Chapter 601 Muscular Dystrophies
The term dystrophy means abnormal growth, derived from the Greek trophe, meaning “nourishment.” A muscular dystrophy is distinguished from all other neuromuscular diseases by four obligatory criteria: It is a primary myopathy, it has a genetic basis, the course is progressive, and degeneration and death of muscle fibers occur at some stage in the disease. This definition excludes neurogenic diseases such as spinal muscular atrophy, nonhereditary myopathies such as dermatomyositis, nonprogressive, and non-necrotizing congenital myopathies such as congenital muscle fiber-type disproportion (CMFTD), and nonprogressive inherited metabolic myopathies. Some metabolic myopathies can fulfill the definition of a progressive muscular dystrophy but are not traditionally classified as dystrophies (muscle carnitine deficiency).
All muscular dystrophies might eventually be reclassified as metabolic myopathies once the biochemical defects are better defined. Muscular dystrophies are a group of unrelated diseases, each transmitted by a different genetic trait and each differing in its clinical course and expression. Some are severe diseases at birth that lead to early death; others follow very slow progressive courses over many decades, may be compatible with normal longevity, and might not even become symptomatic until late adult life. Some categories of dystrophies, such as limb-girdle muscular dystrophy (LGMD), are not homogeneous diseases but rather syndromes encompassing several distinct myopathies. Relationships among the various muscular dystrophies are resolved by molecular genetics rather than by similarities or differences in clinical and histopathologic features.
601.1 Duchenne and Becker Muscular Dystrophies
Duchenne muscular dystrophy (DMD) is the most common hereditary neuromuscular disease affecting all races and ethnic groups. Its characteristic clinical features are progressive weakness, intellectual impairment, hypertrophy of the calves, and proliferation of connective tissue in muscle. The incidence is 1:3,600 liveborn infant boys. This disease is inherited as an X-linked recessive trait. The abnormal gene is at the Xp21 locus and is one of the largest genes. Becker muscular dystrophy (BMD) is a fundamentally similar disease as DMD, with a genetic defect at the same locus, but clinically it follows a milder and more protracted course.
Infant boys are only rarely symptomatic at birth or in early infancy, although some are mildly hypotonic. Early gross motor skills, such as rolling over, sitting, and standing, are usually achieved at the appropriate ages or may be mildly delayed. Poor head control in infancy may be the first sign of weakness. Distinctive facies are not an early feature because facial muscle weakness is a late event; in later childhood, a “transverse” or horizontal smile may be seen. Walking is often accomplished at the normal age of about 12 mo, but hip girdle weakness may be seen in subtle form as early as the 2nd year. Toddlers might assume a lordotic posture when standing to compensate for gluteal weakness. An early Gowers sign is often evident by age 3 yr and is fully expressed by age 5 or 6 yr (see Fig. 584-5). A Trendelenburg gait, or hip waddle, appears at this time. Common presentations in toddlers include delayed walking, falling, toe walking and trouble running or walking upstairs, developmental delay, and, less often, malignant hyperthermia after anesthesia.
The length of time a patient remains ambulatory varies greatly. Some patients are confined to a wheelchair by 7 yr of age; most patients continue to walk with increasing difficulty until age 10 yr without orthopedic intervention. With orthotic bracing, physiotherapy, and sometimes minor surgery (Achilles tendon lengthening), most are able to walk until age 12 yr. Ambulation is important not only for postponing the psychologic depression that accompanies the loss of an aspect of personal independence but also because scoliosis usually does not become a major complication as long as a patient remains ambulatory, even for as little as 1 hr per day; scoliosis often becomes rapidly progressive after confinement to a wheelchair.
The relentless progression of weakness continues into the 2nd decade. The function of distal muscles is usually relatively well enough preserved, allowing the child to continue to use eating utensils, a pencil, and a computer keyboard. Respiratory muscle involvement is expressed as a weak and ineffective cough, frequent pulmonary infections, and decreasing respiratory reserve. Pharyngeal weakness can lead to episodes of aspiration, nasal regurgitation of liquids, and an airy or nasal voice quality. The function of the extraocular muscles remains well preserved. Incontinence due to anal and urethral sphincter weakness is an uncommon and very late event.
Contractures most often involve the ankles, knees, hips, and elbows. Scoliosis is common. The thoracic deformity further compromises pulmonary capacity and compresses the heart. Scoliosis usually progresses more rapidly after the child becomes nonambulatory and may be uncomfortable or painful. Enlargement of the calves (pseudohypertrophy) and wasting of thigh muscles are classic features. The enlargement is caused by hypertrophy of some muscle fibers, infiltration of muscle by fat, and proliferation of collagen. After the calves, the next most common site of muscular hypertrophy is the tongue, followed by muscles of the forearm. Fasciculations of the tongue do not occur. The voluntary sphincter muscles rarely become involved.
