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doi:10.1111/jpc.12868

REVIEW ARTICLE

Duchenne muscular dystrophy Eppie M Yiu1,2,3,4 and Andrew J Kornberg1,3,4 1 4

Neurology Department, Royal Children’s Hospital Melbourne, 2Bruce Lefroy Centre and 3Neurosciences Research, Murdoch Childrens Research Institute, and Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia

Abstract: Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies. Key words:

corticosteroid; Duchenne; gene therapy; muscular dystrophy; non-invasive ventilation; positive pressure.

Duchenne muscular dystrophy (DMD), an X-linked disorder and the most common muscular dystrophy, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness.1 Untreated boys become wheelchair dependent by 12 years of age and die in their late teens; however, advances in management have significantly improved life expectancy and quality of life.2,3 In addition, rapid progress in novel therapies represents an exciting time in the therapeutics of this devastating disorder.

Clinical Features Most boys with DMD present between 3 and 5 years of age. Presenting symptoms include gross motor delay, gait abnormalities, difficulty rising from the ground and frequent falls. Less frequent presentations include language or global developmental delay, raised serum creatine kinase (CK) levels or an

Key Points 1 Duchenne muscular dystrophy is an X-linked disorder and presents in boys in early childhood with proximal muscle weakness, calf hypertrophy and markedly elevated creatine kinase levels. 2 Weakness is progressive, and ambulation is lost early in the second decade. 3 Associated complications that require surveillance and management include restrictive lung disease, cardiomyopathy, scoliosis, corticosteroid side effects, and educational and psychosocial issues. Correspondence: Dr Eppie M Yiu, Neurology Department, Royal Children’s Hospital Melbourne, 50 Flemington Road, Parkville, Vic. 3052, Australia. Fax: +61 3 93455977; email: [email protected] Conflict of interest: The authors have no conflicts of interest. Accepted for publication 29 January 2015.

incidental finding of raised hepatic transaminases. A CK level should always be performed as part of the investigation of gross motor or global developmental delay. Weakness in DMD is typified by proximal lower limb and truncal weakness, followed later by involvement of upper limb and distal muscles. Neck flexor weakness is usually present at presentation, and many boys with DMD are never able to jump. Examination features include a waddling gait, calf enlargement and positive Gowers’ sign, the latter a non-specific sign of proximal weakness and not pathognomonic of DMD. Most boys gain strength and motor skills (albeit to a lesser extent than their peers) until about 6 years of age; after this stage, progressive deterioration in strength occurs. Untreated, most are wheelchair bound by 11–12 years of age.4 Cardiac manifestations include dilated cardiomyopathy and arrhythmias. Clinically apparent cardiomyopathy is first evident after 10 years of age, affects one-third of patients by age 14 years and is present in all patients over 18 years of age. However, pre-clinical cardiac involvement is present in up to 25% of patients under 6 years of age, with a persistent tachycardia commonly noted. Despite the high frequency of cardiac involvement, most boys are relatively asymptomatic due to physical inactivity.5 Chronic respiratory insufficiency secondary to restrictive lung disease is universal. Vital capacity increases until around 12 years of age then decreases by 4–8% per year.6,7 Obstructive sleep apnoea is the predominant cause of sleep-disordered breathing (SDB) in the first decade, while hypoventilation occurs from the second decade. SDB without hypercapnia is the first manifestation of respiratory insufficiency. This progresses to SDB with nocturnal hypercapnia and, finally, diurnal hypercapnia.8,9 The average intelligence quotient (IQ) of the DMD population is 85, one standard deviation below population norms. Verbal IQ is more impaired than performance IQ.10 Intellectual disability in DMD is static and does not correlate with the degree of muscle weakness. Boys with DMD also have higher incidence of

Journal of Paediatrics and Child Health (2015) © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

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attention deficit hyperactivity disorder and autism spectrum disorders.11 Orthopaedic complications are frequent. Scoliosis develops in almost all boys not treated with corticosteroids. Spinal deformity impacts on respiratory vital capacity12 and progresses significantly after loss of ambulation.13 While corticosteroid treatment reduces the risk of scoliosis, it contributes to poor bone health and increased risk of vertebral and long bone fractures.14 Joint contractures are common at the hips, knees, ankle joints and iliotibial bands. Patients with DMD are thought to have increased risk of malignant hyperthermia or malignant hyperthermia-like reactions if exposed to inhalational anaesthetics and depolarising muscle relaxants.15,16

