Advertisement

Current Treatment and Management of Dystrophinopathies

  • Nathalie Goemans
  • Gunnar Buyse
NEUROMUSCULAR DISORDERS (SA RUDNICKI, SECTION EDITOR)
Part of the following topical collections:
  1. Topical Collection on Neuromuscular Disorders

Opinion statement

• Duchenne muscular dystrophy (DMD), the most common and severe type of dystrophinopathy, is a progressive disease affecting primordially skeletal and cardiac muscle. A coordinated multidisciplinary approach is required to address its multisystemic manifestations and secondary problems.

• Treatment with glucocorticosteroids (GCS) is accepted as standard of care in ambulant DMD. Daily and intermittent administrations are both in common use with different efficacy and different side effect profile.

• There are no established guidelines for age/stage at initiation and treatment duration of GCS. Common practice is initiation of GCS before the child is starting to decline (between age 3 and 6 years) and continuation of monitored treatment after loss of ambulation, aiming at delaying cardiac and respiratory manifestations and preventing the development of scoliosis.

• Prevention, monitoring, and treatment of the side effects of long-term chronic GCS use, such as excessive weight gain, hypertension, osteoporosis, impairment of glucose metabolism, delayed puberty, and cataract, should be integrated in the standards of care.

• Noninvasive ventilatory support associated with cough assisting techniques has significantly improved the longevity in DMD.

• Pharmacologic treatment for cardiac manifestations includes the standard treatments of dilated cardiomyopathy and arrhythmia such as the use of angiotensin converting enzyme (ACE) inhibitors, beta-blockers and diuretics. The lack of robust controlled data hampers clear recommendations about preventive treatment with ACE inhibitors.

• DMD is associated with low bone mineral content, which is aggravated by the use of corticosteroids. The use of biphosphonates can be considered in the treatment of painful vertebral fractures. The use of biphosphonates as a preventive treatment should be investigated in randomized controlled studies.

• DMD has evolved from a pediatric disease to an adult condition. This underscores the need to prepare adult neurologists for the optimal surveillance and management of patients with a severe chronic disease that have outgrown the pediatric care and that may develop new disease manifestations with improved longevity.

Keywords

Dystrophinopathies Duchenne Glucocorticosteroids Therapy Muscular dystrophy Treatment Management Muscle degeneration Respiratory management Cardiac management 

Notes

Acknowledgment

Gunnar Buyse is senior clinical investigator of the FWO-Vlaanderen (Belgium)