Unless ankle contractures are severe, ankle deep tendon reflexes remain well preserved until terminal stages. The knee deep tendon reflexes may be present until about 6 yr of age but are less brisk than the ankle jerks and are eventually lost. In the upper extremities, the brachioradialis reflex is usually stronger than the biceps or triceps brachii reflexes.
Cardiomyopathy, including persistent tachycardia and myocardial failure, is seen in 50-80% of patients with this disease. The severity of cardiac involvement does not necessarily correlate with the degree of skeletal muscle weakness. Some patients die early of severe cardiomyopathy while still ambulatory; others in terminal stages of the disease have well-compensated cardiac function. Smooth muscle dysfunction, particularly of the gastrointestinal (GI) tract, is a minor, but often overlooked, feature.
Intellectual impairment occurs in all patients, although only 20-30% have an IQ <70. The majority have learning disabilities that still allow them to function in a regular classroom, particularly with remedial help. A few patients are profoundly mentally retarded, but there is no correlation with the severity of the myopathy. Epilepsy is slightly more common than in the general pediatric population. Dystrophin is expressed in brain and retina, as well as in striated and cardiac muscle, though the level is lower in brain than in muscle. This distribution might explain some of the central nervous system (CNS) manifestations. Abnormalities in cortical architecture and of dendritic arborization may be detected neuropathologically; cerebral atrophy is demonstrated by MRI late in the clinical course. The degenerative changes and fibrosis of muscle constitute a painless process. Myalgias and muscle spasms do not occur. Calcinosis of muscle is rare.
In Becker muscular dystrophy, boys remain ambulatory until late adolescence or early adult life. Calf pseudohypertrophy, cardiomyopathy, and elevated serum levels of creatine kinase (CK) are similar to those of patients with DMD. Learning disabilities are less common. The onset of weakness is later in Becker than in DMD. Death often occurs in the mid to late 20s; fewer than half of patients are still alive by age 40 yr; these survivors are severely disabled.
The serum CK level is consistently greatly elevated in DMD, even in presymptomatic stages, including at birth. The usual serum concentration is 15,000-35,000 IU/L (normal <160 IU/L). A normal serum CK level is incompatible with the diagnosis of DMD, although in terminal stages of the disease, the serum CK value may be considerably lower than it was a few years earlier because there is less muscle to degenerate. Other lysosomal enzymes present in muscle, such as aldolase and aspartate aminotransferase, are also increased but are less specific.
Cardiac assessment by echocardiography, electrocardiography (ECG), and radiography of the chest is essential and should be repeated periodically. After the diagnosis is established, patients should be referred to a pediatric cardiologist for long-term cardiac care.
Polymerase chain reaction (PCR) for the dystrophin gene mutation is the primary test, if the clinical features and serum CK are consistent with the diagnosis. If the blood PCR is diagnostic, muscle biopsy may be deferred, but if it is normal and clinical suspicion is high, the more specific dystrophin immunocytochemistry performed on muscle biopsy sections detects the 30% of cases that do not show a PCR abnormality. Immunohistochemical staining of frozen sections of muscle biopsy tissue detects differences in the rod domain, the carboxyl-terminus (that attaches to the sarcolemma), and the amino-terminus (that attaches to the actin myofilaments) of the large dystrophin molecule, and may be prognostic of the clinical course as Duchenne or Becker disease. More severe weakness occurs with truncation of the dystrophin molecule at the carboxyl-terminus than at the amino-terminus. The diagnosis should be confirmed by blood PCR or muscle biopsy in every case. Dystroglycans and other sarcolemmal regional proteins, such as merosin and sarcoglycans, also can be measured because they may be secondarily decreased.
The muscle biopsy is diagnostic and shows characteristic changes (Figs. 601-1 and 601-2). Myopathic changes include endomysial connective tissue proliferation, scattered degenerating and regenerating myofibers, foci of mononuclear inflammatory cell infiltrates as a reaction to muscle fiber necrosis, mild architectural changes in still-functional muscle fibers, and many dense fibers. These hypercontracted fibers probably result from segmental necrosis at another level, allowing calcium to enter the site of breakdown of the sarcolemmal membrane and trigger a contraction of the whole length of the muscle fiber. Calcifications within myofibers are correlated with secondary β-dystroglycan deficiency.