Pathogenesis and Genetics DMD is caused by is caused by mutations in the DMD gene, which encodes a protein called dystrophin.17,18 Dystrophin localises to the sarcolemma (plasma membrane) of skeletal muscle, forming one component of a large glycoprotein complex (dystrophin-associated glycoprotein complex), and acts as mechanical link between the cytoskeleton and the extracellular matrix.19 The DMD gene contains 79 exons, and its large size makes it susceptible to mutations, with one-third of mutations occurring de novo. Mutations in DMD result in a prematurely truncated, unstable dystrophin protein. The ‘reading frame rule’ explains the majority of the phenotypic differences between DMD and Becker muscular dystrophy (BMD), a milder dystrophinopathy: mutations that disrupt the open reading frame, resulting in an abnormal and truncated dystrophin, cause DMD, whereas mutations which maintain the open reading frame, resulting in a shorter lower molecular weight but partly functional dystrophin, cause BMD.20 The majority of mutations in DMD are intragenic deletions, accounting for 65–70% of all mutations. Deletions occur most commonly in a ‘hotspot’ region spanning exons 45–53. Duplications are found in 7% of patients, and point mutations or small deletions/insertions are found in the remainder.20 The precise mechanism of how dystrophin deficiency leads to degeneration of muscle fibers remains unclear; however, cytoskeletal disruption, sarcolemmal instability and abnormal calcium homeostasis are thought to play a role.21

Investigations Serum muscle enzymes Serum CK levels are markedly raised in DMD and are at least 10–20 times (often 50–200 times) the upper limit of normal before the age of 5 years. Serum CK concentrations are high even in newborns. A serum CK less than 10 times normal in a child with suspected DMD in the first 3 years of life should raise the question of an alternate diagnosis.4 Serum alanine transaminase and aspartate transaminase levels are also raised and correlate with CK levels.

Muscle biopsy Muscle biopsy is not clinically indicated in DMD if genetic testing is conclusive. It is performed when genetic testing is 2

negative or the clinical phenotype is atypical. Features on routine muscle histology include muscle fibre degeneration and necrosis with mononuclear cell invasion, clusters of small regenerating muscle fibres, and increased fibre size variability.4 There is also a significant replacement of muscle by fat and connective tissue. Complete or almost complete absence of dystrophin is typical of DMD and can be demonstrated by immunostaining and/or Western blot analysis.22 Western blot analysis also allows quantification of the amount of dystrophin protein, as well as assessment of dystrophin size.

Genetic testing Molecular genetic testing forms the mainstay of diagnosis. Deletions and duplications (copy number variants) can be detected by multiplex ligation-dependent probe amplification (MLPA) or high-resolution chromosomal microarray. Dystrophin mutations identified by chromosomal microarray still require confirmation using the MLPA method. If these genetic tests are negative, direct sequence analysis of the DMD gene is required to detect point mutations.23 This, however, is costly and not available at all centres.

Carrier Females The majority of female DMD carriers are asymptomatic. Up to 20% have mild to moderate muscle weakness, and CK levels are raised in 50–60%.24 Cardiac involvement may occur, with 8% of carrier females reported to have dilated cardiomyopathy.25

Management Management of boys with DMD is multidisciplinary and revolves around symptomatic and rehabilitative management, surveillance and treatment of expected complications, corticosteroid treatment, and genetic counselling. Advances in management over the past two to three decades have resulted in a marked improvement in survival and quality of life.2,3,26,27 International standards of care for the diagnosis and management of DMD were published in 2010 and provide an excellent resource for clinicians.28,29

Corticosteroid therapy Corticosteroids are the only pharmacologic agent proven to be effective in DMD. Initial short-term randomised controlled trials demonstrated improved muscle strength and respiratory function. Muscle strength improved within 10 days of starting corticosteroids and was maximal at 3 months and maintained up to 18 months.30,31 Subsequent longer-term studies suggest that long-term daily corticosteroids prolong ambulation by up to 3 years, reduce the decline of cardiorespiratory function, reduce the risk of progressive scoliosis and improve life expectancy.14,32–34 The most commonly used corticosteroids are prednisolone and prednisone, at a dose of 0.75 mg/kg/day. Deflazacort (0.9 mg/kg/day) is available in some countries as an alternative. The choice of corticosteroid depends on availability, cost, formulation and side effect profile. Daily corticosteroid dosing is preferred and is more effective than alternate daily dosing.29,31

