Metabolic myopathies: a clinical approach; part II

Review Article

Metabolic Myopathies: A Clinical Approach; Part II Basil T. Darras, MD* and Neil R. Friedman, MBChB† Major recent advances in the field of metabolic myopathies have helped delineate the genetic and biochemical basis of these disorders. This progress has also resulted in the development of new diagnostic and therapeutic methodologies. In this second part, we present an updated review of the main nonlysosomal and lysosomal glycogenoses and lipid metabolism defects that manifest with signs of transient or permanent muscle dysfunction. Our intent is to increase the pediatric neurologist’s familiarity with these conditions and thus improve decision making in the areas of diagnosis and treatment. © 2000 by Elsevier Science Inc. All rights reserved. Darras BT, Friedman NR. Metabolic myopathies: A clinical approach, Part II. Pediatr Neurol 2000;22:171-181.

on the two main enzymes of glycogen metabolism: glycogen synthetase and phosphorylase [2]. Phosphorylase exists as the more active a form and the less active b form (Fig 1). PBK induces the activation of phosphorylase b to phosphorylase a and, concurrently, catalyzes the conversion of glycogen synthetase from a more active to a less active form. Because of these activities, glycogen degradation is active when glycogen synthesis is inactive and vice versa. PBK is a multimeric enzyme consisting of four different subunits, alpha, beta, gamma, and delta [3,4]. The alpha subunit is encoded by two distinct genes (PHKA1 and PHKA2) on the proximal long arm and the distal short arm of the X chromosome [5,6]. PHKA1 encodes a muscle isozyme, and PHKA2 encodes a liver isozyme. Clinical features. The mode of inheritance and the tissue-specific involvement differentiate the four main subtypes of PBK deficiency:

Introduction Patients with metabolic myopathies have an underlying deficiency of energy metabolism in muscle that may be the result of a wide variety of defects, including defects in glycogen/glucose metabolism [1] (Fig 1), lipid metabolism, and other metabolic pathways. In Part I a clinical approach to the evaluation of these patients was discussed. A detailed, updated discussion of these disorders is presented here. Nonlysosomal and Lysosomal Glycogenoses Nonlysosomal Glycogenoses Phosphorylase b Kinase Deficiency (Glycogenosis Type VIII). Biochemistry/molecular genetics. Phosphorylase b kinase (PBK) is an important regulatory enzyme that acts

From the *Neuromuscular Program; Department of Neurology; Children’s Hospital; Department of Neurology (Pediatrics); Harvard Medical School; and †Department of Neurology; Children’s Hospital; Boston, Massachusetts.

© 2000 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00122-8 ● 0887-8994/00/$20.00

1. Myopathy. This subtype presents primarily with exercise intolerance, cramps, myalgias, weakness in exercising muscles, myoglobinuria, and in rare cases, hypotonia in young children and infants [7]; in older individuals, progressive distal weakness is more prominent than proximal weakness [8,9]. Myopathy appears to be inherited as an autosomal-recessive trait; however, in certain patients the possibility of X chromosome-linked inheritance cannot be excluded. 2. Liver and muscle disease. This subtype is characterized by liver enlargement, nonprogressive muscle disease in childhood, and autosomal-recessive inheritance [8]. 3. Fatal infantile cardiomyopathy. Fatal infantile cardiomyopathy has been described in children and is probably inherited as an autosomal-recessive trait [10]. 4. Liver disease alone. This subtype is a benign X-linked or an autosomal-recessive condition manifested by

Communications should be addressed to: Dr. Darras; Director, Neuromuscular Program; Neurology Department; Fegan 11; Children’s Hospital; 300 Longwood Avenue; Boston, MA 02115. Received May 13, 1999; accepted October 11, 1999.

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Figure 1. Metabolic pathways of glycogen metabolism and glycolysis. The diagram illustrates the sites of enzymatic defects that result in clinical glycogenoses of various types (indicated with Roman numerals in parentheses): II: acid maltase; III: debranching; IV: branching; V: muscle phosphorylase; VII: phosphofructokinase (PFK); VIII: phosphorylase b kinase (PBK); IX: phosphoglycerate kinase (PGK); X: phosphoglycerate mutase (PGAM); XI: lactate dehydrogenase (LDH); XII: aldolase A (ALDOA). (Modified with permission from Griggs et al. [1].)

