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Update on the management of Duchenne muscular dystrophy
  1. A Y Manzur,
  2. M Kinali,
  3. F Muntoni
  1. Dubowitz Neuromuscular Centre, Department of Paediatric Neurology, Great Ormond Street Hospital for Children, Institute of Child Health, London, UK
  1. Dr Adnan Y Manzur, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK; manzua{at}


Duchenne muscular dystrophy (DMD) is familiar to paediatricians as the most common childhood muscular dystrophy and leads to severe disability and early death in the late teenage years if untreated. Improvements in general care, glucocorticoid corticosteroid treatment, non-invasive ventilatory support, and cardiomyopathy and scoliosis management have significantly changed the course of DMD in treated individuals, so that survival into adulthood is now a realistic possibility for most patients. This has important implications for the medical and social sectors involved in the transition to adult medical services and the provision of suitable employment and social care. Multidisciplinary team working for optimal management of DMD-specific multisystem complications is essential, and collaboration in disease specific national clinical networks is recommended. Several curative therapeutic strategies including cell and gene therapy are being pursued but are still at an experimental stage.

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Duchenne muscular dystrophy (DMD) affects 1 in every 3500 live male births. Paediatricians are familiar with the course of untreated DMD: common presentation is with abnormal gait, calf hypertrophy and difficulty in rising from the floor between 2 and 5 years of age.1 Progression of muscle weakness and leg contractures leads to loss of walking and complete wheelchair dependence at a mean age of 9.5 years, and the ensuing early teenage years are marked by the development of progressive scoliosis. The leading cause of death is respiratory insufficiency in the late teens or early twenties, although a minority die because of cardiac complications such as dilated cardiomyopathy. Feeding difficulties and weight loss are common in the late stages of the disease.

At present, there is no curative treatment for DMD, but advances in management over the last two decades have altered the natural history of the disease, so it can now be anticipated that most individuals with DMD will survive into adulthood. The multisystem complications of DMD necessitate a multidisciplinary team approach for optimal surveillance and management (table 1). This review describes the advances in management and outlines the challenges to paediatric practice in achieving early diagnosis, the best possible outcome, quality of life and transition to adulthood.

Table 1 The multidisciplinary team for management of DMD


A brief review of the molecular genetic basis of DMD is necessary for understanding the approach to diagnosis and the limitations of the various diagnostic techniques. DMD is caused by mutations in the dystrophin gene on the X chromosome at Xp21. The dystrophin locus contains 85 exons and encodes for a large but low abundance protein called dystrophin.2 Dystrophin is a rod shaped molecule which localises at the cytoplasmic side of the sarcolemma: one end binds to the dystrophin associated glycoprotein complex at the sarcolemma, while the other end binds to the cytoskeletal actin. Dystrophin is postulated to be essential for force transduction by providing a indirect link between the contractile apparatus in the muscle fibre with the extracellular matrix. The mutations in the dystrophin gene which result in DMD cause disruption of the reading frame, resulting in a severe reduction or complete absence of dystrophin in the skeletal and cardiac muscle, which in turn leads to mechanically induced sarcolemmal damage, loss of intracytoplasmic calcium homeostasis, and muscle fibre degeneration. Several dystrophin isoforms are also expressed in brain and their deficiency in this tissue is responsible for the mental retardation which complicates the course of DMD in approximately one third of cases.

Approximately 65% of patients with DMD have intragenic out-of-frame (gross rearrangements) deletions and approximately another 10% have duplications of one or more exons of the dystrophin gene. The remaining patients have point mutations or other smaller gene rearrangements (pure intronic deletions, insertions of repetitive sequences, splice site mutations). As a general rule out-of-frame dystrophin gene mutations lead to a severe reduction or absence of dystrophin in the muscle resulting in the DMD phenotype, whereas in-frame mutations lead to the expression of abnormal but partly functional truncated dystrophin protein, resulting in the milder Becker muscular dystrophy (BMD). The frame shift hypothesis holds true for over 90% of cases and is commonly used both for diagnosis and for differentiating between DMD and BMD. However, there are important exceptions to the frame shift rule: in-frame mutations in the gene coding for the crucial actin-binding domain of dystrophin protein may cause the Duchenne severity phenotype, whereas some out-of-frame mutations are associated with BMD.2

The X linked recessive inheritance of DMD is well recognised, but there is a high incidence of new mutations and two thirds of patients do not have a positive family history at presentation.


