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Muscular Dystrophy
Nimmy Thakolkaran, MD
George G.A. Pujalte, MD, FACSM
image BASICS
  • Primary inherited myopathies caused by dysfunctional proteins of muscle fibers and extracellular matrix
  • Distribution of weakness, other associated symptoms, and disease prognosis depend on the specific gene affected and severity of the mutation.
DESCRIPTION
  • Duchenne muscular dystrophy (DMD)
    • Highest incidence muscular dystrophy, X-linked inheritance, early onset, progressive
    • Patients are wheelchair-dependent prior to age 13 years.
  • Becker muscular dystrophy (BMD)
    • Less severe phenotype than Duchenne, also caused by mutation in DMD gene; later onset and milder clinical course
    • Distinction from DMD is clinical: Patients are usually wheelchair-dependent after age 16 years.
    • Collectively referred to as dystrophinopathies
  • Myotonic muscular dystrophy (MMD)
    • Myotonia (slow relaxation after muscle contraction), distal and facial weakness
    • Second most common inherited muscle disease.
  • Facioscapulohumeral muscular dystrophy (FSHMD)
    • Facial and shoulder muscles most affected
    • Third most common inherited muscle disease.
  • Limb-girdle muscular dystrophy (LGMD)
    • Proximal weakness and atrophy, variable prognosis with many different identified mutations
  • Oculopharyngeal muscular dystrophy (OPMD)
    • Usually adult-onset, affects extraocular and pharyngeal muscles. Presents with ptosis and dysphagia
  • Emery-Dreifuss muscular dystrophy (EDMD)
    • Triad of early development of joint contractures, slowly progressive muscle wasting, and cardiomyopathy. Can present as sudden death in apparently healthy young adults
  • Congenital muscular dystrophies (CMD)
    • Heterogeneous group of autosomal recessive myopathic diseases presenting in infancy with generally poor prognosis
    • Includes Fukuyama CMD, Ullrich CMD, Walker-Warburg syndrome, muscle-eye-brain disease
EPIDEMIOLOGY
Incidence
  • Duchenne: 1/3,600 male births (1)
  • Myotonic dystrophy: 1/10,000 births
  • Other muscular dystrophies vary widely by population but are generally rare.
ETIOLOGY AND PATHOPHYSIOLOGY
Mutations affect proteins connecting cytoskeleton to cell membrane and extracellular matrix, causing muscle fibers to become fragile and easily damaged; muscle weakness and atrophy result.
  • DMD/BMD
    • Defective protein is dystrophin, product of the largest human gene, DMD; Duchenne phenotype results from mutations that cause profound loss of dystrophin, the protein involved in calcium transport in muscle cells and stabilizing fibers during contraction.
    • Becker phenotype results from less severe mutations in DMD gene; patients have low but detectable levels of functional dystrophin.
  • MMD: Trinucleotide repeat expansion in the untranslated region of the gene DMPK on chromosome 19; encodes myotonin-protein kinase
  • LGMD: mutations in genes encoding proteins associated with dystrophin: calpain-, dysferlin-, and fukutin-related proteins are affected most commonly.
  • EDMD: Dysfunctional proteins are associated with the nuclear membrane in muscle fibers; emerin in X-linked form, lamin A/C in autosomal forms
  • OPMD: Trinucleotide repeat expansion in PABPN1 results in nuclear inclusions in muscle cells by hampering normal transport of mRNA from the nucleus.
  • FSHMD: Deletion in untranslated region of chromosome 4; function of deleted genes is unclear, although the most accepted concept is that they likely affect the expression of multiple genes by epigenetic effects.
Genetics
  • X-linked
    • Duchenne and Becker muscular dystrophies
    • Gene located at Xp21
      • 30% of affected males have a de novo mutation (mother is not a carrier).
      • 20% of female carriers have some manifestation of the mutation (usually mild muscle weakness or cardiomyopathy).
