Duchenne Muscular Dystrophy

Even in the severe variety of DMD, affected children are normal at birth. During the second year when the boys begin walking, the clumsiness seen in all toddlers persists. Soon the children have to place one hand on the knee to assume an upright position when rising from the floor (Gower maneuver). Often at this stage, the calf muscles are rather firm and rubbery (pseudohypertrophy) (Fig. 79.9). Within 2 to 3 years, parents notice that the child runs properly and is never able to jump clear of the floor with both feet. In the absence of therapy, tightness across several joints in the legs is noted. The iliotibial bands and the heel cords are usually the first to become tight. This is particularly noticeable in boys who habitually walk on their toes.

Fig. 79.9 Duchenne muscular dystrophy. Calf and thigh hypertrophy in an ambulatory 8-year-old patient.

By 5 or 6 years of age, labored stair climbing is the rule, and moving upward requires use of the railing. Sometime between the ages of 2 and 6, there will be a period of apparent improvement when the child gains motor skills. This is illusory because it simply represents the child’s natural development, which muscle weakness has not yet outpaced. At the age of 6 or 7, the boys often complain of sudden spontaneous falls. At first, these falls occur when the child is in a hurry or knocked off balance by playmates. The fall is quite spectacular to the onlooker; the knees collapse abruptly, and the child drops like a stone to the ground. At approximately 8 to 10 years of age, affected children cease to be able to climb stairs or stand up from the floor, and it is at approximately this time when they begin using a wheelchair for locomotion. Earlier studies suggested that these children began using a wheelchair and lost the ability to walk at about age 9, but in a population treated with bracing, reconstructive surgery, and physiotherapy, the average age of confinement to a wheelchair was 12.2 years. The true natural history of the disease is difficult to ascertain because many physicians and parents put considerable effort into keeping the children straight and the limbs supple.

Contractures of the hips, knees, and ankles become severe when the relatively untreated child spends much of the day in a wheelchair. The hips and knees lock at 90 degrees, and the feet turn downward and inward in an exaggerated position of equinovarus. It is very difficult to get normal shoes to fit them, and it is impossible for them to sleep except in one position: usually with the knees propped up with pillows and slightly turned on one side. Handling the children at this stage becomes very difficult, and back pain and limb pain almost inevitably accompany this severe stage of muscular dystrophy. Development of a severe scoliosis compromises respiratory function.

Characteristic cardiac involvement is degeneration and fibrosis of the posterolateral wall of the left ventricle. Besides the abnormal electrocardiogram (ECG), valve motion, wall thickness, and wall motion are also abnormal. Affected children die from either respiratory failure or a cardiomyopathy that is relatively resistant to treatment.

The least invasive test to confirm the diagnosis is to obtain DNA studies looking for a deletion in the dystrophin gene. In the 30% of patients without a deletion, a muscle biopsy is necessary to establish the absence of dystrophin. Three antibodies are available against the ends (Dys-2 for the carboxyl terminus and Dys-3 for the amino terminus) and the rod region (Dys-1) of the molecule. Absence of the amino terminus, the end that binds with actin, appears to be associated with the more severe symptoms. In dystrophin deficiency, the protein is absent or the stain is irregular and fragmented. Approximately 1% of fibers demonstrate a rim of dystrophin. These are the revertant fibers, in which the gene has undergone another mutation, putting the coding sequence back in-frame. Where doubt exists, immunoblotting shows a decreased amount of dystrophin in the tissue.

The serum concentration of creatine kinase (CK) is markedly elevated in this illness; levels greater than 10,000 mU/mL are common. Electromyography (EMG) shows myopathic changes (see Chapter 32B), and muscle biopsy demonstrates variation in the size of fibers, fibrosis, groups of basophilic fibers, and opaque or hypercontracted fibers (hyaline fibers) (Figs. 79.10 to 79.12).

Fig. 79.10 Duchenne muscular dystrophy: change in serum creatine kinase (CK) level with age. This is a scattergram of serum CK levels in individual patients. Lines represent the 5th, 25th, 50th, 75th, and 95th percentiles.

Fig. 79.11 Duchenne muscular dystrophy: muscle biopsy. Fibers are of variable size and separated by connective tissue. Large heavily stained opaque fibers are noted (Verhoeff-Van Gieson stain).

Fig. 79.12 Duchenne muscular dystrophy. Groups of small basophilic (darkly staining) fibers are scattered in the biopsy (hematoxylin and eosin stain).

Becker Muscular Dystrophy

BMD shares all the clinical characteristics of the severe form of DMD but has a milder course. The disease begins in the first decade, although parents often notice the first signs of weakness later because of the milder symptoms. Occasionally, symptom onset is delayed until the fourth decade or later. The muscular hypertrophy, contractures, and pattern of weakness are similar to that seen in DMD. These boys, however, continue to walk independently past the age of 15 years and may not use a wheelchair until they are in their 20s or even later. Frequent complaints in teenagers with BMD are leg cramps and other muscle pains, which are often associated with exercise and are more severe than in DMD. A significant proportion of these patients have a cardiomyopathy that can be more disabling than the weakness. Cardiac transplantation has been very successful in some patients with this form of the illness.

As with DMD, serum CK levels are elevated but not typically as high. EMG demonstrates myopathic features. These abnormalities are nonspecific, however, and diagnosis requires demonstration of a mutation in the dystrophin gene or reduced quantity or size of dystrophin on muscle biopsy. Immunostaining of muscle tissue with Dys 1, Dys 2, and Dys 3 antibodies may or may not demonstrate an abnormal staining pattern. Therefore, definitive diagnosis often requires quantitation of the dystrophin in the muscle with immunoblot (Western blot) studies.

Because boys do not have much trouble in the first few years, there is a reduced need for aggressive physiotherapy, surgical reconstruction, and night splints. Patients with BMD are less prone to develop kyphoscoliosis, perhaps because they lack wheelchair confinement until after the spine has become fully mature. We have used corticosteroids only occasionally in patients with BMD. The stabilizing effect of steroids is less noticeable when the disease is already fairly stable. In every other respect, including bracing and genetic counseling, disease treatment is the same as that for the severe form.

Other Phenotypes Associated with Dystrophinopathy

With the development of genetic testing and dystrophin analysis, it is becoming clear that dystrophin deficiency is not always associated with the BMD or DMD phenotype. Some patients have only symptoms of exercise intolerance, muscle pain, and myoglobinuria. Others manifest only a cardiomyopathy or are asymptomatic despite elevated serum concentrations of CK.

It is impractical to perform genetic testing on all patients with neuromuscular complaints. However, the presence of muscle pain, mild weakness, an elevated serum CK, and large muscles warrants an analysis of dystrophin and its associated proteins. Attempts to correlate the genetic abnormality with the clinical picture are inexact, but abnormalities in the amino terminus and at the carboxyl terminal domains of dystrophin are associated with the more severe form of disease. Alterations in the rod domain are more variable and may be associated with a mild phenotype. In-frame deletions and insertions are associated with a much milder phenotype than out-of-frame alterations.

Genetic Counseling

Because DMD is an X-linked recessive disorder, we recommend ascertainment of the carrier state of all women related to an affected person by maternal linkage. Up to 30% of cases may be sporadic and due to new mutations or deletions. In the experience of many clinicians, an even higher percentage of new patients arriving in the clinic are sporadic cases, perhaps because genetic counseling is widely available and the women who carry the abnormal gene decide not to have children.

Most female carriers are asymptomatic, but approximately 8% manifest weakness and have a clinical phenotype similar to BMD. Manifesting carriers will usually have an elevated serum CK level and myopathic EMG. Muscle biopsy will usually demonstrate a mosaic pattern or patchy staining of dystrophin on the sarcolemma. However, these laboratory tests and muscle biopsy are insensitive in diagnosing carrier status in asymptomatic females, and diagnosis of carrier status requires genetic studies.