liver enlargement, delayed gross-motor development, fasting hypoglycemia, and failure to thrive [8]. Laboratory findings. The forearm ischemic exercise test reveals a normal or only partially impaired rise of venous lactate. The resting serum creatine kinase (CK) level is usually increased in patients with myopathy. The muscle biopsy is usually normal or reveals subsarcolemmal accumulation of free and structurally normal glycogen particles, primarily in type 2B fibers. Quantitation of muscle glycogen reveals either normal or slightly increased amounts. Immunohistochemical study of frozen muscle sections for phosphorylase is normal, and biochemical determination of PBK activity in muscle reveals either a total absence or markedly decreased activity [3]. Therapy. At present, no specific therapy is available for PBK deficiency. Phosphorylase Deficiency (Glycogenosis Type V or McArdle’s Disease). Biochemistry/molecular genetics. Phosphorylase catalyzes the removal of 1,4-glucosyl residues from the outer branches of the glycogen molecule, thereby liberating glucose-1-phosphate. Phosphorylase exists in three distinct isozymes encoded by three different genes localized to different chromosomes. Phosphorylase deficiency is transmitted as an autosomal-recessive trait. The gene for muscle phosphorylase (M)

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has been mapped on chromosome 11q13 [11]. Rare cases of apparent autosomal-dominant inheritance may be explained by the occurrences of manifesting heterozygotes or compound heterozygotes (i.e., affected individuals with two different mutations; children of parents, one of whom is affected and the other unaffected but a carrier of a different phosphorylase gene mutation [pseudodominance]) [12-14]. Eleven mutations have been identified thus far; the most common (ARG45TGR) in codon 49 of exon 1, was present in a homozygous form in 18 of 40 patients described by Tsujino et al. [15] in 1993 [16]. Clinical features. Myophosphorylase deficiency usually manifests with exercise intolerance, fatigue, myalgia, cramps, myoglobinuria, poor endurance, muscle swelling, and fixed weakness [17]. Stiffness or weakness of exercising muscles can be induced by either brief periods of intense isometric exercise or by less intense but sustained dynamic exercise. Patients with McArdle’s disease experience a second-wind phenomenon defined by the finding that a brief rest after the development of muscle stiffness and myalgia can lead to resumption of physical activity without significant symptoms. This second wind can be explained by increased blood flow, enhanced delivery of free fatty acids, with concurrent activation of fatty acid metabolism, and increased glucose use. The clinical findings of 112 patients with McArdle’s disease have been examined [3,18]. Myoglobinuria was

evident in 50%, half of whom (27% of the total) developed renal failure. Twenty-eight percent of the 112 patients had fixed weakness affecting the proximal more than the distal muscles (which was more often observed in older patients). In 85% the onset was before 15 years of age, and in 50% the diagnosis was made between 10 and 30 years of age. Fifty-three percent of these 112 patients had a positive family history. Four children have been reported with respiratory insufficiency, generalized weakness, and hypotonia evident at or shortly after birth, leading to death in infancy [19,20]. Furthermore, asymptomatic McArdle’s disease associated with high serum CK levels only and the absence of myophosphorylase has been recently described [21]. Laboratory findings. The forearm ischemic lactate test is usually diagnostic of phosphorylase deficiency, exhibiting a flat venous lactate curve [18]. The serum CK is usually elevated in most patients with phosphorylase deficiency (in carnitine palmitoyltransferase [CPT] deficiency the resting CK is usually normal) even between episodes of myoglobinuria. The electromyogram (EMG) at rest is abnormal, characterized by myotonic discharges, fibrillations, and positive waves in 49% of patients [18]. Phosphorus-31 nuclear magnetic resonance spectroscopy has been reported to be abnormal in phosphorylase deficiency [22]. The muscle biopsy may reveal focal subsarcolemmal and intermyofibrillar accumulations (“blebs”) of normally structured glycogen. Quantitatively, the amount of glycogen is either normal or moderately increased to approximately twice that of normal. Histochemical staining for phosphorylase reveals no activity in muscle fibers in most cases, except in patients in whom some residual enzyme activity is present or in whom a significant number of regenerating fibers are present [3]. Histochemical staining may be positive in the latter case because of the existence of a fetal isozyme immunologically different from mature muscle phosphorylase. In classic cases, biochemical determination of phosphorylase activity in muscle reveals no detectable activity; in some, however, up to 10% of normal residual enzyme activity may be evident [23,24]. In erythrocytes, platelets, and cultured skin fibroblasts, phosphorylase activity is normal, probably related to the existence of nonmuscle isozymes. Therapy. Unfortunately, oral administration of glucose or fructose has not resulted in consistent improvement and has also caused significant weight gain. Highfat, low-carbohydrate diets and oral branched-chain amino acid administration [25] have been ineffective. Improvement was documented by Slonim and Goans [26] in a single patient placed on a high-protein diet (50% carbohydrate, 20% fat, and 25-30% protein). Phosphofructokinase Deficiency (Glycogen Storage Disease Type VII). Biochemistry/molecular genetics. Phosphofructokinase (PFK) is a tetrameric enzyme composed of three distinct subunits: L (liver), M (muscle), and P (platelet). The genes for the L, M, and P subunits have been mapped to

