Periodic Paralysis and Congenital Myotonic Disorders

Clinical Presentation

Although most instances of weakness related to periodic paralysis have a symmetric distribution, occasionally a patient may have a focal or asymmetric distribution of weakness. The latter occurs when a few specific muscles are overutilized; for example, we had a jeweler who developed symptoms confined to his dominant hand, obviously the side that he primarily used most of his working day. The hypokalemic patient may also have paralytic events precipitated by rest after exercise, as well as occurring subsequent to either a significant carbohydrate intake, or ethanol ingestion and sometimes cold weather. Bulbar and respiratory muscles are not affected. However, by midlife the periodic events usually cease and some individuals may develop a fixed weakness as illustrated in the above vignette.

Figure 75-1 Periodic Paralysis.

Paramyotonia congenita is an even more uncommon hyperkalemic disorder often associated with periodic paralysis. Similar to myotonia congenita, cold weather exacerbates muscle stiffness in paramyotonia. In contrast to myotonia congenita, where rest promotes weakness, exercise exacerbates the stiffness in paramyotonia congenita patients.

Myotonia congenita, a chloride channelopathy, is especially aggravated by immobility and ameliorated by exercise and warming; here the myotonia per se is easily elicited on examination. Fixed weakness is not usually present in dominant myotonia congenita. A rather unique characteristic of Thomsen disease variant is the pseudo-hypertrophy of the skeletal muscles providing the patient with a rather pseudo-herculean habitus (Fig. 75-2). It may be so profound that athletic coaches enthusiastically encourage these individuals to participate in sports activities. Unfortunately, some of these individuals may develop a mild progressive weakness. Transient episodes of true weakness precipitated by sudden movements after rest that are relieved by exercise are characteristic of myotonia congenita. Interesting examples include a baseball player who cannot run after hitting the ball or a subway rider who wishes to get off when the train stops but is frozen in place or falls when he arises to leave the train.

Figure 75-2 Myotonia Congenita (Thomsen Disease).

Differential Diagnosis

Myasthenia gravis (MG) classically has a remitting relapsing course predominantly confined to ocular as well as bulbar muscles and to a lesser extent proximal extremity musculature. MG is typified by fluctuating, rarely acute weakness with a very definitive diurnal variation (see Chapter 73).

Patients with fatigue and nonorganic weakness often report periods of episodic muscle pain. These symptoms per se are not components of the various channelopathies or MG. Furthermore, these individuals do not have any family history of neuromuscular disease, as do the various channelopathies. The patient with functional weakness frequently has a “consistent inconsistency” or “giveway component” to their weakness. One must take care as on occasion the Lambert–Eaton myasthenic syndrome (LEMS) is confused with this type clinical picture because of its posttetanic potentiation that mimics the giveaway of the nonorganic seen in the nonorganically ill individual.

Addison disease requires urgent consideration during the evaluation of any acute, generally weak patient presenting with hyperkalemia. Because thyrotoxicosis has a symptomatic link to periodic paralysis, such patients, particularly young Asian men, must also be screened for clinical signs and laboratory findings of thyroid dysfunction.

Diagnostic Approach

The clinical history is the best means to diagnose a channelopathy. This may be relatively simple in patients with a positive family history examined while symptomatic and documented to have an abnormal serum potassium level or found to have demonstrable myotonia on EMG. In sporadic cases, diagnosis may prove elusive, especially when clinical examination results are normal and provocative testing does not demonstrate any biochemical or neurophysiologic abnormalities.

Whether the underlying channelopathy leads to hyperkalemia or hypokalemia, the serum potassium is normal between attacks. The clinician rarely has the opportunity to obtain a serum specimen during an event per se. However, during episodes of hyperkalemic periodic paralysis the serum potassium is elevated. It is between events that the cold-induced and EMG-defined myotonia occurs. Similarly, the hypokalemic periodic paralysis patient has low serum potassium findings, also confined to the precise time of paralysis.

Measurement of the serum potassium level is indicated in any patient observed during spontaneous episodes of weakness or, if recurrent, an attack of periodic paralysis.

Currently, the availability of a few DNA studies has greatly enhanced the specificity of the diagnostic evaluation of a patient with a question of periodic paralysis. These include DNA testing for the skeletal muscle sodium channel as seen in HyperKPP and the skeletal muscle calcium channel specific for HypoKPP. The previously used provocative studies, such as carbohydrate loading to make one hypokalemic, are no longer of much value today.