  • Autosomal dominant
    • Generally later onset and less severe than diseases with recessive or X-linked inheritance
    • FSHMD, OPMD, some forms of LGMD and EDMD
    • Myotonic dystrophy
      • Trinucleotide repeat expansion with more severe phenotype in subsequent generations due to accumulation of repeats
  • Autosomal recessive
    • Most types of CMD
GENERAL PREVENTION
Genetic counseling for carriers and prenatal diagnosis
COMMONLY ASSOCIATED CONDITIONS
  • Decreased IQ: on average, 1 SD below the mean in DMD; speech and language delay
  • Dilated cardiomyopathy and conduction abnormalities
    • Can be severe in EDMD
    • Can affect otherwise asymptomatic female carriers of DMD
    • Progressive scoliosis
image DIAGNOSIS
PHYSICAL EXAM
  • DMD/BMD
    • Proximal muscle weakness; Gower sign: use of arms to push upper body into standing posture from lying prone
    • Trendelenburg gait (hip waddling)
    • Hyporeflexia/areflexia
    • Winged scapulae and lordosis
    • Pseudohypertrophy of the calf (caused by replacement of muscle with fibroadipose tissue)
    • Contractures of lower extremity joints and elbows
  • MMD
    • Characteristic facial appearance: narrow face, open triangular mouth, high-arched palate, concave temples, drooping eyelids, frontal balding in males
    • Myotonia: inability to relax muscles after contraction
    • Distal muscle weakness and wasting
  • CMD
    • Arthrogryposis (multiple joint contractures); diffuse hypotonia and muscle wasting in an infant
DIFFERENTIAL DIAGNOSIS
  • Glycogen storage diseases and other metabolic myopathies
  • Mitochondrial myopathies: MELAS (M itochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes), MERRF (Myoclonus with Epilepsy and Ragged-Red Fibers)
  • Inflammatory myopathies: polymyositis, dermatomyositis, inclusion-body myositis
  • Neuromuscular junction diseases: myasthenia gravis, Lambert-Eaton syndrome
  • Motor neuron diseases: amyotrophic lateral sclerosis, spinal muscular atrophy
  • Charcot-Marie-Tooth disease
  • Friedreich ataxia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Creatine kinase (CK): initial screening test if MD is suspected (2)[A]
  • Elevated in DMD (10 to 100 times); elevated at birth, peaks at time of presentation, and falls during illness
  • Initial detected lab abnormality may be elevated aspartate transaminase/alanine transaminase (AST/ALT) originating from muscle.
  • Genetic testing/molecular diagnosis
    • For definitive diagnosis in patient with characteristic presentation and elevated CK
    • Deletion and duplication analysis (MLPA or CGH) will identify most patients; followed by genomic sequencing of DMD gene for point mutations (3)[A].
    • Genetic testing is available clinically for most other muscular dystrophies.
Diagnostic Procedures/Other
  • Muscle biopsy: rarely performed in DMD (dystrophin protein absent); may be helpful in other cases (4)[A]
  • Electromyography and nerve conduction studies are not necessary unless considering alternative diagnoses.
  • ECG: abnormalities found in >90% of males and up to 10% of female carriers of DMD; Q waves in anterolateral leads, tall R waves in V1, shortened PR interval, arrhythmias, resting sinus tachycardia
Test Interpretation
  • Heterogenic muscle fibers: atrophy and hypertrophy of fibers with proliferation of connective tissue in muscle
  • Immunohistochemical staining for dystrophin protein
    • DMD: no detectable dystrophin in most fibers; occasional revertant fibers with normal dystrophin
    • BMD: highly variable staining for dystrophin throughout muscle
P.695

image TREATMENT
Trials of agents that affect gene expression, such as antisense oligonucleotides, and small molecules that cause skipping of premature stop codons (ataluren) are ongoing; however, steroid treatment is the only clinically available therapy that affects disease progression.
GENERAL MEASURES
  • Ambulation prolonged by knee-ankle-foot orthoses
  • Serial casting to treat contractures
  • Diagnose sleep apnea with polysomnography; treat with noninvasive ventilation.
  • Adaptive devices to improve function
  • Avoid overexertion and strenuous exercise.
MEDICATION
  • Prednisone 0.75 mg/kg/day (4)[A]
    • Slows the decline in muscle function, progression to scoliosis, and degradation of pulmonary function; prolongs functional ambulation; prolongs lifespan; improved cardiac outcomes
    • Therapy should be initiated when there is no longer progress in motor skills, but prior to decline (2).
    • Monitor adverse effects.
      • Bisphosphonates should be considered for preventing loss of bone density; annual exam for cataracts; hypertension should be monitored; no NSAIDs due to risk of peptic ulcer disease (PUD); stress-dose steroids during surgeries and illnesses due to adrenal suppression.
      • Patients should be aware of immune suppression and notify emergency providers.
  • Deflazacort (0.9 mg/kg) is an alternative oral steroid that is also considered first-line therapy in DMD; it acts on muscle regeneration and differentiation; not available in the United States (3)
  • ACE inhibitors
    • Treatment of cardiomyopathy; may be used in conjunction with &bgr;-blockers
ISSUES FOR REFERRAL
  • Refer to neuromuscular diseases center for definitive diagnosis and coordinated multidisciplinary care (4).
  • Cardiology for management of cardiomyopathy
  • Pulmonology for monitoring of pulmonary function and clearance regimen
  • Physical medicine and rehabilitation for management of adaptive devices
  • Nutrition/swallowing: for normal weight gain, attention for dysphagia
  • Psychosocial: learning/behavior and coping assessment, social development (2)
ADDITIONAL THERAPIES
Novel medication: Ataluren interferes with premature stop codons, allowing expression of dystrophin protein. In DMD patients with nonsense mutation; FDA approved orphan drug designation (3)
SURGERY/OTHER PROCEDURES
  • Spinal surgery for scoliosis—diminishes rate of deformity progression (5),(6)[A].
