Pediatric Annals

THIS ISSUE: Muscular Dystrophies

Brenda L Wong, MBBS, MRCP

Abstract

The advent of molecular genetics has revolutionized our understanding of muscular dystrophy (MD) and transformed its classification and diagnosis. Traditionally, MD had been defined as a group of inherited disorders characterized by progressive degeneration of skeletal muscle and dystrophic features on muscle histology, without associated central or peripheral nervous system abnormalities. It had been subdivided into various groups based on the severity, clinical distribution of weakness and pattern of inheritance.

Today, with the identification of the numerous genes and protein products found to be associated with MD, the concept of MD has been broadened to include a heterogeneous group of disorders with clinical phenotypes not necessarily associated with progressive muscle wasting and weakness. The patient with Becker MD may have minimal weakness and present with exercise myalgias. Becker MD may be diagnosed in a young man in his early 20s only after he presents with congestive cardiac failure secondary to cardiomyopathy. Some patients with congenital MD show functional improvement instead of progressive muscle weakness and disabilities, and others have associated peripheral neuropathies or central nervous system and eye abnormalities.

Of the many therapeutic agents that have been tried in Duchenne MD, only the corticosteroids prednisone and deflazacort have shown potential to provide temporary improvement. The natural history of Duchenne MD has been altered with the use of chronic steroid therapy. Duchenne MD is the most severe and common form of childhood muscular dystrophy, with an incidence of 1 in 3,500 male live births.1 It is an X-linked recessive disorder resulting from mutations of the dystrophin gene. The absence of dystrophin in the muscle membrane leads to progressive muscle damage in skeletal and cardiac muscle. The clinical course is one of relentless progression of skeletal muscle weakness from onset of signs and symptoms between ages 2 and 4. The typical course is the loss of independent ambulation between ages 6 and 13, and death from respiratory or cardiac dysfunction in the late teens or early 20s.

Corticosteroids slow the rate of progression of the disease. Instead of becoming wheelchair-dependent by age 13, boys with Duchenne MD who are treated with steroids can ambulate for an additional 2 to 4 years. Improved respiratory muscle strength is reflected by improved pulmonary function tests and the delaying of ventilator dependence. Prolongation of ambulation delays the onset of scoliosis, with fewer scoliosis surgeries performed in steroid-treated boys in their teens. Recently, retrospective data showed that cardiac function in steroid-treated boys was better compared with a nonsteroid-treated group.2

Although prednisone at a dose of 0.75 mg/kg per day had been shown to be effective in increasing muscle strength and function in randomized, controlled clinical trials in the late 1980s,3 there was no consensus regarding whether to recommend steroids for the supportive treatment of Duchenne MD until recently.4"6 Side effects of chronic steroid therapy include weight gain, growth delay, osteopenia/osteoporosis with consequent fractures, and cataracts. With judicious dietary intervention and close monitoring, these side effects can be minimized, thus allowing for a greater benefit to risk ratio.

Current consensus of pediatrie neuromuscular specialists is that steroids are the gold standard of treatment in Duchenne MD against which other treatments should be judged.7 However, there is still no consensus on the type of steroid (0.75 mg/kg per day of prednisone versus an equivalent dose of 0.9 mg/ kg per day of deflazacort, an oxazoline derivative of prednisone with reputed bone sparing effect) and the dosing schedule (daily versus intermittent dosing of 10 days on/off schedule or pulsing over the weekends). Although the optimal age to initiate steroid therapy also remains unclear, case reports of functional benefit from treatment…

The advent of molecular genetics has revolutionized our understanding of muscular dystrophy (MD) and transformed its classification and diagnosis. Traditionally, MD had been defined as a group of inherited disorders characterized by progressive degeneration of skeletal muscle and dystrophic features on muscle histology, without associated central or peripheral nervous system abnormalities. It had been subdivided into various groups based on the severity, clinical distribution of weakness and pattern of inheritance.

