a. Muscle phosphorylase deficiency (McArdle disease). This inherited deficiency of skeletal muscle phosphorylase is more common than acid maltase deficiency or PFK deficiency; 60 cases have been reported. The female-to-male ratio is 1:4. Childhood symptoms of fatigue are usually overlooked. A characteristic pattern of exercise-induced muscle pains, stiffness, and weakness, which resolves with rest, occurs after puberty. Prolonged exercise results in severe cramps of the exerted muscles. Myoglobinuria and muscle necrosis may occur if exercise is strenuous; however, exercise tolerance may improve after a nonstrenuous warm-up period ("second-wind" phenomenon). As the result of recurrent attacks of myoglobinuria, some patients have a persistent proximal myopathy. The muscle cramps are actually contractions, which may last several hours.
1. Laboratory studies. Serum CK is increased. Venous lactic acid levels do not rise with the ischemic forearm exercise test (see final the section of this chapter, Laboratory Aids to Diagnosis). Muscle biopsy shows vacuoles that stain with periodic acid-Schiff (PAS) beneath the sarcolemma and scattered necrotic or regenerating muscle fibers.
2. Treatment. There is no long-term effective treatment.
b. Muscle phosphofructokinase deficiency results in a syndrome similar to McArdle disease. Easy fatigability occurs during childhood. Later, exercise-induced muscle pain or cramps with myoglobinuria occur. However, unlike those of McArdle disease, exercise-induced symptoms here often include nausea and vomiting. This is an autosomal recessive disease.
1. Laboratory studies. Serum CK is increased. Venous lactate levels do not rise after the ischemic forearm exercise test. A mild hemolytic anemia occurs when PFK is absent from erythrocytes, which may be helpful diagnostically. Diagnosis is confirmed by the absence of PFK activity on direct measurement in muscle biopsy by biochemical or histochemical methods.
2. Treatment. No generally effective therapy is available.
c. Deficiency of other enzymes in the glycolytic pathway also may lead to myopathy with impaired generation of lactate from glucose. These include the following:
1. Glycogen debrancher.
2. Phosphoglycerate kinase.
3. Phosphoglycerate mutase.
4. Lactate dehydrogenase (M subunit).
B. Disorders of lipid metabolism. Glycogen provides energy for work of short duration, whereas fatty acids provide energy for periods of rest, prolonged low-intensity exercise, and fasting. This knowledge allows prediction of the symptoms of abnormal fatty acid metabolism in muscle.
1. Carnitine palmityltransferase (CPT) deficiency is inherited as an autosomal recessive disorder with a male preponderance. Patients with CPT deficiency tolerate short periods of exercise normally. However, after prolonged exercise or fasting, muscular pains and myoglobinuria develop. Muscle strength is normal between attacks. There is no second-wind phenomenon.
a. Laboratory studies. Serum CK is normal at rest but elevated during attacks. There is a normal rise in venous lactate with the ischemic forearm exercise test. Hypertriglyceridemia, which is probably related to the impaired fatty acid utilization of CPT deficiency, may be found. The muscle biopsy specimen may be normal or show intrafiber lipid droplets. A screening test is a 38-hour fast, which will cause an elevation in serum CK.
Diagnosis is confirmed by biochemical assay of CPT activity in muscle.
b. Treatment. Therapy consists of eating regular meals and avoiding prolonged exertion. A diet high in carbohydrates and low in fats is effective in reducing the incidence of acute attacks.
2. Carnitine deficiency occurs in two forms, an isolated myopathy or a systemic disorder.
a. Isolated muscle carnitine deficiency is characterized by childhood onset of a slowly progressive limb-girdle weakness. Facial and pharyngeal muscles may be involved. Deep tendon reflexes are decreased or absent.
1. Laboratory studies. Serum CK is moderately increased. EMG reveals a myopathic pattern. Serum carnitine levels are normal or slightly decreased. Muscle biopsy shows prominent intrafiber lipid droplets, especially in type 1 fibers. Carnitine levels in muscle are reduced to one-tenth to one-fifth of normal.
2. Treatment. Preferred long-term treatment is oral administration of carnitine with a medium-chain triglyceride diet. Prednisone is effective but not desirable as long-term treatment.
b. Systemic carnitine deficiency presents with myopathy and hepatic insufficiency. Hepatic encephalopathy and attacks of lactic acidosis occur. Death usually occurs by age 20.
1. Laboratory studies. Patients uniformly have decreased levels of serum carnitine. Carnitine deficiency states are often associated with other primary metabolic defects.
2. Treatment with oral carnitine has resulted in improved strength and normalization of hepatic function in some cases.
C. Disorders associated with abnormal serum potassium. These interrelated syndromes of muscular weakness are associated with either hypokalemia or hyperkalemia. The exact pathogenetic role of potassium in these disorders is largely unknown.
1. Familial periodic paralysis. An autosomal dominant disease, this disorder is characterized by attacks of intense weakness of limb muscles that progress to complete paralysis. Attacks begin in adolescence or early adulthood and occur less frequently with age. There is marked hypotonia and absent-to-decreased tendon reflexes during attacks. Strenuous exercise or a high intake of carbohydrates may precipitate attacks. Chronic myopathy may occur after repeated attacks.
a. Laboratory studies. Serum CK is elevated and serum potassium is low during attacks. Muscle biopsy shows vacuolar changes.
b. Differential diagnosis. Hyperaldosteronism and hyperthyroidism with periodic paralysis may mimic the syndrome. The use of diuretics or cathartics may also cause similar symptoms.
c. Treatment is with oral potassium (2 to 8 g of potassium chloride until the attack resolves) or intravenous potassium (50 mEq over several hours).
2. Adynamia episodica hereditaria (Gamstorp's disease). This autosomal dominant disease is characterized by attacks of weakness or paralysis of skeletal muscle, similar to those of familial periodic paralysis. The onset is between ages 5 and 10 years. The disease is most active during the adolescent years, after which it subsides. Attacks are precipitated by prolonged exertion or by administration of 2 to 5 g of potassium chloride.
a. Laboratory studies. During attacks, the serum potassium is elevated, although high normal values have been noted. Between attacks, the patient is asymptomatic and serum potassium is normal, although persistent weakness may last for several days after an attack. Serum CK is elevated.
b. Treatment with potassium-lowering agents, such as 50 to 100 mg of hydrochlorothiazide PO daily, is effective in preventing attacks.
D. Deficiency of myoadenylate deaminase. Deficiency of this enzyme has been associated with post-exertional cramps and myalgia. It has been suggested that impairment in the function of adenylate deaminase may lead to reduced entry of adenine nucleotides into the purine nucleotide cycle during exercise and that this may be responsible for the observed abnormalities.
E. Mitochondrial myopathies. Abnormalities in mitochondrial genetics can produce a variety of myopathic disorders, from ophthalmologic states to myopathies associated with encephalopathy and lactic acidoses. In addition, mitochondrial dysfunction can be manifested in different phenotypes affecting skeletal and cardiac muscle, the nervous system, and the kidneys. Diagnosis can be approached by family history, which may demonstrate a pattern of maternal inheritance; microscopy of biopsied tissue demonstrating structural abnormalities of mitochondria (e.g., subsarcolemmal aggregates in myofibers, the so-called "ragged red" fibers); and biochemical studies demonstrating abnormalities in components of oxidative phosphorylation, such as cytochrome oxidase.
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