DMD is the most severe form of progressive primary muscular degeneration. It affects approximately one in 3,000 live-born male infants, with one-third of all cases representing new mutations. DMD is associated with mutations in a gene located in band 1 of region 2 of the short (p) arm of the X chromosome (Xp21), which encodes for a large protein called dystrophin. DMD is manifest at birth, becomes clinically evident when children are between 3 and 5 years of age, and progresses inexorably over the course of the next 2 decades before culminating in death. Most patients become wheelchair-dependent when they are between 10 and 12 years of age.

Two other disorders share a genetic defect at or near the Xp2.1 locus: BMD and the McLeod syndrome. BMD represents a more benign version of DMD, most commonly due to a deletion in the dystrophin gene that does not alter the reading frame of the transcript (as described earlier, in the section Duchenne Muscular Dystrophy). Current information indicates that BMD and DMD are allelic gene abnormalities. BMD is similar to DMD, but the age of onset is later and the progression is slower (Table 409.1).

Pseudohypertrophy is striking, and frequently pes cavus deformities are present in patients with BMD. Unlike in DMD, cardiac or nervous system involvement is an unusual finding, but “pure” dilated cardiomyopathy can occur in patients with BMD in the absence of muscle weakness. Other unusual clinical phenotypes include recurrent myoglobinuria or idiopathic hyper-CKemia, and weakness confined to the quadriceps (quadriceps myopathy). Patients with BMD may have children, although infertility rates are higher in this population. All female progeny are obligate carriers, and all sons are unaffected.

The EMG in patients with BMD is distinctly myopathic, but neurogenic features also may be present. The results of muscle biopsy are compatible with a dystrophic process, but neurogenic atrophy may be seen in one-half of the cases. The neurogenic features are thought to result possibly from muscle fiber splitting. Dystrophic immunoreactivity is present in muscle obtained on biopsy, but the subsarcolemmal staining pattern demonstrates discontinuities. Western blot analyses often show dystrophin of increased or decreased size. The serum CK values are elevated, but to a less striking degree than those in patients with DMD.

Differentiating between BMD and limb-girdle muscular dystrophy may be difficult in sporadic cases. Often, calf hypertrophy is more marked and persistent in patients with BMD. Loss of ambulation is the single best discriminator between DMD and BMD (see Table 409.1). Contractures, a rigid spine, and the absence of pseudohypertrophy help to distinguish Emery-Dreifuss muscular dystrophy from BMD. The treatment approaches and genetic counseling are similar to those for DMD.

The McLeod syndrome has been viewed by some physicians as the minimal expression of the Xp2.1 gene abnormality. The gene encoding the Kx antigens in the Kell red blood cell antigen system is contiguous to the DMD locus. McLeod syndrome is manifested by absence of the Kx antigens, hemolytic anemia, acanthocytosis, elevated serum CK activity, and a benign nonprogressive myopathy. The skeletal muscle biopsy reveals muscle fiber necrosis and regeneration. One classic patient had the genetic misfortune of having chronic granulomatous disease, McLeod red cell phenotype, DMD, retinitis pigmentosa, idiopathic intestinal pseudo-obstruction, and mental retardation. The McLeod syndrome may be confused with polymyositis.

Emery-Dreifuss syndrome also is inherited as an X-linked recessive condition, but autosomal dominant or recessive inheritance also is seen in a minority of patients. This disease begins in early childhood and progresses very slowly. Weakness is evident first in the legs, with later involvement of the pectoral girdle. Contractures of the elbows and heel cords are prominent, and early features and rigidity of the spine also may be present. Distal muscles are spared, and no pseudohypertrophy ensues. Atrial conduction abnormalities may occur and, ultimately, the cardiac involvement may result in sudden death. Serum CK values are elevated moderately. Scoliosis and hyperextension of the cervical vertebrae are conspicuous features in the rigid spine syndrome, a form of congenital muscular dystrophy. The gene responsible for Emery-Dreifuss syndrome at Xq28 contains only six exons and five introns. It encodes a 254-amino acid serine-rich protein called emerin, which is
localized to the inner nuclear membrane. Patients with autosomal dominant or autosomal recessive forms of Emery-Dreifuss syndrome harbor mutations in the lamin A/C gene (LMNA), which encodes lamins A and C: like emerin, both lamin A and lamin C are components of the nuclear lamina.

Myotonia is divided into two categories: progressive and nonprogressive. Myotonic dystrophy is the only progressive disorder. The nonprogressive disorders include myotonia congenita, paramyotonia, and numerous atypical myotonic disorders.