Delay in the diagnosis of patients without a family history, until they are over 4.5 years of age, continues to be a problem.3 The principal reasons for missing the diagnosis on parents’ initial contact with the health professionals, is the failure to see the child “running” and rising from the floor (thereby missing the valuable clues of waddling gait and Gowers’ manoeuvre). In addition, it is often not appreciated that global developmental delay is a frequent early presentation of DMD.4 Box 1 lists the various presentations of DMD.

Serum creatine kinase (CK) is extremely elevated (10–100 times normal since birth) and should be the first investigation when DMD is suspected. A high CK level should prompt urgent specialist referral for confirmation. A normal CK at presentation excludes the diagnosis. However, CK levels fall with disease progression, reflecting muscle wasting and reduced physical activity. CK therefore is not a reliable screening test in late presenters who are already constant wheelchair users. Electromyography (EMG) has no role in the investigation of DMD and should not be requested.

The last decade has seen important advances in molecular genetic testing to identify dystrophin gene mutations. As most DMD patients carry deletions in two mutational hot spots of the gene, the screening of only 19 exons, following amplification of genomic DNA, could identify mutations in over 65% of patients with DMD.5 However, an important limitation of this technique is its inability to identify rarer mutations or the breakpoint of several common deletions. More recently, other methods such as multiplex ligation dependent probe amplification6 or a combinatorial strategy using fluorescent multiplex quantitative PCR followed by conformation sensitive capillary electrophoresis (CSCE) of the same PCR products on a multi-capillary genetic analyser,7 have brought the efficiency of mutation detection close to 100%. These techniques have the additional advantage of being able to unequivocally detect mutations in carrier females, thus allowing precise genetic counselling of affected families. Molecular genetic documentation of a dystrophin mutation confirms dystrophinopathy (dystrophin gene related muscular dystrophy) and determination of the endpoints of the mutation establish the in/out-of-frame status and may allow assignment of severity as regards Duchenne or Becker phenotype, but exceptions to the frame shift hypothesis have been described.2 Establishing the precise diagnosis of DMD is therefore best achieved by a combination of clinical observation of the patient’s strength and functional abilities, ascertainment of dystrophin levels on muscle biopsy and knowledge of the gene mutation.8

Box 1 The various presentations of Duchenne muscular dystrophy

Motor presentations

  • Walking delayed beyond 18 months

  • Frequent falls

  • Foot posture abnormalities/deformities

  • Toe walking

  • Waddling gait

  • Difficulty running/rising from the floor

Non-motor presentations*

  • Global developmental delay

  • Severe learning difficulties/“autism”

  • Failure to thrive

  • “Liver disease” – elevated ALT, AST discovered incidentally during investigation of intercurrent or other illness

  • Myoglobinuria, rhabdomyolytic hyperkalaemic, malignant hyperthermia-like reaction to suxamethonium, halothane or other halogenated inhaled anaesthetics during anaesthesia

*Motor difficulties are present when specifically looked for but are often missed because the clinical presentation is dominated by other issues.

Dystrophin protein assay on muscle biopsy in DMD shows severe reduction or complete absence and allows the most robust diagnosis. A muscle sample can be obtained by a needle biopsy under oral sedation.9 It is the policy of our unit at the Dubowitz Neuromuscular Centre to offer a muscle biopsy (in addition to molecular genetic testing) as the first and confirmatory test for boys with suspected DMD, unless there is a positive family history in a sibling or presentation is late (after 7 years of age) when the disease course is clearly in the Duchenne severity range.

Female carriers of DMD

Advances in molecular genetics now allow precise evaluation of the carrier status of the relevant females in a family. In addition to accurate counselling and antenatal diagnosis, determination of carrier status is important as carriers have a 10% life time risk of developing cardiomyopathy10 and appropriate surveillance and treatment protocols may need to be set up.


