Duchenne muscular dystrophy

The muscular dystrophies are a group of inherited disorders characterised by progressive muscle wasting and weakness, of which Duchenne muscular dystrophy (DMD) is the most common.

DMD is an X-linked recessive condition which presents in early childhood and inevitably progresses. Some carriers also have symptoms. New mutations are common in DMD; this means that female relatives of a child with DMD are not necessarily carriers of the gene¹.

Epidemiology

DMD affects about 1 in 3,500 newborn males².

Aetiology³

DMD occurs as a result of mutations (mainly deletions) in the dystrophin gene (locus Xp21.2). Mutations lead to an absence of or defect in the protein dystrophin, which results in progressive muscle degeneration. The dystrophin gene is large and many different mutations can affect it⁴. In DMD, no dystrophin is produced (in Becker's muscular dystrophy, there is abnormal dystrophin).

Presentation¹

There is progressive proximal muscular dystrophy with characteristic pseudohypertrophy of the calves. All patients have symptoms by age 3 years but diagnosis is often delayed. Presenting features are:

• Motor milestones delayed.

• Inability to run - waddling gait when attempting to do so.

• Other gait signs - no spring in the step, cannot hop or jump; toe walking; falls.

• Gower's sign - 'climbing up legs' using the hands when rising from the floor.

• Hypertrophy of calf muscles (and possibly other muscles too, including the deltoid, quadriceps, tongue and masseters).

Non-locomotor presenting symptoms:

• Speech delay or global developmental delay.

• Failure to thrive.

• Abnormal LFTs (raised AST or ALT).

• Anaesthetic complications - eg, myoglobinuria, rhabdomyolysis or malignant hyperthermia after certain anaesthetics.

• Fatigue - this is common⁵.

Assessment and diagnosis - general points¹

• Awareness: consider DMD in any boy who is not walking by 18 months, who has delayed motor milestones or global developmental delay.

• Aim to make the diagnosis early, to allow genetic counselling for the family - important if parents are considering another pregnancy.

• NB: it is important to watch the child running and rising from the floor. Look for a waddling gait and Gower's sign. This is more useful than formal examination in a young child.

• Remember that DMD is a devastating diagnosis - follow good practice for disclosing bad news.

Investigation¹

Patients with suspected DMD

• The initial investigation is serum creatine kinase (CK):
  

  • In DMD the CK level is very high (10-100 x normal from birth).

  • A normal CK at presentation excludes DMD. However, later on CK levels fall due to muscle wasting; therefore, it is not reliable as a screening test in those who are already wheelchair users.

• The precise diagnosis is best achieved by a combination of:
  

  • Genetic analysis - can identify most (but not all) of the DMD mutations.

  • Muscle biopsy - with assay for dystrophin protein.

  • Clinical observation of muscle strength and function.

  
  Genetic testing after a positive biopsy diagnosis of DMD is mandatory. A muscle biopsy is not necessary if a genetic diagnosis is already known. However, if genetic testing has been done and no mutation identified, but CK concentrations are increased and signs or symptoms consistent with DMD are present, the next necessary diagnostic step is to do a muscle biopsy. This is also the case if there is a family history of DMD and a suspicion of the diagnosis but no family mutation known³.

Possible carriers of the gene

• Carrier status can usually be identified by genetic analysis. Also, serum CK is usually high in carriers.

• For a subsequent pregnancy, prenatal diagnosis is often (but not always) possible using genetic analysis.

Differential diagnosis

• Other types of muscular dystrophy - particularly Becker's muscular dystrophy, which is similar but progresses more slowly.

• Other myopathies.

• Polymyositis

• Neurological causes of muscle weakness - eg, 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.

• Increased transaminases (aspartate aminotransferase and alanine aminotransferase, which are produced by muscle as well as liver cells). The diagnosis of DMD should thus be considered before liver biopsy in any male child with increased transaminases³.

Management¹

Multidisciplinary care is essential, including psychosocial management. No specific aspect of care can be taken in isolation⁶.

Initial management - after diagnosis

• Information and support for the family.

• Genetic diagnosis and counselling.

• Referral to a specialist and multidisciplinary team.

• Immunisations - influenza and pneumococcal.

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

• Physiotherapy for advice on stretching, to prevent contractures.

• Later, knee-foot-ankle orthoses may help prolong walking.

• Serial casting of the ankles may be helpful (may prevent the need for surgical release of the Achilles tendon).

• Corticosteroids:
  

  • There is moderate quality evidence that corticosteroid therapy in DMD improves muscle strength and function in the short term (twelve months), and strength up to two years⁷.

  • This must be balanced against side-effects, including osteoporosis and vertebral fractures.

  • Prednisolone is the usual treatment. There are recommended dose regimes¹.

• Optimise bone health¹:
  

  • Vitamin D and calcium dietary advice or supplements.

  • Bisphosphonates if vertebral fracture occurs.

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 - orthotics or surgery for contractures and scoliosis. Scoliosis is usually progressive and treated with surgery⁸.

• Cardiac and respiratory surveillance is important (see 'Management of respiratory and cardiac complications', 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 'Management of respiratory and cardiac complications', below).

• Nutritional advice.

• Respite care for the family.

• Palliative care.

• Planning ahead and end-of-life directives; be aware that deterioration can occur suddenly in the later stages of DMD⁹.

