Duchenne and Becker muscular dystrophy

In males, Duchenne muscular dystrophy typically presents in early childhood with delayed motor milestones, persistent toe-walking, and a waddling gait, with mean age at diagnosis of approximately four years and ten months in boys without a family history. Proximal weakness causes difficulty climbing stairs, running, and rising from the floor; affected boys use the Gower manoeuvre, and calf muscles are hypertrophic and firm to palpation. Progression is rapid, with wheelchair dependency typically before age 13 years. Becker muscular dystrophy is characterised by later-onset skeletal muscle weakness; the mild end of the spectrum includes men with symptom onset after age 30 years who remain ambulatory into their 60s. Subclinical or clinical cardiac involvement is present in approximately 90% of individuals with DMD or BMD; respiratory complications and progressive cardiomyopathy are the principal causes of death, with median survival of 24 years in DMD and mean age of death in the mid-40s in BMD. Females are typically heterozygous carriers and are often asymptomatic or mildly affected; however, some may develop classic DMD or BMD manifestations. Cardiac involvement can occur even in the absence of skeletal muscle symptoms, with the reported prevalence of cardiomyopathy ranging from 3% to 33%.

The estimated prevalence is 4.8/100,000 for Duchenne and 1.6/100,000 for Becker muscular dystrophy.

Dystrophinopathies are caused by germline pathogenic variants in DMD (Xp21.2-p21.1), which encodes the cytoskeletal protein dystrophin. Approximately 60-70% of pathogenic variants are out-of-frame or in-frame intragenic deletions, 5-10% are duplications, and 25-35% are single-nucleotide variants or small indels, including nonsense, splice-site, and frameshift changes. The reading-frame rule predicts phenotype with approximately 92% accuracy: variants that disrupt the reading frame typically abolish dystrophin expression and are associated with the severe Duchenne phenotype, whereas in-frame variants preserve a partially functional dystrophin and are associated with the milder Becker phenotype.

The dystrophinopathies are inherited in an X-linked manner. Affected males transmit the pathogenic DMD variant to all daughters (obligate heterozygotes) and to none of their sons. Heterozygous females have a 50% probability of transmitting the variant with each pregnancy; sons who inherit the variant will be affected, and daughters will be heterozygotes. Mothers with more than one affected child are usually obligate heterozygotes. If no DMD variant is detected in the mother’s blood, the empirical risk of maternal germline mosaicism is 15-20%.

Markedly elevated serum creatine kinase (CK) is the principal suggestive laboratory finding: greater than 10-fold the upper limit of normal in DMD and greater than 5-fold in BMD in 100% of affected males. Approximately 50% of DMD and 30% of BMD female heterozygotes show CK concentrations 2 to 10-fold normal. The diagnosis is established by molecular genetic testing of the DMD gene; skeletal muscle biopsy with dystrophin western blot and immunohistochemistry may be performed for cases in which no pathogenic variant is identified by molecular testing.

Main differential diagnoses include:

• : autosomal recessive or dominant proximal muscular dystrophy affecting both sexes, with LGMD R9 (formerly type 2I) phenotypically resembling DMD/BMD with calf hypertrophy and elevated CK; FKRP and other genes encoding sarcoglycans and dystrophin-associated proteins
• : early joint contractures (elbows, ankles, posterior cervical) with humero-peroneal weakness and prominent cardiac conduction defects; EMD, FHL1 (X-linked), LMNA (autosomal dominant/recessive)
• : anterior horn cell disease with tongue fasciculations and absent deep tendon reflexes (presence of fasciculations or sensory loss excludes a dystrophinopathy); SMN1

• Establishing the molecular genetic diagnosis confirms the clinical suspicion and defines the underlying pathogenic variant.
• Identification of the causative variant enables specific, individualised surveillance, and forms the prerequisite for targeted medical care planned by the treating physicians.
• Predictive testing of at-risk relatives is possible once the familial pathogenic variant has been identified, with important implications for family planning.

• Darras BT, Urion DK, Ghosh PS. Dystrophinopathies. 2000 Sep 5 [updated 2018 Apr 26]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:20301298.
• Salari N, Fatahi B, Valipour E, Kazeminia M, Fatahian R, Kiaei A, et al. Global prevalence of Duchenne and Becker muscular dystrophy: a systematic review and meta-analysis. J Orthop Surg Res. 2022;17(1):96. doi:10.1186/s13018-022-02996-8. PMID:; PMCID: PMC8848641.
• Birnkrant DJ, Bushby K, Bann CM, Apkon SD, Blackwell A, Brumbaugh D, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251-67. doi:10.1016/S1474-4422(18)30024-3. PMID:; PMCID: PMC5869704.