Figure 601-1 Muscle biopsy of a 4 yr old boy with Duchenne muscular dystrophy. Both atrophic and hypertrophic muscle fibers are seen, and some fibers are degenerating (deg). Connective tissue (c) between muscle fibers is increased (H&E, ×400).
Figure 601-2 Dystrophin is demonstrated by immunohistochemical reactivity in the muscle biopsies of a normal term male neonate (A), a 10 yr old boy with limb-girdle muscular dystrophy (B), a 6 yr old boy with Duchenne muscular dystrophy (C), and a 10 yr old boy with Becker muscular dystrophy (D). In the normal condition and also in non–X-linked muscular dystrophies in which dystrophin is not affected, the sacrolemmal membrane of every fiber is strongly stained, including atrophic and hypertrophic fibers. In Duchenne dystrophy, most myofibers express no detectable dystrophin, but a few scattered fibers known as revertant fibers show near-normal immunoreactivity. In Becker muscular dystrophy, the abnormal dystrophin molecule is expressed as thin, with pale staining of the sarcolemma, in which reactivity varies not only between myofibers but also along the circumference of individual fibers (×250).
The decision about whether muscle biopsy should be performed to establish the diagnosis sometimes presents problems. If there is a family history of the disease, particularly in the case of an involved brother whose diagnosis has been confirmed, a patient with typical clinical features of DMD and high concentrations of serum CK probably does not need to undergo biopsy. The result of the PCR might also influence whether to perform a muscle biopsy. A first case in a family, even if the clinical features are typical, should have the diagnosis confirmed to ensure that another myopathy is not masquerading as DMD. The most common muscles sampled are the vastus lateralis (quadriceps femoris) and the gastrocnemius.
Despite the X-linked recessive inheritance in DMD, about 30% of cases are new mutations, and the mother is not a carrier. The female carrier state usually shows no muscle weakness or any clinical expression of the disease, but affected girls are occasionally encountered, usually having much milder weakness than boys. These symptomatic girls are explained by the Lyon hypothesis in which the normal X chromosome becomes inactivated and the one with the gene deletion is active (Chapter 75). The full clinical picture of DMD has occurred in several girls with Turner syndrome in whom the single X chromosome must have had the Xp21 gene deletion.
The asymptomatic carrier state of DMD is associated with elevated serum CK values in 80% of cases. The level of increase is usually in the magnitude of hundreds or a few thousand but does not have the extreme values noted in affected males. Prepubertal girls who are carriers of the dystrophy also have increased serum CK values, with highest levels at 8-12 yr of age. Approximately 20% of carriers have normal serum CK values. If the mother of an affected boy has normal CK levels, it is unlikely that her daughter can be identified as a carrier by measuring CK. Muscle biopsy of suspected female carriers can detect an additional 10% in whom serum CK is not elevated; a specific genetic diagnosis using PCR on peripheral blood is definitive. Some female carriers suffer cardiomyopathy without weakness of striated muscles.
A 427-kd cytoskeletal protein known as dystrophin is encoded by the gene at the Xp21.2 locus. This gene contains 79 exons of coding sequence and 2.5 Mb of DNA, 10 times larger than the next largest gene yet identified. This subsarcolemmal protein attaches to the sarcolemmal membrane overlying the A and M bands of the myofibrils and consists of 4 distinct regions or domains: the amino-terminus contains 250 amino acids and is related to the N-actin binding site of α-actinin; the second domain is the largest, with 2,800 amino acids, and contains many repeats, giving it a characteristic rod shape; a 3rd, cysteine-rich, domain is related to the carboxyl-terminus of α-actinin; and the final carboxyl-terminal domain of 400 amino acids is unique to dystrophin and to a dystrophin-related protein encoded by chromosome 6. Dystrophin deficiency at the sarcolemma disrupts the membrane cytoskeleton and leads to loss secondarily of other components of the cytoskeleton.
The molecular defects in the dystrophinopathies vary and include intragenic deletions, duplications, or point mutations of nucleotides. About 65% of patients have deletions, and only 7% exhibit duplications. The site or size of the intragenic abnormality does not always correlate well with the phenotypic severity; in both Duchenne and Becker forms the mutations are mainly near the middle of the gene, involving deletions of exons 46-51. Phenotypic or clinical variations are explained by the alteration of the translational reading frame of mRNA, which results in unstable, truncated dystrophin molecules and severe, classic DMD; mutations that preserve the reading frame still permit translation of coding sequences further downstream on the gene and produce a semifunctional dystrophin, expressed clinically as BMD. An even milder form of adult-onset disease, formerly known as quadriceps myopathy, is also caused by an abnormal dystrophin molecule. The clinical spectrum of the dystrophinopathies not only includes the classic Duchenne and Becker forms but also ranges from a severe neonatal muscular dystrophy to asymptomatic children with persistent elevation of serum CK levels >1,000 IU/L.
