Clinical Manifestations

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.

Death occurs usually at about 18-20 yr of age. The causes of death are respiratory failure in sleep, intractable heart failure, pneumonia, or occasionally aspiration and airway obstruction.

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.

Laboratory Findings

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.

Electromyography (EMG) shows characteristic myopathic features but is not specific for DMD. No evidence of denervation is found. Motor and sensory nerve conduction velocities are normal.

Diagnosis

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.

Genetic Etiology and Pathogenesis

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.

Treatment

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.

Other treatment of patients with DMD involves the use of prednisone, prednisolone, deflazacort, or other steroids. Glucocorticoids decrease the rate of apoptosis or programmed cell death of myotubes during ontogenesis and can decelerate the myofiber necrosis in muscular dystrophy. Strength usually improves initially, but the long-term complications of chronic steroid therapy, including considerable weight gain and osteoporosis, can offset this advantage or even result in greater weakness than might have occurred in the natural course of the disease. Nevertheless, some patients with DMD treated early with steroids appear to have an improved long-term prognosis as well as the short-term improvement, and steroids can help keep patients ambulatory for more years than expected without treatment. One protocol gives prednisone (0.75 mg/kg/day) for the first 10 days of each month to avoid chronic complications. Fluorinated steroids, such as dexamethasone or triamcinolone, should be avoided because they induce myopathy by altering the myotube abundance of ceramide. The American Academy of Neurology and the Child Neurology Society recommend administering corticosteroids during the ambulatory stage of the disease.

Another potential treatment still under investigation is the intramuscular injection of antisense oligonucleotide drugs that induce exon skipping during mRNA splicing to restore the open reading frame in the DMD gene. Stem cell implantation or activation in muscle was theoretically plausible but has not proved practical.

Clinical Manifestations

In the usual clinical course, excluding the severe neonatal form, infants can appear almost normal at birth, or facial wasting and hypotonia can already be early expressions of the disease. The facial appearance is characteristic, consisting of an inverted V-shaped upper lip, thin cheeks, and scalloped, concave temporalis muscles (Fig. 601-4). The head may be narrow, and the palate is high and arched because the weak temporal and pterygoid muscles in late fetal life do not exert sufficient lateral forces on the developing head and face.

Figure 601-4 Facial weakness, inverted V-shaped upper lip, and loss of muscle mass in the temporal fossae are characteristic of myotonic muscular dystrophy, even in infancy, as seen in this 8 mo old girl.

Weakness is mild in the first few years. Progressive wasting of distal muscles becomes increasingly evident, particularly involving intrinsic muscles of the hands. The thenar and hypothenar eminences are flattened, and the atrophic dorsal interossei leave deep grooves between the fingers. The dorsal forearm muscles and anterior compartment muscles of the lower legs also become wasted. The tongue is thin and atrophic. Wasting of the sternocleidomastoids gives the neck a long, thin, cylindrical contour. Proximal muscles also eventually undergo atrophy, and scapular winging appears. Difficulty with climbing stairs and Gowers sign are progressive. Tendon stretch reflexes are usually preserved.

The distal distribution of muscle wasting in myotonic dystrophy is an exception to the general rule of myopathies having proximal and neuropathies having distal distribution patterns. The muscular atrophy and weakness in myotonic dystrophy are slowly progressive throughout childhood and adolescence and continue into adulthood. It is rare for patients with myotonic dystrophy to lose the ability to walk even in late adult life, although splints or bracing may be required to stabilize the ankles.

Myotonia, a characteristic feature shared by few other myopathies, does not occur in infancy and is usually not clinically or even electromyographically evident until about age 5 yr. Exceptional patients develop it as early as age 3 yr. Myotonia is a very slow relaxation of muscle after contraction, regardless of whether that contraction was voluntary or was induced by a stretch reflex or electrical stimulation. During physical examination, myotonia may be demonstrated by asking the patient to make tight fists and then to quickly open the hands. It may be induced by striking the thenar eminence with a rubber percussion hammer, and it may be detected by watching the involuntary drawing of the thumb across the palm. Myotonia can also be demonstrated in the tongue by pressing the edge of a wooden tongue blade against its dorsal surface and by observing a deep furrow that disappears slowly. The severity of myotonia does not necessarily parallel the degree of weakness, and the weakest muscles often have only minimal myotonia. Myotonia is not a painful muscle spasm. Myalgias do not occur in myotonic dystrophy.

