What kind of disease is Duchenne muscular dystrophy?

Duchenne muscular dystrophy (DMD) is a rare genetic disorder that causes progressive muscle damage and degeneration.^1,2 It is the most common and severe form of muscular dystrophy among children, and accounts for over 50% of all cases.³ It is caused by a mutation in the dystrophin gene which leads to the absence of, or defects in, dystrophin – an essential protein in the muscle cell membrane.^1,4

Duchenne is characterised by progressive decline in muscle function, leading to loss of ambulation and respiratory and cardiac failure^1,2

Children with Duchenne suffer with progressive muscle deterioration and an ongoing decline in physical function.⁵

Muscle weakness becomes apparent in early childhood, and, on average, patients require a wheelchair by the early teenage years.^3,5,6

Ultimately, progressive muscle degeneration causes respiratory and cardiac failure, leading to early death.¹

Early intervention may improve patient outcomes^1,2

• Once muscle is lost it cannot be restored^{9, 10}
• Early diagnosis is critical to gain access to the right treatments and services^1,2,11
• The role of primary care is vital as they are in an ideal position to spot early signs of neuromuscular disease, and therefore make a timely referral^2,11,12

Timely and accurate diagnosis can enable the patient and family to receive the care and support they need^1,2,13

Duchenne muscular dystrophy is a severe progressive disease presenting in early childhood that needs an accurate and early diagnosis.¹ Learn how to recognise the early signs and symptoms, click here.

What is muscular dystrophy?

The muscular dystrophies are a group of neuromuscular disorders characterised by progressive muscle degeneration and weakness.¹ They are caused by mutations in genes that produce either dysfunctional, or insufficient levels of, proteins that are essential for muscle cell stability.¹ Children with muscular dystrophy experience progressive muscle deterioration and an ongoing decline in physical function.¹

There are different forms of muscular dystrophy²

The muscular dystrophies differ in age of onset, severity, pattern of inheritance, and the muscle groups and other organs affected.¹

Duchenne^2,3
Duchenne is the most common and severe form of muscular dystrophy among children, and accounts for >50% of all cases. It primarily affects males.

Becker^2,3
Becker is less common and severe than Duchenne but presents with similar symptoms.

Myotonic²
Myotonic is the most common adult form of muscular dystrophy.

Congenital²
Congenital muscular dystrophy appears at birth or by age 2.

Emery-Dreifuss²
Emery-Dreifuss primarily affects boys, with symptoms usually apparent by age 10.

Facioscapulohumeral (FSHD)²
FSHD refers to the areas affected – the face (facio), shoulders (scapulo) and upper arms (humeral). It typically affects adolescents.

Limb girdle²
Most often appears in adolescence or young adulthood. Affects both males and females.

Distal²
Distal muscular dystrophy is less severe and progresses more slowly than other forms of muscular dystrophy. It typically appears at 40–60 years of age.

Oculopharyngeal²
Oculopharyngeal muscular dystrophy occurs in both men and women, typically in a person’s 40s or 50s. It can be mild or severe.

Learn how to recognise neuromuscular disorders, click here to access the RCPCH e-learning module.

What are neuromuscular disorders?

Neuromuscular disorders encompass a wide range of diseases that affect the voluntary muscles and the nerves that control them.¹

They are generally classified depending on the location of involvement, and include:¹

Disorders of the muscle (e.g. Duchenne muscular dystrophy)

Disorders of the neuromuscular junction (e.g. congenital myasthenic syndrome)

Disorders of the motor neuron (e.g. spinal muscular atrophy)

Disorders of the peripheral nerve (e.g. Charcot-Marie-Tooth disease)

The majority of neuromuscular disorders that present in childhood have a genetic basis.¹ The most commonly encountered genetic paediatric neuromuscular condition is Duchenne muscular dystrophy, which affects 1 out of every 3,600–6000 newborn males worldwide.^1-4

What are the signs and symptoms of neuromuscular disorders?

Children with neuromuscular disease experience progressive muscle deterioration and an ongoing decline in physical function.⁵ The earliest and most common sign of neuromuscular disease is muscle weakness, which manifests as delayed motor development.^4,6 Delays in language, speech and cognition should also prompt suspicion that something may be wrong.^4,7–9 To learn more about red flag signs and symptoms click here.