Analysis of the dystrophin protein requires a muscle biopsy and is demonstrated by Western blot analysis or in tissue sections by immunohistochemical methods using either fluorescence or light microscopy of antidystrophin antisera (see Fig. 601-2). In classic DMD, levels of <3% of normal are found; in BMD, the molecular weight of dystrophin is reduced to 20-90% of normal in 80% of patients, but in 15% of patients the dystrophin is of normal size but reduced in quantity, and 5% of patients have an abnormally large protein caused by excessive duplications or repeats of codons. Selective immunoreactivity of different parts of the dystrophin molecule in sections of muscle biopsy material distinguishes the Duchenne and Becker forms (Fig. 601-3). The demonstration of deletions and duplications also can be made from blood samples by the more rapid PCR, which identifies as many as 98% of deletions by amplifying 18 exons but cannot detect duplications. The diagnosis can thus be confirmed at the molecular genetic level from either the muscle biopsy material or from peripheral blood, although as many as 30% of boys with DMD or BMD have a false-normal blood PCR; all cases of dystrophinopathy are detected by muscle biopsy.
Figure 601-3 Quadriceps femoris muscle biopsy specimens from a 4 yr old boy with Becker muscular dystrophy. A, Myofibers vary greatly in size, with both atrophic and hypertrophic forms; at the right is a zone of degeneration and necrosis infiltrated by macrophages, similar to Duchenne muscular dystrophy (H&E, ×250). Immunoreactivity using antibodies against the dystrophin molecule in the rod domain (B), carboxyl-terminus (C), and amino-terminus (D) all show deficient but not totally absent dystrophin expression; most fibers of all sizes retain some dystrophin in parts of the sarcolemma but not around the entire circumference in cross section. Alternatively, the prominence of dystrophin is less, appearing weak, when compared with the simultaneously incubated normal control from another child of similar age (E). F, Merosin expression is normal in this patient with Becker dystrophy, in both large and small myofibers, and is lacking only in frankly necrotic fibers. Compare with classic Duchenne muscular dystrophy illustrated in Figure 601-2C and with Figure 601-5.
The same methods of DNA analysis from blood samples may be applied for carrier detection in female relatives at risk, such as sisters and cousins, and to determine whether the mother is a carrier or whether a new mutation occurred in the embryo. Prenatal diagnosis is possible as early as the 12th wk of gestation by sampling chorionic villi for DNA analysis by Southern blot or PCR and is confirmed in aborted fetuses with DMD by immunohistochemistry for dystrophin in muscle.
There is neither a medical cure for this disease nor a method of slowing its progression. Much can be done to treat complications and to improve the quality of life of affected children. Cardiac decompensation often responds initially well to digoxin. Pulmonary infections should be promptly treated. Patients should avoid contact with children who have obvious respiratory or other contagious illnesses. Immunizations for influenza virus and other routine vaccinations are indicated.
Preservation of a good nutritional state is important. DMD is not a vitamin-deficiency disease, and excessive doses of vitamins should be avoided. Adequate calcium intake is important to minimize osteoporosis in boys confined to a wheelchair, and fluoride supplements may also be given, particularly if the local drinking water is not fluoridated. Because sedentary children burn fewer calories than active children and because depression is an additional factor, these children tend to eat excessively and gain weight. Obesity makes a patient with myopathy even less functional because part of the limited reserve muscle strength is dissipated in lifting the weight of excess subcutaneous adipose tissue. Dietary restrictions with supervision may be needed.
Physiotherapy delays but does not always prevent contractures. At times, contractures are actually useful in functional rehabilitation. If contractures prevent extension of the elbow beyond 90 degrees and the muscles of the upper limb no longer are strong enough to overcome gravity, the elbow contractures are functionally beneficial in fixing an otherwise flail arm and in allowing the patient to eat and write. Surgical correction of the elbow contracture may be technically feasible, but the result may be deleterious. Physiotherapy contributes little to muscle strengthening because patients usually are already using their entire reserve for daily function, and exercise cannot further strengthen involved muscles. Excessive exercise can actually accelerate the process of muscle fiber degeneration.