Compliance with Ethics Guidelines

Conflict of Interest

Nathalie Goemans and Gunnar Buyse declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Emery AE. Population frequencies of inherited neuromuscular diseases–a world survey. Neuromuscul Disord. 1991;1:19–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Mendell JR, Shilling C, Leslie ND, et al. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012;71:304–13.PubMedCrossRefGoogle Scholar
  3. 3.
    Hoffman EP, Brown Jr RH, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51:919–28.PubMedCrossRefGoogle Scholar
  4. 4.
    Brooke MH, Fenichel GM, Griggs RC, et al. Duchenne muscular dystrophy: patterns of clinical progression and effects of supportive therapy. Neurology. 1989;39:475–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Rideau Y, Jankowski LW, Grellet J. Respiratory function in the muscular dystrophies. Muscle Nerve. 1981;4:155–64.PubMedCrossRefGoogle Scholar
  6. 6.
    Muntoni F. Cardiomyopathy in muscular dystrophies. Curr Opin Neurol. 2003;16:577–83.PubMedCrossRefGoogle Scholar
  7. 7.
    Moxley III RT, Pandya S, Ciafaloni E, et al. Change in natural history of Duchenne muscular dystrophy with long-term corticosteroid treatment: implications for management. J Child Neurol. 2010;25:1116–29.PubMedCrossRefGoogle Scholar
  8. 8.
    Eagle M, Baudouin SV, Chandler C, et al. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord. 2002;12:926–9.PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 10.•
    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. This paper is a consensus statement on diagnosis and management of Duchenne muscular dystrophy based on litterature review and scientists opinion.PubMedCrossRefGoogle Scholar
  11. 11.•
    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. This paper is the second part of a consensus statement on diagnosis and management of Duchenne muscular dystrophy based on litterature review and scientists opinion.PubMedCrossRefGoogle Scholar
  12. 12.
    Fisher I, Abraham D, Bouri K, et al. Prednisolone-induced changes in dystrophic skeletal muscle. FASEB J. 2005;19:834–6.PubMedGoogle Scholar
  13. 13.
    Mendell JR, Moxley RT, Griggs RC, et al. Randomized, double-blind six-month trial of prednisone in Duchenne’s muscular dystrophy. N Engl J Med. 1989;320:1592–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Henricson EK, Abresch RT, Cnaan A, et al. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve. 2013;48:55–67.PubMedCrossRefGoogle Scholar
  15. 15.
    Biggar WD, Politano L, Harris VA, et al. Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols. Neuromuscul Disord. 2004;14:476–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Biggar WD, Gingras M, Fehlings DL, et al. Deflazacort treatment of Duchenne muscular dystrophy. J Pediatr. 2001;138:45–50.PubMedCrossRefGoogle Scholar
  17. 17.
    Biggar WD, Harris VA, Eliasoph L, et al. Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord. 2006;16:249–55.PubMedCrossRefGoogle Scholar
  18. 18.
    Dec GW. Steroid therapy effectively delays Duchenne’s cardiomyopathy. J Am Coll Cardiol. 2013;61:955–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Markham LW, Kinnett K, Wong BL, et al. Corticosteroid treatment retards development of ventricular dysfunction in Duchenne muscular dystrophy. Neuromuscul Disord. 2008;18:365–70.PubMedCrossRefGoogle Scholar
  20. 20.
    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.PubMedCrossRefGoogle Scholar
  21. 21.
    Lebel DE, Corston JA, McAdam LC, et al. Glucocorticoid treatment for the prevention of scoliosis in children with Duchenne muscular dystrophy: long-term follow-up. J Bone Joint Surg (Am Vol). 2013;95:1057–61.CrossRefGoogle Scholar
  22. 22.
    Manzur AY, Kuntzer T, Pike M, et al. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2004;(2):CD003725.Google Scholar
  23. 23.
    Manzur AY, Kuntzer T, Pike M, et al. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2008;(1):CD003725.Google Scholar
  24. 24.
    Mesa LE, Dubrovsky AL, Corderi J, et al. Steroids in Duchenne muscular dystrophy–deflazacort trial. Neuromuscul Disord. 1991;1:261–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Griggs RC, Herr BE, Reha A, et al. Corticosteroids in Duchenne muscular dystrophy: Major variations in practice. Muscle Nerve. 2013;48:27–31.PubMedCrossRefGoogle Scholar
  26. 26.
    Griggs RC, Moxley RT, Mendell JR, et al. Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol. 1991;48:383–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Straathof CS, Overweg-Plandsoen WC, van den Burg GJ, et al. Prednisone 10 days on/10 days off in patients with Duchenne muscular dystrophy. J Neurol. 2009;256:768–73.PubMedCrossRefGoogle Scholar
  28. 28.
    Ricotti V, Ridout DA, Scott E, et al. Long-term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy. J Neurol Neurosurg Psychiatry. 2013;84:698–705.PubMedCrossRefGoogle Scholar
  29. 29.