Genetic analysis of all potential carriers is advisable. In a family in which the disease is associated with a deletion, there is little problem in determining whether the woman is carrying the affected X chromosome, using techniques that are presently available. Genetics laboratories now have the ability to identify the presence of a mutant gene over the background contributed by the normal allele. This involves an analysis of the gene “dosage,” comparing two normal alleles that have a double dose against a deleted allele and a normal allele that have a single dose (Voskova-Goldman et al., 1997). The basis for current diagnosis of carrier status after identification of a deletion in a proband is by analysis of a gene dosage. Our diagnostic strategy uses fluorescence in situ hybridization (FISH) to detect female carriers with major deletions in the dystrophin gene. Unfortunately, situations exist in which a mutation is identified in a boy with “sporadic” DMD but not in the mother, and yet the mother is still a carrier. This occurrence is secondary to germline mosaicism in which the mutation in the mother lies only in a percentage of her oocytes. The estimated recurrence rate of DMD is as high as 14% even in such cases. Prenatal diagnosis using amniotic cells or chorionic villus biopsies can identify the affected fetus and, more importantly, those who are unaffected.

Autosomal Dominant Limb-Girdle Muscular Dystrophies

Myofibrillar Myopathy

The characteristic pathological finding in myofibrillar myopathy (MFM) is myofibrillary disruption on EM and excessive desmin accumulation in muscle fibers on immunostains (Amato et al., 1998; Dalakas et al., 2000; DeBleecker et al., 1996; Nakano et al., 1996, 1997). Desmin is not the only protein accumulating, however, so myofibrillar myopathy is the preferred term. This myopathy has been reported as desmin storage myopathy, desmin myopathy, familial desminopathy, spheroid body myopathy, cytoplasmic body myopathy, Mallory body myopathy, reducing body myopathy, familial cardiomyopathy with subsarcolemmal vermiform deposits, myopathy with intrasarcoplasmic accumulation of dense granulofilamentous material, Markesbery-Griggs myopathy, and hereditary inclusion body myopathy (hIBM) with early respiratory failure (Amato et al., 1998). The original classification of many such disorders was as forms of congenital myopathy, but it is now clear that MFM is a muscular dystrophy.

A spectrum of clinical phenotypes is associated with MFM (Amato et al., 1998). Most patients develop weakness between 25 and 45 years of age, but onset can occur from infancy to late adulthood. Either cardiac or skeletal muscles can be involved and dominate the clinical picture. Limb weakness can be predominantly distal and affect either the arms or the legs, but in others, proximal muscles are involved more than distal muscles. Facial and pharyngeal muscles are also affected. Some patients have a facioscapulohumeral or scapuloperoneal distribution of weakness.

The cardiomyopathy may manifest as arrhythmias or conduction defects as well as congestive heart failure. Pacemaker insertion or cardiac transplantation may be required. Severe respiratory muscle weakness can also complicate MFM. In addition, there are rare reports of smooth muscle involvement leading to intestinal pseudo-obstruction.

Muscle histology demonstrates variability in fiber size, increased central nuclei, and occasionally type 1 fiber predominance (Amato et al., 1998; DeBleecker et al., 1996; Nakano et al., 1996, 1997). Muscle fibers with rimmed vacuoles may also be evident. Two major types of lesions are evident on light and EM: hyaline structures and nonhyaline lesions. The hyaline structures are cytoplasmic granular inclusions that are typically eosinophilic on hematoxylin and eosin, and dark blue-green or occasionally red on modified Gomori trichrome stains. They appear as cytoplasmic bodies, spheroid bodies, or Mallory bodies on EM. The nonhyaline lesions appear as dark green areas of amorphous material on Gomori trichrome stains. On EM, these nonhyaline lesions correspond to foci of myofibrillar destruction and consist of disrupted myofilaments, Z-disc-derived bodies, dappled dense structures of Z-disc origin, and streaming of the Z-disc. Immunohistochemistry reveals that both the hyaline and nonhyaline lesions contain desmin, myotilin, and numerous other proteins (Amato et al., 1998; DeBleecker et al., 1996; Nakano et al., 1996, 1997). Interestingly, abnormal muscle fibers also abnormally express several cyclin-dependent kinases in the cytoplasm, including CDC2, CDK2, CDK4, and CDK7 (Amato et al., 1998).

The pathogenesis of MFM is multifactorial (Selcen et al., 2004). Mutations in the myotilin gene on chromosome 5q22-31 cause many autosomal dominant cases. They are thus allelic to LGMD1A (Selcen and Engel, 2004). Mutations in the ZASP gene (chromosome 10 q22.3-10q23.2) cause other autosomal dominant cases (also known as Markesbery-Griggs distal myopathy) (Selcen and Engel, 2005). Less common mutations have been identified in the genes that encode for desmin, αB-crystallin, filamin C, selenoprotein N, Bag-3, and four-and-a-half LIM domain 1 (FHL-1). Of note, almost all of these proteins are important in the formation and stabilization of the Z-disc.

Laminin-α₂ (Merosin) Deficiency

Laminin-α₂, also known as merosin, is one of a large family of glycosylated proteins found in the basement membrane. It is made of three dissimilar chains: α₂, β₁, and γ₁. The amino termini separate to form a cross-like structure, and the other end of the molecule attaches to the dystroglycan complex. In humans, a gene on chromosome 6 codes merosin. Laminin-α₂ is in muscle, skin, and peripheral nerves.

The hallmark of merosinopathy includes severe weakness of the trunk and limbs and hypotonia at birth, sparing the extraocular muscles and face. Prominent contractures of the feet and hips are present. Although intelligence is often normal, the incidence of epilepsy is 12% to 20%. MRI of the brain often reveals increased signal in the white matter on T2-weighted images. Computed tomography (CT) of the head reveals lucencies of the white matter. For the most part, these children are severely disabled, and many remain dependent on their caregivers for their whole lives.

In milder forms of the disease, delayed onset of symptoms and mild weakness occur (Tan et al., 1997). Complete absence of the laminin-α₂ protein usually causes marked muscle destruction, but partial deficiencies cause less severe symptoms. This situation is akin to that seen in dystrophin deficiency. Diagnosis depends on the demonstration of altered merosin in muscle (Sewry et al., 1997). Commercial antibodies are available for this purpose, but not all antibodies demonstrate the abnormality, particularly if part of the laminin-α₂ chain is present. As in dystrophin deficiency, it may be advantageous to use at least two different antibodies. Skin or muscle biopsy reveals merosin deficiency. The ultimate diagnosis rests on showing an abnormality in the merosin gene on chromosome 6 because laminin-α₂ reduction also occurs as a secondary phenomenon in some of the other myopathies with membrane instability.

In 50% of classic MDC cases, muscle biopsy specimens demonstrate absence of merosin. CK concentrations are elevated, a characteristic of any muscle disease with membrane instability. EMG, in addition to demonstrating abnormalities in the muscle, shows slowed nerve conduction velocities, as might be expected from the expression of laminin-α₂ in nerve tissue.

Other Forms of Classical MDC Type 1

There are patients with identical symptoms who do not have a mutation in the laminin α₂ gene (Fig. 79.13). Frequently the muscle symptoms are milder, and children gain function as they grow older and may walk independently. These myopathies progress more slowly than merosin-negative MDCD. Despite a shortened lifespan, many survive to adulthood.

Fig. 79.13 Congenital muscular dystrophy (classic type). This boy also had weakness and contractures of the limbs. His illness was relatively static.

MDC type 1B links to mutations in the gene that encodes for the α₇ subunit of α7β1D integrin (Hayashi et al., 1998). Integrin is a sarcolemmal protein that binds to merosin and is probably important for structural integrity of the muscle membrane. MDC1C with normal merosin occurs in patients with mutations in FKRP (Brockington et al., 2002). As noted in the LGMD section, mutations involving this protein have also been described in LGMD2I. Therefore, as with the dystrophinopathies, sarcoglycanopathies, and merosinopathies, a wide range of clinical phenotypes is possible. FKRP plays a role in glycosylation of other proteins. α-Dystroglycan, which binds merosin, is normally heavily glycosylated. The normal glycosylation of α-dystroglycan is impaired with FKRP mutations, and this most likely also results in loss of stability of the muscle membrane.

Fukuyama-Type Muscular Dystrophy

Inheritance of Fukuyama-type muscular dystrophy, like the other congenital dystrophies, is autosomal recessive. The myopathy links to mutations in the gene that encodes for fukutin, located on chromosome 9q31-33 (Kobayashi et al., 1998). Secondary loss of laminin α₂ and α-dystroglycan occur. Fukutin is an enzyme associated with the Golgi complex that may participate in the glycosylation of other proteins. As already noted, α-dystroglycan is heavily glycosylated. Fukutin mutation likely results in abnormal glycosylation of α-dystroglycan and perhaps other important proteins, altering the normal three-dimensional protein structure and the integrity of the glycoprotein-dystrophin complex. This complex is expressed in the central nervous system (CNS) and probably accounts for the severe CNS manifestations associated with Fukuyama-type muscular dystrophy.