chromosomes 21, 12, and 10, respectively [27-29]. The three genes are variably expressed in different tissues [30]. In patients with typical muscle PFK deficiency, mutations of the M subunit gene lead to a total lack of activity in muscle and a partial deficiency in erythrocytes; in the latter the homotetramer L4 accounts for the residual enzyme activity [31]. PFK deficiency is inherited as an autosomal-recessive trait. A total of 18 mutations have been identified thus far (Human Gene Mutation Database, Cardiff, UK). Clinical features. The main clinical features of PFK deficiency are exercise intolerance, manifested by muscle aches and cramps, and exercise-induced myoglobinuria [32,33]. In a series of 25 patients with PFK deficiency, myoglobinuria occurred in 10 [34,35]. Most of the signs are dynamic; however, a few adult patients have been described with fixed weakness. In addition, because PFKdeficient muscle cannot use glucose, administration of glucose may lead to decreased exercise tolerance, also known as the out-of-wind phenomenon, because of a reduction in the availability of free fatty acids and ketones [36]. Mild hemolytic anemia, occasionally associated with mild jaundice and gout, may be observed in patients with PFK deficiency, sometimes without clinical myopathy [37]. Furthermore, infants with a severe myopathic variant, with or without central nervous system and cardiac muscle involvement, have been reported [35,38-42]. Laboratory findings. The serum CK level is usually elevated. The ischemic forearm exercise test depicts no rise in lactate levels. Hemolytic anemia is evident, reflected by reticulocytosis, hyperbilirubinemia, and hyperuricemia. In most patients, PFK activity in muscle is absent, with a concomitant 50% reduction in erythrocytes [31,43]. Muscle biopsy discloses an accumulation of free glycogen of normal structure [44], with an abnormal polysaccharide evident more frequently in older individuals [45]. Therapy. No specific therapy for PFK deficiency is available. The effect of a high-protein diet has not been adequately studied. A 2-year-old male with PFK deficiency who presented in the newborn period with congenital arthrogryposis and severe myopathy improved significantly on a ketogenic diet [42]. Aldolase A Deficiency (Glycogenosis Type XII). Human aldolase is a homotetrameric enzyme encoded by a single gene on chromosome 16q22-q24 [46,47]. It is one of three isozymes of aldolase (B and C are the other two) responsible for the conversion of fructose-1,6-biphosphate into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate in the glycolytic pathway (Fig 1). A homozygous mutation (Glu 206 Lys) in codon 206 of the aldolase A gene has been described in a 4-year, 6-month-old patient with myopathic symptoms, anemia, jaundice, and rhabdomyolysis during febrile illnesses [48]; the serum CK level was highly elevated, laboratory markers of hemolysis, mild hemoglobinuria, and myoglobinuria were present.

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Debrancher Deficiency (Glycogen Storage Disease Type III).

not completely curative in all cases; one child developed severe cardiomyopathy 2 years after transplantation.

Biochemistry/molecular genetics. The debrancher enzyme is responsible for the removal of the residual stubs of glycogen after digestion by phosphorylase [49]. The gene encoding the glycogen debrancher enzyme (amylo1,6-glucosidase, 1,4-alpha-glucotransferase) has been assigned to chromosome 1p21 [50,51]. Ten mutations causing debrancher enzyme deficiency in muscle and liver have been identified; however, these mutations account for less than half of the total [52-54]. Clinical features. Debrancher deficiency [55] may manifest in childhood with hepatomegaly, liver dysfunction, failure to thrive, and fasting hypoglycemia, occasionally resulting in hypoglycemic seizures. Some patients develop weakness, hypotonia, gross-motor delay, and cardiomyopathy. In adults the symptoms are primarily static (progressive proximal or distal weakness), although dynamic signs, such as exercise intolerance, may also rarely develop [56-59]. Laboratory findings. The serum CK level is elevated in patients with myopathy. The forearm ischemic lactate test depicts a flat curve. The EMG is myopathic, and muscle biopsy is characterized by free glycogen accumulation. The glycogen particles are periodic acid-Schiff positive, digestible by diastase, and appear as normal particles by electron microscopy. Therapy. In infants with fasting hypoglycemia, frequent feedings and nighttime glucose infusions of uncooked cornstarch are indicated [60]. The effect of a high-protein diet has not proved to be consistently positive in a number of published cases [61].