Nerve conduction studies sometimes demonstrate decreased compound motor action potential amplitudes in the rare instance one has the opportunity to examine a patient during an episode of periodic paralysis; otherwise, these are normal. In the EMG laboratory, having the potential periodic paralysis patient exercise for prolonged periods may lead to progressive diminution in compound motor action potential amplitudes. Much more rarely, when evaluating a patient during individual episodes of periodic paralysis, needle EMG will demonstrate that affected muscles are electrically inactive as they are fully depolarized. Myotonic discharges occur on EMG in the sodium channelopathy HyperKPP, as well as the chloride channelopathies. This electrophysiologic finding is particularly useful in the differential diagnosis of hyperkalemic and paramyotonic varieties from the nonmyotonic hypokalemic variety. Clinical myotonia is often not evident in HyperKPP although it may be so in paramyotonia when exposed to the cold.

Provocative testing, such as carbohydrate loading, is occasionally required in patients with clinical histories highly suggestive of periodic paralysis and in whom DNA testing is negative. This allows for documentation of abnormal serum potassium levels during episodes of weakness. A controlled clinical setting with appropriate monitoring equipment and facilities for emergent care must be available before initiating this testing. Serum creatine kinase levels are usually normal or minimally increased in the periodic paralyses and myotonic disorders.

Muscle biopsy is normal early in the course of periodic paralyses. However, after patients develop persistent weakness, biopsy may demonstrate vacuolar myopathy with tubular aggregates. Biopsy is rarely necessary for diagnosis.

Treatment and Prognosis

The treatment of choice for a patient having an acute attack of periodic paralysis is by correction of abnormal potassium levels. Severe hyperkalemia necessitates emergency treatment with intravenous (IV) glucose and insulin. Inhaled β-adrenergic agents or ingestion of carbohydrates is fine for less severe episodes. With any patient experiencing his or her first episode of hyperkalemia-associated paralysis, Addison disease is always a diagnostic possibility; therefore, the administration of IV corticosteroids is indicated after a serum cortisol level is obtained. IV potassium or in the milder case oral supplementation is the best means to care for the patient with a hypokalemic episode. These are prevented by avoiding dietary carbohydrate loads.

Maintenance therapy with the carbonic anhydrase inhibitor (CAI) acetazolamide is usually indicated to prevent attacks. Paradoxically, this is equally effective in patients with hyperkalemic or hypokalemic periodic paralysis. Dichlorphenamide, another CAI, is currently under study; previously it had become a mainstay therapy that seemed to be better than acetazolamide; however, the manufacturer withdrew it from production. It is hoped that this will soon return to the neurologist’s pharmacologic armamentarium. When treatment of myotonia per se is required, therapy with mexiletine or other membrane stabilizers is usually effective.

Generally, a diminution in frequency and severity of periodic paralysis attacks occurs in middle age. However, in some patients with periodic paralysis, as in the initial vignette of this chapter, permanent proximal weakness develops with increasing age. This is only minimally responsive to carbonic anhydrase inhibitors and awaits a better therapy.

Clinical Vignette

A 16-year-old boy presented with severe muscle pain and very dark urine subsequent to outrunning police officers who were concerned about his teenage prank. Because of his persistently dark urine he was taken to his family physician. An evaluation for liver disease was commenced after he was noted to have aspartate aminotransferase (AST) levels that were extraordinarily elevated. Paradoxically all other liver function tests (LFTs) were normal. His liver biopsy demonstrated “excess” glycogen but was otherwise unremarkable, and the serum creatine kinase (CK) level was found to be 50 times normal. Myoglobin was demonstrated in his urine. The patient was admitted to the hospital and treated with vigorous IV hydration. His symptoms resolved within several days.

The forearm exercise test (FET) failed to demonstrate the normally expected postexercise increase in lactate but did have significant and normal elevations of the venous ammonia levels. The latter demonstrated that the patient had successfully stressed his muscle metabolism. The combination of no change in lactate and appropriate rise in ammonia levels was classic for the presence of a glycogen storage disease. Subsarcolemmal blebs seen on a periodic acid-Schiff–stained muscle biopsy specimen were consistent with glycogen excess. Biochemical analysis demonstrated decreased levels of myophosphorylase, confirming the diagnosis of McArdle disease.