Affected children are usually normal at birth. Some are floppy, and joint contractures are present in 70% by the age of 3 months, with the hip, knee, and ankle commonly involved. These children are often severely mentally retarded, sometimes to the extent that speech is never developed, and either major motor or absence seizures are common (Fig. 79.14). Another curious finding is asymmetry of the skull, often noted on clinical examination. Muscle-strength testing is almost impossible, but weakness is diffuse and often disabling so that the child never learns to walk. Weakness occurs in the face and neck. Usually these children are completely dependent on their parents and never attain any degree of unsupervised activity. The muscle disease is moderately or slowly progressive, and survival into early adult life is common.

Fig. 79.14 Congenital muscular dystrophy (Fukuyama type). This severely retarded girl had many seizures and marked contractures of the limbs. She was too weak to support her own weight. The disease was nonprogressive. Her two brothers had the same illness.

The Fukuyama variant does not resemble DMD, and the only real difficulty is in differentiating it from other forms of congenital dystrophy. Serum CK concentration is usually markedly elevated, and muscle biopsy shows dystrophic changes with variability in fiber size and fibrosis. Internal nuclei are common, and the biopsy specimen easily distinguishes this disorder from other congenital nonprogressive myopathies and acquired myopathies such as polymyositis. As in the other congenital dystrophies, muscle biopsy may show changes that indicate an additional neurogenic component. The changes in fiber size may not be random, and some fascicles contain much smaller fibers than others. This nonrandom change differs from denervation atrophy, in which there is a wide random variability in fiber size within individual fascicles (Fig. 79.15).

Fig. 79.15 Biopsy from Fukuyama-type congenital muscular dystrophy. In addition to variability in fiber size and type 1 fiber predominance with fibrosis, note nonrandom distribution of atrophy. Fascicle in lower part of picture contains fibers larger than those in upper part (myosin adenosine triphosphatase stain, pH 9.4).

MRI and CT scans show a variety of abnormalities, but the most striking is the presence of lucencies, particularly in the frontal area (Fig. 79.16). These changes seldom extend to the genu of the corpus callosum and spare the medial subependymal regions along the trigones and occipital horns. As the children grow older, these lucencies disappear in sequence from the occipital to the frontal region in a fashion resembling the progression of normal myelination. Occasionally, marked pallor of the myelin in the centrum semiovale, together with mild gliosis or edema, is noted. Postmortem examination reveals numerous brain malformations including agyria, pachygyria, and microgyria. The cortex may have a cobblestone appearance, absence of gray-matter lamination, and other abnormal cytoarchitectural features. Heterotopias are present in the brainstem and basal meninges, as is micropolygyria of the cerebellum. Ventricular dilatation, enlarged sulci, and aqueductal stenosis are other associated features. In short, there are marked abnormalities in the architecture of the brain.

Fig. 79.16 Computed tomographic scan of head of patient with Fukuyama congenital muscular dystrophy demonstrates lucencies in white matter, particularly toward frontal poles.

Walker-Warburg Syndrome and Muscle-Eye-Brain Disease

The combination of muscular dystrophy, lissencephaly, cerebellar malformations, and severe retinal and eye malformations characterize Walker-Warburg syndrome and the related muscle-eye-brain disease (Haltia et al., 1997). Both are associated with more severe eye abnormalities than Fukuyama-type muscular dystrophy. Walker-Warburg syndrome is the more catastrophic disease, with death often occurring within the first 2 years; eye changes include microphthalmia, colobomas, congenital cataracts and glaucoma, corneal opacities, retinal dysplasia and nonattachment, hypoplastic vitreous, and optic atrophy. Muscle-eye-brain disease is milder and characterized by high myopia and possibly a preretinal membrane or gliosis, but severe structural abnormalities of the eye are not present.

The CNS findings are also different. MRI may be a useful technique to separate the entities (van der Knaap et al., 1997). The changes in Walker-Warburg syndrome are more severe, with various combinations of hydrocephalus, aqueductal stenosis, cerebellar and pontine hypoplasia with a small posterior vermis, Dandy-Walker malformations, and an agyric or pachygyric cobblestone cortex. T1-weighted images show diffuse decreased white-matter signal; T2-weighted images show an increased signal compatible with a defect in myelination. In muscle-eye-brain disease, white-matter changes are focal and the cortical changes milder.

In Walker-Warburg syndrome, mutations have been identified in genes that encode for four proteins: POMT1 and POMT2, fukutin, and FKRP. However, these account for a minority of cases (Beltran-Valero de Bernabe et al., 2002; Cormand et al., 2001; Diesen et al., 2004; van Reeuwijk et al., 2005). Mutations in the POMT1 gene on chromosome 9q31-33 account for 20% of Walker-Warburg syndrome cases (van Reeuwijk et al., 2005). Some cases of muscle-eye-brain disease are caused by mutations in the gene that encodes for O-mannose β-1,2-N-acetylglucosaminyl transferase (POMGnT1) located on chromosome 1p3 (Yoshida et al., 2001). POMT1 forms a complex with POMT2 to catalyze the first step in O-mannosyl glycylation (Muntoni and Voit, 2004, 2005), and subsequently the transfer of N-acetylglucosamine to O-mannose of glycoproteins is catalyzed by POMGnT1.

Ullrich Congenital Muscular Dystrophy

Ullrich congenital muscular dystrophy, also known as atonic-sclerotic dystrophy, is associated with neonatal weakness, multiple contractures, and distal hyperlaxity. Affected children often have marked protrusion of the calcanei in their feet. The clinical course is static or slowly progressive. Serum CKs are normal or only slightly elevated. Mutations in subunits of collagen type VI cause the disorder. Thus, it is allelic to the more benign Bethlem myopathy (Camacho-Vanegas et al., 2001).

Congenital Muscular Dystrophies with Rigid Spine Syndrome

This disorder presents in infancy with hypotonia, weakness, and delayed motor milestones. Reduced mobility of the spine is marked, and many children also develop scoliosis and contractures at the knees and elbows. Serum CK concentrations are normal or moderately elevated. Muscle biopsies may reveal type 1 predominance, increased internal nuclei, and other nonspecific myopathic features. In some kinships, the myopathy links to mutations in the selenoprotein N1 gene located on chromosome 1p3 (Moghadaszadeh et al., 2001). Other myopathic disorders (i.e., Emery-Dreifuss muscular dystrophy) can also be associated with rigid spine syndrome.

X-Linked Emery-Dreifuss Dystrophy (Emerin Deficiency)

Inheritance of the most common form of EDMD is as an X-linked recessive trait. The gene for EDMD (STA) is located at Xq28 and encodes for the nuclear membrane protein, emerin. Emerin localizes to the inner nuclear membrane, from which it projects into the nucleoplasm (Manilal et al., 1996). Emerin belongs to a family of lamina-associated structural proteins and is important in nuclear membrane organization and its attachment to heterochromatin.

The clinical characteristics of EDMD are wasting and weakness of the upper arms, shoulders, and anterior compartment muscles in the legs. This weakness is associated with early contractures, particularly in the elbows, posterior neck, paraspinal muscles, and Achilles tendon. Elbow contractures are characteristic and are severe. As the arm extends, sudden resistance is met, which feels more like bone than the pressure of a tight tendon. The disorder is slowly progressive and often spreads to involve other muscle groups such as those of the hip. Cardiac complications are frequent. Conduction block may explain the sometimes sudden unexpected death of these patients. Atrial paralysis occurs in which the atria are electrically inexcitable, and the heart responds only to ventricular pacing. Other cardiac problems include ventricular myocardial disease with ventricular failure. Female carriers may develop the cardiac abnormalities at a later age, and sudden death occurs. The severity of the cardiopathy in both men and women increases with age.

The clinical picture of EDMD is distinctive. DNA studies showing the gene defect confirm the diagnosis. Because emerin is present in many tissues, skin biopsy showing that the protein is absent from nuclei in the skin confirms the diagnosis. Muscle biopsy and EMG confirm a myopathy. CK levels may be elevated. Every patient with the syndrome should have an ECG repeated at regular intervals, and regular ECG in other family members is recommended; isolated cardiac involvement occurs.