Phosphoglycerate Kinase Deficiency (Glycogen Storage Disease Type IX).

Branching Enzyme Deficiency (Glycogen Storage Disease Type IV). Biochemistry/molecular genetics. The glycogen branching enzyme catalyzes the attachment of short glucosyl chains to a naked peripheral chain of nascent glycogen. The condition is transmitted as an autosomal-recessive trait. Clinical features. Patients with branching enzyme deficiency usually present with liver failure and failure to thrive. Examination reveals hepatomegaly, hypotonia, weakness, and contractures. Cardiomyopathy has been described in a number of children [62]. The disease is progressive in children, most of whom die of hepatic failure before 4 years of age [63]. Laboratory findings. The serum CK level is elevated in some patients. In patients with cardiomyopathy the echocardiogram is abnormal. The diagnosis is made by finding decreased or absent branching enzyme activity in skin fibroblasts. Muscle biopsy reveals storage of periodic acid-Schiff-positive, diastase-negative material. Therapy. Liver transplantation has proved to be beneficial in children with evidence of a reduction in glycogen storage in both heart and skeletal muscle; the mechanism of this reduction is not clear [64]. However, transplantation is

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Biochemistry/molecular genetics. Phosphoglycerate kinase 1 (PGK1) is a monomeric enzyme encoded by a gene on chromosome Xq13. PGK deficiency is inherited as an X-linked recessive trait [65]; a total of nine mutations have been reported to date. Only a subset results in a myopathic phenotype [66]. Clinical features. PGK deficiency [67] may manifest as central nervous system dysfunction, with seizures and mental retardation [68], associated with nonspherocytic hemolytic anemia, or as a myopathy, with exercise intolerance, myoglobinuria, cramps, and slowly progressive weakness. Patients with myoglobinuria do not develop hemolytic anemia [69]. Conversely, patients with hemolytic anemia and central nervous system involvement usually lack evidence of clinical myopathy [70,71]. Laboratory features. In patients with myopathy the resting serum CK level is usually elevated. Although not uniformly observed, muscle biopsy may depict glycogen accumulation. Therapy. No specific therapy for PGK deficiency is currently available. Phosphoglycerate Mutase Deficiency. Biochemistry/molecular genetics. The muscle form of phosphoglycerate mutase (PGAM-M) has been mapped to chromosome 7p13-p12.3 [72]. The gene for the brain (PGAM-B) subunit has been mapped to chromosome 10q25 [73,74]. Three distinct point mutations have been described in five patients with PGAM-M deficiency [75]. Clinical features. PGAM deficiency manifests primarily with dynamic signs, such as exercise intolerance, muscle aches, cramps, and myoglobinuria, after intense physical activity [67,76]. The impairments may begin in childhood or adolescence. Laboratory findings. Between attacks the serum CK levels may be elevated. Muscle biopsy reveals mild glycogen storage in most cases. Therapy. No effective therapy is currently available for PGAM deficiency. Lactate Dehydrogenase Deficiency (Glycogen Storage Disease Type XI). Biochemistry/molecular genetics. Lactate dehydrogenase (LDH) is a tetrameric enzyme comprised of two subunits, M and H, resulting in five isozymes. The gene encoding LDH-M has been mapped to chromosome 11p15.4, and the gene for LDH-H has been localized to chromosome 12p12.2-p12.1. LDH deficiency is inherited as an autosomal-recessive trait. Clinical features. LDH deficiency [77] has been described in a few patients, with excessive fatigue, exercise intolerance, myoglobinuria [78], and normal strength.