    Escolar DM, Hache LP, Clemens PR, et al. Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology. 2011;77:444–52.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Kieny P, Chollet S, Delalande P, et al. Evolution of life expectancy of patients with Duchenne muscular dystrophy at AFM Yolaine de Kepper centre between 1981 and 2011. Ann Phys Rehabil Med. 2013;56:443–54.Google Scholar
  31. 31.
    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.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Finder JD, Birnkrant D, Carl J, et al. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med. 2004;170:456–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Dohna-Schwake C, Ragette R, Teschler H, et al. IPPB-assisted coughing in neuromuscular disorders. Pediatr Pulmonol. 2006;41:551–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Miske LJ, Hickey EM, Kolb SM, et al. Use of the mechanical in-exsufflator in pediatric patients with neuromuscular disease and impaired cough. Chest. 2004;125:1406–12.PubMedCrossRefGoogle Scholar
  35. 35.
    Bach JR, Campagnolo DI, Hoeman S. Life satisfaction of individuals with Duchenne muscular dystrophy using long-term mechanical ventilatory support. Am J Phys Med Rehabil. 1991;70:129–35.PubMedCrossRefGoogle Scholar
  36. 36.
    Kohler M, Clarenbach CF, Boni L, et al. Quality of life, physical disability, and respiratory impairment in Duchenne muscular dystrophy. Am J Respir Crit Care Med. 2005;172:1032–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Rahbek J, Werge B, Madsen A, et al. Adult life with Duchenne muscular dystrophy: observations among an emerging and unforeseen patient population. Pediatr Rehabil. 2005;8:17–28.PubMedGoogle Scholar
  38. 38.•
    Allen HD, Thrush PT, Hoffman TM, et al. Cardiac management in neuromuscular diseases. Phys Med Rehabil Clin North Am. 2012;23:855–68. This paper gives a good review on cardiac aspects of neuromuscular disorders.CrossRefGoogle Scholar
  39. 39.
    Bushby K, Muntoni F, Bourke JP. 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. June 7–9, 2002, Naarden, The Netherlands. Neuromuscul Disord. 2003;13:166–72.PubMedCrossRefGoogle Scholar
  40. 40.
    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.CrossRefGoogle Scholar
  41. 41.
    Mertens L, Ganame J, Claus P, et al. Early regional myocardial dysfunction in young patients with Duchenne muscular dystrophy. J Am Soc Echocardiogr. 2008;21:1049–54.PubMedCrossRefGoogle Scholar
  42. 42.
    Ryoke T, Gu Y, Mao L, et al. Progressive cardiac dysfunction and fibrosis in the cardiomyopathic hamster and effects of growth hormone and angiotensin-converting enzyme inhibition. Circulation. 1999;100:1734–43.PubMedCrossRefGoogle Scholar
  43. 43.
    Spurney CF, Sali A, Guerron AD, et al. Losartan decreases cardiac muscle fibrosis and improves cardiac function in dystrophin-deficient mdx mice. J Cardiovasc Pharmacol Therapeut. 2011;16:87–95.CrossRefGoogle Scholar
  44. 44.
    Duboc D, Meune C, Lerebours G, et al. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol. 2005;45:855–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Jefferies JL, Eidem BW, Belmont JW, et al. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation. 2005;112:2799–804.PubMedCrossRefGoogle Scholar
  46. 46.•
    Politano L, Nigro G. Treatment of dystrophinopathic cardiomyopathy: review of the literature and personal results. Acta Myol. 2012;31:24–30. This paper gives a good review on cardiac aspects of neuromuscular disorders.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Spurney CF. Cardiomyopathy of Duchenne muscular dystrophy: current understanding and future directions. Muscle Nerve. 2011;44:8–19.PubMedCrossRefGoogle Scholar
  48. 48.
    Dubowitz V. Prevention of deformities. Isr J Med Sci. 1977;13:183–8.PubMedGoogle Scholar
  49. 49.
    McDonald CM. Limb contractures in progressive neuromuscular disease and the role of stretching, orthotics, and surgery. Phys Med Rehabil Clin North Am. 1998;9:187–211.Google Scholar
  50. 50.
    McDonald CM, Abresch RT, Carter GT, et al. Profiles of neuromuscular diseases. Duchenne muscular dystrophy. Am J Phys Med Rehabil. 1995;74:S70–92.PubMedCrossRefGoogle Scholar
  51. 51.
    Scott OM, Hyde SA, Goddard C, et al. Prevention of deformity in Duchenne muscular dystrophy. A prospective study of passive stretching and splintage. Physiotherapy. 1981;67:177–80.PubMedGoogle Scholar
  52. 52.
    Bakker JP, de Groot IJ, Beckerman H, et al. The effects of knee-ankle-foot orthoses in the treatment of Duchenne muscular dystrophy: review of the literature. Clin Rehabil. 2000;14:343–59.PubMedCrossRefGoogle Scholar
  53. 53.
    Forst J, Forst R. Lower limb surgery in Duchenne muscular dystrophy. Neuromuscul Disord. 1999;9:176–81.PubMedCrossRefGoogle Scholar
  54. 54.
    Alman BA, Raza SN, Biggar WD. Steroid treatment and the development of scoliosis in males with duchenne muscular dystrophy. J Bone Joint Surg (Am Vol). 2004;86-A:519–24.Google Scholar
  55. 55.
    Yilmaz O, Karaduman A, Topaloglu H. Prednisolone therapy in Duchenne muscular dystrophy prolongs ambulation and prevents scoliosis. Eur J Neurol. 2004;11:541–4.PubMedCrossRefGoogle Scholar
  56. 56.