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There is no good data on the optimal age to begin treatment with corticosteroids or duration of treatment. The current consensus is to initiate corticosteroid treatment once boys reach a plateau of motor skill development (usually around 4–6 years of age) but prior to onset of motor decline (manifest as loss of motor skills, decreased endurance, increase in falls or increased times on timed tasks). Some centres have a more aggressive approach and initiate corticosteroid treatment as soon as clinical symptoms become apparent. Varicella immunisation is recommended prior to commencing corticosteroid therapy. Many centres continue corticosteroid treatment after loss of ambulation, with the goal of reducing scoliosis progression and delaying decline of cardiorespiratory function.29 Careful monitoring and management of corticosteroid-related side effects are vital. Weight gain and Cushingoid side effects occur in most boys. If weight gain is severe, a change from prednisolone to deflazacort, the latter having a lower risk of weight gain, may be beneficial. Behavioural difficulties, if severe, may require adjustment of corticosteroid dosing or agent. Vertebral and long bone fractures occur with increased frequency compared with steroid-naïve boys. Growth suppression is common.29,33

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age 10 years, and annually thereafter.28 Periodic Holter monitoring should be considered in patients with rhythm abnormalities. Boys on corticosteroids require additional monitoring for hypertension. Early treatment of abnormal ventricular function is recommended, with angiotensin converting enzyme inhibitors and/or beta blockers.28,37

Orthopaedic management

Surveillance of the respiratory, cardiac, orthopaedic, nutritional and general medical issues associated with DMD allows anticipation, early detection and treatment of these complications.

Maintenance of ambulation is foremost in the treatment of a child with DMD to prevent development of contractures and scoliosis, and to maintain independence. In the early part of the disease course, passive and active stretching, particularly of the Achilles tendons, iliotibial bands and hip flexors, and the use of night splints helps prevent development or progression of contractures. Despite these efforts, contractures often develop, and surgery is sometimes necessary. Prolongation of ambulation and corticosteroid therapy has been shown to reduce scoliosis progression.14,38 Monitoring for scoliosis should be performed clinically while boys are still ambulant. A spinal radiograph should be obtained as a baseline around the time boys become wheelchair dependent and every 6 months to annually. Spinal fusion is considered in boys with a spinal curvature of greater than 20–25 degrees.28 Baseline cardiac and respiratory function must be assessed prior. Benefits of scoliosis surgery include the prevention of further deformity, reduction in pain due to vertebral fractures and osteoporosis, and slowing the rate of respiratory decline.39

Respiratory management

Bone health management

Baseline pulmonary function tests should begin at 5–6 years of age. Respiratory evaluations should occur annually and then biannually in non-ambulatory boys. Overnight pulse oximetry or sleep studies to detect SDB should be considered in nonambulant boys. All boys should receive the pneumococcal and influenza vaccines. Effective airway clearance methods, including the use of manual and mechanical techniques, should be taught.28,35 Acute respiratory infections require early management with antibiotics, chest physiotherapy and, sometimes, respiratory support. Advanced care directives regarding management of these respiratory deteriorations should be discussed with the patient and their family from an early stage, providing information about the ventilatory and palliative options available. Nocturnal non-invasive intermittent positive pressure ventilation (NIPPV) is a safe and effective treatment for DMD patients. It is indicated in patients who have signs or symptoms of hypoventilation and/or hypercapnia. Benefits of NIPPV include increased quality of life, symptom relief, delay in onset of daytime hypercapnia and improved life expectancy. Life expectancy has increased to the late 20s in patients who receive NIPPV.2,3,26,27 Further progression of respiratory failure requires full time ventilation.36 This is offered in some centres, but the ethical and social implications need to be discussed prior.

