Episodic, reversible weakness or paralysis known as periodic paralysis is associated with transient alterations in serum potassium levels, usually hypokalemia but occasionally hyperkalemia. All familial forms of periodic paralysis are caused by mutations in genes encoding voltage-gated ion channels in muscle: sodium, calcium, and potassium (see Table 603-1). During attacks, myofibers are electrically inexcitable, although the contractile apparatus can respond normally to calcium. The disorder is inherited as an autosomal dominant trait. It is precipitated in some patients by a heavy carbohydrate meal, insulin, epinephrine including that induced by emotional stress, hyperaldosteronism or hyperthyroidism, administration of amphotericin B, or ingestion of licorice. The defective genes are at the 17q13.1-13.3 locus in hyperkalemic periodic paralysis, the same as in paramyotonia congenita, and at the 1q31-32 locus in hypokalemic periodic paralysis.

Attacks often begin in infancy, particularly in the hyperkalemic form, and the disease is nearly always symptomatic by 10 yr of age, affecting both sexes equally. Late childhood or adolescence is the more typical age of onset of the hypokalemic form, Andersen-Tawil syndrome (see later) and paramyotonia congenita. Periodic paralysis is an episodic event; patients are unable to move after awakening and gradually recover muscle strength during the next few minutes or hours. Muscles that remain active in sleep, such as the diaphragm and cardiac muscle, are not affected. Patients are normal between attacks, but in adult life the attacks become more frequent, and the disorder causes progressive myopathy with permanent weakness even between attacks. The usual frequency of attacks in childhood is once a week. The differential diagnosis includes thyrotoxic periodic paralysis, myotonia congenita, and paramyotonia congenita. A triad of periodic paralysis, potentially fatal cardiac ventricular ectopy (due to a defect in Kir2.1 channels for terminal repolarization), and characteristic physical features is known as Andersen-Tawil syndrome.

Alterations in serum potassium level occur only during acute episodes and are accompanied by T-wave changes in the electrocardiogram. Hypokalemia may be due to alterations in calcium gradients. The creatine kinase (CK) level may be mildly elevated at those times. Plasma phosphate levels often decrease during symptomatic periods. Muscle biopsy findings are often normal between attacks, but during an attack a vacuolar myopathy is demonstrated. Pathologic changes in the periodic paralyses are similar whether the disease is due to a sodium or a potassium channel defect, suggesting that they might result from the recurrent paralytic state rather than the specific channelopathy. The vacuoles are dilated sarcoplasmic reticulum and invaginations of the extracellular space into the cytoplasm, and they may be filled with glycogen. Hypoglycemia does not occur. Loci for the majority of periodic paralyses have been demonstrated and the genes at least partially characterized, but many patients with the same clinical phenotype exhibit no mutations in the identified genes.

(See also Chapter 81.1.)

Glycogenosis I (von Gierke disease) is not a true myopathy because the deficient liver enzyme glucose-6-phosphatase is not normally present in muscle. Nevertheless, children with this disease are hypotonic and mildly weak for unknown reasons.

Glycogenosis II (Pompe disease) is an autosomal recessively inherited deficiency of the glycolytic lysosomal enzyme acid maltase. Of the 12 known glycogenoses, type II is the only one with a defective lysosomal enzyme. The defective gene is at locus 17q23. Two forms are described. The infantile form is a severe generalized myopathy and cardiomyopathy. Patients have cardiomegaly and hepatomegaly and are diffusely hypotonic and weak. The serum CK level is greatly elevated. A muscle biopsy specimen reveals a vacuolar myopathy with abnormal lysosomal enzymatic activities such as acid and alkaline phosphatases. Evidence of a secondary mitochondrial cytopathy also is often demonstrated; it includes electron microscopic demonstration of paracrystallin structures within muscle mitochondria and low concentrations of respiratory chain enzymes. Death in infancy or early childhood is usual; however, enzyme replacement therapy has improved the outcome.

The late childhood or adult form is a much milder myopathy without cardiac or hepatic enlargement. It might not become clinically expressed until later childhood or early adult life but may be symptomatic as myopathic weakness and hypotonia even in early infancy. Even in late adult-onset acid maltase deficiency, >50% of the patients report difficulties with muscle strength dating from childhood. Ultrastructural evidence of secondary mitochondrial cytopathy also occurs, as with infantile Pompe disease.