Today, with the identification of the numerous genes and protein products found to be associated with MD, the concept of MD has been broadened to include a heterogeneous group of disorders with clinical phenotypes not necessarily associated with progressive muscle wasting and weakness. The patient with Becker MD may have minimal weakness and present with exercise myalgias. Becker MD may be diagnosed in a young man in his early 20s only after he presents with congestive cardiac failure secondary to cardiomyopathy. Some patients with congenital MD show functional improvement instead of progressive muscle weakness and disabilities, and others have associated peripheral neuropathies or central nervous system and eye abnormalities.

Of the many therapeutic agents that have been tried in Duchenne MD, only the corticosteroids prednisone and deflazacort have shown potential to provide temporary improvement. The natural history of Duchenne MD has been altered with the use of chronic steroid therapy. Duchenne MD is the most severe and common form of childhood muscular dystrophy, with an incidence of 1 in 3,500 male live births.1 It is an X-linked recessive disorder resulting from mutations of the dystrophin gene. The absence of dystrophin in the muscle membrane leads to progressive muscle damage in skeletal and cardiac muscle. The clinical course is one of relentless progression of skeletal muscle weakness from onset of signs and symptoms between ages 2 and 4. The typical course is the loss of independent ambulation between ages 6 and 13, and death from respiratory or cardiac dysfunction in the late teens or early 20s.

Corticosteroids slow the rate of progression of the disease. Instead of becoming wheelchair-dependent by age 13, boys with Duchenne MD who are treated with steroids can ambulate for an additional 2 to 4 years. Improved respiratory muscle strength is reflected by improved pulmonary function tests and the delaying of ventilator dependence. Prolongation of ambulation delays the onset of scoliosis, with fewer scoliosis surgeries performed in steroid-treated boys in their teens. Recently, retrospective data showed that cardiac function in steroid-treated boys was better compared with a nonsteroid-treated group.2

Although prednisone at a dose of 0.75 mg/kg per day had been shown to be effective in increasing muscle strength and function in randomized, controlled clinical trials in the late 1980s,3 there was no consensus regarding whether to recommend steroids for the supportive treatment of Duchenne MD until recently.4"6 Side effects of chronic steroid therapy include weight gain, growth delay, osteopenia/osteoporosis with consequent fractures, and cataracts. With judicious dietary intervention and close monitoring, these side effects can be minimized, thus allowing for a greater benefit to risk ratio.

Current consensus of pediatrie neuromuscular specialists is that steroids are the gold standard of treatment in Duchenne MD against which other treatments should be judged.7 However, there is still no consensus on the type of steroid (0.75 mg/kg per day of prednisone versus an equivalent dose of 0.9 mg/ kg per day of deflazacort, an oxazoline derivative of prednisone with reputed bone sparing effect) and the dosing schedule (daily versus intermittent dosing of 10 days on/off schedule or pulsing over the weekends). Although the optimal age to initiate steroid therapy also remains unclear, case reports of functional benefit from treatment beginning at age 48 have resulted in the use of steroids from ages 4 to 7 - that is, beginning at the time of diagnosis for most patients.

Previously, steroid treatment would be terminated following the loss of ambulation. However, with recent data indicating positive benefit for cardiac and pulmonary function, steroids continue to be prescribed indefinitely in the absence of severe side effects. Currently, steroids have not been recommended for other types of MD. However, similar positive benefits in patients with limb girdle muscular dystrophy with a severe clinical phenotype like Duchenne MD have been reported anecdotally.

IN THIS ISSUE

In our article 'The Diagnosis of Muscular Dystrophy," Dr. El-Bohy and I describe the presenting clinical features of childhood muscular dystrophy and reviewed the diagnostic approach to muscular dystrophy. The general classification of muscular dystrophy into six forms - Duchenne-type, fascioscapulohumeral, limb-girdle, congenital, distal, and oculopharyngeal - was based on the distribution of predominant muscle weakness. This clinical classification has been transformed to a gene/protein-based system of nomenclature with the identification of numerous molecularly defined subtypes of MD. We now encounter as many as 10 subtypes of congenital MD, one of the most common neuromuscular disorders, and 17 subtypes of limb-girdle MD.