Monitoring motor development can help to identify developmental delay earlier, allowing for timely referral to aid the diagnostic process.⁷

Why early diagnosis matters

Even though neuromuscular diseases are not curable, management and treatment options are available. ^10,11

An early diagnosis can facilitate access to the right treatment and services, which may help improve outcomes and help to avoid life-threatening complications. ^4,6,10

An early diagnosis can help improve outcomes and avoid life-threatening complications^4,6,10 If you suspect a neuromuscular disorder, order a creatine kinase (CK) blood test, click here to learn more.

Duchenne muscular dystrophy is a progressive disease presenting in early childhood that needs an accurate and early diagnosis

Once muscle is lost, it cannot be restored.^1–3 Therefore, early testing and diagnosis are critical to gain access to the right treatments and services^1,4-6

The timeline provides a summary of key motor and non-motor developmental milestones that may be missed in a child presenting with a neuromuscular disorder and children with Duchenne muscular dystrophy.

Recognising red flag signs and symptoms

Children with developmental delays or other signs of Duchenne muscular dystrophy should have a creatine kinase (CK) test
For more information about CK testing, click here

 

Duchenne muscular dystropy (DMD): What is it and how is it managed?

From the recognition of symptoms to management and supportive care, there are multiple stages in the management of a patient with DMD.

In this video, Prof. Ros Quinlivan from the National Hospital for Neurology and Neurosurgery in London, UK describes the early key signs and symptoms that would trigger a suspicion and further testing. She also describes the progressive nature of the disease and discusses her centre’s experience in the management of patients with DMD.

This video is based on professional and expert opinion of Prof. Ros Quinlivan.

Children with developmental delays should have a creatine kinase (CK) test

If a child is failing to meet developmental milestones, it could be due to a neuromuscular disorder.^1,2 Primary care physicians are ideally placed to recognise the early signs and symptoms of neuromuscular disorders, so that children can be referred to a neuromuscular specialist without delay.^1,2 To check the red flag signs and symptoms click here.

If you suspect a neuromuscular disorder, order a CK blood test.¹
• Elevated CK levels reflect muscle damage, and are a sign of certain neuromuscular disorders^1–5
• A CK test is quick, simple and inexpensive^1,3,6

A CK test should be carried out if:

• Examination and medical history suggest progressive muscle weakness^7-9
• A child has delayed motor function, such as not walking well or not able to rise to stand by 18 months^2,7,8,10
• A child shows developmental delay, including delays with mixed presentation (e.g. speech and cognition), and evaluation suggests a peripheral neuromuscular problem⁷
• A child has a positive family history of Duchenne muscular dystrophy and suspicion of abnormal muscle function²
• Blood tests reveal an unexplained increase in transaminases ²

Refer all patients with elevated CK levels or missed motor milestones^8,11

All patients who have elevated CK levels should be promptly referred to a neuromuscular specialist.^8,11

Normal or mildly elevated CK does not rule out neuromuscular disorder. If a patient has missed motor milestones, they should also be referred to a neuromuscular specialist.⁸

Prompt referral is vital to give your patients the best chance of better outcomes^1,2

A neuromuscular specialist can then:²

Identify the child’s exact mutation²
Confirm Duchenne muscular dystrophy with a genetic diagnosis and identify the specific mutation causing the disease²

Define best management options²
Decide upon appropriate treatment and interventions to help delay disease progression²

Developmental delay should trigger a CK test

Prompt CK testing can help to achieve the correct diagnosis and bring reassurance to families.^3,13 Learn more about CK testing here.

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 dystrophy^1,3,4

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

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

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

Dystrophin protein structure and interactions

Dystrophin:

• Links internal cytoskeleton to sarcoglycans/dystroglycansin the membrane and the extracellular matrix^5,6
• Provides mechanical stability and structure to muscle cell membrane during contraction^5–7
• Critical to structure/stability of all muscles, including respiratory and cardiac muscles⁵

The absence of dystrophin leads to muscle degeneration and fibrosis^11,12

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

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 weakness^3-5

Cardiomyopathy^3,4

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.

How common is Duchenne muscular dystrophy (DMD)?

DMD is an x-linked recessive disorder that primarily affects males.^1,2 While a rare disease, it is the most prevalent of all neuromuscular disorders, affecting 1 out of every 3,600–6000 newborn males worldwide.^2-4

If a female carries the mutation in the dystrophin gene on one of the two X-chromosomes, she may also be affected by DMD. Approximately 10% of female carriers show some disease manifestations, with cardiac involvement a frequent finding.^2,5

Adapted from MDA⁶

Duchenne muscular dystrophy primarily occurs in males, but can affect females in some cases.^1,2 Learn about carriers of Duchenne muscular dystrophy; symptoms and care here.