Maintenance of bone density is important to prevent fractures. Bone health assessments include monitoring of calcium, phosphate, alkaline phosphatase, 25-OH vitamin D levels and bone density scans. Supplementation of calcium and vitamin D should be considered in all boys. Some require bisphosphonate therapy.28

General management and surveillance

Cardiac management Cardiac surveillance with an electrocardiogram and echocardiogram should occur at diagnosis and continue every 2 years until

General medical, educational and psychosocial issues Appropriate nutrition is an essential part of management and an increasingly important area of research.40 There is also limited evidence regarding the type of exercise to recommend. Highresistance strength training is not recommended, while submaximal aerobic exercise (such as swimming) is more appropriate. Gastrointestinal issues such as constipation, gastrooesophageal reflux and dysphagia (later in the disease course) are not uncommon.28,29 A medi-alert bracelet, letter (or USB stick) from the treating specialist, and education of boys and their families regarding the risks of anaesthesia are paramount.15 Behavioural issues can be a significant problem, exacerbated by corticosteroids, and are common around the time of loss of ambulation and independence. Depression is probably underrecognised. Assistance from a psychologist or psychiatrist is sometimes needed. The provision of extra educational and physical assistance in the classroom is important, allowing many boys with DMD to attend mainstream schools. Some adolescents are able to proceed through the normal secondary education stream and undertake tertiary education. Obtaining

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meaningful employment remains a major issue. Early and ongoing discussions regarding palliative care options are an important issue.

Genetic counselling All families with an affected male with DMD should be referred for genetic counselling. Detection and counselling of female carriers are important for disease prevention. Prenatal diagnosis is available for carrier mothers. In addition, periodic cardiovascular screening of carrier females is recommended, commencing in early adulthood.37,41 Newborn screening for DMD, performed in very few countries in the world, remains a controversial issue and an active area of research.42,43

Novel Therapies Novel approaches to therapy of DMD include gene therapies (e.g. viral vectors), stem cell therapies and dystrophin restoration approaches,44 the latter having reached clinical trial stage. Stop codon suppression agents such as Ataluren promote ribosomal read-through of stop codons, allowing continuation of translation and production of a functioning protein.45 These agents are only applicable to boys with nonsense mutations. While a Phase 2b double-blind, randomised, placebo-controlled trial of Ataluren failed to meet its primary endpoint, trends indicating improvement in clinically meaningful endpoints were seen in boys receiving low-dose Ataluren.46 A Phase 3, double-blind, placebo-controlled trial is currently underway (clinicaltrials.gov identifier: NCT01826487). Antisense oligonucleotides induce exon skipping at the premRNA level, allowing one or more exons to be omitted to restore the dystrophin reading frame. About 13% of patients with DMD have mutations correctable by skipping exon 51. Two antisense oligonucleotides that induce exon 51 skipping have undergone Phase 2 randomised, placebo-controlled trials. Increased dystrophin expression and improvements in ambulation were seen in treated patients compared with placebo; however, both trials were underpowered, and larger studies are required.47,48 Challenges of these novel therapies are numerous and include appropriate clinical trial design, adequate systemic delivery, mutation specificity of some therapies, safety and tolerability, and host immune responses.44

Conclusions DMD is a devastating condition that continues to affect many boys and their families. Advances in management with corticosteroids and respiratory support in particular have increased life expectancy and quality of life. There is much hope that progress in development of novel treatments will result in true diseasemodifying therapies becoming available in the near future.

Acknowledgements EMY is supported by a National Health Medical Research Council of Australia (NHMRC) Early Career Fellowship. The Murdoch Childrens Research Institute is supported by the 4

Victorian Government’s Operational Infrastructure Support Program. AJK reports no disclosures.