Comment: This is a classic example of muscle phosphorylase deficiency (Fig. 75-3) with onset in adolescence when individuals for the first time have the muscle power to allow them to stress their metabolic system to the point of actual muscle necrosis and subsequent myoglobinuria, the feature that most commonly brings them to medical attention.

Figure 75-3 McArdle Disease.

Glycogen storage disorders (GSDs) are very uncommon clinical entities. The classic picture is one of exercise-induced painful muscle cramps, associated with myoglobinuria. The concomitant laboratory documentation of profound elevated serum CK levels and myoglobinuria strongly implicates either a carbohydrate or lipid enzymatic deficiency of inborn metabolism (Fig. 75-4; Table 75-3). Very rarely prolonged use of one extremity, in isolation, will uncover the presence of a previously unsuspected glycogen storage disease (GSD). Muscle phosphorylase deficiency, an inborn error of glycogen metabolism, is the most common of these GSD myopathies.

Figure 75-4 Myoglobinuric Syndromes.

Table 75-3 Myopathies Presenting with Exercise Intolerance

Pathophysiology

Skeletal muscle function is extremely energy dependent. Normal muscle metabolism requires the presence of both circulating glucose and free fatty acids (Figs. 75-5 and 75-6). At rest, muscles use fatty acids for basal metabolic demands. When one first begins to vigorously exercise, usually within the first 10 minutes, the glycolysis of glycogen, already stored within muscle tissues, is the primary energy source as its breakdown produces glucose but for a relatively short time period. However, when the vigorous exercise is prolonged past these first few minutes, the body shifts to anaerobic glycolysis. This is manifested clinically by the second wind phenomenon. Here lipid stores, in the form of free fatty acids, are mobilized as the primary source of energy. Effective glycolysis is blocked in the various muscle glycogenoses. This essentially deprives muscle of the initial need for glucose, and consequently an accumulation of underutilized glycogen occurs within muscle. In essence, that is, these muscles are inappropriately stressed by what for most healthy persons is no more than strenuous exercise.

Figure 75-5 Metabolism of the Muscle Cell.

Figure 75-6 Regeneration of ATP for Source of Energy in Muscle Contraction.

Genetics

Muscle phosphorylase deficiency usually has a dominant inheritance pattern. In contrast, the much more rare phosphoglycerate kinase deficiency is usually X-linked. The remaining other glycogenoses, as well as the various disorders of lipid metabolism, the respiratory chain defects, and muscle adenylate deaminase deficiency are usually recessively inherited. As based on the specific enzyme deficiency, there are 12 different types (I-XII) of GSDs. Type V, McArdle disease, is the most common, presenting with classic exercise-induced painful symptomatology (see Fig. 75-3). Similar phenotypes occur with types VII, IX, X, and XI GSDs.

Clinical Presentation

Severe painful muscle cramping and stiffness occurring after exertion are the hallmark of an enzymatic deficiency glycogen or lipid storage disorder. There may be a characteristic second-wind phenomenon, where brief periods of rest at the onset of myalgia alleviate symptoms and enable prolonged exercise. Symptomatic relief may come with rest (see Fig. 75-4). Recurrent myoglobinuria is common, and permanent weakness may develop in older patients. Patients with myalgias and exercise intolerance, with or without hyperCKemia, are commonly evaluated by neuromuscular specialists. The exercise-induced symptomatology with the subsequent myalgia (in contrast to joint or soft tissues), muscle stiffness, and myoglobinuria provide the primary diagnostic criteria for investigating the possibility of a metabolic myopathy. Although specific defects of muscle energy metabolism, as described in this chapter, are sometimes precisely defined, more commonly and very frustratingly, specific enzymatic defects cannot be identified in this setting.

A few patients with a GSD, particularly acid maltase deficiency in the adult, present with fixed, often progressive weakness. These individuals have no typical history of episodic symptomatology.

Muscle adenylate deaminase deficiency is a controversial “disorder” because it is not clear that this is a discrete biochemical disorder. These patients also experience exertional muscle cramping, stiffness, weakness, and pain. However, in contradistinction to a GSD they do not demonstrate an appropriate increase in serum ammonia levels after forearm exercise, but do have the normal increase in serum lactate, indicating normal glycogen metabolism. Myoglobinuria is rare in muscle adenylate deaminase deficiency, which may represent a disorder of defective purine metabolism.

