How genetic mutations cause Duchenne muscular dystrophy (DMD)

Approximately one-third of DMD cases are thought to arise because of de novo mutations, with the remaining two-thirds of cases inheriting the mutation from carrier mothers.1,2

How is DMD inherited?

DMD is inherited in an X-linked recessive pattern. Since males have only one X chromosome, a mutation in the gene responsible for DMD is sufficient to cause the condition.4

Females have two X chromosomes, so a mutation would have to occur in both copies of the gene responsible for DMD to cause the disorder.4

In X-linked recessive inheritance, a female with one mutated copy of the gene can pass it on to her children. Every son and daughter of a female carrier has a 50% chance of inheriting the faulty gene. Sons who inherit the faulty gene will have DMD, while daughters will be carriers.4

DID YOU KNOW: Duchenne muscular dystrophy is inherited in an X-linked recessive pattern4

The dystrophin gene

The dystrophin gene is located on the X chromosome and is the largest gene in the human genome.1 This may make it more susceptible to mutations.2 So far, more than 7,000 individual mutations in the dystrophin gene have been identified.1

Dystrophin gene mutations

Deletion, duplication, point and other small mutations can cause Duchenne muscular dystrophy1,3,4

Why mutation type matters

Knowing the mutation type can be helpful for medical management options, and the possibility of enrolling into clinical trials.4,5

Large mutations can be detected using multiplex ligation-dependent probe amplification (MLPA). Small deletions, such as nonsense mutations, require gene sequencing. 4

Adapted from references 1, 3 and 4. 

Only genetic testing can identify the dystrophin gene mutation type; this is important for genetic counselling, prenatal diagnosis and considering mutation-specific therapies

What causes Duchenne muscular dystrophy?

Mutations in the dystrophin gene lead to the absence of, or defects in, dystrophin – an important component of the muscle cell membrane.1,2

Dystrophin is an important component of the muscle cell membrane1

Adapted from Marieb EN, et al. 20133 and MDA4

Dystrophin is present in all muscles, including skeletal, cardiac and respiratory muscle.2,4,5 Dystrophin is a structural protein that provides mechanical stability5–7

Dystrophin protein structure and interactions

Adapted from Goemans N, et al. 20141
Dystrophin:
  • Links internal cytoskeleton to sarcoglycans/dystroglycansin the membrane and the extracellular matrix5,6
  • Provides mechanical stability and structure to muscle cell membrane during contraction5–7
  • Critical to structure/stability of all muscles, including respiratory and cardiac muscles5

The absence of dystrophin leads to muscle degeneration and fibrosis11,12

Once muscle is lost it cannot be replaced.2,10,12 The absence of dystrophin in Duchenne muscular dystrophy results in ongoing muscle damage, and replacement of muscle fibres by scar tissue and fat12

Adapted from Sweeney HL. 201413
With permission from H Lee Sweeney, PhD, Myology Institute, University of Florida, FL, USA.

By the age of 5, prominent muscle weakness becomes evident with a 50–60% drop in strength14

By age 6, only 60% of predicted muscle mass is retained, decreasing to just 20% at age 1615

Early intervention is critical to help delay disease progression and treat potentially life-threatening complications.2,8–10

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Carriers of Duchenne muscular dystrophy (DMD): symptoms & care

Approximately 10% of female carriers show some disease manifestations,1,2 which include:
muscle

Muscle weakness3-5

Cardiomyopathy3,4

Central nervous system manifestations4

Adapted from references 3-5

The 2018 Duchenne Care Considerations recommend performing cardiac assessment in all female carriers in early adulthood every 3–5 years.3 This should consist of an electrocardiogram and non-invasive imaging. Assessments should be more frequent in those who are symptomatic or imaging-positive.3

Diagnosis of DMD in children takes an average of 2 years from parental concern. Therefore, carrier women may have more children without realising that they carry a DMD mutation.6-8

Carriers may be at risk of Duchenne muscular dystrophy symptoms.3 Learn about the importance of carrier screening for Duchenne muscular dystrophy here.

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