Becker muscular dystrophy

Becker muscular dystrophy (BMD) is an X-linked recessive genetic dystophinopathy – a genetic condition caused by variants in the dystrophin gene (DMD). It is characterised by progressive muscle degeneration that results in weakness, loss of motor function and, in some cases, cardiorespiratory complications. While caused by variants in the same gene, BMD has a later onset, milder severity and slower progression than Duchenne muscular dystrophy (DMD) due to variants resulting in a partially functional dystrophin protein.

Affected individuals tend to present in late childhood or early adulthood with proximal muscle weakness and atrophy. As BMD is inherited in an X-linked recessive pattern, the vast majority of patients are boys. The mean age of symptom onset is 11 years.

Common presenting features include:

• difficulty walking, running, hopping and/or jumping;
• difficulty climbing stairs;
• exercise intolerance;
• frequent falls;
• anomalous gait; and
• incidental findings of raised creatinine kinase.

Progressive muscle weakness occurs as the condition advances. The pattern is usually one of worsening disability, but most patients remain ambulant until adulthood and may only lose their ability to walk in their fourth or fifth decade.

Another feature of BMD is cardiac involvement, characterised by:

• dilated cardiomyopathy;
• conduction anomalies; and
• arrhythmia.

Lifespan is often shortened due to heart disease and respiratory complications; however, most people with BMD survive into middle and older age.

Female carriers of BMD are usually unaffected but may manifest cardiac involvement (around 10%).

Differential diagnoses include DMD and limb girdle muscular dystrophy.

BMD is caused by genetic variants in the dystrophin gene (DMD), which result in reduced expression or function of the dystrophin protein. More damaging genetic variants in DMD, causing absent or very low dystrophin expression (less than 5% of normal expression), lead to Duchenne muscular dystrophy, which has a more severe clinical presentation.

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

BMD tends to be caused by in-frame genetic variants. These are usually deletions or duplications that juxtapose in-frame exons; however, splice variants and missense variants also occur.

Diagnosis of BMD is usually based on:

• clinical features;
• raised creatinine kinase; and
• genomic testing (where indicated).

Where genomic tests are negative, or where the consequence of a genetic variant cannot be predicted but a high clinical index of suspicion remains, 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 genomic testing, see Presentation: Child with progressive muscle weakness or suspected muscular dystrophy.

BMD is an X-linked recessive condition.

• X-linked recessive conditions are usually only present 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 affected only mildly.
• 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.

About 50% of BMD cases occur de novo and 50% are inherited from the mother. It is important to establish whether the mother carries the variant, because if she does, any future male pregnancies have a 50% chance of being affected and any future female pregnancies have a 50% chance of being a carrier. In addition, 10% of female carriers with dystrophin variants (DMD or BMD) manifest cardiac symptoms.

Where blood tests do not identify the genetic variant in the mother, there remains a 20% chance of a future son being affected (with an overall chance to a future pregnancy of 5%) due to a significant rate of germline mosaicism.

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

Management of children with BMD is complex and should be delivered via a multidisciplinary team. A common model is care led by a paediatric neurologist together with a community paediatrician. Children often require input from the respiratory, cardiac, orthopaedic and endocrine teams, in addition to intensive physiotherapy and occupational therapy input and psychosocial support.

Experimental therapies such as gene therapy and exon skipping are under investigation in preclinical and early clinical trials, but these approaches are not yet available for routine clinical use.

For clinicians

• GeneReviews: Dystrophinopathies
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• Genetic and Rare Diseases Information Center: Becker muscular dystrophy
• NHS England: National Genomic Test Directory
• OMIM: 300376 Becker muscular dystrophy (BMD)
• US National Library of Medicine: ClinicalTrials.gov database

For patients

• Contact UK: Becker muscular dystrophy
• Muscular Dystrophy UK: Becker muscular dystrophy