Myotonic dystrophy type 1 follows a pattern of autosomal dominant inheritance and has been subdivided into a “classical form” (Steinert disease) or dystrophia myotonica type 1 (DM-1) and two proximal myotonic dystrophy syndromes (PROMM), DM-2/PROMM and DM3/PROMM. In DM-1, gene mapping studies have localized the defect to the long arm of chromosome 19 and characterized it as an unstable CTG repeat expansion in the noncoding region of a serine-threonine protein kinase (DMPK) gene. This trinucleotide amplification correlates with the clinical phenomenon of anticipation. The clinical manifestations of myotonic dystrophy are protean, and this disorder is viewed more properly as a systemic disorder with muscle involvement. Virtually all systems are involved. Severe brain involvement may occur in the congenital form, and adults have mental deterioration. Smooth, striated, and cardiac muscle tissues are affected. Myotonia involves striated muscle and anal sphincter; smooth-muscle involvement has been seen in the gastrointestinal tract, gallbladder, uterus, ureter, and ciliary body of the eye. Endocrine disturbances include testicular tubular atrophy, pituitary dysfunction, and diabetes mellitus associated with peripheral insulin resistance. Baldness and cataracts are common manifestations, as is hypogammaglobulinemia. Cataracts are represented as multicolored subcapsular opacities visualized best by slit-lamp examination.

In virtually all affected infants with congenital myotonic dystrophy, the mother is the affected parent, despite the fact that the gene is transmitted as an autosomal dominant trait. Numerous complications of pregnancy have been recognized, including an increased rate of spontaneous abortion, reduced fetal movements, polyhydramnios, uterine inertia during labor, and postpartum hemorrhage (often associated with retained placental fragments). The neonatal mortality rate is increased, and affected infants display numerous abnormal features. Neonatal respiratory distress, paralyzed diaphragm, hypotonia, bilateral facial weakness, talipes, and delayed motor and mental retardation are common clinical features. Myotonia is conspicuously absent and is not clinically evident until later in the patient’s first decade of life. Congenital hip dislocation and hernias are the result of muscular laxity. Mild mental retardation is evident in most, if not all, affected children, and hydrocephalus has been reported in some instances. The correlation between maternal myotonic dystrophy and the congenital form of the disease is overwhelming but unexplained.

The muscle histopathology of myotonic dystrophy is distinctive. Type I fiber atrophy and centrally placed nuclei are characteristic, even in the congenital form. These and other findings suggest an arrest in muscle development: hypoplasia rather than active degeneration. Other common features include ringed fibers, sarcoplasmic masses, and nuclear chains.

Myotonic dystrophy type 2 (DM-2/PROMM) typically starts in adults and is characterized by myotonic stiffness or weakness of proximal leg muscles or finger flexors. Myalgia is a common finding; it is unrelated to exercise or to the severity of myotonia and typically fluctuates in intensity. Unlike patients with DM-1, patients with DM-2/PROMM do not show facial muscle weakness and wasting or distal limb muscle wasting. Myotonia is elicited best by percussion of forearm or thenar muscles. Cataracts are common findings. The gene defect on chromosome 3q21 is an unstable quadruplet (CCTG) repeat expansion in the gene for the zinc finger 9 protein (ZNF9). Some families with autosomal dominant inheritance of very similar symptoms and signs do not show linkage to the DM-1 or the DM-2 loci, and their gene defect is unknown: this form of myotonic dystrophy is called DM-3/PROMM.

Treatment of the various types of myotonia is directed toward their symptoms and toward the debilitating features of myotonic dystrophy specifically. The myotonia may be relieved with quinine sulfate, procainamide, or phenytoin. Patients with myotonic dystrophy need general medical supervision and support. Cardiac conduction disturbances and sensitivity to various anesthetics may be life-threatening. Medical and rehabilitative intervention, insertion of cardiac pacemakers, treatment of respiratory problems, and the use of various orthotic devices are helpful.

These clinically diverse conditions all are caused by mutations in genes encoding subunits of ion channels (sodium, calcium, or potassium) and, therefore, often are labeled collectively as channelopathies.

Many primary muscle diseases may present in early infancy, but only a few are known as congenital types of muscular dystrophy. This distinction, therefore, is arbitrary and, to some degree, confusing. The conditions discussed here are two syndromes that cause dystrophic changes in skeletal muscle, as noted by biopsy. These syndromes are distinguished by the presence or absence of nervous system pathology.

Congenital muscular dystrophy without nervous system involvement (also called classical, occidental, or pure CMD) appears to be inherited as an autosomal recessive trait, although many cases are sporadic. Affected infants are weak at birth, and often hypotonia is present, although not invariably. Similarly, joint contractures frequently accompany the weakness (arthrogryposis multiplex congenita). Respiratory difficulties may be present and largely determine the outcome. The “dystrophic” process itself is rather stationary, in part controverting the use of the term. Affected infants do reasonably well if they survive
past infancy. Weakness does not progress in any measurable way, but orthopedic complications may supervene and require therapeutic intervention.