Laboratory findings. The serum CK level is elevated in combination with a normal serum LDH level. The forearm ischemic exercise test demonstrates no elevation in venous lactate but an excessive increase in pyruvate [1]. LDH activity is reduced or absent in muscle or erythrocytes. Therapy. No specific treatment for LDH deficiency is available. Lysosomal Glycogenosis Acid Maltase Deficiency (Glycogen Storage Disease Type II). Biochemistry/molecular genetics. Acid maltase deficiency (AMD) is inherited as an autosomal-recessive trait. The gene for acid maltase (alpha-1,4-glucosidase) was assigned to chromosome 17q25.2-q25.3 [79,80]. More than 40 mutations have been identified thus far [81]. If the genetic defect is not known, prenatal diagnosis is still feasible by measuring acid maltase activity in cultured amniocytes. Clinical features. There are three main clinical syndromes: (1) infantile AMD or Pompe’s disease, (2) childhood AMD, and (3) adult AMD. The infantile variety usually manifests with hypotonia and weakness during the first few weeks after birth [82]. Infants have significant cardiomegaly, moderate hepatomegaly, and macroglossia. Most die of cardiorespiratory failure before 2 years of age. In the childhood variety of AMD, patients usually present with delayed gross-motor development and progressive limb-girdle weakness; associated respiratory muscle weakness is present, leading to respiratory failure and death in the second or third decade. Older children with AMD usually do not have cardiomegaly. No primary heart or liver involvement has been observed [83,84]; however, cor pulmonale in an adult patient with AMD was recently reported [85]. Laboratory findings. The serum CK level is elevated in all types of AMD. The forearm ischemic lactate test is normal [1], and the EMG is characteristic, with evidence of myopathic discharges, sometimes associated with abundant myotonic and complex repetitive discharges most prominent in the paraspinal muscles. In infants the electrocardiogram reveals a short PR interval with giant QRS complexes in all leads, suggestive of biventricular hypertrophy. In adult patients the vital capacity is reduced substantially. Muscle biopsy demonstrates vacuolar myopathy with glycogen storage within lysosomes and free glycogen in the cytoplasm by electron microscopy. The vacuoles are periodic acid-Schiff positive and digestible by diastase and are also positive for acid phosphatase (lysosomal marker). Acid maltase activity is reduced in muscle to less than 10% of normal. AMD can also be demonstrated in leukocytes and urine. Therapy. Benefits have been observed with a highprotein, low-carbohydrate diet [86] or just a high-protein diet in adults with AMD [87,88]. In the childhood or adult

types of AMD, mechanical ventilation is usually necessary eventually. No specific treatment is available for the infantile variety. However, encouraging results have been obtained with intravenous injection of high doses of recombinant acid-glucosidase in a quail model of AMD [89]. Furthermore, phenotypic correction of AMD has been achieved in vitro by adenovirus-mediated transfer of the acid alpha-glucosidase gene into cultured skeletal muscle from a patient with infantile-onset AMD; it may be a good model system for further in vivo gene-therapy studies [90]. Disorders of Lipid Metabolism Carnitine Deficiency Syndromes Carnitine deficiency (CD) can be primary or secondary. The criteria for primary CD are as follows: (1) severely reduced plasma or tissue carnitine levels, (2) secondary impairment of fatty acid oxidation (FAO) by the low carnitine levels, (3) absence of a primary defect in FAO, and (4) clinical improvement in most patients when carnitine levels are restored [91,92]. Three different forms of primary CD syndrome have been described: (1) primary muscle CD associated with lipid myopathy, first described in 1973 [93]; (2) primary systemic CD associated with hepatic encephalopathy and myopathy, reported in 1975 [94]; and (3) primary systemic CD associated with progressive cardiomyopathy, initially described in 1981 [95]. Although many cases of primary muscle CD proved to be cases of secondary CD or heterozygotes for the systemic form [96], it is currently accepted that primary muscle CD does occur but is rare. Primary Muscle CD. True primary muscle CD is difficult to differentiate from systemic CD because nonmuscle tissues, such as liver or heart, are usually not easily available for biochemical analysis [97]. Additionally, intramitochondrial betaoxidation defects can imitate muscle CD and were not excluded in most early reported cases of presumed primary muscle CD [98,99]. Furthermore, in many patients, elevated esterified plasma or muscle carnitine levels have been documented, which suggest a secondary deficiency [92]. Most patients present with progressive proximal muscle weakness, possible exercise intolerance, myalgias, or myoglobinuria. Laboratory findings include a lipid storage myopathy, low carnitine levels in skeletal muscle (20% of normal or less), variable plasma carnitine levels (normal or mildly reduced), normal esterified carnitine in plasma (in true primary cases), normal liver or heart carnitine levels, and absence of dicarboxylic organic acids in the urine. Treatment with oral l-carnitine has been clinically beneficial, ranging from moderate improvement to normalization of muscle strength; however, this regimen does not replenish the muscle carnitine stores [100, 101].

