Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked recessive dystophinopathy – a genetic condition caused by variants in the dystrophin gene (DMD). It is characterised by progressive muscle degeneration resulting in weakness, loss of motor function, cardiomyopathy, respiratory complications and variable non-progressive neurodevelopmental/behavioural difficulties.

Because it is X-linked, the vast majority of DMD patients are boys. The mean age of symptom onset is two to three years. Life expectancy is reduced, typically as a result of cardio-respiratory complications.

• Common presenting features of DMD are:
  • delay in achieving motor milestones;
  • toe-walking;
  • frequent falls; and
  • positive Gower’s sign.
• As the condition advances, there is progressive muscle weakness and atrophy, as well as pseudohypertrophy of muscle (due to fatty fibrous replacement of muscle), most often noticed in the calves.
• Creatine kinase levels are typically very elevated.
• Most patients lose ambulation towards the end of childhood (the mean age is nine years in those not receiving treatment).
• Cardiac involvement is typical from mid-teens and can feature:
  • dilated cardiomyopathy; and
  • conduction anomalies and arrhythmias (less commonly).
• Progressive muscle weakness eventually results in respiratory failure.
• A complex behavioural and cognitive profile is recognised and may include:
  • non-progressive intellectual disability (in around 30% of patients);
  • broader neurobehavioural difficulties (such as deficits in social communication and focus); and/or
  • neuropsychiatric disorders.
• In older and non-ambulant patients we see:
  • progressive scoliosis requiring surgery; and
  • impaired feeding ability, requiring gastrostomy feeding.
• Death in early to mid-adulthood is usually due to cardiac or respiratory complications.
• Differential diagnoses of DMD include Becker muscular dystrophy (BMD) and limb girdle muscular dystrophy.
• Female carriers of DMD are usually unaffected, though have a risk of cardiac involvement (around 20% of female carriers are affected).

DMD is caused by genetic variants in the dystrophin gene (DMD), which result in dystrophin protein expression levels of less than 5% of normal. Less damaging genetic variants cause Becker muscular dystrophy, which features higher levels of dystrophin expression and a less severe clinical presentation.

Dystrophin forms part of a complex that anchors actin to the cell membrane, and is important in stabilising the muscle cell membrane. Loss of dystrophin expression results in myofiber loss, subsequent muscle damage and degeneration.

• About 60%–65% of cases of DMD are caused by large out-of-frame deletions that remove one or more exons of the DMD gene.
• Approximately 10% are the result of duplication of one or more exons.
• The remaining 30%–35% are caused by nonsense, frameshift or splicing variants. These produce a severely truncated dystrophin protein that is degraded.
• Rarer causes include intronic variants and chromosomal structural rearrangements.
• Becker muscular dystrophy (BMD) is caused by in-frame genetic variants that result in an abnormal shortened dystrophin protein that nevertheless retains some function, hence the milder phenotype.

Note that where genomic test results are negative for DMD, or where the consequence of a genetic variant cannot be predicted but a high clinical index of suspicion remains, muscle biopsy with staining for dystrophin expression may be useful.

• A clinical diagnosis of DMD may be suspected in light of:
  • a suggestive family history;
  • delayed walking (>18 months);
  • positive Gower’s sign;
  • toe walking;
  • calf hypertrophy.
• Serum creatine kinase would typically be found to be significantly increased.
• A molecular diagnosis is confirmed with the finding of a hemizygous (male) or heterozygous (female) pathogenic variant in DMD.
• Where a genetic diagnosis is not made but the clinical suspicion of DMD is high, referral to specialist neuromuscular services should be considered, to review if a muscle biopsy with staining for dystrophin expression may need also to be performed.

For information about testing, see Presentation: Child with progressive muscle weakness/suspected muscular dystrophy.

• DMD affects one in 3,500 to 5,000 newborns. There is no higher risk for any ethnic group.
• As an X-linked recessive condition, it usually only presents in males.
• Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
• Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or have milder muscle weakness. Up to 20% develop cardiac abnormalities.
• Approximately a third of cases of DMD occur de novo and two thirds are inherited from the affected individual’s mother.
• Sons of female carriers of X-linked recessive conditions have a 1 in 2 (50%) chance of being affected by the condition, and their daughters have a 1 in 2 (50%) chance of being carriers.
• Where blood tests do not identify a pathogenic variant in the mother, there remains a 20% chance of a future son being affected (overall probability to a future pregnancy is 5%). This is because of the significant rate of germline mosaicism.