Analysis and treatment of the cardiac problems are the most pertinent parts of therapy. Most patients with EDMD need a cardiac pacemaker. Some may need treatment of congestive cardiac failure due to ventricular failure. Because the atrial block may be sudden, unpredictable, and fatal, it is wise to implant a pacemaker when the diagnosis is first established. It is important to realize that a pacemaker does not retard development of a cardiomyopathy and only protects the patient against the complications of conduction block. Female carriers should be screened with ECG after age 35.

Autosomal dominant EDMD can be caused by mutations in lamin A/C, as discussed in the section on LGMD1A. Rare causes of autosomal dominant EDMD link to mutations in the genes that encode for the nuclear proteins, nesprin-1 and nesprin-2. The clinical phenotype is essentially identical to that seen with emerin and lamin A/C mutations.

Facioscapulohumeral Dystrophy

FSHD is inherited as an autosomal dominant trait. Its prevalence is around 1 to 2 per 100,000 population. Most cases (FSHD type 1) are caused by a deletion in a 3.3-kb repeating sequence termed D4Z4 at chromosome 4q35 (Tawil and Van Der Maarel, 2006). Digestion by the endonuclease, EcoRI, produces a fragment shorter than 34 kb in most families who have the illness, compared to more than 40 kb in normal individuals. Recent studies have demonstrated that this D4Z4 region is hypomethylated compared to normal (de Greef et al., 2009).

Some 5% of patients with FSHD do not have a deletion (so-called FSHD type 2), but similar to FSHD1, the D4Z4 region is hypomethylated, and this hypomethylation causes the myopathy. The DUX4 gene within the D4Z4 region appears to be responsible. The DUX4 protein may control expression of other genes. Hypomethylation of the gene may lead to overexpression of DUX4 and dysregulation of transcription of other genes (de Greef et al., 2009).

With FSHD1, the severity of the illness bears a relationship to the size of the deletion: the smallest fragments tend to be associated with severe illness. Another phenomenon exhibited by these families is anticipation of the illness, where cases occur with more severity and at a younger age with successive generations (Tawil and Van Der Maarel, 2006). This suggests the mutation is a dynamic one that may become increasingly severe with each generation, as is the case with myotonic dystrophy. That said, FSHD varies in severity even within the same family. Some patients may have mild facial weakness that can go unnoticed throughout life. Others may have total facial paralysis and severe weakness of most other muscles in the body, causing wheelchair confinement by the age of 9 or 10 years. In a prototypical case, the onset is during adolescence. Facial weakness expresses itself as difficulty blowing up balloons or drinking through a straw. The child sleeps with the sclera of the eyes showing through partially opened lids. Facial expression is relatively preserved, but the smile is often flattened and transverse as opposed to the upward curve of the usual smile. When the patient attempts to whistle, the lips move awkwardly and have a peculiar pucker (Fig. 79.17). The mouth also may have a pouting quality called bouche de tapir.

Fig. 79.17 Facioscapulohumeral dystrophy. Note characteristic appearance of shoulders, downward-sloping clavicles, and bulge in trapezius muscle region due to scapula being displaced upward on attempted elevation of arms. Patient also is attempting to purse his lips.

Weakness of the shoulder muscles particularly affects fixation of the scapula. With the arms outstretched in front, the scapulae jut backward, with the inferomedial corner pointing backward. The deltoid muscle is usually quite bulky and its strength well preserved even late in the illness. The biceps and triceps muscles are often weak. The shoulders’ unusual appearance, “chicken wings,” when seen in the locker room is a source of embarrassment. The forearm muscles are less involved, although a discrepancy between the stronger wrist flexors and weaker wrist extensors often supports the diagnosis. Although leg weakness is not part of the name FSHD, the legs are involved. Hip flexor and quadriceps weakness is common. The ankle dorsiflexors are weak, whereas plantar flexor strength is often preserved. Often the ankle dorsiflexors are involved very early in the illness, and foot drop may be the presenting complaint, blending this illness with the scapuloperoneal syndromes. Asymmetry of the weakness is almost the rule, often leading the clinician to doubt the diagnosis of muscular dystrophy and seek a superimposed peripheral nerve lesion where none exists. Rare patients present with symmetrical proximal leg weakness greater than arm weakness, with sparing of facial muscles such that they resemble an LGMD.

The most severe form of FSHD occurs in infancy. Unlike patients with the more typical mildly disabling adult form, these babies have severe weakness. They may have no movement at all in the face, which remains passive and expressionless. Weakness of the limbs, although it conforms to the general pattern of FSHD, is so severe that such children may lose the ability to walk by 9 or 10 years of age. One striking feature of this illness is the extreme lumbosacral lordosis seen when the child walks or stands. This initially disappears on sitting, indicating that it is a compensatory mechanism the child uses to maintain balance. Deafness is frequent, and an association with Coats disease, an oxidative vascular degeneration of the retina, exists.

DNA studies reliably establish the diagnosis for FSHD1, but routine testing for FSHD2 by assessment of the methylation status of the D4Z4 region is not commercially available. The serum CK concentration usually is elevated several-fold above normal. Muscle biopsy may show general dystrophic features or tiny fibers scattered throughout the biopsy sample that suggest neuropathic change, or scattered inflammatory cellular foci associated with muscle fibers and in the interstitial tissue in patients with more severe disease (Fig. 79.18). EMG shows myopathic potentials (see Chapter 32B).

Fig. 79.18 Facioscapulohumeral dystrophy. Cellular responses occur in biopsy samples from many patients with this illness. These are more often associated with necrotic fibers than with blood vessels (hematoxylin and eosin stain).

Treatment of FSHD is supportive. There is no known way of reversing the illness. If lack of scapular fixation renders the patient unable to raise the arms above the head, surgical stabilization of the scapula may be beneficial (Twyman et al., 1996). This is particularly true in the majority of patients with preserved deltoid function. It is more usual for ambulatory patients to undertake this procedure. Wheelchair-confined patients, because of the severity of the general weakness, do not find the problems in shoulder movements to be out of proportion to the rest of the muscular weakness. Such patients find a forearm orthosis or ball-bearing feeder device to be more useful than undertaking rather lengthy surgery.

An ankle-foot orthosis may be beneficial for patients with foot drop. Because the posterior tibial tendon acts to invert and dorsiflex the foot, surgical transposition of the tendon to the dorsum of the foot can be an effective reconstructive procedure that may normalize walking. The posterior tibial muscle remains relatively unaffected until very late in the illness. If patients have severe weakness of the anterior tibial group, overactivity of the posterior tibial muscle may be seen in an attempt to dorsiflex the foot and allow the toes to clear the ground. This results in marked inversion of the foot while walking and may lead to an equinovarus contracture. It also may make the use of an ankle-foot orthosis impossible.

A trial of prednisone in a small group of patients did not have dramatic results.

Scapuloperoneal Syndromes

Weakness of the muscles of the shoulder and the anterior compartment of the lower leg are the early symptoms of scapuloperoneal syndromes. Some forms of scapuloperoneal dystrophy may relate to FSHD, but most cases show no linkage to the FSH site on 4q35 (Tawil and Van Der Maarel, 2006). Mutations in the desmin gene on chromosome 2q35 and FHL1 on Xq26.3 have been demonstrated to cause some cases of scapuloperoneal dystrophy; these are also categorized as myofibrillar myopathies. In FSHD, a discrepancy exists between the strength of the ankle dorsiflexors, which are weak, and the plantar flexors, which are strong. The same is true of the scapuloperoneal syndrome, but facial muscles are spared. Often the patient presents with a foot drop, and examination reveals the shoulder weakness. Biopsy, EMG, and other laboratory tests reveal nonspecific myopathic features. Because other hereditary scapuloperoneal syndromes due to neuropathy and anterior horn cell disease exist, it is important to confirm the diagnosis with appropriate tests in any patient with a scapuloperoneal syndrome. Ankle-foot orthoses are the only useful treatment and may improve function by correcting foot drop.

Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is another illness with an uneven geographical distribution, although now recognized worldwide. It is an inherited autosomal dominant disorder with almost complete penetrance. Foci of the illness occur in Quebec, Germany, Uruguay (Montevideo), and the Spanish-American populations of Colorado, New Mexico, and Arizona. Isolated families appear throughout the rest of the world. The disease is caused by mutations (expansion of GCG repeats) in the gene that encodes for polyadenylate-binding protein nuclear 1 (PABPN1, formerly PABP2) located on chromosome 14q11.2-13 (Brais et al., 1995; Stajich et al., 1996). This nuclear protein is involved in mRNA polyadenylation, but the mechanisms by which mutations cause OPMD are not yet clear.

OPMD usually begins in the fifth or sixth decade of life, but onset can be in the fourth decade. Patients present with eye-muscle weakness and mild ptosis. Initially the ptosis may be quite asymmetrical, but as the muscles weaken, both lids eventually become severely ptotic, and eye movements diminish in all directions (Fig. 79.19). Considerable variation in the severity of the extraocular palsies exists, but ptosis is constant. Concomitant with or shortly after the development of ocular symptoms, patients notice difficulty swallowing. Saliva pools in the pharynx, and at the extreme stages of the illness, dysphagia may be complete. Facial weakness occurs in a number of patients, and hip and shoulder weakness is common in the late stages. Death may occur from emaciation and starvation. The terminal event is often pneumonia initiated by aspiration of secretions. Although the symptoms associated with this disease may be severe, patients’ lifespans may be unaffected, making management of their nutritional status all the more important.

Fig. 79.19 Oculopharyngeal dystrophy. Facial appearance of patient who has ptosis and no eye movements.

Muscle biopsy can usually be avoided, since genetic testing reveals the diagnosis. However, biopsy of weak muscles may show dystrophic findings, random variation in fiber size, necrotic fibers, some fibrosis, and occasional internal nuclei. In addition, fibers may contain autophagic vacuoles (rimmed vacuoles) (Fig. 79.20), a feature common to this illness as well as to inclusion body myositis and various hereditary distal myopathies/dystrophies.

Fig. 79.20 Oculopharyngeal dystrophy. Rimmed vacuoles are common in this illness (hematoxylin and eosin stain).

A hallmark of the illness is the presence of small 8- to 10-nm intranuclear tubulofilaments. These occur as palisading filamentous inclusions. The filaments are unbranched and may be stacked side by side or may occur in tangles. In addition, there is often evidence of abnormal mitochondria as well as nemaline rods, particularly in pharyngeal muscles. PABPN1 is an integral part of the muscle OPMD inclusions. The inclusions also contain components of the ubiquitin-proteasome pathway, transcription factors, and mRNA binding proteins.

As in most of the muscular dystrophies, treatment of oculopharyngeal dystrophy is supportive. The swallowing difficulties should be treated first by a soft diet; pureed foods represent the next step in treatment. Feeding with a nasogastric tube may be a temporary solution, but eventually gastrostomy is essential. Surgery to correct ptosis may be very successful, as opposed to results seen in other causes of ptosis such as myasthenia or Kearns-Sayre syndrome.

Miyoshi Myopathy

Inherited as an autosomal recessive disease, Miyoshi myopathy begins early, often in adolescence (Bejaoui et al., 1995). Although originally described in Japanese individuals, this common distal myopathy occurs worldwide. The weakness is characteristically in the foot plantar flexors, with severe gastrocnemius atrophy. This causes a thin, tapering leg. Patients are unable to stand on their toes, and they walk up stairs in a clumsy, jerky fashion. The illness is progressive, although it remains confined to the legs. Ultimately, hip weakness develops, and ambulation may become difficult in midlife. The serum CK concentration is extremely elevated and reaches levels of several thousand international units even before the patient becomes symptomatic. Mutations in the gene that encodes the sarcolemmal protein, dysferlin, located on chromosome 2p12-14, are responsible for Miyoshi myopathy. The same gene is responsible for LGMD2B (discussed earlier). Families exist in which some members exhibit a distal myopathy and others the more traditional proximal variety. The muscle biopsy shows dystrophic changes but no autophagic vacuoles.

Welander Myopathy

This autosomal dominant myopathy has only been reported in Scandinavians, where it remains relatively common. Welander myopathy begins in the hands (finger and wrist drop) around age 40 to 60 and later involves the legs and feet (foot drop). The distal distribution may suggest a neuropathy, but laboratory tests show little evidence of denervation and much evidence of a myopathy. Careful evaluation may show mild distal hypesthesia and temperature loss associated with some loss of small myelinated fibers. The disease is not entirely restricted to muscle. Muscle biopsy shows myopathic findings, superimposed on which are the rimmed vacuoles characteristic of several other distal myopathies. Serum CK concentration is normal or slightly elevated.

Udd Myopathy

Udd myopathy is an autosomal dominant myopathy with a predilection for the anterior tibial muscles. Foot drop is the initial feature. Rarely, the proximal legs and arms become involved. Symptom onset typically begins after age 35.

Serum CK concentration is normal or only slightly elevated. Muscle biopsy specimens demonstrate myopathic features along with rimmed vacuoles. The genetic basis is mutation in the gene that encodes for titin on chromosome 2q31-33 (Hackman et al., 2002). Titin is a giant sarcomeric protein that serves as a ligand for calpain-3.

Markesbery-Griggs Myopathy

Markesbery-Griggs myopathy is similar to Udd myopathy in that it presents with progressive foot drop, usually after age 35, and its inheritance is autosomal dominant. Over time, proximal leg and distal arm weakness (wrist and finger extensors) become weak. Unlike Udd myopathy, cardiomyopathy is very common. The serum CK concentration is usually mildly elevated, and EMG reveals an irritative myopathy. Muscle biopsies demonstrate rimmed vacuoles and features of myofibrillar myopathy.

Because some of the clinical and laboratory features are similar to Udd distal myopathy, they were thought to be allelic disorders. However, the identification of mutations in the gene encoding ZASP separates it from Udd myopathy with titin mutations (Griggs et al., 2007).

Serum CK concentration is normal or usually only slightly increased. The ECG may demonstrate conduction defects or arrhythmia. An echocardiogram may reveal a dilated or hypertrophic cardiomyopathy. EMG demonstrates markedly increased insertional and spontaneous activity with fibrillation potentials, positive sharp waves, and myotonic discharges. Motor units are myopathic in morphology and recruit early. Muscle biopsies demonstrate fibers with rimmed vacuoles and other features seen in the myofibrillar myopathies (Selcen and Carpén, 2008). Therefore, Markesbery-Griggs myopathy can be classified as one of the myofibrillar myopathies, discussed in greater detail later.

Nonaka Myopathy/Autosomal Recessive Hereditary Inclusion Body Myopathy

Nonaka and colleagues initially described this early adult-onset distal myopathy in Japan. Other groups reported similar patients with so-called autosomal recessive hereditary inclusion body myopathy (hIBM) (Udd, B., 2009). The clinical phenotype is similar to that of Markesbery-Griggs and Udd myopathies, with weakness initially involving the anterior tibial muscles in the legs and extensor forearm muscles. However, inheritance is in an autosomal recessive fashion and onset occurs at less that 30 years of age. The muscle biopsy results are also quite similar to those of Markesbery-Griggs, Udd, and Welander myopathies in that rimmed vacuoles are observed. Further EM reveals 15- to 18-nm tubular filaments typical of inclusion body myositis. However, unlike inclusion body myositis, no significant inflammatory process occurs in this hIBM.

Nonaka myopathy/autosomal recessive inclusion body myopathy is caused by mutations in the gene encoding for UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase, or GNE, on chromosome 9p1-q1 (Eisenberg et al., 2001). The mechanisms by which mutations in this gene lead to the myopathy are unknown but may relate to a secondary reduction in sialic acid production.

Laing Distal Myopathy

This autosomal dominant distal myopathy is characterized by weakness of the anterior tibial muscle groups and the neck flexors (Laing et al., 1995). Onset is in childhood or early adult life. Serum CK concentrations are normal or only slightly elevated, and EMG is myopathic. Cardiomyopathy is sometimes the initial symptom. Unlike Markesbery-Griggs myopathy, Udd myopathy, and Nonaka myopathy/hIBM, rimmed vacuoles are not a feature of the muscle specimen in Laing distal myopathy. Mutations in the slow/beta cardiac myosin heavy chain 1 (MyHC1) gene or MYH7 located on chromosome 14q11 are causative (Lamont et al., 2006). MyHC is the major myosin isoform expressed in type 1 muscle fibers. Of note, MYH7 mutations have also been identified in hyaline body myopathy (discussed later in Congenital Myopathies) (Tajsharghi et al., 2003).

Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (dystrophic myotonia type 1 or DM1) is a muscle disorder characterized by muscle wasting and weakness associated with myotonia and several other systemic abnormalities. It is inherited in an autosomal dominant fashion and has an incidence of approximately 1 per 8000 live births. The myopathy is caused by mutations in the gene that encodes for myotonic dystrophy protein kinase (DMPK), located on chromosome 19q13.3. The mutation occurs in an untranslated region of the gene. This region normally contains 5 to 30 repeating sequences of three nucleotides (CTG trinucleotide repeats). In DM1, these CTG repeats expand into the hundreds or thousands.

In general, the size of the expansion reflects the severity of the illness. Children with severe congenital myotonic dystrophy may have very large expansions (>750 repeats). Mothers with more than 100 repeats are more at risk for having a child with the severe infantile form than are mothers with a smaller expansion. The tendency of the expansion to grow with each meiosis explains the phenomenon of anticipation, in which succeeding generations experience the illness earlier and more severely. The reverse is true of some rare patients with paternally inherited myotonic dystrophy, in which the expansion reduces in size and the clinical state may return to normal or near normal. Further complicating the issue of relating the severity of the phenotype to the genetic defect is the fact that the degree of the gene’s expansion may vary among the different tissues in the body.

The mutation is not in the coding region of the gene, and other experiments with knockout mice or mice that overexpress the protein show no marked abnormality in the muscle or other systems. Studies have demonstrated that the transcribed mRNA is directly toxic, in part by sequestering RNA binding proteins such as muscleblind protein, thereby leading to abnormal splicing of various mRNA transcripts, including those of muscle chloride ion channel (Mankodi et al., 2002; Mulders et al., 2009; Osborne et al., 2009; Wheeler and Thornton, 2007).

Few diseases are as easy to recognize as DM1 once the diagnosis is considered. Conversely, misdiagnosis occurs when the presenting complaint may be unrelated to the basic problem. Patients may present to many different specialists—cardiologists for heart block, gastroenterologists for gastric immotility, and developmental pediatricians for mental retardation. The severity of DM1 ranges from mild weakness in some adults to profound mental retardation and severe weakness in children.

The more typical picture is of an illness beginning in early teenage life, starting with noticeable weakness of the hands and often foot drop. DM1 is one of the rare forms of dystrophy that seems to affect the distal muscles more severely. A predilection for neck muscle involvement exists, and the sternocleidomastoid muscles are often atrophic and poorly defined. A rather long face with a mournful expression is accentuated by hollowing of the temples associated with masseter and temporalis atrophy. In the fully developed disease, the eyes are hooded and the mouth slack and often tented (Fig. 79.21). The muscular weakness is not limited to the distal muscles; shoulder, hip, and leg weakness may be quite prominent.

Fig. 79.21 Myotonic dystrophy type 1. Facial appearance includes ptosis, hollowing of the masseter and temples, and facial weakness.

In middle age, repeated falls are common. With time, the weakness of individual muscles becomes severe, and the myotonia may be lost. Patients with advanced disease may have no myotonia of the small muscles of the hand, although pronounced myotonia of the deltoids or forearm muscles exists. The voice alters; it may be hollow and echoing, suggesting palatal weakness. Facial weakness makes it difficult to pronounce consonants. Difficulty in swallowing is common but usually a minor complaint. Recurrent dislocation of the jaw occurs, particularly when the patient attempts to open the mouth wide, as in biting an apple.

The demonstration of myotonia is either by sharp percussion of the muscle with a reflex hammer or after firm voluntary contraction. Either maneuver elicits a sustained involuntary contraction of the muscle, which fades slowly over a matter of seconds. Percussion of the thenar eminence, a popular way of eliciting myotonia, produces a sharp abduction of the thumb and a firm contraction of the thenar eminence, which gradually relaxes and allows the thumb to return to the resting position. It is often easier to demonstrate percussion myotonia by percussion of the posterior muscles of the forearm. The normal response to percussion of the forearm is also a brisk contraction of the finger extensors or the wrist extensors, but the wrist or fingers then fall into the resting position without delay. In the myotonic patient, the fingers extend sharply, with a subsequent drift downward toward the normal position or even wrist extension that maintains for some seconds. Patients seldom complain spontaneously about myotonia, but when questioned, they may confess to finding it difficult to release a key after firmly grasping it or to let go of a hammer or vacuum cleaner, particularly in cold weather.

Cardiac disease is a common complication of DM1. Understanding of the heart component has increased by recent advances in both molecular techniques and cardiological investigations. Conduction disturbances and tachyarrhythmias occur commonly in DM1. The cardiomyopathy correlates in severity with the neuromuscular disease and the extent of the molecular defect in some but not all studies; the rate of progression differs widely among individuals. The cause of sudden death may be ventricular arrhythmias or complete heart block, and this can occur at an early stage of disease. Some studies show a familial tendency toward cardiac complications. The histopathology is of fibrosis (primarily in the conducting system and sinoatrial node), myocyte hypertrophy, and fatty infiltration (Phillips and Harper, 1997). EM shows prominent I-bands and myofibrillar degeneration. Suggestions for clinical management include a careful cardiac history and a 12-lead ECG at least every year, with a low threshold for use of 24-hour Holter monitoring. General anesthetic carries some risks, and the occurrence of complications, usually respiratory, was almost 10% in one series (Mathieu et al., 1997).

Excessive daytime somnolence is a common problem in DM1 (Damian et al., 2001; Giubilei et al., 1999). The uncontrollable urge to sleep may be mistaken for narcolepsy. It is accompanied by a disturbance of the nighttime sleep pattern. Patients have an abnormal central ventilatory response, without the usual hyperpnea produced by an increasing carbon dioxide concentration. This is associated with an abnormal sensitivity to barbiturates, morphine, and other drugs that depress the ventilatory drive. Anesthesiologists must be aware of the possibility of complications with these drugs. Several other organs are commonly involved in the disease. Cataracts are almost universal. Detection may only be by slit-lamp examination. Commonly, multihued specks appear in the anterior and posterior subcapsular zones. Endocrine abnormalities include disturbances of the thyroid, pancreas, hypothalamus, and gonads. Testicular atrophy, with disappearance of the seminiferous tubules, leads to male infertility. In the female, habitual abortion and menstrual irregularities are common. Although diabetes mellitus is no more common in the myotonic population than in the general population, a glucose tolerance test is often associated with abnormally high glucose levels, particularly late in the test. An associated overproduction of insulin seems to be due to abnormal resistance of the insulin receptor. Smooth muscle involvement accounts for several problems. Cholecystitis and symptoms referable to gallbladder function are frequent. Mild dysphagia and decreased peristalsis in the hypopharynx and proximal esophagus are present. Patients often complain of constipation and urinary tract symptoms.

DNA analysis is the definitive diagnostic test for myotonic dystrophy. Patients with clinical evidence of disease and individuals at risk require testing. Prenatal diagnosis is reliable and uses chorionic villus biopsies or cultured amniotic cells. EMG is the most helpful laboratory study. In addition to the presence of myopathic features, the characteristic myotonic discharges are seen (see Chapter 32B). On insertion of the needle, bursts of repetitive potentials are noted. These potentials wax and wane in both amplitude and frequency; when played over a loudspeaker, they resemble the sound of a diving propeller airplane and are called dive bomber or motorcycle potentials. Muscle biopsy in the fully developed illness is markedly abnormal (Figs. 79.22 and 79.23), demonstrating random variability in the size of fibers and fibrosis. In addition, multiple nuclei pepper the interior of the fibers. Ring fibers are numerous, in which small bundles of myofibrils are oriented at 90 degrees to the majority, rather like a thread wrapped around a stick. Other laboratory studies are less helpful. Serum muscle enzymes are often abnormal. Some patients demonstrate low levels of immunoglobulin G. Abnormalities seen on head MRI include cerebral atrophy, increased white-matter signals on T2-weighted images, and thickening of the cranial vault (Miaux et al., 1997). These abnormalities have little significance.