The speech of patients with myotonic dystrophy is often articulated poorly and is slurred because of the involvement of the muscles of the face, tongue, and pharynx. Difficulties with swallowing sometimes occur. Aspiration pneumonia is a risk in severely involved children. Incomplete external ophthalmoplegia sometimes results from extraocular muscle weakness.

Smooth muscle involvement of the gastrointestinal tract results in slow gastric emptying, poor peristalsis, and constipation. Some patients have encopresis associated with anal sphincter weakness. Women with myotonic dystrophy can have ineffective or abnormal uterine contractions during labor and delivery.

Cardiac involvement is usually manifested as heart block in the Purkinje conduction system and arrhythmias rather than as cardiomyopathy, unlike most other muscular dystrophies.

Endocrine abnormalities involve many glands and appear at any time during the course of the disease so that endocrine status must be re-evaluated annually. Hypothyroidism is common; hyperthyroidism occurs rarely. Adrenocortical insufficiency can lead to an addisonian crisis even in infancy. Diabetes mellitus is common in patients with myotonic dystrophy; some children have a disorder of insulin release rather than defective insulin production. Onset of puberty may be precocious or, more often, delayed. Testicular atrophy and testosterone deficiency are common in adults and are responsible for a high incidence of male infertility. Ovarian atrophy is rare. Frontal baldness is also characteristic in male patients and often begins in adolescence.

Immunologic deficiencies are common in myotonic dystrophy. The plasma immunoglobulin (Ig)G level is often low.

Cataracts often occur in myotonic dystrophy. They may be congenital, or they can begin at any time during childhood or adult life. Early cataracts are detected only by slit-lamp examination; periodic examination by an ophthalmologist is recommended. Visual evoked potentials are often abnormal in children with myotonic dystrophy and are unrelated to cataracts. They are not usually accompanied by visual impairment.

About half of the patients with myotonic dystrophy are intellectually impaired, but severe mental retardation is unusual. The remainder are of average or occasionally above-average intelligence. Epilepsy is not common. Cognitive impairment and mental retardation might result from accumulations of mutant DMPK mRNA and aberrant alternative splicing in cerebral cortical neurons.

A severe congenital form of myotonic dystrophy appears in a minority of involved infants born to mothers with symptomatic myotonic dystrophy. All patients with this severe congenital disease to date have had the DM1 form. Clubfoot deformities alone or more extensive congenital contractures of many joints can involve all extremities and even the cervical spine. Generalized hypotonia and weakness are present at birth. Facial wasting is prominent. Infants can require gavage feeding or ventilator support for respiratory muscle weakness or apnea. Those requiring ventilation for <30 days often survive, and those with prolonged ventilation have an infant mortality of 25%. Children ventilated for <30 days have better motor, language, and daily activity skills than those requiring prolonged ventilation. One or both leaves of the diaphragm may be nonfunctional. The abdomen becomes distended with gas in the stomach and intestine because of poor peristalsis from smooth muscle weakness. The distention further compromises respiration. Inability to empty the rectum can compound the problem.

Laboratory Findings

The classic myotonic electromyogram is not found in infants but can appear in toddlers or children in the early school years. The levels of serum CK and other serum enzymes from muscle may be normal or only mildly elevated in the hundreds (never the thousands).

ECG should be performed annually in early childhood. Ultrasound imaging of the abdomen may be indicated in affected infants to determine diaphragmatic function. Radiographs of the chest and abdomen and contrast studies of GI motility may be needed.

Endocrine assessment should be undertaken to determine thyroid and adrenal cortical function and to verify carbohydrate metabolism (glucose tolerance test). Immunoglobulins should be examined, and, if needed, more extensive immunologic studies should be performed.