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Primary Systemic CD With Hepatic Encephalopathy. Primary systemic CD with hepatic encephalopathy is a group of conditions that affect the transport of carnitine across cell membranes, thereby resulting in depletion of tissue and body fluid carnitine. Most patients, particularly infants, present with Reye’s syndrome-like encephalopathy, with associated hepatomegaly, hyperammonemia, hypoketotic hypoglycemia, elevation of liver enzymes, metabolic acidosis, prolonged prothrombin time, and reduced carnitine levels in plasma, muscle, liver, and heart [102]. Infants with primary systemic CD have mild weakness and hypotonia but no evidence of an overt myopathy [102-104]. Free carnitine levels are reduced in plasma and several tissues (usually less than 10% of normal), and the levels of esterified carnitine are proportionately reduced as well. Four mutations in a gene, OCTN2, a novel carnitine transporter protein that encodes a sodium-dependent carnitine transporter, were identified in three systemic CD pedigrees [105]. Some patients with systemic CD have responded to oral l-carnitine therapy [94]; however, this therapy has been ineffective in other patients [106]. Primary Systemic CD With Cardiomyopathy. Patients with systemic CD present with lipid myopathy and dilated cardiomyopathy and, occasionally, hypoketotic hypoglycemia [107], without a dicarboxylic aciduria. The cardiomyopathy is progressive and can lead to death if not treated. The carnitine content in muscle, heart, liver, and plasma is low. Total and free carnitine levels in plasma are less than 10% of normal, and carnitine esters are not increased. Pathologically, lipid storage in skeletal muscle, heart, and liver is evident. If untreated, patients die of heart failure soon after birth. Patients respond dramatically to carnitine supplementation at a usual dose of 2-6 gm of oral l-carnitine daily in adults or 100-200 mg/kg daily in four divided doses in children [108]. Side effects of carnitine supplementation include diarrhea and a fishy body odor. Secondary CDs. Secondary CD has been described with organic acidurias and in a few patients with mitochondrial respiratory chain defects, methylene tetrahydrofolate reductase deficiency, renal Fanconi’s syndrome [109], chronic hemodialysis, and therapy with valproate [110], pivampicillin [111], and zidovudine (AZT). Fatty Acid Transport Defects The disorders of fatty acid transport into the mitochondria include the following: CPT I, CPT II, and carnitine: acylcarnitine translocase defects. These defects are not associated with abnormal dicarboxylic aciduria [83] principally because dicarboxylic acids formed by microsomal omega-oxidation can enter the mitochondria. Their entry is

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not dependent on the carnitine transport system. With intact beta-oxidation, they are converted into shorter species and then excreted in the urine. Nevertheless, dicarboxylic aciduria was observed in two patients with severe CPT II deficiency and also in a patient with CPT I deficiency presenting with a Reye-like syndrome [112-114]. Carnitine:Acylcarnitine Translocase and CPT I Defects. In carnitine:acylcarnitine translocase deficiency, involvement of both heart and skeletal muscle is observed. Cardiac involvement includes progressive hypertrophic or dilated cardiomyopathy (or both). The initial manifestations are usually severe hypoketotic hypoglycemia, ventricular arrhythmias, and sudden neonatal death [115-117]. In patients with CPT I deficiency, a Reye-like syndrome and renal tubular acidosis have been described [118]. Muscle signs are not present. Serum carnitine levels are normal or increased, with a high free/total ratio. In either condition, carnitine supplementation has not been therapeutic. CPT II Deficiency. Biochemistry/molecular genetics. CPT II, which is located in the inner mitochondrial membrane, is part of the mechanism whereby long-chain fatty acids are transferred from the cytosolic compartment to the mitochondrial matrix to undergo beta-oxidation. The CPT II gene was mapped to chromosome 1p32 [119,120]. To date, 15 mutations have been reported [121-123]. Given the high frequency of four missense mutations in the typical adult form of CPT II deficiency, the clinical diagnosis can be confirmed by molecular analysis of the blood without resorting to a muscle biopsy [124]. Because the reduction in activity varies depending on the severity of the mutation, and the critical threshold differs among various tissues, a wide spectrum of phenotypic severity is clinically observed (e.g., severe infantile, late-onset myopathic, and hepatic forms) [122]. Clinical features. In approximately two thirds of patients with myopathic CPT II the first intermittent signs are evident during the first or second decade but may appear as late as the fifth decade. In between episodes, patients are well, without episodes of hypoglycemia. The signs of CPT II deficiency consist of myalgias, cramps, muscle stiffness or tenderness, weakness, and, occasionally, myoglobinuria [125]. Signs usually develop after prolonged exertion (usually more than 30 minutes), and patients do not have reduced tolerance to brief, intense isometric exercise. They do not experience a second-wind or out-of-wind phenomenon. Similar clinical manifestations may also be induced by fasting, exposure to cold, viral infections, fever, or even emotional distress. Other factors that may induce rhabdomyolysis are general anesthesia, ibuprofen, and high doses of diazepam. Although uncommon, persistent proximal weakness has been described in a few patients after repeated rhabdomyolysis.

