The muscular dystrophies are a group of inherited disorders characterised by progressive muscle wasting and weakness, of which Duchenne's 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 gene.¹

Epidemiology²

The incidence in the UK is around 1 in 3,500 male births, or about 100 boys with DMD born each year in the UK.

Aetiology³

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; many different mutations can affect it. In DMD, no dystrophin is produced (cf. Becker's muscular dystrophy, where 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 deltoid, quadriceps, tongue and masseters)

Non-locomotor presenting symptoms:

• Speech delay or global developmental delay
• Failure to thrive
• Abnormal liver function tests (raised AST or ALT)
• Anaesthetic complications - e.g. myoglobinuria, rhabdomyolysis or malignant hyperthermia after certain anaesthetics

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.
• Note: it is important to watch the child running and rising from the floor. Look for a waddling gait and Gowers' 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.

Investigation^1,4

Patients with suspected Duchenne's muscular dystrophy

• 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

Possible carriers of the gene

• Carrier status can usually be identified by genetic analysis. Also, serum creatine kinase 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.
• 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.

Management^1,4

Initial management - after diagnosis

• Information and support for the family.
• Genetic diagnosis and counselling.
• Refer to a specialist and multidisciplinary team.
• Immunisations - influenza and pneumococcal.

Early stage management - while 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:
  • These prolong ambulation by 6-24 months. They may also help regarding respiratory function, cardiomyopathy and scoliosis.⁵
  • This must be balanced against side-effects, including osteoporosis and vertebral fractures.
  • Prednisolone is the usual treatment. There are recommended dose regimes.¹
• Optimise bone health:¹
  • 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.
• 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 DMD.⁶

Anaesthetics:⁷

• Anaesthetic procedures require careful pre-operative assessment and close monitoring.
• Avoid certain anaesthetic drugs (risk of complications - see Presentation).

Complications¹

• Joint contractures.
• Respiratory complications:⁶
  • Respiratory muscle failure is progressive, leading to hypoventilation, loss of coughing and respiratory infections.
  • Early symptoms may be non-specific, so awareness and monitoring is needed.
  • Respiratory failure is the usual cause of death.
• Cardiac complications:
  • 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.
  • Cardiac arrythmias can occur.
• 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, e.g. 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 care^1,6

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 non-specific, e.g. morning drowsiness, headaches, nausea, fatigue, poor concentration.

Good care improves symptoms and survival. Recommendations are:

• Monitoring, e.g. by forced vital capacity (FVC), cough peak flows and pulse oximetry.
• Regular review by respiratory physician if using wheelchair/reduced FVC/age 12 onwards.
• Treat chest infections promptly.
• Physiotherapy.⁸
• Non-invasive ventilation (NIV) relieves symptoms and prolongs survival. There are various types and options.
• Assist coughing and airway clearance, e.g. by manual techniques, cough assist devices or tracheostomy.⁸

Cardiac care^1,9

• Symptoms of cardiac failure may go unrecognised; early screening should be in place to identify cardiomyopathy before it becomes symptomatic, e.g. 6-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 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 severe cardiac impairment.

Prognosis¹

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

• Walking ability is lost by age 12.
• Previously, few patients survived beyond age 20.
• Currently with improved respiratory and cardiac care, most patients live into adulthood, e.g. late 20s or beyond.
• Severity and progression varies between individuals.

Female carriers of Duchenne's 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 affected.¹⁰
• One review suggests that there is a 10% lifetime risk of cardiomyopathy for DMD carriers.
• An international workshop in 2002 recommend regular cardiac screening for all DMD carriers,⁹ although this recommendation has been questioned.¹⁰

Manifesting carriers^11,12,13

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 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.¹³

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.

Research¹⁴

Current research includes:

• Gene therapy - currently being trialled using the 'exon skipping' approach.¹⁵
• Stem cell therapy.
• Utrophin protein.

Document references

1. Manzur AY, Kinali M, Muntoni F; Update on the management of Duchenne muscular dystrophy. Arch Dis Child. 2008 Nov;93(11):986-90. Epub 2008 Jul 30. [abstract]
2. Factsheet: Duchenne muscular dystrophy. Muscular dystrophy campaign. Updated April 2008.
3. Emery AE; The muscular dystrophies. BMJ. 1998 Oct 10;317(7164):991-5.
4. Muscular Dystrophy Campaign: Duchenne muscular dystrophy factsheet by Bushby, KMD, Professor of Neuromuscular Genetics, University of Newcastle upon Tyne, 2008
5. Manzur A, Kuntzer T, Pike M, et al; Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003725. [abstract]
6. American Thoracic Society Documents: Respiratory Care of the Patient with Duchenne Muscular Dystrophy; ATS Consensus Statement 2004.
7. Birnkrant DJ, Panitch HB, Benditt JO, et al; American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation. Chest. 2007 Dec;132(6):1977-86. [abstract]
8. British Thoracic Society. Patient information leaflet: Respiratory (chest) physiotherapy for people with neuromuscular disease. May 2009.
9. No authors listed; Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics. 2005 Dec;116(6):1569-73. [abstract]
10. Holloway SM, Wilcox DE, Wilcox A, et al; Life expectancy and death from cardiomyopathy amongst carriers of Duchenne and Becker muscular dystrophy in Scotland. Heart. 2007 Oct 11;. [abstract]
11. Manzur AY, Muntoni F; Diagnosis and new treatments in muscular dystrophies. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):706-14. [abstract]
12. Muscular dystrophy campaign factsheet. Manifesting carriers of Duchenne MD. Updated April 2008.
13. Grain L, Cortina-Borja M, Forfar C, et al; Cardiac abnormalities and skeletal muscle weakness in carriers of Duchenne and Becker muscular dystrophies and controls. Neuromuscul Disord. 2001 Mar;11(2):186-91. [abstract]
14. Research page, muscular dystrophy campaign. Accessed September 2009.
15. Kinali M, Arechavala-Gomeza V, Feng L, et al; Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 2009 Oct;8(10):918-28. Epub 2009 Aug 25. [abstract]

Internet and further reading

• Muscular Dystrophy Campaign: a UK charity giving information and links for all types of muscular dystrophy and related conditions.
• Howard RS, Davidson C; Long term ventilation in neurogenic respiratory failure. J Neurol Neurosurg Psychiatry. 2003 Sep;74 Suppl 3:iii24-30.
• Caliskan E, Sener M, Kocum A, et al; Duchenne muscular dystrophy: how I do it? Regional or general anesthesia? Paediatr Anaesth. 2009 Jun;19(6):624-5.
• Davidson ZE, Truby H; A review of nutrition in Duchenne muscular dystrophy. J Hum Nutr Diet. 2009 Oct;22(5):383-93. [abstract]
• Parker AE, Robb SA, Chambers J, et al; Analysis of an adult Duchenne muscular dystrophy population. QJM. 2005 Oct;98(10):729-36. Epub 2005 Aug 31. [abstract]
• Cheuk DK, Wong V, Wraige E, et al; Surgery for scoliosis in Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005375. [abstract]
• Muir LA, Chamberlain JS; Emerging strategies for cell and gene therapy of the muscular dystrophies. Expert Rev Mol Med. 2009 Jun 25;11:e18. [abstract]

Acknowledgements