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Muscular dystrophies are inherited, progressive muscle disorders resulting from defects in one or more genes needed for normal muscle structure and function. They are distinguished by the selective distribution of weakness and the specific nature of the genetic abnormality involved.
Duchenne dystrophy is the most common and severe form of muscular dystrophy. Becker dystrophy, although closely related, has a later onset and causes milder symptoms. Other forms include Emery-Dreifuss dystrophy, myotonic dystrophy, limb-girdle dystrophy, facioscapulohumeral dystrophy, and congenital dystrophies.
Duchenne Muscular Dystrophy and Becker Muscular Dystrophy
Duchenne muscular dystrophy and Becker muscular dystrophy are X-linked recessive disorders characterized by progressive proximal muscle weakness caused by muscle fiber degeneration. Becker dystrophy has later onset and causes milder symptoms. Diagnosis is suggested clinically and is confirmed by analysis of the protein product (dystrophin) of the mutated gene. Treatment focuses on maintaining function through physical therapy and the use of braces and orthotics; prednisone is given to some patients with severe functional decline.
Duchenne dystrophy and Becker dystrophy are caused by mutations of the dystrophin gene, the largest known human gene, at the Xp21.2 locus. In Duchenne dystrophy, this mutation results in the severe absence (< 5%) of dystrophin, a protein in the muscle cell membrane. In Becker dystrophy, the mutation results in production of abnormal dystrophin or insufficient dystrophin. Duchenne dystrophy affects 1/4700 live male births. Becker dystrophy affects 1/30,000 live male births. Female carriers may have asymptomatic elevated CK levels and possibly calf hypertrophy.
Symptoms and Signs
Duchenne dystrophy
This disorder manifests typically between ages 2 yr and 3 yr. Weakness affects proximal muscles, typically in the lower limbs initially. Children frequently toe walk and have a waddling gait and lordosis. They have difficulty running, jumping, climbing stairs, and rising from the floor. Children fall frequently, often causing arm or leg fractures (in about 20% of patients). Progression of weakness is steady, and limb flexion contractures and scoliosis develop in nearly all children. Firm pseudohypertrophy (fatty and fibrous replacement of certain enlarged muscle groups, notably the calves) develops. Most children are confined to a wheelchair by age 12 and die of respiratory complications by age 20. Consequences of cardiac muscle involvement include dilated cardiomyopathy, conduction abnormalities, and arrhythmias. Such complications occur in about 33% of patients by age 14 and in all patients over age 18; however, because these patients are not able to exercise, cardiac involvement is usually asymptomatic until late in the disease. About one third have mild, nonprogressive intellectual impairment that affects verbal ability more than performance.
Becker dystrophy
This disorder typically becomes symptomatic much later and is milder. Ambulation is usually preserved until at least age 15, and many children remain ambulatory into adulthood. Most affected children survive into their 30s and 40s.
Diagnosis
Diagnosis is suspected by characteristic clinical findings, age at onset, and family history suggestive of X-linked recessive inheritance. Myopathic changes are noted on electromyography (rapidly recruited, short duration, low-amplitude motor unit potentials) and muscle biopsy (necrosis and marked variation in muscle fiber size not segregated by motor unit). CK levels are elevated to up to 100 times normal.
Diagnosis is confirmed by analysis of dystrophin with immunostaining of biopsy samples. Dystrophin is undetectable in patients with Duchenne dystrophy. In patients with Becker dystrophy, dystrophin is typically abnormal (lower molecular weight) or present in low concentration. Mutation analysis of DNA from peripheral blood leukocytes can also confirm the diagnosis by identifying abnormalities in the dystrophin gene (deletions in about 70% of patients with Duchenne dystrophy and 85% of patients with Becker dystrophy and duplications in about 10% of both groups).
Patients with Duchenne dystrophy should have a baseline assessment of cardiac function with ECG and echocardiography at the time of diagnosis or by age 6 yr.