Diagnosis

The primary diagnostic test is a DNA analysis of blood to demonstrate the abnormal expansion of the CTG repeat. Prenatal diagnosis also is feasible. The muscle biopsy specimen in older children shows many muscle fibers with central nuclei and selective atrophy of histochemical type I fibers, but degenerating fibers are usually few and widely scattered, and there is little or no fibrosis of muscle. Intrafusal fibers of muscle spindles are also abnormal. In young children with the common form of the disease, the biopsy specimen can even appear normal or at least not show myofiber necroses, which is a striking contrast with DMD. In the severe neonatal form of myotonic dystrophy, the muscle biopsy reveals maturational arrest in various stages of development in some and congenital muscle fiber-type disproportion in others. It is likely that the sarcolemmal membrane of muscle fibers not only has abnormal properties of electrical polarization but is also incapable of responding to trophic influences of the motor neuron. Muscle biopsy is not usually required for diagnosis, which in typical cases can be based on the clinical manifestations including family history. Neonatal myotonic dystrophy must be distinguished from amyoplasia, congenital muscular dystrophy with or without merosin expression, congenital myasthenia gravis, spinal muscular atrophy, and arthrogryposis secondary to oligohydramnios.

Genetics

The genetic defect in myotonic muscular dystrophy is on chromosome 19 at the 19q13 locus. It consists of an expansion of the DM gene that encodes a serine-threonine kinase (DMPK), with numerous repeats of the CTG codon. Expansions range from 50 to >2,000, with the normal alleles of this gene ranging in size from 5-37; the larger the expansion, the more severe the clinical expression, with the largest expansions seen in the severe neonatal form. Rarely, the disease is associated with no detectable repeats, perhaps a spontaneous correction of a previous expansion but a phenomenon still incompletely understood. Another myotonic dystrophy (PROMM) is a clinical entity linked to at least 2 different chromosomal loci than classic myotonic dystrophy but 1 that shares a common unique pathogenesis in being mediated by a mutant mRNA. Defects in RNA splicing explain the insulin resistance in myotonic dystrophies as well as the myotonia.

Clinical and genetic expression can vary between siblings or between an affected parent and child. In the severe neonatal form of the disease, the mother is the transmitting parent in 94% of cases, a fact not explained by increased male infertility alone. Several cases of paternal transmission have been reported. Genetic analysis reveals that symptomatic neonates usually have many more repeats of the CTG codon than do patients with the more classic form of the disease, regardless of which parent is affected. Myotonic dystrophy often exhibits a pattern of anticipation in which each successive generation has a tendency to be more severely involved than the previous generation. Prenatal genetic diagnosis of myotonic dystrophy is available.

Treatment

There is no specific medical treatment, but the cardiac, endocrine, GI, and ocular complications can often be treated. Physiotherapy and orthopedic treatment of contractures in the neonatal form of the disease may be beneficial.

Myotonia may be diminished, and function may be restored by drugs that raise the depolarization threshold of muscle membranes, such as mexiletine, phenytoin, carbamazepine, procainamide, and quinidine sulfate. These drugs also have cardiotropic effects; thus, cardiac evaluation is important before prescribing them. Phenytoin and carbamazepine are used in doses similar to their use as anticonvulsants (Chapter 586.6); serum concentrations of 10-20 µg/mL for phenytoin and 5-12 µg/mL for carbamazepine should be maintained. If a patient’s disability is caused mainly by weakness rather than by myotonia, these drugs will be of no value.

Other Myotonic Syndromes

Most patients with myotonia have myotonic dystrophy. However, myotonia is not specific for this disease and occurs in several rarer conditions.