  • Scapular fixation for scapular winging may be beneficial; also lacking clinical trials
  • Consider surgical treatment of ankle/knee contractures.
  • Surgical procedures should be performed at a center experienced in DMD; total IV anesthesia should be used.
image ONGOING CARE
  • Individualized education plan and developmental evaluation for school accommodations
  • Maintenance of current influenza and pneumococcal vaccination status
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Electrocardiogram (ECG), echocardiogram, and consultation with a cardiologist at diagnosis and annually after age 10 years
    • Female carriers of DMD mutation should be monitored every 5 years.
  • Annual spinal radiography for scoliosis
  • Dual-energy x-ray absorptiometry (DEXA) scanning and serum marker testing for osteoporosis
  • Pulmonary function testing twice yearly if no longer ambulatory
  • Psychosocial: coping, emotional adjustment, depression
DIET
  • Obesity is common due to steroid treatment and wheelchair confinement: Weight control can improve quality of life.
  • Diet may be limited by dysphagia; swallow evaluation can determine appropriate foods; may require gastrostomy
  • Calcium and vitamin D supplementation for patients on steroids; monitor vitamin D levels.
PATIENT EDUCATION
  • Muscular Dystrophy Association: http://www.mda.org
  • Parent Project Muscular Dystrophy: http://www.endduchenne.org
PROGNOSIS
  • DMD/BMD
    • Progressive weakness, contractures, inability to walk
    • Kyphoscoliosis and progressive decline in respiratory vital capacity with recurrent pulmonary infections.
    • Significantly shortened lifespan (DMD: 16 ± 4 years; BMD: 42 ± 16 years). Respiratory failure cause of death in 90%; remaining due to myocardial disease (heart failure and dysrhythmia) (5)
  • Other types: slow progression and near-normal lifespan with functional limitations
REFERENCES
1. Chung J, Smith AL, Hughes SC, et al. Twenty-year follow-up of newborn screening for patients with muscular dystrophy [published online ahead of print August 11, 2015]. Muscle Nerve. doi:10.1002/mus.24880.
2. 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(1):77-93.
3. Falzarano MS, Scotton C, Passarelli C, et al. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules. 2015;20(10):18168-18184.
4. 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(2):177-189.
5. Roberto R, Fritz A, Hagar Y, et al. The natural history of cardiac and pulmonary function decline in patients with Duchenne muscular dystrophy. Spine (Phila Pa 1976). 2011;36(15):E1009-E1017.
6. van Ruiten HJ, Straub V, Bushby K, et al. Improving recognition of Duchenne muscular dystrophy: a retrospective case note review. Arch Dis Child. 2014;99(12):1074-1077.
Additional Reading
&NA;
  • American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics. 2005;116(6):1569-1573.
  • Cheuk DKL, Wong V, Wraige E, et al. Surgery for scoliosis in Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2013;(2):CD005375.
  • Cossu G, Sampaolesi M. New therapies for Duchenne muscular dystrophy: challenges, prospects and clinical trials. Trends Mol Med. 2007;13(12):520-526.
  • Emery AE. The muscular dystrophies. Lancet. 2002;359(9307):687-695.
  • Fairclough RJ, Bareja A, Davies KE. Progress in therapy for Duchenne muscular dystrophy. Exp Physiol. 2011;96(11):1101-1113.
  • Manzur AY, Kuntzer T, Pike M, et al. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2008;(1):CD003725.
  • Orrell RW, Copeland S, Rose MR. Scapular fixation in muscular dystrophy. Cochrane Database Syst Rev. 2010;(1):CD003278.
  • Schram G, Fournier A, Leduc H, et al. All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy. J Am Coll Cardiol. 2013;61(9):948-954.
  • Takami Y, Takeshima Y, Awano H, et al. High incidence of electrocardiogram abnormalities in young patients with Duchenne muscular dystrophy. Pediatr Neurol. 2008;39(6):399-403.
  • van der Kooi EL, Lindeman E, Riphagen I. Strength training and aerobic exercise training for muscle disease. Cochrane Database Syst Rev. 2005;(1):CD003907.
Codes
&NA;
ICD10
  • G71.0 Muscular dystrophy
  • G71.11 Myotonic muscular dystrophy
  • G71.2 Congenital myopathies
Clinical Pearls
&NA;
  • Primary care providers should have a low threshold to obtain serum CK as a screening test in the face of gross motor delay/muscular weakness, especially in boys.
  • Steroids should be initiated in patients with DMD when gross motor function ceases to progress.
  • High-quality care of patients requires a medical home; a multidisciplinary team of physicians, therapists, and other providers; and extensive patient and family support.