Carrier detection and prenatal diagnosis are possible by using conventional studies (eg, pedigree analysis, CK determinations, fetal sex determination) combined with recombinant DNA analysis and dystrophin immunostaining of muscle tissue.
Treatment
No specific treatment exists. Gentle (ie, submaximal), active exercise is encouraged for as long as possible to avoid disuse atrophy or complications of inactivity. Passive exercises may extend the period of ambulation. Orthopedic interventions should be aimed at maintaining function and preventing contractures. Ankle-foot orthoses worn during sleep may help prevent flexion contractures. Leg braces may temporarily help preserve ambulation or standing. Corrective surgery is sometimes needed, particularly for scoliosis. Obesity should be avoided; caloric requirements are likely to be less than normal because of decreased physical activity. Respiratory insufficiency may be treated with noninvasive ventilatory support (eg, nasal mask—see Respiratory Failure and Mechanical Ventilation: Status asthmaticus (SA)). Elective tracheotomy is gaining acceptance, allowing children with Duchenne dystrophy to live into their 20s. For children with dilated cardiomyopathy, an ACE inhibitor and/or a β-blocker may help prevent or slow progression.
In Duchenne dystrophy, daily prednisone is considered for patients > age 5 yr with declining muscle skills. Daily prednisone improves muscle strength and forced vital capacity by about 10% and improves muscle mass (as estimated by urinary creatinine excretion) by > 30%. Alternate-day prednisone is not effective. Weight gain and cushingoid facies are common adverse effects after 6 to 18 mo. Risk of vertebral compression and long bone fractures also is increased. Use of prednisone in Becker dystrophy has not been adequately studied.
Gene therapy is not yet available. Genetic counseling is indicated (see Prenatal Genetic Counseling and Evaluation).
Key Points
Other Forms of Muscular Dystrophy
Emery-Dreifuss dystrophy
This disorder can be inherited as an autosomal dominant, autosomal recessive (the rarest), or X-linked recessive disorder. The overall incidence is unknown. Females can be carriers, but only males are affected clinically by X-linked inheritance. Genes associated with Emery-Dreifuss dystrophy encode for the nuclear membrane proteins lamin A/C (autosomal) and emerin (X-linked).
Muscle weakness and wasting can begin any time before age 20 and commonly affect the biceps and triceps and, less often, distal leg muscles. Early contractures are characteristic. The heart is frequently involved, with atrial paralysis, conduction abnormalities (atrioventricular block), cardiomyopathy, and a high likelihood of sudden death.
Diagnosis is indicated by clinical findings, age at onset, and family history. The diagnosis is supported by mildly increased serum CK levels and myopathic features on electromyography and muscle biopsy and is confirmed by DNA testing.
Treatment involves therapy to prevent contractures. Cardiac pacemakers are sometimes lifesaving in patients with abnormal conduction.
Myotonic dystrophy
Myotonic dystrophy, the most common form of muscular dystrophy among whites, affects about 1/8000 in the general population. Inheritance is autosomal dominant with variable penetrance. Two genetic loci—DM 1 and DM 2—cause the abnormality.
Symptoms and signs begin during adolescence or young adulthood and include myotonia (delayed relaxation after muscle contraction), weakness and wasting of distal limb muscles (especially in the hand) and facial muscles (ptosis is especially common), and cardiomyopathy. Intellectual disability, cataracts, and endocrine disorders can also occur. Death is most commonly due to respiratory and cardiac disease, and patients who develop cardiac arrhythmias and severe muscle weakness at a younger age are at increased risk of premature death. A mean age at death of 54 yr is often reported.
Diagnosis is indicated by characteristic clinical findings, age at onset, and family history and is confirmed by DNA testing.
Myotonia may respond to membrane-stabilizing drugs (eg, mexiletine, procainamide, quinidine, phenytoin, carbamazepine). However, it is weakness, for which no treatment is available, and not myotonia that disables the patient; braces for footdrop are usually required as the disease progresses.