Myotonic chondrodystrophy (Schwartz-Jampel disease) is a rare congenital disease characterized by generalized muscle hypertrophy and weakness. Dysmorphic phenotypical features and the radiographic appearance of long bones are reminiscent of Morquio disease (Chapter 82), but abnormal mucopolysaccharides are not found. Dwarfism, joint abnormalities, and blepharophimosis are present. Several patients have been the products of consanguinity, suggesting autosomal recessive inheritance. The muscle protein perlecan, encoded by the SJS1 gene, a large heparan sulfate proteoglycan of basement membranes and cartilage, is defective in some cases of Schwartz-Jampel disease and explains both the muscular hyperexcitability and the chondrodysplasia.

EMG reveals continuous electrical activity in muscle fibers closely resembling or identical to myotonia. Muscle biopsy reveals nonspecific myopathic features, which are minimal in some cases and pronounced in others. The sarcotubular system is dilated.

Myotonia congenita (Thomsen disease) is a channelopathy (Table 601-1) and is characterized by weakness and generalized muscular hypertrophy so that affected children resemble bodybuilders. Myotonia is prominent and can develop at age 2-3 yr, earlier than in myotonic dystrophy. The disease is clinically stable and is apparently not progressive for many years. Muscle biopsy specimens show minimal pathologic changes, and the EMG demonstrates myotonia. Various families are described as showing either autosomal dominant (Thomsen disease) or recessive (Becker disease, not to be confused with BMD or DMD) inheritance. Rarely, myotonic dystrophy and myotonia congenita coexist in the same family. The autosomal dominant and autosomal recessive forms of myotonia congenita have been mapped to the same 7q35 locus. This gene is important for the integrity of chloride channels of the sarcolemmal and T-tubular membranes.

Paramyotonia is a temperature-related myotonia that is aggravated by cold and alleviated by warm external temperatures. Patients have difficulty when swimming in cold water or if they are dressed inadequately in cold weather. Paramyotonia congenita (Eulenburg disease) is a defect in a gene at the 17q13.1-13.3 locus, the identical locus identified in hyperkalemic periodic paralysis. By contrast with myotonia congenita, paramyotonia is a disorder of the voltage-gated sodium channel caused by a mutation in the α subunit. Myotonic dystrophy also is a sodium channelopathy (see Table 601-1).

In sodium channelopathies, exercise produces increasing myotonia, whereas in chloride channelopathies, exercise reduces the myotonia. This is easily tested during examination by asking patients to close the eyes forcefully and open them repeatedly; it becomes progressively more difficult in sodium channel disorders and progressively easier in chloride channel disorders.

Clinical Manifestations

Facioscapulohumeral dystrophy shows the earliest and most severe weakness in facial and shoulder girdle muscles. The facial weakness differs from that of myotonic dystrophy; rather than an inverted V-shaped upper lip, the mouth in facioscapulohumeral dystrophy is rounded and appears puckered because the lips protrude. Inability to close the eyes completely in sleep is a common expression of upper facial weakness; some patients have extraocular muscle weakness, although ophthalmoplegia is rarely complete. Facioscapulohumeral dystrophy has been associated with Möbius syndrome on rare occasions. Pharyngeal and tongue weakness may be absent and are never as severe as the facial involvement. Hearing loss, which may be subclinical, and retinal vasculopathy (indistinguishable from Coats disease) are associated features, particularly in severe cases of facioscapulohumeral dystrophy with early childhood onset.

Scapular winging is prominent, often even in infants. Flattening or even concavity of the deltoid contour is seen, and the biceps and triceps brachii muscles are wasted and weak. Muscles of the hip girdle and thighs also eventually lose strength and undergo atrophy, and Gowers sign and a Trendelenburg gait appear. Contractures of the extremities are rare. Finger and wrist weakness occasionally is the first symptom. Weakness of the anterior tibial and peroneal muscles can lead to footdrop; this complication usually occurs only in advanced cases with severe weakness. Lumbar lordosis and kyphoscoliosis are common complications of axial muscle involvement. Calf pseudohypertrophy is not a usual feature but is described rarely.

Facioscapulohumeral muscular dystrophy can also be a mild disease causing minimal disability. Clinical manifestations might not be expressed in childhood and are delayed into middle adult life. Unlike most other muscular dystrophies, asymmetry of weakness is common. About 30% of affected patients are asymptomatic or show only mild scapular winging and decreased tendon stretch reflexes, of which they were unaware until formal neurologic examination was performed.

