gene that produce a partially functional, truncated dystrophin and a milder phenotype. DMD live-birth incidence in male infants is approximately 1 in 3,500 to 1 in 5,000. Female carriers can manifest cardiomyopathy and skeletal-muscle symptoms, and require lifelong cardiac surveillance.

DMD is not currently on the federal Recommended Uniform Screening Panel. Several states added DMD to their newborn screening programs starting in the early 2020s, beginning with a New York pilot and a Minnesota program, using creatine kinase MM as a first-tier dried blood spot marker followed by DMD sequencing on positive screens. ACHDNC review and federal nomination have been ongoing.

Treatments to date

Glucocorticoids have been standard of care for ambulatory boys with DMD since the 1990s, slowing the loss of muscle strength and delaying loss of ambulation. Prednisone and prednisolone are used widely. Deflazacort (Emflaza) was FDA approved in February 2017 with a different side-effect profile from prednisone. Vamorolone (Agamree), a dissociative steroid designed to reduce bone and growth side effects, was FDA approved in October 2023 for ages 2 and older.

Exon-skipping antisense oligonucleotides were approved under the FDA accelerated-approval pathway based on dystrophin restoration on muscle biopsy as a surrogate endpoint. Eteplirsen (Exondys 51) was approved in September 2016 for variants amenable to exon 51 skipping. Golodirsen (Vyondys 53) was approved in December 2019 for exon 53 skipping. Viltolarsen (Viltepso) was approved in August 2020, also for exon 53 skipping. Casimersen (Amondys 45) was approved in February 2021 for exon 45 skipping. Each exon-skipping therapy addresses a specific subset of out-of-frame deletions, and combined coverage is roughly 30 percent of the DMD population.

Delandistrogene moxeparvovec (Elevidys), an adeno-associated virus serotype rh74 gene therapy delivering a micro-dystrophin transgene, was FDA approved in June 2023 for ambulatory boys ages 4 to 5 under accelerated approval, and the indication was expanded in June 2024 to include ambulatory and non-ambulatory individuals ages 4 and older. After two reports of fatal acute liver failure in non-ambulatory recipients, the FDA in November 2025 added a boxed warning for serious liver injury and acute liver failure, restricted the indication to ambulatory individuals 4 and older, and removed the non-ambulatory indication. Elevidys is the first gene therapy approved for DMD and remains under post-marketing confirmatory study.

Givinostat (Duvyzat), an oral histone deacetylase inhibitor, was FDA approved in March 2024 for ambulatory boys ages 6 and older. Givinostat reduces inflammation and fibrosis in dystrophin-deficient muscle and showed preservation of motor function relative to placebo in the EPIDYS trial (Mercuri et al., Lancet Neurology, 2024). Cardiac and respiratory care, including ACE inhibitors or angiotensin receptor blockers, beta blockers, and noninvasive ventilation, remains central to extending survival.