Carnitine palmitoyltransferase II deficiency is the most common disorder of lipid metabolism. Dynamic symptoms include myalgia without muscle cramping. Most commonly, young men present with recurrent myoglobinuria after prolonged but not necessarily strenuous exercise. Brief periods of exercise are usually well tolerated. Episodes also may be triggered by fasting, cold, or stress. Unlike the glycogenoses, no second-wind phenomenon is seen, fixed weakness does not develop, and serum CK values may normalize between episodes.

Mitochondrial myopathies need to be considered in the setting of ptosis and ophthalmoparesis. These are the clinical signatures of these very uncommon disorders; however, these clinical findings are not present in every phenotype. These myopathies are defined by alterations in mitochondrial structure and function; there is a rather marked clinical heterogeneity. Furthermore, the involvement of other end organs, particularly those with high energy requirements such as the kidneys, liver, and brain, is typically found in patients with a mitochondrial myopathy. However, on occasion these rare myopathies occur in a solitary fashion mimicking the glycogen and lipid storage disorders.

Diagnostic Approach

Precise diagnosis of a GSD requires biochemical findings manifested by an abnormal FET. Baseline measurement of plasma lactate, pyruvate, and ammonia are obtained. The patients then vigorously exercise their hand for 1–2 minutes (see Fig. 75-6). Subsequently serial lactate and ammonia determinations are made immediately after exercise and 1, 3, 6, and 10 minutes thereafter. Normally there is a fivefold rise in serum lactate and a tenfold rise in the serum ammonia level. Glycogen metabolism storage disorders are suspected where there is failure to achieve the normal increase of serum lactate. Muscle adenylate deaminase deficiency is defined by a lack of the expected increase in plasma ammonia after exercise and the normal increase in serum lactate. The test sensitivity is dependent on patient effort. Permanent weakness or rhabdomyolysis, leading to renal impairment, either one precipitated by the ischemic testing format has been rarely reported. Therefore we no longer include an induced ischemic component to this study.

Muscle tissue histochemical analysis is also important. Here one obtains a muscle biopsy and then utilizes specific stains looking for the presence, or absence, of the enzyme muscle phosphorylase. When this is not abnormal, then other GSDs, or even more rarely, inborn errors in muscle lipid metabolism must also be assessed. Genetic testing for CPT2 is available, so biopsy can be avoided if clinical suspicion is high.

Idiopathic HyperCKemia

It is normal to find a moderate postexercise hyperCKemia increase in healthy individuals. Typically, this CK elevation is less than five times the upper limit of normal after a moderately vigorous exercise, whether skiing or playing an intense game of singles tennis or participating in various types of football, basketball, or rugby, for example. These elevated CK levels return to normal standards within 3–8 days postexercise.

Evaluation of patients who have nonspecific symptoms or who are serendipitously found to have increased CK is often frustrating in the absence of clinically demonstrated weakness or specific EMG abnormalities. The yield of muscle biopsy in search of glycogen or lipid storage changes is relatively low, even with extensive histochemical staining and DNA tests. Abnormalities found on routine analysis of muscle biopsy specimens do not accurately predict abnormalities on biochemical testing. Some metabolic myopathies are skeletal muscle specific. Here one needs to specifically study the involved muscles. Other metabolic disorders of muscle are more systemically distributed and can be detected on enzymatic testing of fibroblasts or leukocytes.

Respiratory chain mitochondrial disorders are characterized by marked increases in baseline serum lactate or pyruvate, as well as demonstration of metabolic acidosis and dicarboxylic or aminoaciduria.

EMG generally does not provide a useful diagnostic medium as it is usually normal in these various energy metabolic defects. The one exception is if one has the opportunity to perform the EMG while the patient is actually experiencing an active and often painful contracture, when there will be total electrical silence. This finding is unique to glycogen storage disorders. GSD type II, also known as acid maltase (alpha glucosidase) deficiency, is the one other exception where there are classic EMG findings of a very active myopathy mimicking polymyositis; the findings here are frequently most profound in the paraspinal musculature. Parenthetically, adult-onset acid maltase patients most commonly present with clinical findings similar to polymyositis. Overall the primary utility of EMG in this group of metabolic skeletal muscle disorders is to provide a means to exclude other motor unit processes before moving on to other studies.