Laboratory Findings

Serum levels of CK and other enzymes vary greatly, ranging from normal or near normal to elevations of several thousand. ECG should be performed, although the anticipated findings are usually normal. EMG reveals nonspecific myopathic muscle potentials. Diagnostic molecular testing in individual cases and within families is indicated for prediction.

Diagnosis and Differential Diagnosis

Muscle biopsy distinguishes more than one form of facioscapulohumeral dystrophy, consistent with clinical evidence that several distinct diseases are embraced by the term FSH dystrophy. Muscle biopsy and EMG also distinguish the primary myopathy from a neurogenic disease with a similar distribution of muscular involvement. The general histopathologic findings in the muscle biopsy material are extensive proliferation of connective tissue between muscle fibers, extreme variation in fiber size with many hypertrophic as well as atrophic myofibers, and scattered degenerating and regenerating fibers. An “inflammatory” type of facioscapulohumeral muscular dystrophy is also distinguished, characterized by extensive lymphocytic infiltrates within muscle fascicles. Despite the resemblance of this form to inflammatory myopathies, such as polymyositis, there is no evidence of autoimmune disease, and steroids and immunosuppressive drugs do not alter the clinical course. A precise histopathologic diagnosis has important therapeutic implications. Mononuclear cell “inflammation” in a muscle biopsy sample of infants <2 yr old is usually facioscapulohumeral dystrophy or, less often, a congenital muscular dystrophy.

Treatment

Physiotherapy is of no value in regaining strength or in retarding progressive weakness or muscle wasting. Foot drop and scoliosis may be treated by orthopedic measures. In selected cases, surgical wiring of the scapulas to the thoracic wall provides improved shoulder stability and abduction of the arm, but brachial plexopathy, frozen shoulder, and scapular fractures are reported complications. Cosmetic improvement of the facial muscles of expression may be achieved by reconstructive surgery, which grafts a fascia lata to the zygomatic muscle and to the zygomatic head of the quadratus labiae superioris muscle. Exercise of facial muscles can help minimize secondary disuse atrophy. No effective pharmacologic treatment is available.

Clinical Manifestations

Infants often have contractures or arthrogryposis at birth and are diffusely hypotonic. The muscle mass is thin in the trunk and extremities. Head control is poor. Facial muscles may be mildly involved, but ophthalmoplegia, pharyngeal weakness, and weak sucking are not common. A minority have severe dysphagia and require gavage or gastrostomy. Tendon stretch reflexes may be hypoactive or absent. Arthrogryposis is common in all forms of congenital muscular dystrophy (Chapter 600.10). Congenital contractures of the elbows have a high association with the Ullrich type of congenital muscular dystrophy owing to a defect in 1 or more of the 3 collagen VI genes, each at a different locus.

The Fukuyama type of congenital muscular dystrophy is the second most common muscular dystrophy in Japan (after DMD); it has also been reported in children of Dutch, German, Scandinavian, and Turkish ethnic backgrounds. In the Fukuyama variety, severe cardiomyopathy and malformations of the brain usually accompany the skeletal muscle involvement. Signs and symptoms related to these organs are prominent: cardiomegaly and heart failure, mental retardation, seizures, microcephaly, and failure to thrive. The genetic defect in Fukuyama congenital muscular dystrophy has been identified at the 8q31-33 locus in Japanese patients.

Central neurologic disease can accompany forms of congenital muscular dystrophy other than Fukuyama disease. Mental and neurologic status are the most variable features; an apparently normal brain and normal intelligence do not preclude the diagnosis if other manifestations indicate this myopathy. The cerebral malformations that occur are not consistently of one type and vary from severe dysplasias (holoprosencephaly, lissencephaly) to milder conditions (agenesis of the corpus callosum, focal heterotopia of the cerebral cortex and subcortical white matter, cerebellar hypoplasia).

