Muscular dystrophy.

Abstract

After completing this article, readers should be able to:The term “muscular dystrophy” refers to a group of genetically determined disorders characterized by progressive degeneration of skeletal muscle without primary structural abnormality in the lower motor neuron. These disorders have been classified on the basis of the clinical distribution and severity of muscle weakness and by pattern of inheritance. The majority of muscular dystrophies are associated with progressive muscle weakness and atrophy and elevated concentrations of serum creatine kinase (CK), but these are not absolute findings. Some of the milder varieties, such as facioscapulohumeral dystrophy, may appear relatively static, and patients who have congenital muscular dystrophy even may show functional improvement. Most of the muscular dystrophies have marked,albeit nonspecific, structural abnormalities in muscle biopsies, such as loss (necrosis) of muscle fibers and increased connective tissue(endomysial fibrosis). It is possible that the identification of specific muscle protein abnormalities will lead to a reclassification of the muscular dystrophies.The findings of weakness and elevated CK concentration are common to other disorders of the lower motor neuron, including anterior horn cell disease, peripheral neuropathies, and other metabolic and nonprogressive myopathic conditions. Motor dysfunction of central origin usually presents with hypotonia rather than actual weakness.The overall incidence of muscular dystrophy varies because this term encompasses disorders that have different inheritance patterns. Duchenne/Becker dystrophy is the most common type of muscular dystrophy to present in childhood. Its incidence, based on population studies and neonatal screening programs, is approximately 1 in 3,500 male births. In addition, this disorder has a high spontaneous mutation rate, with approximately one third of cases estimated to be due to new mutations. Of the muscular dystrophies presenting in adulthood, myotonic dystrophy is the most common. The incidence in all age groups is reported to be approximately 13.5 per 100,000 population, with a prevalence of 5 cases per 100,000. The incidences of the less common types of muscular dystrophy—facioscapulohumeral dystrophy, limb-girdle dystrophy, and congenital muscular dystrophy—have not been determined.The muscular dystrophies are genetically determined disorders, but in many instances, the pathogenesis is complicated by the same clinical phenotype possibly having different modes of inheritance. Furthermore,there appears to be no consistent correlation between the size or location of gene deletions and the severity of the clinical condition. The known inheritance patterns, gene locations, and gene product abnormalities of the common types of muscular dystrophy that present in childhood are summarized in Table 1. The genetic aspects of myotonic dystrophy require further elaboration. Although this disorder has an autosomal dominant inheritance pattern,the most severely affected individuals present at birth. Congenital myotonic dystrophy always is transmitted by the mother. The gene affected in myotonic dystrophy, which is located on chromosome 19, has an unstable DNA triplet repeat sequence (CTG). Affected individuals have an expanded number of triplet repeats, usually more than 50. However, the severity of the disease cannot be predicted precisely from the number of triplet repeats, although there is a correlation. The number of triplet repeats tends to increase in affected individuals in successive generations. This explains the phenomenon of “genetic anticipation,” which refers to increasing disease severity within an affected family over several generations.Although all types of muscular dystrophy are characterized by progressive skeletal muscle weakness, the distribution of weakness and rate of progression differ for each disorder. Similarly, the prognosis varies considerably for the different types of muscular dystrophy. In addition, the progressive skeletal changes of most dystrophies (eg,joint contractures, scoliosis) are related to muscle weakness. In severe cases, weakness of respiratory muscles leads to restrictive lung disease and eventual respiratory failure. In this review, discussion is limited to the clinical aspects of muscular dystrophies that present during childhood, and the prognosis is discussed in the context of each specific disorder.With the classic clinical presentation, affected boys are asymptomatic during early infancy and have normal motor milestones. Less commonly, some boys present with global developmental delay or delayed achievement of early motor milestones. At approximately 4 years of age, affected boys develop a waddling gait and difficulty climbing stairs due to pelvic weakness. Toewalking results from tightness of the Achilles tendon. These boys are unable to jump, and