Disorders of carbohydrate metabolism

Handbook of Clinical Neurology, Vol. 86 (3rd series) Myopathies F. L. Mastaglia, D. Hilton-Jones, Editors # 2007 Elsevier B. V. All rights reserved

Chapter 7

Disorders of carbohydrate metabolism SALVATORE DIMAURO*, ORHAN AKMAN AND ARTHUR P. HAYS Columbia University Medical Center, New York, NY, USA

7.1. Introduction The two major energy sources for muscle contraction are glycogen and fatty acids, whose metabolic pathways converge into acetyl-CoA for final intramitochondrial oxidation through the Krebs cycle and the respiratory chain. Defects of substrate utilization in muscle cause two main clinical presentations: (i) acute, recurrent, reversible muscle dysfunction, manifesting as exercise intolerance, myalgia with or without painful cramps (contractures), often culminating in muscle breakdown and myoglobinuria; or (ii) fixed, often axial and proximal limb weakness, sometimes simulating dystrophic or inflammatory processes. Fig. 7.1 is an updated version of a similar scheme that we first published in 1985 (DiMauro, 1985). Three new glycogenoses (aldolase deficiency, b-enolase deficiency, and deficiencies of AMP-activated protein kinase) have been discovered in the intervening 20 years, and Lafora disease has been included among the glycogenoses. There are several recent detailed descriptions of the muscle glycogen storage diseases (GSD; Chen, 2001; DiMauro et al., 2004; Engel et al., 2004). This chapter, therefore, summarizes typical clinical presentations, muscle morphology and biochemistry, focusing instead on molecular genetics and physiopathology.

7.2. Glycogen as muscle fuel The “fuel” utilized by muscle depends on several factors, most importantly the type, intensity and duration of exercise, but also diet and physical conditioning. At rest, muscle utilizes predominantly fatty acids. At the opposite end of the spectrum, the energy for extremely intense exercise (close to one’s maximal oxygen uptake, or VO2max, in dynamic exercise, or to maximal force

generation in isometric exercise) derives from anaerobic glycolysis (i.e., glycogen metabolism), especially when there is a “burst” of activity with rapid acceleration to maximal exercise. During submaximal exertion, the type of fuel utilized by muscle depends on the relative intensity of exercise. At low intensity (below 50% VO2max), the primary source of energy is represented by blood glucose and free fatty acids (FFA). At higher intensities, the proportion of energy derived from carbohydrate oxidation increases, and glycogen becomes an important fuel: at 70–80% VO2max, aerobic metabolism of glycogen is the crucial source of energy, and fatigue appears to set in when glycogen is exhausted. The type of circulating substrate utilized during mild exercise varies with time, and there is a gradual increase in the utilization of FFA over glucose until, a few hours into exercise, lipid oxidation becomes the major source of energy (Haller and Vissing, 2004a). In agreement with the concept that glycogen metabolism is crucial for anaerobic or intense aerobic exercise, the complaints of patients with muscle glycogenoses are almost invariably related to an identifiable, and usually strenuous, bout of exertion. Also, the muscles that hurt, swell, or go into contracture are those that have been engaged in that particular type of exercise. The effect of diet is interesting. Whereas fasting is a potential trigger of myoglobinuria in patients with carnitine palmitoyltransferase II (CPT II) deficiency, who cannot utilize free fatty acids, patients with myophosphorylase deficiency (McArdle disease) note a beneficial effect of fasting on their exercise ability, which is explained by the mobilization of circulating FFA, an alternative fuel to the unavailable endogenous glycogen. Patients with McArdle disease also benefit from glucose administration or from a sucrose load before exercise (Vissing and Haller, 2003a) because their metabolic block, which

*Correspondence to: Salvatore DiMauro, MD, 4–420 College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. E-mail: [email protected], Tel: þ1-212-305-1662, Fax: þ1-212-305-3986.