Affected mothers and, only rarely, fathers with DM 1 mutations may have offspring with a severe form of myotonia referred to as congenital myotonic dystrophy. This form is characterized by severe hypotonia (floppy infant), feeding and respiratory difficulties, skeletal deformities, facial weakness, and delayed psychomotor development. Up to 40% of infants do not survive, usually because of respiratory failure and perhaps cardiomyopathy. Up to 60% of survivors have intellectual disability.
Limb-girdle dystrophy
Limb-girdle dystrophy currently has 21 known subtypes, 15 autosomal recessive and 6 autosomal dominant. The overall incidence is unknown. Males and females are affected equally. Insights from molecular biology have redefined the way these disorders are classified. Autosomal dominant forms are classified as LGMD 1A, -1B, -1C, and so on, and recessive forms are classified as LGMD 2A, -2B, -2C, and so on. Several chromosomal loci have been identified for autosomal dominant (5q [no known gene product]) and recessive (2q, 4q [beta-sarcoglycan], 13q [gamma-sarcoglycan], 15q [calpain, a Ca-activated protease], and 17q [alpha-sarcoglycan or adhalin]) forms. Structural (eg, dystrophin-associated glycoproteins) or nonstructural (eg, proteases) proteins can be affected.
Patients typically present with slowly progressive, symmetric, proximal muscle weakness with or without facial involvement and diminished or absent tendon reflexes. The pelvic or the shoulder girdle muscles can be affected first. Onset of symptoms ranges from early childhood to adulthood. Onset of symptoms for autosomal recessive types tends to be during childhood, and these types primarily have a pelvic-girdle distribution.
Diagnosis is indicated by characteristic clinical findings, age at onset, and family history and requires muscle histology, immunocytochemistry, Western blot analysis, and genetic testing for specific proteins.
Treatment focuses on maintaining function and preventing contractures.
Facioscapulohumeral muscular dystrophy
Facioscapulohumeral muscular dystrophy (FSHMD) is an autosomal dominant disorder. In about 98% of patients, FSHMD is caused by a deletion on the long arm of chromosome 4, at the 4q35 locus. In about 10 to 33% of patients, the mutation is de novo (sporadic) rather than inherited. FSHMD is the third most common muscular dystrophy after Duchenne dystrophy and myotonic dystrophy and affects 1/20,000 whites.
FSHMD is characterized by weakness of the facial muscles and shoulder girdle. Symptoms may develop in early childhood and are usually noticeable in the teenage years; 95% of cases manifest by age 20. Initial symptoms are slowly progressive and may include difficulty whistling, closing the eyes, and raising the arms (due to weakness of the scapular stabilizer muscles). Patients eventually notice a change in facial expression. The course is variable. Many patients do not become disabled and have a normal life expectancy. Other patients are confined to a wheelchair in adulthood. An infantile variety, characterized by facial, shoulder, and hip-girdle weakness, is rapidly progressive, and disability is always severe. Nonmuscular symptoms frequently associated with this disorder include sensorineural hearing loss and retinal vascular abnormalities.
Diagnosis is indicated by characteristic clinical findings, age at onset, and family history and is confirmed by DNA testing.
There is no treatment for the weakness, but physical therapy may help maintain function. Monitoring for retinal vascular abnormalities is essential to prevent blindness.
Congenital muscular dystrophy
Congenital muscular dystrophy is not a single disorder but instead refers to muscular dystrophy evident at birth, occurring from any of several rare forms of muscular dystrophy. All such dystrophies are genetically recessive and result from mutations in a variety of different genes including those that encode for structural proteins of the basal membrane or the extracellular matrix of skeletal muscle fibers. The diagnosis is suspected in any floppy neonate but must be distinguished from congenital myopathy by muscle biopsy.
Treatment consists of supportive care including physical therapy, which may help preserve function.
Last full review/revision March 2013 by Michael Rubin, MDCM
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