they fall frequently. The progressive difficulty in arising from the floor because of proximal pelvic girdle weakness results in the Gower maneuver. Rising from a supine position requires the child to assume a prone position, followed by extension of the knees and elbows. He then lets go of one hand at a time, supporting it on the knee, and gradually straightens into a standing position by “climbing up himself” with his hands.Pseudohypertrophy of muscles, particularly pseudohypertrophy of the calf muscles, is common. Pseudohypertrophic muscles feel rubbery and firmer than normal. Histologic examination shows replacement of muscle fibers by fatty and fibrous tissue as well as some hypertrophy of remaining muscle fibers. Weakness of hip extensors leads to compensatory lumbar lordosis to maintain an upright posture (Fig. 1). Weakness of the arms (proximal more than distal) becomes apparent as the disease progresses. The age at which the ability to walk is lost varies, but this occurs generally before 13 years in Duchenne dystrophy. Following loss of ambulation,fixed skeletal deformities, such as equinovarus deformities of the feet(Fig. 2) and scoliosis (Fig. 3), develop rapidly. Sphincter control usually is unaffected, and there are no difficulties with chewing or swallowing. Weakness of intercostal muscles leads to progressive restrictive respiratory defect with nocturnal hypoventilation in the late teens to early 20s. Eventually respiratory failure occurs, at which time the option for assisted ventilation must be addressed. Although electrocardiographic abnormalities are present in the early stages of the disease, symptoms and signs of progressive cardiomyopathy develop only in the mid-teens. Most boys who have Duchenne dystrophy die from cardiac or pulmonary problems in the late second or third decade.In addition to muscle and skeletal abnormalities, there is nonprogressive intellectual impairment affecting especially the verbal intelligence quotient (IQ) in approximately 30% of patients. There is also a higher incidence of emotional disturbances than in other physically handicapped children.Becker dystrophy results from deletions or mutations in the same gene as Duchenne dystrophy. It has a similar clinical appearance and distribution of weakness, albeit milder in severity and with slower deterioration (Fig. 4). Some individuals may present with severe cramps on exertion. The onset of symptoms often is later in childhood, and affected individuals remain ambulatory beyond 16 years of age. Cardiac involvement may be severe and disproportionate to the skeletal muscle weakness. Clinically apparent cardiomyopathy is present in approximately 15% of patients younger than 16 years of age and in 75% of those older than 40 years. Affected individuals may survive into late adulthood.Myotonic dystrophy has a variable presentation. The principal clinical features in older children and adults are facial weakness,muscle myotonia, and more marked distal muscle weakness. Cardiac muscle involvement in advanced disease manifests as conduction defects, with arrhythmias in approximately 50% of affected patients. Smooth muscle involvement results in dysphagia, constipation, urinary tract symptoms,and cholecystitis. Other organ involvement includes cataracts and endocrine disturbances (eg, diabetes, testicular atrophy, and menstrual irregularities). There may be intellectual impairment that worsens over time.Congenital myotonic dystrophy, which almost invariably is transmitted maternally, is associated with the worst prognosis. Affected infants most commonly are hypotonic, requiring respiratory and nutritional support. Respiratory insufficiency is a major cause of mortality in early infancy. Respiratory function may improve gradually. Other clinical features include preterm birth, facial diplegia, feeding difficulties, arthrogryposis, and cognitive abnormalities (Fig. 5). Clinical myotonia presents at a later age. Thus, if congenital myotonic dystrophy is suspected, clinical myotonia should be investigated in the mother (eg, the “handshake test”).Affected infants present with hypotonia and weakness at birth. There may be joint contractures of variable severity and respiratory and swallowing difficulties. Some types of congenital muscular dystrophy (eg, Fukuyama type, muscle-eye-brain disease,Walker-Warburg syndrome) are characterized by intellectual retardation,seizures, hydrocephalus, and evidence of structural brain abnormalities or ocular abnormalities. Children who have “pure” congenital muscular dystrophy often have a relatively static, nonprogressive course in contrast to those who have central nervous system involvement and exhibit progressive deterioration.Early signs and symptoms, which begin in late childhood or early adolescence, include facial weakness and weakness of scapulohumeral muscles with preservation of deltoid strength (Fig. 6). Weakness of the