Elsevier

The Lancet Neurology

Volume 9, Issue 1, January 2010, Pages 77-93
The Lancet Neurology

Review
Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management

https://doi.org/10.1016/S1474-4422(09)70271-6Get rights and content

Summary

Duchenne muscular dystrophy (DMD) is a severe, progressive disease that affects 1 in 3600–6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation–University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.

Introduction

Duchenne muscular dystrophy (DMD; Online Mendelian Inheritance in Man [OMIM] reference 310200) is an X-linked disease that affects 1 in 3600–6000 live male births.1, 2, 3 Affected individuals can have mildly delayed motor milestones and most are unable to run and jump properly due to proximal muscle weakness, which also results in the use of the classic Gowers' manoeuvre when arising from the floor. Most patients are diagnosed at approximately 5 years of age, when their physical ability diverges markedly from that of their peers.4 Untreated, muscle strength deteriorates, and boys require the use of a wheelchair before their teens. Respiratory, orthopaedic, and cardiac complications emerge, and without intervention, the mean age at death is around 19 years. Non-progressive cognitive dysfunction might also be present.5

DMD occurs as a result of mutations (mainly deletions) in the dystrophin gene (DMD; locus Xp21.2). Mutations lead to an absence of or defect in the protein dystrophin, which results in progressive muscle degeneration leading to loss of independent ambulation by the age of 13 years.6 Variable phenotypic expression relates mainly to the type of mutation and its effect on the production of dystrophin. Milder allelic forms of the disease also exist, including intermediate muscular dystrophy and Becker muscular dystrophy, which cause loss of ambulation at 13–16 years or over 16 years, respectively. With the use of corticosteroids to prolong ambulation, these boundaries are less distinct. However, that these phenotypes exist is important, and if progression is milder than expected for DMD, assessment for these alternative forms should be done. Some patients with dystrophin mutations also have an isolated cardiac phenotype.7, 8, 9, 10, 11, 12 Approximately 10% of female carriers show some disease manifestations that might include or even exclusively affect cognitive and/or cardiac function.13, 14, 15 Although the disorder in affected girls is usually much milder than in boys, a few cases do have disease severity similar to that seen in affected boys.13, 14, 15 Apart from a few cases associated with chromosomal rearrangements, most girls are assumed to be affected as a result of skewed X inactivation.

The molecular basis of DMD has been known for over 20 years.16, 17 Many promising therapeutic strategies have since been developed in animal models.18 Human trials of these strategies have started, leading to the hope of definitive treatments for this currently incurable disease.18 Although specific treatments for DMD have not yet reached the clinic, the natural history of the disease can be changed by the targeting of interventions to known manifestations and complications. Diagnosis can be swiftly reached; the family and child can be well supported, and individuals who have DMD can reach their full potential in education and employment. Corticosteroid, respiratory, cardiac, orthopaedic, and rehabilitative interventions have led to improvements in function, quality of life, health, and longevity, with children who are diagnosed today having the possibility of a life expectancy into their fourth decade.19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32

Advocacy organisations report variable and inconsistent health care for individuals with DMD. Although anticipatory and preventive clinical management of DMD is essential, recommendations exist in only a few areas. Addressing the many complications of DMD in a comprehensive and consistent way is crucial for planning multicentre trials, as well as for improving care worldwide.

The development and implementation of standardised care recommendations were initially emphasised by stakeholders in the DMD community, including government agencies, clinicians, scientists, volunteer health agencies, and advocacy organisations such as the Muscular Dystrophy Association and Parent Project Muscular Dystrophy. In the USA, the Muscular Dystrophy Community Assistance, Research, and Education Amendments of 2001 directed increased research and public health initiatives towards the muscular dystrophies.33 Development of these care recommendations are part of these activities. In Europe, a European Union-funded Network of Excellence (EC036825), TREAT-NMD, received funding to advance the treatment and care for neuromuscular diseases, with standardisation of care in DMD as one of their priorities. The US Centers for Disease Control and Prevention (CDC) has facilitated the development of these care recommendations as a collaborative effort among these stakeholders.