No fixed cardiomyopathy has been described [126]. Between attacks, typically no weakness is evident. Several cases of severe infantile CPT II deficiency have been described. Affected infants present with a Reye-like syndrome, with hepatomegaly, hypoketotic hypoglycemia, elevated serum amino transferases and CK, cardiomegaly, cardiac arrhythmias, and lipid storage in heart, skeletal muscle, and other tissues. In these patients the CPT II activity in cultured fibroblasts was less than 10% percent of control values. In comparison, in classic CPT II deficiency, at least 25% residual activity is present [112, 127-129]. In most cases the diagnosis is confirmed by measuring CPT II activity in cultured fibroblasts or directly in muscle tissue. Laboratory findings. At rest and between episodes of myoglobinuria the serum CK level is usually normal. However, prolonged exercise and prolonged fasting may elevate the serum CK level. Serum triglycerides and cholesterol may also be elevated in some patients. Total serum carnitine is usually low and the acylcarnitine fraction increased, without dicarboxylic aciduria; longchain acylcarnitines may be increased in serum. The ischemic forearm exercise test depicts a normal lactate and ammonia response. EMG is also normal between attacks. Muscle specimens obtained several months after episodes of myoglobinuria are normal. Glycogen content is normal, and no or only a slight lipid excess in type 1 fibers is evident. In most, but not all, patients with CPT II deficiency the fasting ketogenesis is abnormal; as an example, a 38- to 72-hour fast induces no rise or only a partial rise in ketone bodies. Therapy. To prevent myoglobinuria, a high-carbohydrate (70-75%), low-fat (10-15%), and low-protein (15%) diet, with frequent meals and extra carbohydrate intake before sustained exercise, appears to be preventive. Prolonged aerobic exercise (more than 30 minutes), prolonged fasting, and cold exposure should be avoided.

has been documented in most intramitochondrial enzymatic defects at times of catabolic crisis. In severe CPT II, LCAD/VLCAD, and trifunctional enzyme deficiencies, however, persistent hepatic dysfunction has been documented. Myopathy has been described in all intramitochondrial beta-oxidation defects, with the exception of hydroxy methylglutaryl-CoA lyase deficiency [136]. Myoglobinuria has been described in patients with both longchain (e.g., LCAD, LCHAD, and VLCAD deficiency) and short-chain defects (e.g., SCHAD deficiency). Trifunctional enzyme deficiency presents in children as hypoketotic hypoglycemia, a Reye-like syndrome, cardiomyopathy, hypotonia, and liver disease with fatty infiltration and cirrhosis, leading to death before 20 years of age [137, 138]. However, a deficiency of this enzyme may not be universally fatal [139]. For specific FAO defects, certain types of treatment may be beneficial [83]: 1. Riboflavin. Some cases of ETF or ETF-CoQ deficiency are responsive to treatment with riboflavin at a dose of 50 mg three times daily in young children and 100 mg three times daily in older children and adults. 2. Carnitine. There is no objective evidence that carnitine supplementation is beneficial in cases of intramitochondrial beta-oxidation defects with secondary CD. In fact, it appears that carnitine administration may be arrhythmogenic in long-chain FAO defects; thus, its use is not recommended. 3. Medium-chain triglycerides. Medium-chain triglycerides can be used in patients with long-chain FAO defects. The dose of medium-chain triglyceride oil is 0.5 gm/kg daily in three divided doses; the dose can be gradually increased to 1-1.5 gm/kg daily. Excess medium-chain triglyceride oil, however, can be converted into long-chain fats in adipocytes, which limits the effectiveness of this treatment.

Defects of Beta-oxidation Enzymes. Defects of intrami tochondrial beta-oxidation involve the following enzymes: long-chain acyl-coenzyme A (CoA) dehydrogenase (LCAD) [130,131], medium-chain acyl-CoA dehydrogenase (MCAD) [132,133], short-chain acyl-CoA dehydrogenase (SCAD) [134], very–long-chain acyl-CoA dehydrogenase (VLCAD), short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) [135], electron transfer flavoprotein (ETF), electron transfer flavoprotein-coenzyme Q oxidoreductase (ETF-CoQ), trifunctional enzyme, and hydroxy methylglutaryl-CoA lyase. Defects in ETF or in ETF dehydrogenase result in multiple acyl-CoA dehydrogenase deficiencies or glutaric aciduria type II. Patients with defects in beta-oxidation enzymes may have similar presentations; however, there are distinct differentiating features. Cardiomyopathy is more common in the long-chain defects (e.g., LCAD, VLCAD, trifunctional enzymes) but has also been described in a single case of SCHAD deficiency. Transient hepatic dysfunction