Lymphocyte or cultured skin fibroblast analysis supersedes the need for muscle biopsy in certain metabolic myopathies. Testing is available for many glycogenoses and disorders of lipid metabolism. With the exception of complex IV deficiency, analysis for respiratory chain disorders is generally available only on a research basis.

Muscle Biopsy

Abnormal accumulation of glycogen or lipid may be detected in a muscle biopsy specimen using periodic acid-Schiff or oil red O staining, respectively. Muscle phosphorylase, phosphofructokinase, and myoadenylate deaminase deficiency are the primary enzyme-specific stains available for metabolic myopathies. Lipid stains may be normal or show mild lipid accumulation in carnitine palmitoyltransferase II deficiency. Biochemical testing of muscle is available for some myopathies (Table 75-4).

The diagnosis of a mitochondrial myopathy is supported by finding ragged red fibers. These are detected by the modified Gomori trichrome and succinic dehydrogenase stains or by myofibers that do not stain with cytochrome-c oxidase. Mitochondrial mutational analysis is available for a limited number of mutations.

Treatment and Prognosis

One crucial caveat is that patients with hyperCKemia, regardless of cause, have an increased risk for development of malignant hyperthermia (see Fig. 75-4, bottom). This is a potentially life-threatening anesthesia-induced complication of certain fluorinated hydrocarbon inhalation agents such as halothane. Thus, we suggest that any patient with hyperCKemia wear a MedicAlert bracelet at all times to alert the anesthesiologist to the potential for this life-threatening disorder.

Most patients with metabolic myopathies learn to adapt to limited exercise tolerance. No specific treatments are available for most of these conditions. Isolated reports attribute clinical benefit in the glycogenoses to aerobic training, high-protein diets, and creatine supplementation. However, none are proven reliable therapies. Patients with carnitine palmitoyltransferase II deficiency often can prevent attacks by increasing dietary carbohydrate intake before prolonged exercise or during febrile illness.

Myoglobinuria is always a major concern as it is a major risk for acute renal failure because there is deposition of myoglobin within renal tubules potentially leading to renal shutdown. This is a significant problem with the various muscle metabolism glycogenoses and lipid storage disorders. As much as 50% of patients with recurrent myoglobinuria experience episodes of acute renal insufficiency. Patients who are at risk for myoglobinuria are advised to seek prompt medical attention if such occurs. Treatment includes forced diuresis and alkalinization. A complete recovery is expected if the episodes are appropriately managed.

Metabolic myopathies are generally nonprogressive disorders, although fixed weakness develops with increasing age in some patients who have a glycogenosis. This is particularly the case with acid maltase deficiency. Once this disorder presents in middle age, there is early potential for significant respiratory compromise. In a few patients with the very rare carnitine palmitoyltransferase II deficiency, respiratory muscle involvement also occurs. This may require ventilatory support during episodes of severe weakness. Generally, these episodes are reversible with appropriate supportive care.

Myotonic Muscular Dystrophy, Type 1 (DM1)

The classic autosomal dominant form usually presents in early adulthood but may be recognized from the neonatal period presenting as a floppy infant similar to some of the congenital myopathies and congenital dystrophies (Fig. 75-8). This condition presents with distal weakness that progresses to involve proximal muscles. Myotonia is delayed skeletal muscle relaxation and is best demonstrated with a forceful handgrip or by thenar muscle eminence percussion. Temporalis, masseter, and sternocleidomastoid wasting, frontal balding, and ptosis contribute to the characteristic myotonic facies (Fig. 75-9). Facial, pharynx, tongue, and neck muscles are also weak. Limb weakness predominantly affects distal extensor muscle groups and then progresses proximally.

Figure 75-8 Congenital Myopathies: Floppy Infant.

Figure 75-9 Myotonic Dystrophy.