Physiotherapy to promote walking and prevent joint deformities remains important and detailed recommendations are available.11 Rehabilitation in knee-ankle-foot orthoses (KAFOs) is offered to boys with DMD at the end of independent ambulation, and is effective in prolonging walking for an average of 18 months to 2 years.12 The technique entails custom-built KAFOs, and in the past used to require surgical release of the Achilles tendon to reduce ankle contracture and allow fitting of the KAFO, and is generally well tolerated.13 We have recently shown that serial casting of the ankles can be offered instead of the surgical release of the Achilles tendons in many cases.14


To date, glucocorticoid corticosteroids have been the most effective medication in DMD, and a Cochrane systematic review of the use of glucocorticoids in DMD is available.15

Randomised controlled trials (RCTs) have shown that treatment with prednisone can stabilise strength and function for 6 months to 2 years.15 Prednisone has been the most widely used medication and the starting dose is 0.75 mg/kg/day. Non-randomised studies with prednisone or deflazacort have documented prolongation of walking ability, preservation of respiratory function and reduction in the incidence of scoliosis and cardiomyopathy in boys with DMD who tolerated long-term daily dose corticosteroids.16 Predictably, daily glucocorticosteroid therapy has significant side effects. Notably, in the short-term weight gain can be bothersome and dietetic input from initiation of steroid therapy helps prevent/ameliorate this problem. Vertebral fractures are also a significant side effect in approximately a third of long-term treated patients.17 The Dubowitz intermittent regime was recommended to reduce the adverse effects associated with daily steroid regimes; a 6 month RCT of prednisone 0.75 mg/kg/day for the first 10 days of every month demonstrated slowing of functional deterioration,18 and an international RCT to compare daily dose prednisone and deflazacort with an intermittent prednisone regime is planned.19

Consensus on the role of corticosteroids in DMD is emerging after careful consideration of the advantages and disadvantages of long-term steroid treatment, based on expert and evidence based reviews.19 20 Corticosteroids should preferably be started in all early ambulant patients (4–6 years of age) and in most of the older ambulant children, unless contraindicated. Treatment needs to be monitored for benefit and adverse effects. The optimal starting dose of prednisolone 0.75 mg/kg/day is often not tolerated in the long term and, over the course of years, careful dose adjustment is required. Regular reviews, in collaboration with a specialist centre, allow for appropriate monitoring, dosing and management of adverse effects. Optimising bone health in corticosteroid treated patients includes dietary advice regarding calcium and vitamin D, and supplementation if plasma vitamin D levels are low.21 There is currently no evidence that oral bisphosphonates should be used prophylactically in children receiving steroids; however, their acute administration is recommended in the treatment of vertebral fractures, where they are very effective.

In the UK, the NorthStar Clinical Network for Paediatric Neuromuscular Disorders (NSCN) is a Muscular Dystrophy Campaign UK (MDC) sponsored collaboration between 16 specialist centres caring for boys with DMD ( The clinicians in the NSCN agree on the treatment and standardised assessment protocols for the use of glucocorticosteroids in DMD and are prospectively collecting data on a web based database to allow audit of clinical practice and refinement of the protocols. It is anticipated that this approach will standardise steroid related DMD management in the UK regardless of postcode.


The teenage years in patients with DMD are marked by worsening respiratory reserve and sleep hypoventilation, which is the result of respiratory muscle weakness, REM sleep, related hypoxemic dips22 and obstructive apnoeas.23 The resulting effects may include morning drowsiness, poor appetite, headaches, nausea, fatigue, tiredness, poor concentration at school, failure to thrive, reduced coughing ability or overt respiratory failure in the course of “minor” respiratory infections. Untreated patients who become hypercapnic survive for less than a year.24