Fig. 79.22 Myotonic dystrophy type 1. There are numerous internal nuclei, some scattered pyknotic nuclear clumps, and marked variability in fiber size. One ring fiber can be identified by its circular dark-staining appearance (hematoxylin and eosin stain).

Fig. 79.23 Myotonic dystrophy type 1. Myosin adenosine triphosphatase stain at pH 9.4 demonstrates that the majority of type 1 fibers are small. Type 1 fiber atrophy is noted in early cases and is obscured as the disease becomes more severe.

Supportive treatment of DM1 includes the use of ankle-foot orthoses to treat foot drop. Wrist splints are less useful. In theory, they should give added function to the hand, but most myotonic patients prefer not to use them. Breathing exercises and postural drainage can be helpful in severe myotonia to ward off frequent respiratory infections. Drugs to treat myotonia include quinine, phenytoin, procainamide, mexiletine, and acetazolamide. Their lack of efficacy in clinical situations is probably because myotonic patients are bothered more by weakness than myotonia. Modafinil, 200 to 400 mg/day, improves hypersomnolence in DM1 patients (Damian et al., 2001).

Once a diagnosis of myotonic dystrophy has been established in one family member, other family members require genetic screening, but a curious problem decreases the efficacy of genetic counseling. The element of denial is distinctly different from other muscle diseases. Many affected family members deny illness, including those seen in the muscle clinic, and some with marked disease pay little attention to genetic counseling.

Congenital Myotonic Dystrophy

Congenital myotonic dystrophy occurs in infants of affected mothers. Cardinal features are hypotonia, facial paralysis, failure to thrive, and feeding difficulties. Affected infants are prone to frequent respiratory infections, which may develop into pneumonia. The upper lip forms an inverted V or “shark mouth” (Fig. 79.24). Clubfeet are common, and the children are severely mentally retarded. The cause of the neonatal illness is a marked increase in the trinucleotide repeat region that seems to occur with maternal transmission, particularly if the mother has a sizable expansion herself.

Fig. 79.24 Infantile myotonic dystrophy. This child is severely retarded and has a marked inverted-V mouth.

Myotonic Dystrophy Type 2 or Proximal Myotonic Myopathy

Whereas DM1 has a predilection for distal muscles, patients with proximal myotonic myopathy (PROMM) experience proximal stiffness, pain, and weakness (Moxley, 1996; Udd et al., 1997). Like DM1, PROMM is an autosomal dominant trait, and cataracts are characteristic. Gonadal atrophy and cardiac abnormalities occur, but less frequently than in DM1.

Initial complaints usually arise in adult life and are a combination of muscle stiffness and unusual muscle pain, which commonly affects the thighs and may be asymmetrical. Grip myotonia is noted, and the relaxation phase is jerky. The severity of the myotonia may vary from day to day, and a “warm-up” phenomenon occurs in which the stiffness disappears after repeated contraction and relaxation. The pain is a sense of discomfort and varies from sharp to a deep visceral ache.

Prognosis is relatively good. Individuals with PROMM do not show the slow decline in ability and early cardiorespiratory death so often noted in myotonic dystrophy. EMG shows myotonic discharges only after a careful search in several muscles. Muscle biopsy shows features similar to DM1. Serum CK concentration may be elevated.

The genetic defect has been localized to mutations in the gene that encodes for zinc finger 9 (ZNF9) on chromosome 3q21 (Liquori et al., 2001). The mutations are expanded CCTG repeats in intron 1. As with DM1, this expanded repeat leads to expression of a toxic pre-mRNA, which as in DM1, sequesters RNA binding proteins, leading to aberrant splicing of other mRNA species including those of ion channels (Wheeler and Thornton, 2007; Mulders et al., 2009; Osborne et al., 2009).

Potassium-Sensitive Periodic Paralysis

The potassium-sensitive periodic paralyses and myotonias are associated with mutations in the SCNA4A gene that encodes the α subunit of the sodium channel; the gene is located on chromosome 17q. Even in early descriptions of these disorders, the association of decreased electrical activity, paralysis, and signs of hyperactivity (paramyotonia) were recognized. The proper activity of the sodium channel depends on a complicated series of activation and deactivation processes that open the pore to allow the passage of sodium but also protect the cell against inadvertent excess sodium flux. The channel may exist in a number of different states: closed, open, and inactivated. Physiological studies have suggested that the domain IV S3 segment has a dominant role in the recovery of inactivated channels, whereas the S4 segment is concerned with deactivation and inactivation of the open channel (Ji et al., 1996). Among the several known mutations of the sodium channel, some impair fast inactivation of the sodium channel or shift the impulse to hyperpolarization. Evidence exists that two common mutations in hyperkalemic periodic paralysis in domain II (S5) and domain IV (S6) cause defective slow inactivation, accentuating the weakness (Hayward et al., 1997). Mutations within the domain III-IV linker, which cause myotonia with or without weakness, do not impair slow inactivation.

Studies of muscle during a paralytic attack show that it is slightly depolarized. Intracellular potassium levels decrease and sodium, water, and chloride content are increased. Studies of intercostal muscle biopsies in vitro show a high level of spontaneous muscle activity, even in normal physiological saline. Increasing the external concentration of potassium gradually depolarizes the cells and is associated with an increase in sodium conductance. Tetrodotoxin increases sodium conductance, implying that this part of the sodium channel function is unaffected. Examination of sodium currents of cultured myotubes from the muscles of patients using increased potassium concentrations in the medium resulted in an increased open time or slowed inactivation of the sodium channel associated with sustained depolarization.

In patients with paramyotonia congenita, cooling of intact muscle fibers obtained from intercostal biopsy samples reduced the resting membrane potential from approximately −80 to −40 mV, at which point the fibers were inexcitable. As the muscle cools, it passes through a phase of hyperexcitability. Tetrodotoxin prevents inexcitability by blocking sodium channels. The clinical features reflect the physiological findings.

The predominant symptom in patients with hyperkalemic periodic paralysis is weakness provoked by potassium exposure. Myotonia may be present, and some patients complain of the symptom, but the predominant difficulty is recurrent bouts of paralysis. The allelic disease, paramyotonia congenita, causes muscle stiffness, and bouts of weakness are mild, often provoked by exposure to cold. In some families, the distinction seems clear, but there are others with a somewhat mixed picture. The clinical features of the two conditions follows.

Hyperkalemic Periodic Paralysis

Inheritance of potassium-sensitive periodic paralysis (hyperKPP) is autosomal dominant, with strong penetrance and involvement of both sexes (Matthews et al., 2010). Onset of symptoms is during infancy or early childhood. The infant’s cry may become suddenly altered or unusual, or the child may be found lying quietly in the crib. Some parents notice an unusual stare as these babies develop, particularly on exposure to cold. The first attack commonly occurs in the first few weeks of school because of the enforced sitting. By adolescence, the attacks are characteristic. Often, rest after exercise provokes an attack, and the weakness develops quite rapidly, often within a matter of minutes. The weakness is milder than in the hypokalemic variety, and the attacks last for a shorter period. Patients may be able to walk off the symptoms if they undertake exercise early in the attack. Many prefer not to do so because an attack itself is mild and followed by a period of relative freedom from symptoms. In addition to rest after exercise, other provocative factors include exposure to cold, anesthesia, and sleep. Patients often avoid fruit juices with high potassium content, having noticed their deleterious effect. Many patients have two kinds of attacks, light and heavy. During a light attack, there is a feeling of fatigue and mild weakness that usually disappears in less than an hour. A heavy attack, however, may be associated with more severe paralysis, even to the point where the patient is unable to arise from the chair or bed. The frequency varies from two or three mild attacks a day to episodes months apart. Residual weakness may occur in middle age and beyond.

Paramyotonia Congenita

Mutations in the SCNA4A gene also lead to paramyotonia congenita. This condition may or may not be associated with episodic weakness (Matthews et al., 2010). Unlike the myotonia in myotonic dystrophy, in paramyotonia, repeated exercise accentuates myotonia, a feature most easily appreciated in the eyelids. Patients may complain of this as aching or stiffness. A clinical test is to have the patient forcibly close his or her eyes in a repetitive manner. After each repetition, the difficulty with relaxation may be accentuated until eventually the patient cannot open the eyes at all. Exposure to cold not only worsens the myotonia but may provoke muscle weakness, symptoms patients may notice when swallowing ice cream or going out into winter weather to shovel snow. A useful test for paramyotonia is to soak a small towel in ice water and lay it over the patient’s eyes for 2 minutes. Eyelid myotonia is demonstrable by having the patient sustain an upward gaze for a few seconds and then look down. The eyelids remain up, baring the sclera above the iris. When muscle is sufficiently chilled, the paramyotonia disappears, and the muscle is flaccid and paralyzed. The weakness may far outlast the exposure to cold, and it is common for the muscle not to regain its full use for hours after returning to room temperature. Strong voluntary contraction also may be associated with a long-lasting decrease in strength, which is not clearly due to an increase in myotonia. Immersing the forearm in ice water may also produce obvious weakness, which may have been lacking on the initial examination.