The serum CK level is greatly elevated, and the muscle biopsy findings are diagnostic even in the presymptomatic stage. The diagnosis of glycogenosis II is confirmed by quantitative assay of acid maltase activity in muscle or liver biopsy specimens. A rare KM variant of the milder form of acid maltase deficiency can show muscle acid maltase activity in the low normal range with only intermittent decreases to subnormal values, but the muscle biopsy findings are similar although milder. In another form, Danon disease, transmitted as an X-linked recessive trait at the Xq24 locus, the primary deficiency is lysosomal membrane protein-2 (LAMP2) and results in hypertrophic cardiomyopathy, proximal myopathy, and mental retardation.

Glycogenosis III (Cori-Forbes disease), deficiency of debrancher enzyme (amylo-1,6-glucosidase), is more common than is usually diagnosed, and it is generally the least severe. Hypotonia, weakness, hepatomegaly, and fasting hypoglycemia in infancy are common, but these features often resolve spontaneously, and patients become asymptomatic in childhood and adult life. Others experience slowly progressive distal muscle wasting, hepatic cirrhosis, recurrent hypoglycemia, and heart failure. This more serious chronic course is particularly seen in the Inuit population. Minor myopathic findings including vacuolation of muscle fibers are found in the muscle biopsy specimen.

Glycogenosis IV (Andersen disease) is a deficiency of brancher enzyme, resulting in the formation of an abnormal glycogen molecule, amylopectin, in the liver, reticuloendothelial cells, and skeletal and cardiac muscle. Hypotonia, generalized weakness, muscle wasting, and contractures are the usual signs of myopathic involvement. Most patients die before age 4 yr because of hepatic or cardiac failure. A few children without neuromuscular manifestations have been described.

Glycogenosis V (McArdle disease) is due to muscle phosphorylase deficiency inherited as an autosomal recessive trait at locus 11q13. Exercise intolerance is the cardinal clinical feature. Physical exertion results in cramps, weakness, and myoglobinuria, but strength is normal between attacks. The serum CK level is elevated only during exercise. A characteristic clinical feature is lack of the normal rise in serum lactate level during ischemic exercise because of inability to convert pyruvate to lactate under anaerobic conditions in vivo. Myophosphorylase deficiency may be demonstrated histochemically and biochemically in the muscle biopsy tissue. Some patients have a defect in adenosine monophosphate (AMP)-dependent muscle phosphorylase-b-kinase, a phosphorylase enzyme activator. Muscle phosphorylase deficiency was the first neuromuscular disease to be diagnosed by MR spectroscopy, which shows that intramuscular pH does not decrease with exercise and there is no depletion of adenosine triphosphatase (ATPase), but the phosphocreatine concentration falls excessively. This noninvasive technique may be useful in some patients if the radiologist is experienced with the disease.

A rare neonatal form of myophosphorylase deficiency causes feeding difficulties in early infancy, may be severe enough to result in neonatal death, or can follow a course of slowly progressive weakness resembling a muscular dystrophy. The long-term prognosis is good. Patients must learn to moderate their physical activities, but they do not develop severe chronic myopathic handicaps or cardiac involvement.

Glycogenosis VII (Tarui disease) is muscle phosphofructokinase deficiency. Although this disease is rarer than glycogenosis V, the symptoms of exercise intolerance, clinical course, and inability to convert pyruvate to lactate are identical. The distinction is made by biochemical study of the muscle biopsy specimen. It is transmitted as an autosomal recessive trait at the 1cenq32 locus.

(See also Chapters 81.4 and 591.2.)

Several diseases involving muscle, brain, and other organs are associated with structural and functional abnormalities of mitochondria, producing defects in aerobic cellular metabolism, the electron transport chain, and the Krebs cycle. The structural aberrations are best demonstrated by electron microscopy of the muscle biopsy sample, revealing a proliferation of abnormally shaped cristae including stacked or whorled cristae that fuse to form paracrystalline structures. Histochemical study of the muscle biopsy specimen reveals abnormal clumping of oxidative enzymatic activity and scattered myofibers, with loss of cytochrome-c oxidase activity and with increased neutral lipids within myofibers and/or ragged-red muscle fibers in some mitochondrial myopathies, with accumulations of membranous material beneath the muscle fiber membrane, best demonstrated by special stains.

These characteristic histochemical and ultrastructural changes are most consistently seen with point mutation in mitochondrial transfer RNA. The large mitochondrial DNA (mtDNA) deletions of 5 or 7.4 kb (the single mitochondrial chromosome has 16.5 kb) are associated with defects in mitochondrial respiratory oxidative enzyme complexes, if as few as 2% of the mitochondria are affected, but minimal or no morphologic or histochemical changes may be noted in the muscle biopsy specimen, even by electron microscopy; hence, quantitative biochemical studies of the muscle tissue are needed to confirm the diagnosis. Because most of the subunits of the respiratory chain complexes are encoded by nuclear DNA (nDNA) rather than mtDNA, mendelian autosomal inheritance is possible rather than maternal transmission as with pure mtDNA point mutations. Serum lactate is elevated in some diseases, and cerebrospinal fluid (CSF) lactate is more consistently elevated, even if serum concentrations are normal.