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Fig. 7.1. Scheme of glycogen metabolism and glycolysis. Roman numerals denote muscle glycogenoses due to defects in the following enzymes: I, glucose-6-phosphatase; II, acid maltase; III, debrancher; IV, brancher; V, myophosphorylase; VI, liver phosphorylase; VII, muscle phosphofructokinase; VIII, phosphorylase b kinase; IX, phosphoglycerate kinase; X, phosphoglycerate mutase; XI, lactate dehydrogenase; XII, aldolase; XIII, b-enolase. Symbols in italics indicate glycogenoses causing fixed weakness; standard symbols indicate glycogenoses causing exercise intolerance, cramps and myoglobinuria. Defects of 50 AMP-activated protein kinase (AMPK) cause familial hypertrophic cardiomyopathy with Wolff–Parkinson–White syndrome (FHC/WPWS). Defects in laforin or malin cause accumulation of polyglucosan by an unknown mechanism. Reproduced in modified form from DiMauro et al. (1984) with permission from Taylor & Francis, Inc, http://www.taylorandfrancis.com.

is far upstream in carbohydrate metabolism, impairs glycogen but not glucose utilization (Fig. 7.1). In contrast, meals rich in carbohydrate exacerbate the exercise intolerance of patients with phosphofructokinase (PFK) deficiency for two reasons: (i) due to the metabolic

block downstream in glycolysis (Fig. 7.1), their muscle cannot utilize either glycogen or glucose; (ii) glucose decreases the blood concentration of the alternative fuels FFA and ketones, a situation dubbed the “out of wind” phenomenon (Haller and Lewis, 1991).

DISORDERS OF CARBOHYDRATE METABOLISM 7.2.1. Glycogenoses causing exercise intolerance and myoglobinuria Throughout this chapter, we will follow the metabolic “flow” in the glycogenolytic and glycolytic pathways rather than the historical numeration (Fig. 7.1). 7.2.1.1. Phosphorylase kinase deficiency (GSD VIII) Phosphorylase kinase (Phk) is a key regulatory enzyme in glycogen metabolism because it activates glycogen phosphorylase in response to neuronal or hormonal stimuli. Phk deficiency has been associated with four distinct clinical presentations, which are distinguished on the basis of tissue involvement (liver, muscle, heart, or liver and muscle) and mode of inheritance (autosomal or X-linked). This clinical and genetic heterogeneity is explained by the complexity of the enzyme, a decahexameric protein composed of four subunits (abgd)4. The a and b subunits are regulatory, the g subunit is catalytic, and the d subunit is identical to calmodulin and confers calcium sensitivity to the enzyme. In addition, two different isoforms of the a subunit (aM for muscle and aL for liver) are encoded by two different genes on the X chromosome (PHKA1, PHKA2), while the b subunit, two isoforms of the g subunit (gM for muscle and gTL for testis/liver), and three isoforms of calmodulin are encoded by autosomal genes (PHKB, PHKG1, PHKG2, CALM1–3). The complexity of this enzyme explains, in part at least, the clinical heterogeneity of disorders due to Phk deficiency. Thus, two X-linked forms of hepatic glycogenosis, one also involving blood cells, XLG1, the other sparing blood cells, XLG2, have been associated with different mutations in PHKA2. The autosomal-recessive and relatively benign liver and muscle variant has been associated to mutations in PHKB, whereas the more severe purely hepatopathic variant is due to mutations in PHKG2 (Burwinkel et al., 2003a). Not surprisingly, the myopathic variant of Phk deficiency presents clinically like a mild form of myophosphorylase deficiency (McArdle disease), with exercise intolerance, cramps and recurrent myoglobinuria in young adults. Less frequent presentations include infantile weakness and respiratory insufficiency or late-onset weakness. Muscle morphology shows subsarcolemmal deposits of normal-looking glycogen, and muscle biochemistry shows moderately increased glycogen concentration and markedly reduced Phk activity. The predominance of affected men suggested that the X-linked aM isoform may be involved, a concept bolstered by reports of mutations in the PHKA1 gene in two patients (Wehner et al., 1994; Bruno et al., 1998).