The diagnosis of potassium-sensitive conditions relies on demonstration of the genetic defects. However, the diagnosis should be suspected when high serum potassium levels coincide with bouts of weakness. In patients with paramyotonia, EMG of the resting muscles at room temperature shows myotonic discharges that are present on percussion or with movement of the needle. The most remarkable findings are demonstration of decrementing CMAP amplitudes on the repeated short exercise test, which is worse when performed with the extremity cooled (Fournier et al., 2004, 2006). Additionally, there are often after-discharges evident following brief activity on CMAP studies.

The ECG may show the changes of hyperkalemia, and the serum CK concentration may be elevated during or after an attack. Provocative testing, if considered, requires care because the administration of potassium may be dangerous. The presence of any cardiac abnormality contraindicates provocative testing. Oral potassium may be administered using approximately 1 mEq/kg. The maximum rise in potassium occurs 90 to 180 minutes after administration. If this dose of potassium does not provoke an attack and the index of suspicion is high, administer 2 mEq/kg orally on a subsequent occasion.

Muscle biopsies show tubular aggregates in patients with paralysis, particularly in patients with fixed weakness. Myopathic changes include internal nuclei, vacuoles, and fibrosis. The muscle biopsy may be abnormal in paramyotonia congenita, showing variability in the size of fibers, with internal nuclei and occasional vacuoles.

Acute attacks usually do not require treatment because they are mild and brief. Often patients learn to eat a candy bar or drink a sweet drink as a way of warding off an attack. Intravenous calcium gluconate treats greater weakness. Intravenous sodium chloride sometimes may abort an attack. Maintenance therapy with dichlorphenamide or acetazolamide can be helpful. The combination of hydrochlorothiazide with potassium may be effective, although the reason is unclear. Mexiletine, a drug related to lidocaine and tocainide, blocks the sodium channel. It may provide dramatic relief to patients with myotonia. The initial dose is 200 mg 3 times a day. Most patients who derive benefit do so at relatively low doses.

Potassium-Aggravated Myotonias

This group of disorders includes myotonia fluctuans, myotonia permanens, and acetazolamide-responsive myotonia. Mutations in the SCNA4A gene are causative. Myotonia made worse by exercise or potassium ingestion, usually beginning in adolescence, is characteristic. Affected individuals do not suffer attacks of weakness. Myotonia is only sometimes evident in myotonia fluctuans but more consistently evident in myotonia permanens. The myotonia may improve with mexiletine. Acetazolamide-responsive myotonia resembles myotonia congenita clinically, but affected patients also often have significant muscle pain; the myotonia and pain are relieved by acetazolamide.

Secondary Hyperkalemic Periodic Paralysis

Weakness due to high levels of potassium occurs in situations other than familial hyperkalemic periodic paralysis. The difference between secondary hyperkalemic periodic paralysis and the familial condition is that extremely high levels of potassium are required in secondary hyperkalemic periodic paralysis before weakness occurs. Causes for secondary hyperkalemic periodic paralysis include renal failure or potassium administration associated with potassium-retaining diuretics.

Hypokalemic Periodic Paralysis Type 2

Although the majority of patients with hypokalemic periodic paralysis (type 1) have mutations in the calcium channel, approximately 9% of cases are due to mutation in the SCNA4A muscle sodium channel gene, as previously discussed (hypoKPP2) (Bulman et al., 1999; Cannon, 2010; Sternberg et al., 2001). The clinical and laboratory features are similar to the more common type of hypokalemic periodic paralysis, but there are some differences that may help distinguish the subtypes. Patients with hypoKPP2 may be more likely to have severe myalgias following the paralytic attacks, tubular aggregates on muscle biopsy rather than vacuoles, and worsening of symptoms on acetazolamide.

Andersen-Tawil Syndrome

Although the occurrence of cardiac dysrhythmias with periodic weakness is well recognized, it has not received the attention it deserves. A series of reports emphasized the constellation of findings: periodic paralysis, cardiac dysrhythmias, and dysmorphic features. These are termed Andersen-Tawil syndrome (ATS) (Sansone et al., 1997). The disorder is a genetically heterogeneous syndrome inherited in an autosomal dominant fashion. Some cases are caused by mutations in the potassium channel gene (KCNJ2) located on chromosome 17q23.

The attacks of paralysis may occur in early childhood or be delayed until later. Attack frequency is low and occurs with both high and low potassium. It therefore differs from the more usual hypokalemic variety, in which low potassium levels are expected. Affected members of the family often show dysmorphic features including wide-spaced eyes, low-set ears, a small chin, clinodactyly of the fifth finger, and syndactyly of the toes. Permanent muscle weakness occurred in several patients.

The importance of recognizing the syndrome lies in the frequent occurrence of cardiac involvement. This varies from a prolongation of the QT interval through ventricular tachycardia to fatal cardiac arrest. The risk of cardiac complications is sufficiently high that provocative hypokalemic or hyperkalemic testing is contraindicated. Several members of affected families have been described in whom only fragments of the syndrome exist (e.g., clinodactyly, an abnormal QT interval), so a full evaluation of the pedigree is necessary.

Myotonia Congenita

Two major forms of myotonia congenita exist: autosomal dominant and autosomal recessive (Matthews et al., 2010). Both are associated with abnormalities in the chloride channel, the gene for which (CLCN1) resides on chromosome 7q35. Introducing the mutant chloride channel into a cell system abolishes the chloride current and deranges the normal function of the chloride channel (Fahlke et al., 1997). The patient’s muscles show reduced chloride conductance and greater than normal membrane resistance. The action potential in a normal muscle cell is associated with an outflow of potassium, which may accumulate in the transverse tubules simply because the physical structure of the tubule does not favor easy diffusion. Ordinarily, this does not present a problem because the chloride conductance is so large that the relatively free passage of chloride ions negates the effect of any small change in potassium. With impeded chloride conductance, the increase in potassium concentration in the transverse tubules may lead to enough depolarization to activate the sodium channels again and hence lead to repetitive electrical discharge of the membrane, producing electrical and clinical myotonia.

The original description of the dominant disease was by Thomsen among members of his family. It is usually milder than the recessive form described by Becker, in which myotonia may be associated with some weakness. It is sometimes difficult when faced with a sporadic case to decide on the pattern of inheritance. This is true because members of affected families who carry the abnormal mutation may be asymptomatic or only mildly involved. This necessitates a thorough evaluation of the family, with appropriate genetic testing.

On initial examination, especially if the patient has been sitting in the waiting room for some time, apparent weakness may be present because a severely myotonic muscle lacks full voluntary power. With repetitive activity, the muscle loosens up, and strength usually returns to normal. This is particularly true of proximal limb muscles. Symptom descriptions are stereotyped. After resting, the muscles are stiff and difficult to move. This is obvious when the patient arises from a chair. They move en bloc, with a stiff wooden appearance. As they continue, they then can walk freely and finally can run with ease. All the muscles of the body share this abnormality, and while most noticeable in the limbs, the face and tongue are also involved. In addition, particularly in the recessive form of the illness, muscular hypertrophy may be pronounced.

In myotonia congenita, EMG shows well-marked myotonia with none of the associated dystrophic features. Unlike paramyotonia congenita, the short-exercise nerve conduction study test is usually normal (Fournier et al., 2004, 2006). Muscle biopsy may demonstrate an absence of type 2B fibers, an unexplained finding, and also may reveal some increase in the size of fibers and internal nuclei as well as other mild nonspecific changes.

Unlike most patients with myotonic dystrophy, in myotonia congenita, the myotonia may be disabling. Treatment with mexiletine is worth trying and may provide relief in some patients. Older medicines include quinine, procainamide, and phenytoin.