Congenital muscular dystrophy is a consistent association with cerebral dysgenesis in the Walker-Warburg syndrome and in muscle-eye-brain disease of Santavuori. The neuropathologic findings are those of neuroblast migratory abnormalities in the cerebral cortex, cerebellum, and brainstem. Mutations in genes of O-mannosylation of α-dystroglycan (POMT1 and POMGnT1), essential for neuroblast migration in the fetal brain, have been demonstrated. Studies indicate considerably more genetic overlap between Walker-Warburg, Fukuyama, and muscle-eye-brain forms of congenital muscular dystrophy that explain mixed and transitional phenotypes, so that, for example, the Fukutin (FKRP) gene can cause a Walker-Warburg or muscle-eye-brain presentation, or POMGnT1 also can produce phenotypes other than classic Walker-Warburg disease.

Another separate form of congenital muscular dystrophy is characterized by microcephaly and mental retardation.

Laboratory Findings

Serum CK level is usually moderately elevated from several hundred to many thousand IU/L; only marginal increases are sometimes found. EMG shows nonspecific myopathic features. Investigation of all forms of congenital muscular dystrophy should include cardiac assessment and an imaging study of the brain. Muscle biopsy is essential for the diagnosis.

Diagnosis

Muscle biopsy is diagnostic in the neonatal period or thereafter. An extensive proliferation of endomysial collagen envelops individual muscle fibers even at birth, also causing them to be rounded in cross-sectional contour by acting as a rigid sleeve, especially during contraction. The perimysial connective tissue and fat are also increased, and the fascicular organization of the muscle may be disrupted by the fibrosis. Tissue cultures of intramuscular fibroblasts exhibit increased collagen synthesis, but the structure of the collagen is normal. Muscle fibers vary in diameter, and many show central nuclei, myofibrillar splitting, and other cytoarchitectural alterations. Scattered degenerating and regenerating fibers are seen. No inflammation or abnormal inclusions are found.

Immunocytochemical reactivity for merosin (α₂ chain of laminin) at the sarcolemmal region is absent in about 40% of cases and normally expressed in the others (Figs. 601-5 and 601-6). Merosin is a protein that binds the sarcolemmal membrane of the myofiber to the basal lamina or basement membrane. Its defect is a mutation of the LAMA2 gene at the 6q22-q23 locus. Merosin also is expressed in brain and in Schwann cells. The presence or absence of merosin does not always correlate with the severity of the myopathy or predict its course, but cases with merosin deficiency tend to have more severe cerebral involvement and myopathy. Adhalen (α-dystroglycan) may be secondarily reduced in some cases. Collagen VI is selectively reduced or absent in Ullrich disease because of a mutation in the COL6A gene. Mitochondrial dysfunction may be a secondary defect.

Figure 601-5 Quadriceps femoris muscle biopsy of a 6 mo old girl with congenital muscular dystrophy associated with merosin (α₂-laminin) deficiency. A, Histologically, the muscle is infiltrated by a great proliferation of collagenous connective tissue; myofibers vary in diameter, but necrotic fibers are rare. B, Immunocytochemical reactivity for merosin (α₂-laminin) is absent in all fibers, including the intrafusal myofibers of a muscle spindle seen at bottom. C, Dystrophin expression (rod domain) is normal. Compare with Figures 601-2, 601-3, and 601-6.

Figure 601-6 Quadriceps femoris muscle biopsy specimen of a 2 yr old girl with congenital muscular dystrophy. A, The fascicular architecture of the muscle is severely disrupted, and muscle is replaced by fat and connective tissue; the remaining small groups of myofibers of variable size are seen, including a muscle spindle at top. B, Merosin expression is normal in both extrafusal fibers of all sizes and in intrafusal spindle fibers. The severity of the myopathy does not relate to the presence or absence of merosin in congenital muscular dystrophy. Compare with Figure 601-5.

Treatment

Only supportive therapy is available in general. Cyclosporin A might correct the mitochondrial dysfunction and muscular apoptosis in collagen VI myopathy.