Various systemic problems occur concomitantly with myotonic muscular dystrophy, Type 1 (DM1): impaired gastrointestinal dysmotility, alveolar hypoventilation, cardiac conduction defects, and cardiomyopathy. The last three often shorten life expectancy. Neurobehavioral manifestations include hypersomnolence, apathy, depression, personality disorders, and cognitive impairment. Premature posterior subcapsular cataracts are common and may sometimes provide the essential clue leading to the initial diagnosis of DM1. Testicular atrophy and impotence occur in men. Pregnant women have a high rate of fetal loss.

Laboratory investigations demonstrate that the CK may be mildly elevated. Nerve conduction studies are normal. Needle EMG predominantly demonstrates myotonic potentials. Muscle biopsy is characterized by an increase in internal nuclei, atrophy, pyknotic clumps, and ring fibers. Genetic testing for the myotonin protein kinase (DMPK) will reveal >37 CTG repeats on chromosome 19q13.2. Greater repeat lengths are associated with more severe disease. Amplification of repeat size occurs in newborn babies of mothers with DM1 resulting in congenital dystrophy.

Proximal Myotonic Myopathy (DM2)

Proximal myotonic myopathy (PROMM) DM2 is another autosomal dominant myotonic disorder that presents in adults or, rarely, in children. Patients present with myotonia, myalgia, and proximal weakness. Weakness begins in the legs and is slowly progressive. Patients may describe episodic fluctuation in their weakness and may experience severe muscle pain. Ptosis, facial weakness, and weakness of the respiratory muscles are uncommon in DM2. Associated systemic abnormalities include cataracts, cardiac arrhythmias, and testicular atrophy. The proximal weakness and absence of signature features make DM2 a more difficult clinical diagnosis than DM1.

Serum CK may be mildly increased. EMG demonstrates myotonia, which often provides an important diagnostic clue when evaluating patients with typical clinical pictures of proximal myopathies. Genetic studies for zinc finger protein 9 on chromosome 3 will reveal >177 base pairs CCTG expansion.

Limb-Girdle Muscular Dystrophies

Limb-girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of disorders wherein the precise classification is rendered more complicated by the frequency of variable phenotypes resulting from mutations of the same gene. It is difficult to distinguish clinically the various subtypes of LGMD, although patterns of weakness or other clinical features may suggest various genotypes. Classification of LGMDs is by number (1 for dominant inheritance, 2 for recessive) and letter (usually in the order of discovery of the chromosomal locus) (see Table 75-1).

Weakness in these individuals typically has a symmetric limb-girdle pattern, usually affecting the proximal leg muscles before the shoulder girdle. There is relative sparing of facial, oculomotor, pharyngeal, and neck muscles. Onset is usually before the age of 20 years, although LGMD is frequently unrecognized until early middle life, and women and men are affected as frequently. Systemic involvement is uncommon. CK increases range from normal to 20 times normal. Genetic testing is available for some of the LGMD.

Dystrophinopathies

These dystrophinopathies are the most common muscular dystrophies occurring during childhood and in some adults. Dystrophin is a subsarcolemmal protein present in skeletal and cardiac muscle. Dystrophin along with the sarcolemmal proteins forms the dystrophin-sarcoglycan complex (Fig. 75-10).

Figure 75-10 Sarcoglycan Complex and Sarcomere Proteins.

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a primarily X-linked recessive dystrophinopathy; however, in a third of patients this occurs sporadically, presenting in early childhood with proximal weakness and difficulty walking (Fig. 75-11). Untreated patients, usually boys, become wheelchair dependent by midadolescence. Calf hypertrophy, heel cord shortening, and blunted intellect help to differentiate this disorder from other myopathies. Common initial signs are a clumsy gait, frequent falls, and proximal lower extremity weakness. Children cannot rise from a squatting position on the floor and use their hands to push off on their legs (Fig. 75-12). Most patients are wheelchair bound by 12 years of age.

Figure 75-11 Duchenne Muscular Dystrophy.

Figure 75-12 Duchenne Muscular Dystrophy: Gowers maneuver.

An associated cardiomyopathy is common and can cause arrhythmias or congestive heart failure. Respiratory failure due to neuromuscular weakness may be exacerbated by the development of kyphoscoliosis and contractures. Most patients die of respiratory or cardiac complications in the second or third decade of life unless they choose long-term mechanical ventilation. Smooth muscle involvement may occur, manifesting as an ileus or gastric atony.

Female carriers often have asymptomatic hyperCKemia but very rarely do present with symptomatic myopathies as adults.