Until the 1990s, the onset of symptomatic sleep hypoventilation signified imminent death, as the only way to prolong life was by mechanical ventilation through tracheostomy, and this was limited by the complex ethical issues of invasive ventilation of patients with totally incapacitating and incurable disease. However, in recent years, domiciliary non-invasive ventilation (NIV) has proven effective in relieving symptoms and prolonging survival.25 The patient’s breathing at night is augmented with breaths delivered by a compact, portable ventilator with a snugly fitting facial or nose mask. NIV corrects sleep hypoventilation and affords symptom relief without significant encroachment on living space or travel restrictions. NIV, and if needed, the use of cough assist devices, can extend average survival to the mid-twenties and in some cases to the fourth decade.26 27 This has led to the opinion that denying NIV to hypercapnic patients with DMD is unethical.25 28

Forced vital capacity (FVC) predicts the development of hypercapnia and survival.29 Regular monitoring for symptoms of sleep hypoventilation and FVC, and overnight sleep studies when the FVC falls below 50%, allow for timely initiation of NIV. Gradual initiation of NIV in individuals with nocturnal hypercapnia but daytime normocapnia is a valid approach, as waiting for daytime ventilatory failure exposes patients to minor chest infections and uncontrolled decompensation.24


Dilated cardiomyopathy (DCM) occurs in up to 90% of DMD individuals ⩾18 years old.30 The severity of the physical disability in boys with DMD in their late teens and later masks the clinical symptoms of cardiac failure unless these are very florid. Traditionally, cardiomyopathy was considered responsible for death in up to 20% of individuals with DMD; however, this proportion is likely to increase over the coming years in individuals in whom NIV prevents respiratory related mortality. The optimal timing of introducing therapy for DCM remains an unresolved issue. Duboc et al31 reported that early treatment with perindopril delayed the onset and progression of prominent left ventricular dysfunction and was associated with lower mortality32 in DMD. Some cardiologists suggest that treatment is not necessary for a complication that is often asymptomatic for a long time before deteriorating into clear-cut cardiac failure,33 although this view is at odds with the current evidence on related forms of DCM, which shows that early treatment is clearly superior to late therapy.34 Indeed, considering the well-described incidence and clinical course of DCM in DMD, and the recent claims of several groups that therapeutic intervention has a positive effect, the most logical approach appears to be to intervene before severe damage has occurred.

While awaiting the results of RCTs, published consensus documents recommend the use of angiotensin converting enzyme (ACE) inhibitors, β blockers and diuretics in patients with early cardiomyopathy.34 It is important to look for and treat co-existing nocturnal hypoventilation, which aggravates cardiac dysfunction.

The risk of cardiac involvement in carriers of DMD is approximately 10%, and this may occur in the absence of muscle weakness.35 Genetic counselling should include informing the carriers of the cardiac risks and plans for surveillance and treatment.


Scoliosis usually develops after loss of walking, rapidly progresses during the pubertal growth spurt and adversely affects respiratory function, feeding, sitting and comfort. The reduced incidence and severity of scoliosis in glucocorticosteroid treated boys16 is likely to be secondary to prolongation of walking and increase in truncal muscle strength.

Progression of the spinal curve is the indication for surgical spinal fusion. The decision is best made when the range of the spinal curve’s Cobb angle is 200–400,36 the FVC is above 30% predicted for height, and cardiac function, as demonstrated by echocardiogram, is good. A multidisciplinary team input when making the decision to offer surgery and pre-operative assessment are essential to ensure that the operation is safe. Spinal surgery can be performed when the FVC is between 20% and 30%, but the risks are greater and the operation should be undertaken in specialised centres.37

A spinal brace (jacket) does not prevent the progression of scoliosis but may be useful in postural management, especially in cases where spinal surgery is contraindicated or is not acceptable to the patient.


Nutritional difficulties include initial presentation with failure to thrive, obesity during the late ambulant phase (especially in corticosteroid treated individuals) and severe wasting in the spinal surgery post-operative period and the late teenage years. Regular weight monitoring and dietary advice to avoid obesity should be available to all patients with DMD, especially those treated with daily corticosteroids.