Anaesthetics¹⁰

• Patients with DMD may experience a variety of life-threatening complications during and after general anaesthesia, including malignant hyperthermia and disease-related cardiac complications¹¹.

• Anaesthetic procedures require careful pre-operative assessment and close monitoring.

• Avoid certain anaesthetic drugs (risk of complications - see 'Presentation', above).

Future prospects¹²

Potential future developments include gene therapy and exon skipping¹³. Exon skipping is used to cause cells to skip over faulty sections of the genetic code¹⁴¹⁵. There have been encouraging results obtained with adult stem cells to treat muscular dystrophies¹⁶.

Complications¹

• Joint contractures.

• Respiratory complications⁹:
  

  • Respiratory muscle failure is progressive, leading to hypoventilation, loss of coughing, and respiratory infections.

  • Early symptoms may be nonspecific, so awareness and monitoring are needed.

  • Respiratory failure is the usual cause of death.

• Cardiac complications:
  

  • The severity of cardiomyopathy and congestive heart failure may not parallel the severity of skeletal muscle disease. Atrial and ventricular arrhythmias may be life-threatening. The degree of hypoventilation and pulmonary dysfunction also affects cardiac function in muscular dystrophy¹⁷.

  • Dilated cardiomyopathy is common, because cardiac muscle is also affected by the disease. Symptoms are less likely and usually occur later in the course of DMD. Only a minority of patients die from cardiac complications.

• Smooth muscle can also be affected, causing gastrointestinal symptoms such as gastric dilation or pseudo-obstruction.

• Educational: about 20% of DMD patients have learning difficulty. This is nonprogressive and may affect verbal ability more than other performance.

• Complications of immobility and/or steroids - eg, constipation, osteoporosis, obesity, hypertension.

• Weight loss can occur in the late stage of DMD.

• Anaesthetic complications (see 'Presentation' and 'Management', above).

Management of respiratory and cardiac complications

Respiratory care¹¹⁸

Respiratory function tends to decline after the child needs a wheelchair. The problems are:

• Reduced ventilation - initially during sleep.

• Loss of effective cough - leading to infections and atelectasis.

• Early symptoms are often nonspecific - eg, morning drowsiness, headaches, nausea, fatigue, poor concentration.

Good care improves symptoms and survival. Recommendations are:

• Monitoring - eg, by forced vital capacity (FVC), cough peak flows and pulse oximetry.

• Regular review by a respiratory physician if using a wheelchair/reduced FVC/age 12 onwards.

• Treat chest infections promptly.

• Physiotherapy.

• Non-invasive ventilation (NIV) relieves symptoms and prolongs survival. There are various types and options.

• Assist coughing and airway clearance - eg, by manual techniques, cough assist devices or tracheostomy.

Cardiac care¹¹⁹

• Symptoms of cardiac failure may go unrecognised²⁰.

• Early screening should be in place to identify cardiomyopathy before it becomes symptomatic - eg, six-monthly cardiology review from early childhood.

• Standard tests such as electrocardiogram (ECG) and echocardiogram (echo) may be difficult to interpret due to scoliosis.

• Cardiac impairment and arrhythmias are treated in the standard way using angiotensin-converting enzyme (ACE) inhibitors, diuretics and beta-blockers.

• Treat nocturnal hypoventilation (which exacerbates cardiac problems).

• If glucocorticoids are given, increased cardiac monitoring is needed, and watch weight gain and blood pressure.

• Patients are at increased risk of thromboembolism; consider anticoagulation if there is severe cardiac impairment.

Prognosis

• There is progressive muscle weakness.The hand muscles are often spared until late on, and extraocular muscle function is preserved¹.

• Affected boys are normally confined to a wheelchair by 12 years of age and die from respiratory or cardiac complications in their 20s or 30s²¹.

• Severity and progression vary between individuals²².

Female carriers of Duchenne muscular dystrophy

Cardiomyopathy risk

• Female carriers of the DMD gene may have an increased risk of cardiomyopathy.

• The extent of the risk is debatable; evidence is conflicting regarding rates of cardiomyopathy in carriers and regarding whether life expectancy is affected²³.

• One review suggests that there is a 10% lifetime risk of cardiomyopathy for DMD carriers.

• An international workshop in 2002 recommended regular cardiac screening for all DMD carriers¹⁹. However, this recommendation has been questioned²³.

Manifesting carriers²⁴

Most carriers are asymptomatic, but a small percentage (2-5%) may have skeletal muscle symptoms; they are known as manifesting carriers of DMD:

• The reason why the gene manifests in some women but not in others may be through the mechanism of 'X-inactivation', where the normal X chromosome is inactive and the X chromosome carrying the DMD mutation is the active one.

• As with DMD boys, there may be no family history of the disease.

• Some cases of DMD-manifesting carriers were previously diagnosed as having another type of muscular dystrophy but, with new techniques such as dystrophin staining, have been identified as having DMD.

• Clinical features:
  

  • There is wide individual variation in the severity of symptoms - from mild muscle weakness, aches or calf muscle enlargement, to a disease as severe as that in boys.

  • Onset of symptoms can be in adulthood.

  • There is usually some gradual progression of symptoms with time.

  • Cardiac involvement can occur.

• Diagnosis:
  

  • Muscle biopsy looking at dystrophin is usually helpful.

  • Genetic tests, including X-inactivation patterns.

• Management, follow-up and prognosis:
  

  • This varies depending on individual severity of symptoms.