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However, a thorough molecular study of six myopathic patients, five men and one woman, revealed only one novel mutation in PHKA1, whereas no pathogenic mutations were found in any of the six genes (PHKA1, PHKB, PHKG1, CALM1, CALM2, CALM3) encoding muscle subunits of Phk in the other five patients (Burwinkel et al., 2003b). This surprising result suggested that most myopathic patients with low Phk activity either harbor elusive mutations in Phk genes or mutations in other unidentified genes. A mystery concerning the fatal infantile cardiopathic variant of Phk deficiency — there are no heart-specific Phk isozymes — has been at least partially solved. In three of five reported cases, Burwinkel et al found no mutations in PHK genes, but a functionally severe mutation (R531Q) in the gene (PRKAG2) encoding the g2-subunit of AMP-activated protein kinase (AMPK complex) (Burwinkel et al., 2005). It is not clear how dysfunction of the AMPK complex causes Phk deficiency in the hearts of these infants. 7.2.1.2. AMP-activated Protein Kinase (AMPK) deficiency The AMPK complex appears to function as a sensor of the energy status of the cell through binding sites for ATP and AMP. It is a heterotrimer composed of a catalytic a subunit, and two regulatory subunits (b and g). As mentioned above, a severe mutation (R531Q) in the g2-subunit of the AMPK complex underlies many (but not all) cases of fatal infantile cardiomyopathy with glycogen storage and Phk deficiency (Burwinkel et al., 2005). Milder mutations in the same gene (PRKAG2) cause autosomal-dominant familial hypertrophic cardiomyopathy with Wolff–Parkinson–White syndrome (FHC/WPWS; Arad et al., 2002; 2005). Interestingly, much of the polysaccharide stored in this condition has the staining and ultrastructural features of polyglucosan, suggesting that AMPK deficiency somehow tips the ratio of glycogen synthetase and branching enzyme in favor of the former (see below). One patient with FHC/WPWS also had exercise intolerance, increased serum CK and morphological evidence of glycogen storage in muscle (Laforet et al., 2006), indicating that AMPK deficiency should now be included in the differential diagnosis of muscle/heart glycogenoses, which was thus far confined to Pompe disease (GSD II), debrancher deficiency (GSD III) and branching enzyme deficiency (GSD IV). In addition, mutations in PRKAG3, the gene encoding the muscle-specific g3-subunit of AMPK, cause glycogen storage in porcine skeletal muscle, making this gene a good candidate for unexplained human muscle glycogenoses (Milan et al., 2000).

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7.2.1.3. Myophosphorylase deficiency (GSD V; McArdle disease) In 1951, on the basis of astute clinical observation and a few critically chosen laboratory tests, Brian McArdle gave a remarkably precise description of the metabolic problem in a young man with exercise intolerance and cramps (McArdle, 1951). He noted that ischemic exercise resulted in painful cramps of forearm muscles, and that no electrical activity was recorded from the shortened muscles, indicating that they were in a state of contracture. He also noted that oxygen consumption and ventilation were normal at rest but increased excessively with exercise. Having observed that venous lactate and pyruvate did not increase after exercise, McArdle concluded that his patient’s disorder was “characterized by a gross failure of the breakdown of glycogen to lactic acid”. Nor was the specific involvement of muscle lost on McArdle, who noted that epinephrine elicited a normal rise of blood glucose and “shed blood” in vitro accumulated lactate normally, leading him to conclude that “the disorder of carbohydrate metabolism affected chiefly if not entirely the skeletal muscles”. There are three isoforms of glycogen phosphorylase: brain/heart, liver and muscle, encoded by different genes. The gene for myophosphorylase (PYGM) is on chrosome 11q13 and McArdle disease is due to mutations in PGYM. The clinical picture is characterized by exercise intolerance, with myalgia and stiffness or weakness of exercising muscles, which is relieved by rest. Two types of exertion are more likely to cause symptoms: brief intense

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isometric exercise, such as pushing a stalled car, or less intense but sustained dynamic exercise, such as walking in the snow. Moderate exercise, such as walking on level ground, is usually well tolerated. In contrast, strenuous exercise often results in painful cramps, which are real contractures because — as noted by McArdle — the shortened muscles are electrically silent. An interesting phenomenon almost always reported or recognized by patients with McArdle disease is the “second wind” that they experience when they rest briefly at the first appearance of exercise-induced myalgia (Haller and Vissing, 2002). Although myoglobinuria (with the attendant risk of renal shutdown) occurs in only about half the patients, McArdle disease is the second most common cause of recurrent myoglobinuria in adults, after CPT II deficiency (Tonin et al., 1990). The clinical diagnosis of McArdle disease is suggested by cramps and myalgia following strenuous exercise and affecting engaged muscles. Electromyography (EMG) can be normal or show non-specific myopathic features at rest, but it documents electrical silence in contractured muscles. As in most muscle glycogenoses, resting serum creatine kinase (CK) is elevated in patients with McArdle disease. Muscle histochemistry shows subsarcolemmal accumulation of periodic acid-Schiff (PAS)-positive material (glycogen) that is normally digested by diastase (Fig. 7.2). A specific histochemical stain for phosphorylase can be diagnostic except when the muscle specimen is taken too soon after an episode of myoglobinuria because regenerating fibers express