For information about carrier testing for DMD, see Presentation: Pregnancy at risk of Duchenne or Becker muscular dystrophy.

Families should be offered counselling by the local clinical genetics service in advance of future conception. Prenatal and/or pre-implantation genetic testing (PGT) may be considered. Non-invasive prenatal diagnosis (NIPD) can also be performed for a number of X-linked conditions, including DMD, from approximately eight to nine weeks’ gestation. This will determine the sex of the fetus at an early stage; if it is male, invasive testing may then be offered for the familial pathogenic variant known to cause DMD.

Management of children with DMD is complex and should be delivered via a multidisciplinary team; detailed suggested approaches have been published by several authors. Commonly, care will be led by a paediatric neurologist with the support of community paediatric teams. Children also require input from the respiratory, cardiac, orthopaedic and endocrine teams, in addition to intensive physiotherapy and occupational therapy input and psychosocial support.

Corticosteroid therapy forms a key component of care and newer therapies, including Givinostat (aimed at reducing muscle inflammation and fibrosis), have also been approved by the MHRA (Medicines and Healthcare Products Regulatory Agency) but not by NICE (National Institute for Health and Care Excellence) at the time of writing.

Gene-directed therapies and trials

Ataluren (Translarna)

• Currently available through the NHS in the UK for children aged two and over with DMD.
• Variant specific – nonsense only.
• Restores the synthesis of dystrophin by allowing ribosomes to read through premature stop codons that cause incomplete dystrophin synthesis in nonsense variants.
• Orally administered.

Antisense oligonucleotide (ASO) therapies

• Currently undergoing clinical trials.
• Only a subset of patients would be eligible and, as of 2025, only four have been approved by the FDA (the US Food and Drug Administration), targeting exons 45, 51 and 53.
• Exon skipping – passing over the DMD deletion – leads to a restoration of the reading frame, thereby improving dystrophin expression level (albeit of a truncated form of the protein).
• Administered via weekly intravenous infusion.

Gene therapies

• In the UK, gene therapy for DMD is not yet an approved treatment but clinical trials are underway.
• In a few other countries worldwide, including the USA, ELEVIDYS, an adeno-associated virus vector-based micro-dystropin gene therapy, is now available for treatment of patients older than four years of age.

For clinicians

• • Genereviews: Dystrophinopathies
  • Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
  • NHS England: National Genomic Test Directory
  • OMIM: 310200 Duchenne muscular dystrophy
  • U.S. National Library of Medicine: ClinicalTrials.gov database

References:

• Birnkrant DJ, Bushby K, Bann C and others. ‘Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and neuromuscular, rehabilitation, endocrine and gastrointestinal and nutritional management’. The Lancet Neurology 2018: volume 17, issue 3, pages 251–267. DOI: 10.1016/S1474-4422(18)30024-3
• Birnkrant DJ, Bushby K, Bann C and others. ‘Diagnosis and management of Duchenne muscular dystrophy, part 2: Respiratory, cardiac, bone health and orthopaedic management’. The Lancet Neurology 2018: volume 17, issue 4, pages 347–361. DOI: 10.1016/S1474-4422(18)30025-5
• Birnkrant DJ, Bushby K, Bann C and others. ‘Diagnosis and management of Duchenne muscular dystrophy, part 3: Primary care, emergency management, psychosocial care, and transitions of care across the lifespan’. The Lancet Neurology 2018: volume 17, issue 5, pages 445–455. DOI: 1016/S1474-4422(18)30026-7
• Verhaart IEC and Aartsma-Rus A. ‘Therapeutic developments for Duchenne muscular dystrophy’. Nature Reviews Neurology 2019: volume 15, issue 7, pages 373 –386. DOI: 10.1038/s41582-019-0203-3

For patients

• Duchenne Family Support Group
• Muscular Dystrophy UK