    Smith AD, Koreska J, Moseley CF. Progression of scoliosis in Duchenne muscular dystrophy. J Bone Joint Surg (Am Vol). 1989;71:1066–74.Google Scholar
  57. 57.
    Bianchi ML, Biggar D, Bushby K, et al. Endocrine aspects of Duchenne muscular dystrophy. Neuromuscul Disord. 2011;21:298–303.PubMedCrossRefGoogle Scholar
  58. 58.
    Leung DG, Germain-Lee EL, Denger BE, et al. Report on the Second Endocrine Aspects Of Duchenne Muscular Dystrophy Conference December 1-2, 2010, Baltimore, Maryland, USA. Neuromuscul Disord. 2011;21:594–601.PubMedCrossRefGoogle Scholar
  59. 59.
    Bianchi ML, Mazzanti A, Galbiati E, et al. Bone mineral density and bone metabolism in Duchenne muscular dystrophy. Osteoporos Int. 2003;14:761–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Bothwell JE, Gordon KE, Dooley JM, et al. Vertebral fractures in boys with Duchenne muscular dystrophy. Clin Pediatr. 2003;42:353–6.CrossRefGoogle Scholar
  61. 61.
    Larson CM, Henderson RC. Bone mineral density and fractures in boys with Duchenne muscular dystrophy. J Pediatr Orthoped. 2000;20:71–4.Google Scholar
  62. 62.
    Nagel BH, Mortier W, Elmlinger M, et al. Short stature in Duchenne muscular dystrophy: a study of 34 patients. Acta Paediatr. 1999;88:62–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Rutter MM, Collins J, Rose SR, et al. Growth hormone treatment in boys with Duchenne muscular dystrophy and glucocorticoid-induced growth failure. Neuromuscul Disord. 2012;22:1046–56.PubMedCrossRefGoogle Scholar
  64. 64.
    Bertelloni S, Baroncelli GI, Garofalo P, et al. Androgen therapy in hypogonadal adolescent males. Horm Res Paediatr. 2010;74:292–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Casteels K, Fieuws S, van Helvoirt M, et al. Metformin therapy to reduce weight gain and visceral adiposity in children and adolescents with neurogenic or myogenic motor deficit. Pediatr Diabetes. 2010;11:61–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Hoffman EP, Hudecki MS, Rosenberg PA, et al. Cell and fiber-type distribution of dystrophin. Neuron. 1988;1:411–20.PubMedCrossRefGoogle Scholar
  67. 67.
    Jaffe KM, McDonald CM, Ingman E, et al. Symptoms of upper gastrointestinal dysfunction in Duchenne muscular dystrophy: case-control study. Arch Phys Med Rehabil. 1990;71:742–4.PubMedGoogle Scholar
  68. 68.
    Haenggi T, Fritschy JM. Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue. Cell Mol Life Sci. 2006;63:1614–31.PubMedCrossRefGoogle Scholar
  69. 69.
    Haenggi T, Schaub MC, Fritschy JM. Molecular heterogeneity of the dystrophin-associated protein complex in the mouse kidney nephron: differential alterations in the absence of utrophin and dystrophin. Cell Tissue Res. 2005;319:299–313.PubMedCrossRefGoogle Scholar
  70. 70.
    Matsumura T, Saito T, Fujimura H, et al. Renal dysfunction is a frequent complication in patients with advanced stage of Duchenne muscular dystrophy. Rinsho Shinkeigaku = Clin Neurol. 2012;52:211–7.CrossRefGoogle Scholar
  71. 71.
    Matsumura T, Saito T, Fujimura H, Shinno S, Sakoda S. A longitudinal cause-of-death analysis of patients with Duchenne muscular dystrophy. Rinsho Shinkeigaku = Clin Neurol. 2011;51:743–50.CrossRefGoogle Scholar
  72. 72.
    Costa MF, Oliveira AG, Feitosa-Santana C, Zatz M, Ventura DF. Red-green color vision impairment in Duchenne muscular dystrophy. Am J Hum Genet. 2007;80:1064–75.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Pascual Pascual SI, Molano J, Pascual-Castroviejo I. Electroretinogram in Duchenne/Becker muscular dystrophy. Pediatr Neurol. 1998;18:315–20.PubMedCrossRefGoogle Scholar
  74. 74.
    Pillers DA, Fitzgerald KM, Duncan NM, et al. Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations. Hum Genet. 1999;105:2–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Topin N, Matecki S, Le Bris S, et al. Dose-dependent effect of individualized respiratory muscle training in children with Duchenne muscular dystrophy. Neuromuscul Disord. 2002;12:576–83.PubMedCrossRefGoogle Scholar
  76. 76.
    Sveen ML, Jeppesen TD, Hauerslev S, et al. Endurance training improves fitness and strength in patients with Becker muscular dystrophy. Brain. 2008;131:2824–31.PubMedCrossRefGoogle Scholar
  77. 77.
    Jansen M, van Alfen N, Geurts AC, et al. Assisted bicycle training delays functional deterioration in boys with duchenne muscular dystrophy: the randomized controlled trial “no use is disuse”. Neurorehabil Neural Repair. 2013;27:816–27.PubMedCrossRefGoogle Scholar
  78. 78.•
    Anziska Y, Sternberg A. Exercise in neuromuscular disease. Muscle Nerve. 2013;48:3–20. This paper reports the latest published evidences and highlights the areas of controversies in relation to exercise modalities in neuromuscular disorders.PubMedCrossRefGoogle Scholar
  79. 79.
    Markert CD, Case LE, Carter GT, et al. Exercise and Duchenne muscular dystrophy: where we have been and where we need to go. Muscle Nerve. 2012;45:746–51.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Child NeurologyUniversity Hospitals LeuvenLeuvenBelgium

Personalised recommendations