Duchenne's Muscular Dystrophy

Synonyms - Duchenne muscular dystrophy, muscular dystrophy Duchenne type, Pseudohypertrophic progressive muscular dystrophy, Meryon's disease

The muscular dystrophies (MD) are a group of inherited disorders characterised by progressive muscle wasting and weakness,^1,2 of which Duchenne's muscular dystrophy (DMD) is the most common. It is an X linked recessive condition which presents in early childhood and inevitably progresses. Women who are carriers of DMD may have mild features of the disease.

The incidence in the UK is around 1 in 3,500 boys.³

DMD is caused by abnormalities of the dystrophin gene, which is responsible for a cytoskeletal protein named dystrophin, located in muscle fibres. The dystrophin gene is large, and many different mutations can affect it. In Duchenne MD, no dystrophin is produced (in contrast with the milder Becker type MD, where there is abnormal but partly functional dystrophin).

DMD is an X-linked recessive trait, "carried" by females and manifest in males, therefore:

• Female relatives (through the maternal line) of DMD patients may be carriers and may need to be tested. They are not necessarily carriers, because many DMD cases arise from new mutations.
• Sons of carriers have a 50:50 chance of being affected. For daughters of carriers, there is a 50:50 chance that they will also be carriers.
• Sons of men with DMD will not have DMD themselves or carry the gene. Daughters of men with DMD will be carriers.

For carriers:

• Most carriers in a family can be identified through creatinine kinase measurement and/or genetic analysis.
• Female carriers sometimes have mild muscle weakness and can develop cardiomyopathy⁶ (see below).
• For a subsequent pregnancy, prenatal diagnosis is often (but not always) possible using genetic analysis.

The distinctive feature of Duchenne muscular dystrophy is a progressive proximal muscular dystrophy with characteristic pseudohypertrophy of the calves. All patients have symptoms by age 3 years, but diagnosis is often later. Symptoms and signs are:

• Motor milestones delayed (50% not walking by 18 months)
• Inability to run - with waddling gait when attempting to do so
• Inability to jump or hop, no spring in the step
• 'Climbing up legs' using the hands when rising from the floor (Gower's sign)
• Hypertrophy of calf muscles (other muscles may also be hypertrophied, including deltoid, quadriceps, tongue and masseters.
• The child may 'slip through the hands' on being lifted, due to hypotonia of muscles around the shoulder.

Non-locomotor presenting symptoms are:

• Speech may be delayed.
• Global developmental delay may be the presenting feature.⁷
• Anaesthetic complications, rarely, are the presentation.

• Awareness: consider DMD in any boy who is not walking by 18 months, who has delayed motor milestones or global developmental delay.⁷
• Aim to make the diagnosis early, to allow genetic counselling for the family. This is important if they are considering another pregnancy.
• Observe the child walking and attempting to run, jump, climb stairs and rise from the floor. Watch for lack of spring in the step and lack of fluidity in attempted running. This is often more useful than formal examination in a young child.
• If DMD is suspected, test the serum creatinine kinase. This is always massively elevated in DMD (creatinine kinase is also raised in some other muscular dystrophies). If so, refer to a specialist at this stage, for diagnosis and genetic counselling.
• Remember that DMD is a devastating diagnosis, and follow good practice for disclosing bad news: privacy, time for questions, support and further information.

• Serum creatinine kinase is always massively raised, even to >200 times normal. A normal creatinine kinase excludes DMD.
• Electromyograpy (EMG) shows non-specific dystrophic changes.
• Muscle biopsy establishes the diagnosis, showing reduced or absent dystrophin.
• Genetic analysis can confirm the diagnosis in about 70% (when a deletion of the dystrophin gene is present).
• Carrier status can usually be identified by genetic analysis. Also, serum creatinine kinase is usually high in carriers.

• Other muscular dystrophies - particularly Becker MD which is similar but progresses more slowly. The clinical features, muscle biopsy and genetic analysis help distinguish DMD from the other muscular dystrophies.
• Other types of myopathy
• Neurological causes of muscle weakness, e.g. spinal cord lesions, spinal muscular atrophy, motor neurone disease, multiple sclerosis. These conditions are likely to have additional features such as sensory loss, upper motor neurone signs or muscle fasciculation.

There is progressive muscle weakness.The hand muscles are often spared until late on, and extraocular muscle function is preserved. Complications are:

• Joint contractures are usual.
• Respiratory muscle failure is progressive, leading to hypoventilation, loss of coughing and respiratory infections.
• Cardiomyopathy is common, although actual symptoms are less likely and usually occur late on in DMD. Cardiac arrythmias can occur.
• Respiratory failure, pneumonia and/or cardiomyopathy are the usual cause of death.
• Smooth muscle can also be affected, causing gastrointestinal symptoms such as gastric dilation or pseudo-obstruction.
• Nutritional problems and weight loss can occur in the late stage of DMD.
• Educational: about 20% of DMD patients have learning difficulty. This is nonprogressive and may affect verbal ability more than other performance.
• Ophthalmic: there may be an increased incidence of colour blindness.
• Complications of immobility, e.g. constipation, osteoporosis.¹

Walking ability is lost by age 12. DMD shortens life: previously, few patients survived beyond age 20; now with improved respiratory and cardiac care, they may live into their late 20s or beyond. Severity and progression varies between individuals. Some predictors of prognosis are:

• Individual clinical features
• Early onset of cardiomyopathy is a poor prognostic sign.
• From muscle biopsies, there is a correlation between dystrophin abundance and severity of DMD. (Serum creatinine kinase levels are not correlated with severity.)

Initial management - after diagnosis

• Information and support for the family
• Genetic diagnosis and counselling
• Referral of the child to a multidisciplinary team
• Influenza and pneumococcal immunisations are recommended for life

Early stage management - while child is walking, up to age 11 years

• Physiotherapy for advice on stretching, to prevent contractures
• Later, callipers or orthoses may be needed for walking
• Surgical lengthening of the Achilles tendon is often needed
• Corticosteroids can probably prolong ambulation, but this must be balanced against side effects.⁸

Management after walking ability is lost

Boys with DMD lose independent mobility around age 8-11 years. Once this occurs, management involves:

• Help with mobility - usually an electric wheelchair
• Orthopaedic care - surgery for contractures and scoliosis is often needed
• Cardiac and respiratory surveillance is important - see below
• Support and adaptations for school
• Counselling and support with adolescence

Management in later stages

This may be from the boy's late teens, and may involve:

• Support for increasing weakness and fatigue; wheelchair and other living adaptations are needed
• Optimise respiratory and cardiac treatments (see below)
• Nutritional support
• Respite care for the family
• Palliative care
• Planning ahead and end of life directives ( a 'living will'): remember that deterioration can occur suddenly as well as gradually.⁹

Some carriers of DMD develop symptoms of muscle weakness, but in a milder form to male DMD patients. Involvement of cardiac muscle is also possible, even if there are no skeletal muscle symptoms.^3,6 For this reason, the following cardiac surveillance is recommended:¹⁰

• Patient education about the risk, symptoms and signs of cardiomyopathy
• Specialist cardiac evaluation starting in late adolescence, or earlier if any symptoms or signs appear
• Continue cardiac screening every 5 years

However, recent data from Scotland found no increase in cardiac deaths among DMD and Becker's MD carriers.¹¹

Currently there are no specific treatments for DMD, but various strategies have been suggested: cell-based therapy using myoblast or stem cell transfer; pharmacological treatment with utrophin, a homologue of dystrophin; and gene therapy.