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Fig. 7.2. Muscle biopsy in phosphorylase deficiency. (A) Excessive sarcoplasmic glycogen appears as darkly stained aggregates within the subsarcolemmal region of muscle fibers (arrows) of a transverse section of muscle. This pattern of glycogen accumulation is typical of deficiency of phosphorylase, debrancher enzyme, phosphofructokinase and other glycolytic enzymes. Semithin plastic section, toluidine blue–periodic acid Schiff reagent (PAS), bar ¼ 25 mm. (B) Glycolytic enzyme defects appear as accumulation of normal-appearing small glycogen particles in the subsarcolemmal zone (arrows) by electron microscopy. The surface membrane of the myofiber borders the mass of glycogen but does not surround it. This contrasts with the lysosomal disorder, acid maltase deficiency, which shows that much of the glycogen is completely surrounded by a unit membrane (see Fig. 7.4(C)). Bar ¼ 1.0 mm.

DISORDERS OF CARBOHYDRATE METABOLISM transiently the brain isoform of phosphorylase, thus masking the deficiency of myophosphorylase. Biochemical analysis of muscle provides the definitive answer, but muscle biopsy may be avoided altogether in Caucasian patients if the clinical suspicion of McArdle disease is strong enough. In these cases, it is expedient to look for the common mutation (R49X) in genomic DNA isolated from blood cells. The presence of the mutation — even in heterozygosity — establishes the diagnosis. The forearm ischemic exercise (FIE) test is informative but is being abandoned because: (i) it depends on the ability and willingness of the patient to exercise vigorously; (ii) it is not specific of McArdle disease, as lactate is not formed anaerobically in all defects of glycolysis (Fig. 7.1); (iii) it is painful and may provoke local muscle damage. Alternative diagnostic tests include a nonischemic version of the FIE (Kazemi-Esfarjani et al., 2002) and a cycle test based on the decrease in heart rate shown characteristically by patients with McArdle disease between the 7th and the 15th minute of moderate exercise and reflecting the second-wind phenomenon (Vissing and Haller, 2003b). Clinical variants of McArdle disease include the fatal infantile myopathy described in a few cases, and fixed weakness in older patients (DiMauro et al., 2004). However, some degree of fixed weakness develops with age also in patients with typical McArdle disease and is probably due to focal muscle necrosis, which occurs in these patients even with everyday activities and is reflected by their chronically elevated serum CK levels. After the first description of three mutations in PGYM (Tsujino et al., 1993a), the number of pathogenic mutations has rapidly escalated to over 40 (Martin et al., 2003; Quintans et al., 2004). As mentioned above, by far the most common mutation in Caucasian patients is the R49X (Arg49Stop) mutation, which accounts for 81% of the alleles in British patients (Bartram et al., 1993) and 63% of alleles in US patients (El-Schahawi et al., 1996). It is important to keep in mind that the frequency of different mutations varies in different ethnic groups: for example, the R49X mutation has never been described in Japan, where a single codon deletion 708/ 709 seems to prevail (Tsujino et al., 1994). The plot thickened when it was documented that an apparently innocent polymorphism in the PYGM gene impaired cDNA splicing and was, in fact, pathogenic (Fernandez-Cadenas et al., 2003). This “echo of silence” (Mankodi and Ashizawa, 2003) has to be taken into account in patients with McArdle disease not having clearly pathogenic mutations. The many different mutations are spread all over the gene (Martin et al., 2003), and it is not easy to discern any genotype–phenotype correlation. Even patients with the same genotype (e.g., homozygous for the commonest