Several distinct mitochondrial diseases that primarily affect striated muscle or muscle and brain are identified. These can be divided into the ragged red fiber diseases and non–ragged fiber diseases. The ragged red fiber diseases include Kearns-Sayre, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) syndrome, MERRF (myoclonic epilepsy with ragged-red fibers) syndrome, and progressive external ophthalmoplegia syndromes, which are associated with a combined defect in respiratory chain complexes I and IV. The non–ragged fiber diseases include Leigh encephalopathy and Leber hereditary optic atrophy; they involve complex I or IV alone or, in children, the common combination of defective complexes III and V. Kearns-Sayre syndrome is characterized by the triad of progressive external ophthalmoplegia, pigmentary degeneration of the retina, and onset before age 20 yr. Heart block, cerebellar deficits, and high CSF protein content are often associated. Visual evoked potentials are abnormal. Patients usually do not experience weakness of the trunk or extremities or dysphagia. Most cases are sporadic.

Chronic progressive external ophthalmoplegia may be isolated or accompanied by limb muscle weakness, dysphagia, and dysarthria. A few patients described as having ophthalmoplegia plus have additional central nervous system (CNS) involvement. Autosomal dominant inheritance is found in some pedigrees, but most cases are sporadic.

MERRF and MELAS syndromes are other mitochondrial disorders affecting children. The latter is characterized by stunted growth, episodic vomiting, seizures, and recurrent cerebral insults causing hemiparesis, hemianopia or even cortical blindness, and dementia. The disease behaves as a degenerative disorder, and children die within a few years.

Other “degenerative” diseases of the CNS that also involve myopathy with mitochondrial abnormalities include Leigh subacute necrotizing encephalopathy (Chapter 81.4) and cerebrohepatorenal (Zellweger) disease (Chapter 80.2). Another recognized mitochondrial myopathy is cytochrome-c oxidase deficiency. Oculopharyngeal muscular dystrophy is also fundamentally a mitochondrial myopathy. Mitochondrial depletion syndrome of early infancy is characterized by severely decreased oxidative enzymatic activities in all 5 of the complexes; in addition to diffuse muscle weakness, neonates and young infants can show multisystemic involvement, with failure of liver, kidney, and heart functions; encephalopathy; and sometimes bullous skin lesions or generalized edema. Many other rare diseases with only a few case reports are suspected of being mitochondrial disorders. It is also now recognized that secondary mitochondrial defects occur in a wide range of non-mitochondrial diseases, including inflammatory autoimmune myopathies, Pompe disease, and some cerebral malformations, and also may be induced by certain drugs and toxins, so that interpretation of mitochondrial abnormalities as primary defects must be approached with caution.

mtDNA is distinct from the DNA of the cell nucleus and is inherited exclusively from the mother; mitochondria are present in the cytoplasm of the ovum but not in the head of the sperm, the only part that enters the ovum at fertilization. The rate of mutation of mtDNA is 10 times higher than that of nDNA. The mitochondrial respiratory enzyme complexes each have subunits encoded either in mtDNA or nDNA. Complex II (succinate dehydrogenase, a Krebs cycle enzyme) has 4 subunits, all encoded in nDNA; complex III (ubiquinol or cytochrome-b oxidase) has 9 subunits, only 1 of which is encoded by mtDNA and 8 of which are programmed by nDNA; complex IV (cytochrome-c oxidase) has 13 subunits, only 3 of which are encoded by mtDNA. For this reason, mitochondrial diseases of muscle may be transmitted as autosomal recessive traits rather than by strict maternal transmission, even though all mitochondria are inherited from the mother.

In Kearns-Sayre syndrome, a single large mtDNA deletion has been identified, but other genetic variants are known; in MERRF and MELAS syndromes of mitochondrial myopathy, point mutations occur in transfer RNA (see Table 600-1).

Investigation for mitochondrial cytopathies includes serum and sometimes CSF lactate, cardiac evaluation, and molecular markers in blood for the common diseases with known mtDNA point mutations. The muscle biopsy provides the best evidence of all mitochondrial myopathies and should include histochemistry for oxidative enzymes, electron microscopy, and quantitative biochemical assay of respiratory chain enzymes complexes and coenzyme-Q10; muscle tissue also can be analyzed for mtDNA.