Other Metabolic Myopathies Myoadenylate Deaminase Deficiency Biochemistry/molecular genetics. Myoadenylate deaminase (MADA) converts adenosine monophosphate to inosine monophosphate and ammonia during muscle exercise (see Part I, Fig 2). The gene that encodes for the M subunit has been cloned and mapped to the short arm of chromosome 1 [140-142]. Clinical features. MADA deficiency is a common finding in muscle biopsies, detected in approximately 1-3% of the specimens [143]. Classic or primary MADA deficiency is characterized by dynamic signs related to exertion and consists primarily of muscle aches and cramps, which are sometimes mild and poorly defined; it can also manifest with myoglobinuria [144]. MADA deficiency has also been observed in patients with other myopathies and appears to be secondary. Whether MADA

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deficiency is a disease has been the subject of debate [145,146]. Laboratory findings. The resting serum CK level is usually normal. The muscle biopsy is histologically normal, but MADA deficiency can be detected by immunohistochemistry [147]. The forearm ischemic exercise test reveals a normal lactate curve but no increase in the ammonia or inosine monophosphate level. Mitochondrial Defects Most mitochondrial diseases present with myopathic signs that are usually progressive, but dynamic features may also be observed. Given the enormous complexity and breadth of this topic, only the reported defects with primarily dynamic myopathic signs are referenced. Myoglobinuria, with or without other symptoms of exercise intolerance, has been described in a number of patients with mitochondrial defects [148-154]. References [1] Griggs R, Mendell J, Miller R. Metabolic myopathies. In: Griggs R, Mendell J, Miller R, eds. Evaluation and treatment of myopathies. Philadelphia: FA Davis, 1995:247-93. [2] Heilmeyer L. Molecular basis of signal integration in phosphorylase kinase. Biochim Biophys Acta 1991;1094:168-74. [3] DiMauro S, Tsujino S. Nonlysosomal glycogenoses. In: Engel A, Banker B, eds. Myology. New York: McGraw-Hill, 1994:1554-76. [4] Jones TA, da Cruz e Silva EF, Spurr NK, Sheer D, Cohen PT. Localisation of the gene encoding the catalytic gamma subunit of phosphorylase kinase to human chromosome bands 7p12-q21. Biochim Biophys Acta 1990;1048:24-9. [5] Francke U, Darras BT, Zander NF, Kilimann MW. Assignment of human genes for phosphorylase kinase subunits alpha (PHKA) to Xq12-q13 and beta (PHKB) to 16q12-q13. Am J Hum Genet 1989;45: 276-82. [6] Davidson JJ, Ozcelik T, Hamacher C, Willems PJ, Francke U, Kilimann MW. cDNA cloning of a liver isoform of the phosphorylase kinase alpha subunit and mapping of the gene to Xp22.2-p22.1, the region of human X- linked liver glycogenosis. Proc Natl Acad Sci U S A 1992;89:2096-100. [7] Sahin G, Gunger T, Rettwitz-Volk W, et al. Infantile muscle phosphorylase deficiency. A case report. Neuropediatrics 1998;29:48-50. [8] Van der Berg I, Berger R. Phosphorylase b kinase deficiency in man: a review. J Inherit Metab Dis 1990;13:442-51. [9] Abarbanel JM, Bashan N, Potashnik R, Osimani A, Moses SW, Herishanu Y. Adult muscle phosphorylase “b” kinase deficiency. Neurology 1986;36:560-2. [10] Servidei S, Metlay LA, Chodosh J, DiMauro S. Fatal infantile cardiopathy caused by phosphorylase b kinase deficiency. J Pediatr 1988;113:82-5. [11] Lebo RV, Gorin F, Fletterick RJ, et al. High-resolution chromosome sorting and DNA spot-blot analysis assign McArdle’s syndrome to chromosome 11. Science 1984;225:57-9. [12] Chui L, Munsat T. Dominant inheritance of McArdle syndrome. Arch Neurol 1976;33:636-41. [13] Schmidt B, Servidei S, Gabbai AA, Silva AC, de Sousa Bulle de Oliveira A, DiMauro S. McArdle’s disease in two generations: Autosomal recessive transmission with manifesting heterozygote. Neurology 1987;37:1558-61. [14] Papadimitriou A, Manta P, Divari R, Karabetsos A, Papadimitriou E, Bresolin N. McArdle’s disease: Two clinical expressions in the same pedigree. J Neurol 1990;237:267-70.

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