We are now able to make a precise diagnosis in a child presenting with MD. Precision of diagnosis results in improved information for the family with regards to prognosis and genetic counseling. Reviews of advances in the congenital and limb-girdle muscular dystrophies by Dr. Mercuri, Dr. Longman, and Dr. Bonnemann provide an overview of the outstanding progress made in these entities during the past decade. A greater understanding of the subtypes of MD aids in the planning of specific management of each patient.

Unfortunately, the breakthroughs in molecular diagnosis and protein characterization have not been paralleled by breakthroughs in curative treatments for MD. Until a definitive cure for the genetic defect becomes available, current management centers on medical, surgical, and rehabilitative approaches to optimize and maintain function and comfort. Recent advances in the respiratory and cardiac care of the patient with MD have improved the outlook for these patients. The availability of new technologies has enabled caregivers to adopt a more aggressive, supportive approach in contrast to the traditional noninterventional one.

In their article "Pulmonary Management of the Patient with Muscular Dystrophy," Drs. Kalra and Amin highlight the treatable nature of the respiratory disease in these disorders. With aggressive pulmonary management improving and maintaining pulmonary function, cardiac disease will emerge as the main cause of mortality and morbidity associated with severe childhood muscular dystrophies such as Duchenne MD. Traditionally, care of the heart commences in the teen years when the cardiomyopathy associated with Duchenne MD is associated with poor cardiac function. The current approach emphasizes earlier surveillance of cardiac function with more sophisticated imaging modalities from the time of diagnosis and initiation of cardioprotective intervention before the patient presents with signs and symptoms of cardiac failure. Drs. Markham, Spicer, and Cripe review the signs and symptoms of cardiac dysfunction in their article 'The Heart in Muscular Dystrophy." Early cardiac surveillance in patients with MD can alert pediatricians to a high index of suspicion of early cardiac dysfunction in this patient population in the presence of nonspecific complaints of fatigue or unexplained weight gain or loss.

New technologies have enabled rapid advances in research involving gene therapy for muscular dystrophy. A definitive cure with gene therapy is our ultimate goal, but this still remains on the distant horizon. In the interim, we work to improve the quality of life and maintain optimal function with minimal morbidity. Optimal care of the multi-systemic health issues of a child with MD requires an integrative team of healthcare providers, including the primary pediatrician, who are familiar with the patient, the family, and the goals of treatment Dr. Weidner's review, "Developing an Interdisciplinary Palliative Care Plan for the Patient With Muscular Dystrophy," provides insight into the interdisciplinary model of care for patients with muscular dystrophy, which incorporates the palliative care needs of these patients and families early in the trajectory of the illness.

SUMMARY

The rapid technological advances in this new millennium have brought about a broadened concept of the definition of MD, improved medical care, and the prospect of a definitive cure with gene therapy. While we await a cure, aggressive supportive treatment by an integrative team of health care providers is the key to improving quality and length of life of patients with MD.

REFERENCES

1. Emery AEH. Population frequencies of inherited neuromuscular disease - a world survey. Neuromusc Disord. 1991;1(1): 9-29.

2. Silversides CK, Webb GD, Harris VA, Biggar DW. Effect of deflazacort on left ventricular function in patients with Duchenne muscular dystrophy. Am J Cardiol 2003;91(6):769-772.

3. Mendell JR, Moxley RT, Griggs RC, et al. Randomized double-blind sixmonth trial of prednisone in Duchenne's muscular dystrophy. N Engl J Med. 1989;320(24):1592-1597.

4. Wong BL, Christopher C. Corticosteroids in Duchenne muscular dystrophy: a reappraisal. J Child Neural. 2002;17(3):183-190.

5. Moxley RT 3rd, 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(1): 13-20.

6. ManzurAY, KuntzerT, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2004;(2):CD003725.

7. Bushby K, Muntoni F, Urtizberea A, et al. Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of steroids. 2-4 April 2004, Naarden, The Netherlands. Neuromusc Disord. 2004;14(8-9):526-534.

8. Dubowitz V, Kinali M, Main M et al. Remission of clinical signs in early Duchenne muscular dystrophy on intermittent low-dosage prednisolone therapy. Eur J Paediair Neural. 2002;6(3): 153-159.

10.3928/0090-4481-20050701-04

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