There is no effective treatment of mitochondrial cytopathies, but various “cocktails” are often used empirically to try to overcome the metabolic deficits. These include oral carnitine supplements, riboflavin, coenzyme-Q₁₀, ascorbic acid (vitamin C), vitamin E, and other antioxidants. Although some anecdotal reports are encouraging, no controlled studies that prove efficacy have been published.

(See Chapter 80.4.)

Considered as metabolic organs, skeletal muscles are the most important sites in the body for long-chain fatty acid metabolism because of their large mass and their rich density of mitochondria where fatty acids are metabolized. Hereditary disorders of lipid metabolism that cause progressive myopathy are an important, relatively common, and often treatable group of muscle diseases. Increased lipid within myofibers is seen in the muscle biopsy of some mitochondrial myopathies and is a constant, rather than an unpredictable, feature of specific diseases. Among the ragged red fiber diseases, Kearns-Sayre syndrome always shows increased neutral lipid, whereas MERRF and MELAS syndromes do not, a useful diagnostic marker for the pathologist.

Muscle carnitine deficiency is an autosomal recessive disease involving deficient transport of dietary carnitine across the intestinal mucosa. Carnitine is acquired from dietary sources but is also synthesized in the liver and kidneys from lysine and methionine; it is the obligatory carrier of long- and medium-chain fatty acids into muscle mitochondria.

The clinical course may be one of sudden exacerbations of weakness or can resemble a progressive muscular dystrophy with generalized proximal myopathy and sometimes facial, pharyngeal, and cardiac involvement. Symptoms usually begin in late childhood or adolescence or may be delayed until adult life. Progression is slow but can end in death.

Serum CK level is mildly elevated. Muscle biopsy material shows vacuoles filled with lipid within muscle fibers in addition to nonspecific changes suggestive of a muscular dystrophy. Mitochondria can appear normal or abnormal. Carnitine measured in muscle biopsy tissue is reduced, but the serum carnitine level is normal.

Treatment stops the progression of the disease and can even restore lost strength if the disease is not too advanced. It consists of special diets low in long-chain fatty acids. Steroids can enhance fatty acid transport. Specific therapy with L-carnitine taken orally in large doses overcomes the intestinal barrier in some patients. Some patients also improve when given supplementary riboflavin, and other patients seem to improve with propranolol.

Systemic carnitine deficiency is a disease of impaired renal and hepatic synthesis of carnitine rather than a primary myopathy. Patients with this autosomal recessive disease experience progressive proximal myopathy and show muscle biopsy changes similar to those of muscle carnitine deficiency; however, the onset of weakness is earlier and may be evident at birth. Endocardial fibroelastosis also can occur. Episodes of acute hepatic encephalopathy resembling Reye syndrome can occur. Hypoglycemia and metabolic acidosis complicate acute episodes.

The concentration of carnitine is reduced in serum as well as in muscle and liver. A similar clinical syndrome may be a complication of renal Fanconi syndrome because of excessive urinary loss of carnitine or loss during chronic hemodialysis.

Treatment with L-carnitine improves the maintenance of blood glucose and serum carnitine levels but does not reverse the ketosis or acidosis or improve exercise capacity.

Muscle carnitine palmitoyltransferase (CPT) deficiency manifests as episodes of rhabdomyolysis, coma, and elevated serum CK level that may be indistinguishable from Reye syndrome. CPT transfers long-chain fatty acid acyl coenzyme A residues to carnitine on the outer mitochondrial membrane for transport into the mitochondria. Exercise intolerance and myoglobinuria resemble glycogenoses V and VII. The degree of exercise that triggers an attack varies among individuals, ranging from casual walking to strenuous exercise. Myoglobinuria is an inconstant feature. Fasting hypoglycemia can occur. Some patients present only in late adolescence or adult life with myalgias. Genetic transmission is autosomal recessive and is caused by a defect on chromosome 1 at the 1p32 locus. Administration of valproic acid can precipitate acute rhabdomyolysis with myoglobinuria in patients with CPT deficiency; it should be avoided in the treatment of seizures or migraine if they occur.

In experimental animals, deficiency of vitamin E (α-tocopherol, an antioxidant also important in mitochondrial superoxide generation) produces a progressive myopathy closely resembling a muscular dystrophy. Myopathy and neuropathy are recognized in humans who lack adequate intake of this antioxidant. Patients with chronic malabsorption, those undergoing long-term dialysis, and premature infants who do not receive vitamin E supplements are particularly vulnerable. Treatment with high doses of vitamin E can reverse the deficiency. Myopathy due to chronic hypervitaminosis E also occurs.