The laboratory abnormalities are variable. CK values are elevated, but tend to decrease with time. The EMG is distinctly myopathic, and fibrillations are scarce. The muscle tissue is abnormal, with fiber diameter variability and an abundance of endomysial and perimysial connective tissue. Necrosis of single muscle fibers is a fairly unusual occurrence.

The clinical course of affected patients is influenced largely by the respiratory complications that develop. The muscle disease appears to be primarily nonprogressive in most patients, and many of these children are very bright. Aggressive support and orthopedic corrective surgery are warranted in any children who have survived past infancy.

Approximately one-half of patients with typical congenital muscular dystrophy show deficiency of laminin-2, also known as merosin, a protein that links the dystroglycan complex of the sarcolemma with the extracellular matrix (see Fig. 409.1). The dystroglycans, together with dystrophin and with the sarcoglycans, are essential in maintaining the integrity of muscle membranes during the harsh mechanical stress imposed by muscle contraction. For additional information about merosin in CMD, see Box 409.2.

Congenital muscular dystrophy with nervous system pathology has a less favorable prognosis. In Japan, the birth incidence of Fukuyama syndrome is approximately one-half that of DMD. Mothers of affected infants report decreased fetal movements, and the newborn is weak and hypotonic. Sucking efforts and crying are weak, and facial expression is decreased. The calves may be enlarged, and contractures of the knee joints and elbows are common findings; tendon reflexes are decreased or absent. Generalized convulsions may occur in one-half of affected patients, and motor retardation is evident during later development. Eventually, many children sit or crawl, but few are able to walk. Atrophy of limb muscles is increasingly evident, and most affected children die within their first decade.

The association of Fukuyama muscular dystrophy and xeroderma pigmentosum led to the identification of the locus for Fukuyama muscular dystrophy on chromosome 9q31–33. The gene has been identified, and at least two independent point mutations have been identified in affected individuals. The gene encodes a novel protein called fukutin, which is expressed in various tissues in normal individuals but not in patients in whom the mutated gene contains a retrotransposal insertion of sequences repeated in tandem.

The serum CK values are elevated ten- to 50-fold in most instances, and the EMG is distinctly myopathic. The skeletal muscle examined at biopsy is abnormal, with variation of fiber-type diameter, necrosis of fibers, scattered foci of inflammation, and increased endomysial and perimysial connective tissue. The neuropathology is equally remarkable and descriptive of altered neuronal migration and cortical sulcation. The cortex is thick and smooth, particularly in the temporal and occipital regions. These findings are indicative of lissencephaly or polymicrogyria. Reduction in central white matter and associated cerebral ventricular enlargement are evident.

Another condition combining congenital muscular dystrophy and congenital brain abnormalities is the Muscle-Eye-Brain disease (MEB), first described in Finland, where the disease is encountered most frequently. Patients have congenital hypotonia, mental retardation, and visual failure, including severe progressive myopia, retinal degeneration, and optic atrophy. Seizures are common manifestations. Dystrophic changes occur in muscle, with normal immunohistochemistry for dystrophin but often secondary partial defect of laminin alpha-2. Brain abnormalities include cobblestone lissencephaly, frontal pachygyria, and occipital micropolygyria. White matter is affected minimally. After the locus for MEB was assigned to chromosome 1p32–34 by linkage analysis and homozygosity mapping, mutations were identified in a gene (POMGnT1) that encodes a glycosyltransferase. A third condition, clinically similar to MEB, is Walker-Warburg Syndrome (WWS; MIM 236670). WWS is inherited as an autosomal recessive trait and characterized clinically by ocular abnormalities, muscular dystrophy, and severe neuronal migration defects. The condition results from mutations in the O-mannosyltransferase gene POMT1. These recent studies suggest that glycosylation defects are important causes of congenital muscular dystrophies and that overexpression of the gene LARGE, which encodes a glycosyltransferase, can circumvent the defective glycosylation of alpha-dystroglycan in cells from patients. This observation opens new vistas on therapeutic approaches.

In 1954, Walton and Nattrass introduced the term limb-girdle muscular dystrophy to describe, in a number of patients, a disorder that did not fulfill the clinical criteria for DMD or FSH dystrophy. Affected patients were of both genders, often were in middle to late childhood, and had serum enzyme, EMG, and skeletal muscle biopsy abnormalities of the type commonly encountered in patients with a muscular dystrophy.
This large and ill-defined group of patients has been subdivided into 15 entities associated with specific gene defects. The conventional nomenclature assigns the number 1 (LGMD1) to the forms transmitted by autosomal dominant inheritance and the number 2 (LGMD2) to the autosomal recessive forms. The capital letters that follow (LGMD1A-E and LMGD2A-J) identify specific gene defects (Table 409.2). Figure 409.1 shows the proteins involved in these and other muscular dystrophies. Although LGMDs traditionally are considered diseases of adults, many of them can start in childhood and are outlined in Table 409.2.