CK levels are significantly elevated to approximately 30–50 times normal. Serum molecular genetic testing for mutations in the dystrophin gene is the first step in children in whom a dystrophinopathy is suspected. This is positive in approximately two thirds of these boys. When DNA analysis is negative, a muscle biopsy is indicated for dystrophin immunostaining, immunoblotting, or Western blot analysis. Immunostaining demonstrates that most fibers are devoid of dystrophin in DMD. Electrodiagnostic studies and muscle biopsy, once the mainstays of diagnosis, are no longer necessary in most cases. Needle EMG demonstrates myopathic-appearing motor units as well as profuse fibrillation potentials.

Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral (FSH) muscular dystrophy is a dominantly inherited disorder with variable penetrance. Patients may present with facial weakness and scapular winging in the second to fifth decade of life (Fig. 75-13). Atrophy and weakness of biceps and triceps muscles typically occur; paradoxically, there is relative sparing of deltoid and forearm strength. Ankle dorsiflexors are usually first affected in the lower extremity. An asymmetric pattern of weakness is a common feature. Abdominal muscle weakness and a Beevor sign (caudal or rostral movement of the umbilicus with head flexion) may be present. Variations in phenotype include the rare absence of any demonstrable facial weakness. An infantile form presents with a rapidly progressive course leading to wheelchair dependency by the age of 10 years.

Figure 75-13 Other Types of Muscular Dystrophy.

Electrodiagnostic studies demonstrate myopathic findings. Genetic testing (a D4Z4 repeat contraction on chromosome 4q35) reveals mutations on the 4q35 chromosomal region. More recently a subset of patients with FSHD who do not have this contraction has been observed.

Scapuloperoneal Syndromes

These various disorders need consideration in the differential diagnosis of FSH. The genetic pattern in scapuloperoneal syndromes may be autosomal dominant or recessive, sometimes X-linked, or even sporadic. Usually, these children present with arm weakness before a foot drop is recognized. Most patients have normal longevity with relatively mild disability.

Emery–Dreifuss Muscular Dystrophy

This is inherited in either an X-linked or autosomal dominant manner. Distinctive features include a humeroperoneal (elbow flexion and extension, foot dorsiflexion) pattern of weakness and contractures (especially of the Achilles tendons, elbows, and posterior cervical muscles). Most patients present with contractures causing difficulty extending the elbows and dorsiflexing the ankles.

Cardiac conduction defects are common causes of stroke and life-threatening arrhythmias, and sometimes the clinically presenting feature of this disorder. Genetic tests will reveal mutations in the EMD gene on chromosome Xq28(X-linked form) or in the LMNA gene on chromosome 1q11-23 (autosomal dominant form).

Bethlem Myopathy

This is an autosomal disorder similar to Emery–Dreifuss muscular dystrophy with early childhood onset. It is an indolent myopathy also having prominent elbow flexion contractures but without cardiac complications.

Oculopharyngeal Muscular Dystrophy

This autosomal dominant myopathy is particularly prevalent in North America among individuals of French Canadian ancestry. Most patients present in mid- to late adulthood with ptosis and dysphagia. Mild proximal weakness and ophthalmoparesis may develop. Genetic testing for the presence of a GCG repeat in the PABN1 gene on chromosome 14q11.1 if positive will confirm the diagnosis (see Fig. 75-13, bottom right panel).

Myofibrillar (Desmin) Myopathy

Genetically and phenotypically, this disorder is characterized by desmin or other protein accumulation within the muscle. Electron microscopy (EM) findings demonstrate the presence of myofibrillar disruption, probably due to Z-disk disruption. The clinical phenotype is varied. Diagnosis is made by the presence of the characteristic histologic features. It can present at any age with proximal or distal weakness. Surveillance for associated cardiomyopathy, ventilatory insufficiency, or both is required. Mutations have been identified in myotilin, ZASP, filamin-C, desmin, selenoprotein n, alphabeta crystallin, and bag-3. Pattern of inheritance is variable.

Congenital Muscular Dystrophies

These are a heterogeneous group of recessively inherited neonatal disorders commonly confused with congenital myopathies, particularly when infants are hypotonic, often presenting as floppy babies. Children with congenital muscular dystrophy often have joint contractures or arthrogryposis. Some forms are associated with associated brain or ocular abnormalities. These clinical features coupled with increased CK values and dystrophic muscle histology distinguish congenital muscular dystrophies from congenital myopathies and other infantile neuromuscular disorders.