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mutation, R49X) may have very different clinical manifestations, varying from relatively mild exercise-related discomfort to almost crippling myalgia and recurrent myoglobinuria. Although these differences can be due in part to different lifestyles or dietary regimens, other factors must play a role. For example, rare cases of genetic “double trouble”, such as the coexistence in the same individual of homozygous mutations in PYGM and in the gene for adenylate deaminase, may explain more severe phenotypes (Tsujino et al., 1995; Martinuzzi et al., 2003). Perhaps more importantly, screening for insertion/deletion polymorphism in the angiotensinconverting enzyme (ACE) in 47 patients showed a good correlation between clinical severity and number of ACE genes harboring deletion (Martinuzzi et al., 2003). Our ignorance about genetype–phenotype correlation is best illustrated by two children, both homozygous for the R49X mutation: one had fatal infantile myopathy (Tsujino et al., 1993a), the other had sudden infant death syndrome (SIDS; El-Schahawi et al., 1997). There is no specific therapy for McArdle disease, although several pharmacological and nutritional remedies have been tried, as reviewed by Quinlivan and Beynon (2004). Probably, the most important therapy is aerobic exercise (Haller, 2000), although oral sucrose may have a prophylactic effect when taken before planned activity (Vissing and Haller, 2003a). 7.2.1.4. Phosphofructokinase (PFK) deficiency (Tarui disease; GSD VII) Phosphofructokinase is a tetrameric enzyme under the control of three autosomal genes, PFKM on chromosome 12, which encodes the muscle subunit (Nakajima et al., 2002); PFKL on chromosome 21, which encodes the liver subunit; and PFKP on chromosome 10, which encodes the platelet subunit. Mature human muscle expresses only the M subunit and contains exclusively the M homotetramer (M4), whereas erythrocytes, which contain both the M and the L subunits, contain five isozymes, the two homotetramers (M4 and L4) and three hybrid forms (M1L3, M2L2, M3L1). In patients with typical PFK deficiency, mutations in PFKM cause total lack of activity in muscle but only partial PFK deficiency in red blood cells, where the residual activity approximates 50% and is accounted for by the L4 isozyme. Clinically, PFK deficiency, first described in 1965 in a Japanese family (Tarui et al., 1965), is indistinguishable from McArdle disease, except for the absence of the second-wind phenomenon. In fact, comparative exercise studies of 29 patients with McArdle disease and 5 patients with PFK deficiency showed that a spontaneous second wind (manifested by decreased heart rate and perceived exertion) occurred in all McArdle patients

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but in no PFK-deficient patient (Haller and Vissing, 2004b). Some laboratory tests help in the differential diagnosis, including increased bilirubin concentration and reticulocyte count, reflecting a compensated hemolytic trait. Thus, the diagnosis of PFK deficiency is based on the combination of muscle symptoms (exercise intolerance, cramps, and recurrent myoglobinuria) and compensated hemolytic anemia; the only other muscle glycogenosis with similar features is phosphoglycerate kinase (PGK) deficiency (see below). Of the two main clinical variants, one manifests as fixed weakness in adults (most of whom, however, recognize having suffered from exercise intolerance in their youth), while the other affects infants or young children, who have both generalized weakness and symptoms of multisystem involvement (seizures, cortical blindness, corneal opacifications or cardiopathy; DiMauro et al., 2004). The infantile variant is difficult to explain purely on the basis of muscle PFK deficiency (in fact, no mutation in the PFK-M gene has been documented in these children) and is probably genetically different from the typical adult myopathy. As mentioned earlier, patients with PFK deficiency notice worsening of their exercise intolerance after high-carbohydrate meals, which was attributed to the fact that glucose lowers the blood concentration of alternative muscle fuels, such as free fatty acids and ketone bodies (Haller and Lewis, 1991). Muscle histochemistry shows predominantly subsarcolemmal deposits of glycogen, most of which stains normally with the PAS and is normally digested by diastase. However, in addition to normal glycogen, patients with PFK deficiency also accumulate polyglucosan, which stains intensely with the PAS reaction but is resistant to diastase digestion and — in the electron microscope — appears to be composed of finely granular and filamentous material, similar to the polysaccharide in branching enzyme deficiency and in Lafora disease (Fig. 7.3). A plausible explanation for the deposition of polyglucosan in PFK-deficient muscle is a skewed activity ratio of glycogen synthetase and branching enzyme, probably due to the accumulation of glucose6-phosphate, a physiological activator of glycogen synthetase (Agamanolis et al., 1980; Hays et al., 1981). This concept is supported by experiments in transgenic mice, in which the activity of glycogen synthetase in muscle had been upregulated (Raben et al., 2001). Although the clinical diagnosis is supported by the presence of polyglucosan in the muscle biopsy and by the lack of the histochemical reaction for PFK, conclusive evidence comes from the biochemical documentation of PFK deficiency. A word of caution is needed here: the muscle specimen for biochemical analysis should be flash-frozen at the time of biopsy because