References 1 Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L. Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK). Eur. J. Hum. Genet. 2013; 21: 1049–53. 2 Eagle M, Bourke J, Bullock R et al. Managing Duchenne muscular dystrophy – the additive effect of spinal surgery and home nocturnal ventilation in improving survival. Neuromuscul. Disord. 2007; 17: 470–5. 3 Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul. Disord. 2002; 12: 926–9. 4 Darras BT, Menache-Starobinski CC, Hinton V, Kunkel LM. Dystrophinopathies. Chapter 30. In: Darras BT, Jones H, Ryan M, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood, and Adolescence A Clinicians Approach, 2nd edn. London: Elsevier, 2015; 551–92. 5 Nigro G, Comi LI, Politano L, Bain RJ. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int. J. Cardiol. 1990; 26: 271–7. 6 Khirani S, Ramirez A, Aubertin G et al. Respiratory muscle decline in Duchenne muscular dystrophy. Pediatr. Pulmonol. 2014; 49: 473–81. 7 Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Am. J. Respir. Crit. Care Med. 2001; 164: 2191–4. 8 Suresh S, Wales P, Dakin C, Harris M-A, Cooper DGM. Sleep-related breathing disorder in Duchenne muscular dystrophy: disease spectrum in the paediatric population. J. Paediatr. Child Health 2005; 41: 500–3. 9 Ragette R, Mellies U, Schwake C, Voit T, Teschler H. Patterns and predictors of sleep disordered breathing in primary myopathies. Thorax 2002; 57: 724–8. 10 Leibowitz D, Dubowitz V. Intellect and behaviour in Duchenne muscular dystrophy. Dev. Med. Child Neurol. 1981; 23: 577–90. 11 Hendriksen JG, Vles JS. Neuropsychiatric disorders in males with duchenne muscular dystrophy: frequency rate of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, and obsessive – compulsive disorder. J. Child Neurol. 2008; 23: 477–81. 12 Smith AD, Koreska J, Moseley CF. Progression of scoliosis in Duchenne muscular dystrophy. J. Bone Joint Surg. Am. 1989; 71: 1066–74. 13 Rodillo EB, Fernandez-Bermejo E, Heckmatt JZ, Dubowitz V. Prevention of rapidly progressive scoliosis in Duchenne muscular dystrophy by prolongation of walking with orthoses. J. Child Neurol. 1988; 3: 269–74. 14 King WM, Ruttencutter R, Nagaraja HN et al. Orthopedic outcomes of long-term daily corticosteroid treatment in Duchenne muscular dystrophy. Neurology 2007; 68: 1607–13. 15 Birnkrant DJ. The American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation. Pediatrics 2009; 123 (Suppl. 4): S242–4. 16 Hayes J, Veyckemans F, Bissonnette B. Duchenne muscular dystrophy: an old anesthesia problem revisited. Paediatr. Anaesth. 2008; 18: 100–6. 17 Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987; 51: 919–28. 18 Kunkel LM, Hejtmancik JF, Caskey CT et al. Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy. Nature 1986; 322: 73–7.

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19 Rando TA. The dystrophin-glycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. Muscle Nerve 2001; 24: 1575–94. 20 Aartsma-Rus A, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve 2006; 34: 135–44. 21 Deconinck N, Dan B. Pathophysiology of Duchenne muscular dystrophy: current hypotheses. Pediatr. Neurol. 2007; 36: 1–7. 22 Hoffman EP, Fischbeck KH, Brown RH et al. Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne’s or Becker’s muscular dystrophy. N. Engl. J. Med. 1988; 318: 1363–8. 23 Laing NG, Davis MR, Bayley K, Fletcher S, Wilton SD. Molecular diagnosis of duchenne muscular dystrophy: past, present and future in relation to implementing therapies. Clin. Biochem. Rev. 2011; 32: 129–34. 24 Hoogerwaard EM, Bakker E, Ippel PF et al. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study. Lancet 1999; 353: 2116–19. 25 Hoogerwaard EM, van der Wouw PA, Wilde AA et al. Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy. Neuromuscul. Disord. 1999; 9: 347–51. 26 Passamano L, Taglia A, Palladino A et al. Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients. Acta Myol. 2012; 31: 121–5. 27 Rall S, Grimm T. Survival in Duchenne muscular dystrophy. Acta Myol. 2012; 31: 117–20. 28 Bushby K, Finkel R, Birnkrant DJ et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 2010; 9: 177–89. 29 Bushby K, Finkel R, Birnkrant DJ et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010; 9: 77–93. 30 Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst. Rev. 2004; (2): CD003725, update of, PMID: 15106215]. Cochrane Database Syst Rev 2008:CD003725. 31 Moxley RT III, Ashwal S, Pandya S et al. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2005; 64: 13–20. 32 Balaban B, Matthews DJ, Clayton GH, Carry T. Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: long-term effect. Am. J. Phys. Med. Rehabil. 2005; 84: 843–50. 33 Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul. Disord. 2006; 16: 249–55. 34 Daftary AS, Crisanti M, Kalra M, Wong B, Amin R. Effect of long-term steroids on cough efficiency and respiratory muscle strength in patients with Duchenne muscular dystrophy. Pediatrics 2007; 119: e320–4. 35 Birnkrant DJ, Bushby KM, Amin RS et al. The respiratory management of patients with duchenne muscular dystrophy: a DMD care considerations working group specialty article. Pediatr. Pulmonol. 2010; 45: 739–48. 36 Toussaint M, Steens M, Wasteels G, Soudon P. Diurnal ventilation via mouthpiece: survival in end-stage Duchenne patients. Eur. Respir. J. 2006; 28: 549–55. see comment.