The aim of this Review is to present recommendations for DMD management based on analysis of independent expert ratings of assessments and interventions. These recommendations focus attention on the many positive areas promoting efficient diagnosis and effective management in DMD. They are intended for the wide range of health-care providers who work with individuals who have DMD and their families, from primary care to the multidisciplinary team. The purpose of these recommendations is to provide a framework for recognising the primary manifestations and possible complications and for planning optimum treatment across different specialties with a coordinated multidisciplinary team. In the first part of this Review, we describe the methods used, and provide recommendations for diagnosis, pharmacological treatment, and psychosocial management. In the second part,34 we will discuss the implementation of multidisciplinary care.

Section snippets

Methods

Very few large-scale randomised controlled trials (RCTs) have been done in DMD. In areas in which such trials exist (eg, for the use of corticosteroids), the evidence that can be derived from these studies has been emphasised. For most of the other recommendations, the CDC chose the RAND Corporation–University of California Los Angeles Appropriateness Method (RAM) to guide their development.35 RAM combines scientific evidence with the collective judgment of experts to determine the

The multidisciplinary team and the toolkit

Each panel defined the toolkit of assessments and interventions applicable to DMD management (figure 1). The multidisciplinary approach to caring for patients with DMD and the range of expertise required are key features of this process. The patient and family should actively engage with the medical professional who coordinates clinical care. Depending on the patient's circumstances, such as area/country of residence or insurance status, this role might be served by, but is not limited to, a

Diagnosis of DMD

The aim of care around diagnosis is to provide an accurate and prompt diagnosis, allowing initiation of appropriate interventions, continuing support and education, and minimising the length and impact of a potentially protracted diagnostic process. Diagnosis should be done by a neuromuscular specialist who can assess the child clinically and can rapidly access and interpret appropriate investigations in the context of the clinical presentation. Family follow-up and support after diagnosis will

Neuromuscular and skeletal assessments

Clinical assessment in DMD includes taking a standard medical and family history and undertaking a physical examination, with a focus on the musculoskeletal system and related functional impairments. The neuromuscular specialist should be experienced in the expected disease course for DMD to understand the implications of a deviation from this course (eg, the possibility that a milder course might indicate a less severe dystrophinopathy or that more severe disease might suggest concomitant

Pharmacological interventions for muscle strength and function

Pharmacological intervention has begun to change the natural history of DMD, and further advances and more effective treatment of the underlying pathology of DMD should continue to offer an improved course, potentially including small-molecule and gene therapies. The most devastating and obvious effect of DMD is on the skeletal musculature with resulting loss of strength and function. The progression of muscle degeneration in DMD is well documented both in terms of pathophysiology and

Psychosocial management

The medical care of a patient who has DMD and his family is not complete without support for their psychosocial wellbeing.85, 86 For many parents, the stress caused by the psychosocial problems of their child exceeds the stress associated with the physical aspects of the disease.87 Needs vary with the age of the patient and stage of disease (figure 2), but several general statements are valid.

DMD is a multilevel/multisystem disease. Biological factors (including the lack of dystrophin and/or

Conclusions

The recommendations presented in the two parts of this Review represent the outcome of an international collaboration of clinical experts working to inform optimum care for DMD. Because of a paucity of data from RCTs for DMD (a common situation in rare disorders), a well-established method was chosen to generate statements about the appropriateness or inappropriateness and necessity of clinical interventions. RAM offers several benefits compared with other consensus-based methods, including

Search strategy and selection criteria

Peer-reviewed literature was searched using the key search terms of “Duchenne” or “muscular dystrophy”, or both, paired with one of 410 other search terms related to a comprehensive list of assessment tools and interventions used in DMD management. The full list of search terms is available on request. The databases used included Medline, Embase, Web of Science, and the Cochrane Library. Initial inclusion criteria consisted of available abstracts of human studies published in English

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