Young adults with DMD may have chewing and swallowing difficulties, prolonged mealtimes, choking on food and failure to thrive.38 Appropriate facilities for weighing the wheel chair dependent adolescents should be available in clinics to allow for regular weight monitoring. Patients with failure to thrive and/or swallowing difficulties benefit from dietetic and speech and language assessment for nutritional supplementation; observation of mealtimes and swallowing videofluoroscopy allow further advice about postural management, feeding aids or gastrostomy insertion.


The improvements in general care and the frequent provision of NIV since the 1990s has increased the mean survival of patients with DMD in the UK to 27 years of age,26 27 and further prolongation of survival is anticipated as the currently corticosteroid treated cohort matures and experiences the long-term beneficial effects, particularly as regards respiratory function.16 This change in the natural history of treated DMD means that it is now anticipated that most of these adolescents will reach adulthood. This underlines the need for the development of robust protocols for transition of care to the adult medical teams, and in particular, for improvement in rehabilitation, employment, social participation and social services for adults with DMD.39


Major advances in the understanding of molecular genetics and the pathogenesis of DMD has raised expectations of curative treatment with gene therapy. Research in this area has been greatly facilitated by the use of two naturally occurring animal models: the dystrophic golden retriever dog (GRMD), which suffers a fatal clinical course similar to that in humans, and the mdx mouse, which although it has a stop codon in exon 23 resulting in dystrophin deficient muscle fibres, is not overtly weak and has only slightly shorter survival than the wild type mouse. A detailed discussion of the various genetic strategies aimed at restoration of dystrophin in affected muscles40 is beyond the scope of this article, but they are listed with a basic description and current status in table 2.

Table 2 Strategies for gene therapy in Duchenne muscular dystrophy

Of particular interest is the UK Department of Health funded “molecular patch therapy” trial, utilising the exon skipping approach (, which is a good example of collaborative efforts between basic and clinical scientists, parent and patient organisations, governmental funding bodies and the pharmaceutical industry. The strategy behind the “molecular patches” is the modification of dystrophin mRNA splicing using antisense oligonucleotides. These small RNA-like molecules prevent the normal splicing of the gene by masking crucial areas of the messenger RNA during the splicing process, and induce exon skipping. In DMD patients with out-of-frame deletions (which represent ∼65% of all boys), the manipulation of exon skipping can result in deletions that maintain the open reading frame, similar to the situation found in the milder BMD. Early proof of the efficacy of this approach was obtained in concept studies of cell cultures of the mdx mouse and subsequently demonstrated in DMD cells. Systemic administration of antisense oligonucleotides in the mdx mouse also resulted in appreciable induction of exon skipping which resulted in expression of functional levels of dystrophin in skeletal muscles throughout the mdx mouse, with corresponding improvement in muscle function.41 However, antisense oligonucleotides have a couple of limitations. Firstly, different deletions will require different antisense oligonucleotides and secondly, the treatment is not permanent but is limited to the period in which the antisense oligonucleotides persist in the tissue. Antisense oligonucleotide treatment will therefore need to be repeatedly administered for the entire life of the patient with DMD, and whether this will be associated with any toxicity is not known. Nevertheless, antisense oligonucleotides have a fairly good safety profile according to data available from human trials. Two European consortia are testing the safety and local efficacy of intramuscularly administered AOs with a view to performing systemic AO trials. One group, based in Holland, has recently reported local synthesis and partial dystrophin restoration at the site of PRO051 AO injection into the tibialis anterior muscle of four patients, without adverse events.42 The results from the UK group ( are expected in 2008, and this will inform the feasibility of future systemic antisense oligonucleotide delivery studies.


The three authors wish to thank the Muscular Dystrophy Campaign for the support for the Dubowitz Neuromuscular Centre and the UK NorthStar Clinical Network for Paediatric Neuromuscular Disorders.


View Abstract


  • Funding: The study is funded by the Department of Health.

  • Competing interests: Adnan Manzur is the lead clinician for the UK NorthStar Clinical Network for Paediatric Neuromuscular Disorders, which is in part funded by Muscular Dystrophy Campaign UK. Francesco Muntoni and Maria Kinali are involved in the phase I/IIa trial using morpholino antisense oligomers in DMD.

  • Imperial College London is the study sponsor.