pelvic girdle may result in a lordotic posture. There usually is no cardiac or intellectual involvement. Some individuals develop retinal vasculopathy and sensorineural hearing loss.This rapidly progressive, autosomal recessive dystrophy, which is similar in severity to Duchenne dystrophy, has been described particularly in families from North Africa. Other cases are milder,with loss of ambulation between 20 and 30 years of age. To date,this group of disorders has not been classified in detail.Progressive clinical symptoms that include muscle weakness are the basis for diagnosing muscular dystrophy. Laboratory investigations play a lesser role.The normal range of CK varies between laboratories. At our center,a CK level below 365 U/L is considered to be normal. It is important not to depend on a single CK level for important decisions,but always to repeat the test on separate occasions. Elevated levels of this enzyme may indicate a significant amount of skeletal or cardiac muscle necrosis. In Duchenne/Becker dystrophy, levels as high as 50 to 100 times normal are common. Interestingly, levels of CK are highest in the early stages of Duchenne/Becker dystrophy, when the patient is asymptomatic, and subsequently decline gradually over time as muscle tissue is lost and disease progresses. In other types of muscular dystrophy or myopathy, levels of CK vary and even may be normal.CK levels may be moderately elevated in severe, chronic neurogenic disorders such as spinal muscular atrophy. It is important to recognize that up to 10-fold elevations in CK may occur following normal vaginal delivery or acute hypoxic-ischemic cerebral injury. Other common causes of elevated CK include intramuscular injections, trauma to muscles, and recent vigorous exercise. An assay of CK isoenzymes may be useful in this context.The quantity of this enzyme may be mildly elevated in muscular dystrophy. In fact, many patients who have Duchenne/Becker dystrophy have had a liver biopsy performed for investigation of“unexplained” elevation of AST.An enlarged cardiac silhouette suggests cardiomyopathy. Thin ribs may be a clue to neuromuscular disease of prenatal onset.EMG shows low-amplitude, short-duration polyphasic motor unit action potentials. Although this test may identify a myopathic process,its results are relatively nonspecific, and it often is technically difficult to perform, especially in the young infant. It has a minor role in the investigation of muscular dystrophy.Electrocardiography may demonstrate conduction defects or arrhythmias. Echocardiography may document cardiomyopathy.This procedure may be performed as either an open, surgical biopsy or as a needle biopsy. Characteristic features of muscular dystrophy include muscle degeneration and regeneration and proliferation of connective tissue. (Fig. 7) During the early stages of a disorder, or in milder types of muscular dystrophy(eg, facioscapulohumeral dystrophy), changes may be minimal. Specialized immunocytochemical techniques, such as staining for dystrophin, have greatly improved the specificity of this study.Identification of specific gene deletions or DNA triplet repeat amplifications are rapidly becoming the techniques of choice for confirming the diagnosis of common types of muscular dystrophy (eg,Duchenne muscular dystrophy, myotonic dystrophy). For example,demonstration of a deletion within the Xp21 gene on DNA blood screening has made invasive muscle biopsy unnecessary in approximately two thirds of cases of Duchenne/Becker dystrophy. Similar genetic techniques are invaluable for identifying carrier status and establishing prenatal diagnosis.Unfortunately, there is no definitive cure for muscular dystrophy. General management includes both supportive therapy (Table 2) and medical/drug therapy.Although there have been numerous attempts at treatment of muscular dystrophy with a wide variety of medications, most claims are not substantiated. The only medication of proven benefit in Duchenne dystrophy is prednisone. Several randomized, double-blind, multicenter,controlled studies showed that administration of prednisone at a dosage of 0.75 mg/kg per day increased muscle strength within 10 days. The beneficial effect was maintained for at least 18 months. Such benefits have been considered to be sufficiently impressive to recommend steroid therapy for ambulatory patients older than 5 years of age if side effects are not severe. Similar beneficial effects have been reported in small randomized trials of deflazacort, a derivative of prednisolone that may have fewer side effects, but that is not available routinely in North America. The value of steroids in the treatment of other types of muscular dystrophy remains unproven.At present, supportive therapies and possibly steroid therapy are used to slow the progression of disease while the potential benefits of definitive cell or gene therapy are being explored.