Distal Myopathies or Muscular Dystrophies

The distal myopathies are rare and present with progressive, distal weakness and may be sporadic or inherited. The distal myopathies are classified based on the inheritance, pattern of weakness, and histopathologic findings (Table 75-5). It is important to remember that other myopathies can present with a distal pattern of weakness, for example, DM1, EDMD, FSHD, scapuloperoneal, nemaline myopathy, and centronuclear myopathy due to dynamin-2 mutation.

Congenital Myopathies

These disorders are usually evident at birth or in infancy. They may be severe but often tend to be only minimally progressive if the child survives infancy. Affected children are often limited in their physical capacities, but many live to adulthood. These myopathies are typically named for key histologic features, for example, nemaline (threadlike) rods.

The most common congenital myopathies are centronuclear (myotubular) myopathy, central core disease, and nemaline myopathy (see Fig. 75-8, bottom panel). These are well-defined clinically and genetically heterogeneous disorders. Concomitant congenital skeletal changes such as high arched palates and kyphoscoliosis are commonplace and are suggestive of these genetically determined disorders. Although the presentation is usually that of a floppy infant, some individuals are mildly affected and may not present until early to midadulthood. Babies surviving infancy tend to have minimal progression and reasonable life expectancy.

Centronuclear myopathy, previously called myotubular myopathy, is a disorder associated with characteristic muscle biopsy findings of central nuclei. It is seen as an X-linked recessive neonatal disorder frequently causing death from respiratory insufficiency in infancy, or rarely presents indolently in childhood or early adulthood. Ptosis and ophthalmoparesis help distinguish this from other congenital myopathies. Muscle biopsy demonstrates nuclei in the center of the fiber, sometimes forming longitudinal chains. Mutations in myotubularin or dynamin are linked to this condition.

Central core myopathy presents in infancy or childhood with generalized weakness. Muscle biopsies demonstrate cores that appear in type 1 fibers and are seen on NADH stains as nonstaining regions. Z-band streaming and myofibrillar disruption may result in the formation of cores. This condition is associated with an increased risk for malignant hyperthermia; this is particularly seen on exposure to volatile anesthetics or depolarizing neuromuscular blockers.

Nemaline myopathy can present at any age from infancy to adulthood and is phenotypically and genetically heterogeneous. Affected children have delayed motor milestones, but those surviving past infancy eventually achieve some degree of functional independence. On muscle biopsy there is type 1 predominance, with the presence of nemaline rods in the subsarcolemmal region best seen on Gomori trichrome stain. EM is useful to confirm the presence of the rods. The rods are thought to represent disrupted Z-disk structure.

The diagnosis of congenital myopathies is usually confirmed with routine histochemical staining of muscle in concert with the appropriate phenotype. A few metabolic myopathies can be diagnosed by histochemical staining, but many require biochemical analysis of the muscle biopsy specimen or other tissue.

Hereditary Inclusion Body Myopathy

The hereditary inclusion body myopathies (IBMs) are difficult to classify. They manifest in the second or third decades of life and are histologically identical to sporadic IBMs but without inflammation. Two forms are allelic to distal myopathies. Their genetic bases relate to mutations in the gene encoding the enzyme complex UDP-N-acetylglucosamine-2-epimerase-N-acetylmannosamine kinase (GNE), which catalyzes the rate-limiting step in sialic acid production. An autosomal dominant form of hereditary IBM associated with frontotemporal dementia and Paget disease of the bone has been linked to mutations in the gene encoding for valsolin containing protein (VCP). Another form presents with congenital arthrogryposis and has been linked to mutations in the MYH2 gene.

Diagnostic Approach to Genetic Myopathies

The diagnostic testing required in patients with generalized chronic myopathies varies depending on clinical presentation (Table 75-6), as provided in guidelines for routinely and selectively ordered tests. Many diagnostic tools are available for evaluating a patient with an apparent myopathy. Extensive analyses of muscle should be undertaken only when warranted by a reasonable index of clinical suspicion.

Table 75-6 Evaluation of a Patient with Suspected Muscle Disease*