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37 American Academy of Pediatrics Section on C, Cardiac S. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics 2005; 116: 1569–73. see comment. 38 Kinali M, Main M, Eliahoo J et al. Predictive factors for the development of scoliosis in Duchenne muscular dystrophy. Eur. J. Paediatr. Neurol. 2007; 11: 160–6. 39 Velasco MV, Colin AA, Zurakowski D, Darras BT, Shapiro F. Posterior spinal fusion for scoliosis in duchenne muscular dystrophy diminishes the rate of respiratory decline. Spine 2007; 32: 459–65. 40 Davidson ZE, Truby H. A review of nutrition in Duchenne muscular dystrophy. J. Hum. Nutr. Diet. 2009; 22: 383–93. 41 Nolan MA, Jones OD, Pedersen RL, Johnston HM. Cardiac assessment in childhood carriers of Duchenne and Becker muscular dystrophies. Neuromuscul. Disord. 2003; 13: 129–32. 42 Mendell JR, Shilling C, Leslie ND et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann. Neurol. 2012; 71: 304–13. 43 Parsons EP, Clarke AJ, Hood K, Lycett E, Bradley DM. Newborn screening for Duchenne muscular dystrophy: a psychosocial study. Arch. Dis. Child. Fetal Neonatal Ed. 2002; 86: F91–5. 44 Pichavant C, Aartsma-Rus A, Clemens PR et al. Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol. Ther. 2011; 19: 830–40. 45 Welch EM, Barton ER, Zhuo J et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007; 447: 87–91. 46 Bushby K, Finkel R, Wong B et al. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve 2014; 50: 477–87. 47 Mendell JR, Rodino-Klapac LR, Sahenk Z et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann. Neurol. 2013; 74: 637–47. 48 Voit T, Topaloglu H, Straub V et al. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol. 2014; 13: 987–96.

Multiple choice questions 1. Corticosteroid therapy: a. Results in improved muscle strength and function in ambulant boys b. Reduces the progression of scoliosis c. Reduces the decline of respiratory function d. Can prolong ambulation by up to 3 years e. All of the above Answer: e Corticosteroids improve muscle strength and respiratory function in the short term, and in the long term prolong ambulation, reduce progression of scoliosis and decline in cardiorespiratory function, and improve life expectancy. 2. Which of the following anaesthetic/sedative agents are contraindicated in boys with DMD? a. Midazolam b. Inhalational anaesthetics only c. Inhalational anaesthetic and depolarising muscle relaxants d. Nitrous oxide e. Propofol Answer: c

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Use of inhalational anaesthetics and depolarising muscle relaxants or neuromuscular blockers, such as succinylcholine, is contraindicated in boys with DMD due to the risk of malignant hyperthermia-like reactions, with the potential for cardiac arrest and death. A total intravenous anaesthetic technique is recommended for boys requiring surgery. 3. The initial investigation of choice in a boy with suspected DMD is: a. Muscle biopsy b. Nerve conduction studies c. DMD gene sequencing d. DMD multiplex ligation probe amplification e. Linkage analysis

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Answer: d In most centres, multiplex ligation probe amplification (MPLA) is the initial investigation performed to confirm a diagnosis of DMD. It detects exonic deletions and duplications, which account for at least 70% of all mutations. High-resolution chromosomal microarray may be performed as an alternative; however, MLPA is still required to confirm the diagnosis. Gene sequencing, if available, detects point mutations but not deletions/duplications, and should only be performed if MLPA or microarray is negative. Muscle biopsy is usually only required if the available genetic testing methods are negative or the clinical presentation is atypical.

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Duchenne muscular dystrophy.

Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness...
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