PFK is notoriously labile. As in the case of McArdle disease, muscle biopsy can be avoided if the clinical presentation is typical and a known pathogenic mutation can be documented in blood DNA; however, the task here is made more difficult by the lack of a common mutation. The first molecular defect in PFK deficiency was identified in the Japanese family originally described by Tarui and coworkers (Nakajima et al., 1990), and soon thereafter Raben and her coworkers described two mutations, which turned out to be common among Ashkenazi Jewish patients (Raben et al., 1993; Sherman et al., 1994). At least 15 mutations have been reported in the PFKM gene of patients with typical PFK deficiency (Nakajima et al., 2002; DiMauro et al., 2004). Therapeutic attempts at bypassing the metabolic block are more difficult than in McArdle disease because glucose is not an alternative substrate in PFK deficiency. In fact, the “out-of-wind” phenomenon suggests that patients should avoid high-carbohydrate meals (Haller and Lewis, 1991). A 2-year-old boy with the infantile (and usually rapidly fatal) form of PFK deficiency, including arthrogryposis multiplex congenita, respiratory insufficiency, slowed motor nerve conductions and abnormal EEG, seemed to benefit remarkably from a ketogenic diet (Swoboda et al., 1997). There was clear improvement in strength, electromyographic features, and EEG pattern. Unfortunately, the child worsened suddenly at 35 months and died of complications of pneumonia. Still, ketogenic diet might be considered, at least in children with the more severe variant of PFK deficiency. 7.2.1.5. Phosphoglycerate kinase (PGK) deficiency (GSD IX) Phosphoglycerate kinase is a single polypeptide encoded by a gene (PGK1) on Xq13 for all tissues except spermatogenic cells. Although this enzyme is virtually ubiquitous, clinical presentations depend on the isolated or associated involvement of three tissues, erythrocytes (hemolytic anemia), central nervous system (CNS, with seizures, mental retardation, stroke) and skeletal muscle (exercise intolerance, cramps, myoglobinuria). The most common clinical association, seen in 8 of 27 reported patients, is non-spherocytic hemolytic anemia and CNS dysfunction. The second most common presentation is isolated myopathy (seven patients), followed by isolated blood dyscrasia (six patients), and by myopathy with CNS dysfunction (three patients; Morimoto et al., 2003). Only one patient had myopathy and hemolytic anemia, while two patients showed involvement of all three tissues. The seven myopathic cases were clinically indistinguishable from McArdle disease, but muscle biopsies

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Fig. 7.3. Phosphofructokinase deficiency (PFK). (A) A defect of PFK produces an excess of glycogen that predominates along the periphery of muscle fibers as exhibited in phosphorylase deficiency. In addition, some patients with PFK deficiency demonstrate discrete PAS-positive deposits (arrow) of abnormal glycogen within a small percent of myofibers as displayed in this transverse section of muscle. The material has long peripheral glucose chains and forms compact inclusions known as polyglucosan bodies. Cryosection, PAS, bar ¼ 50 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com. (B) Prior digestion of the tissue section by a-amylase or diastase removes normal finely granular glycogen, but does not remove all of the polyglucosan material (arrow) indicating that it is diastase-resistant. Cryosection, PAS-diastase, bar ¼ 50 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com. (C) A longitudinal section of a semithin plastic section demonstrates that the polyglucosan bodies are arranged in columns in a myofiber in the lower half of the figure. The bodies consist of pale PAS-positive material but contain kernels of intense PAS staining (dark, arrows). The sarcoplasm contains no detectable normal glycogen. The upper half of the field has another myofiber that contains normal glycogen (dark). Toluidine blue–PAS, bar ¼ 15 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com. (D) An electron micrograph of the same myofiber demonstrates abnormal glycogen that is composed of unbranched filaments 6–8 nm wide. An inner part of the body (upper third of the figure) contains material of greater electron opacity (arrows). This part consists of finely granular material as well as filaments and corresponds to the intensely PAS-positive kernels demonstrated in Figure 7.3(C). Bar ¼ 0.5 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com.

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showed less severe glycogen accumulation (DiMauro et al., 1983; Tonin et al., 1992; Cohen-Solal et al., 1994; Ookawara et al., 1996; Schroder et al., 1996; Aasly et al., 2000; Hamano et al., 2000). Mutations in PGK1 were identified in four of the seven myopathic patients. The various involvement of single or multiple tissues is difficult to explain and may relate to the severity of different mutations and the amount of residual PGK activity in individual tissues. 7.2.1.6. Phosphoglycerate mutase (PGAM) deficiency (GSD X) In contrast to PGK deficiency, PGAM deficiency affects only muscle, causing exercise intolerance, cramps and recurrent myoglobinuria. This is because PGAM is a dimeric enzyme composed of a muscle-specific (M) and a brain-specific (B) subunit, and normal muscle contains predominantly the MM homodimer, which accounts for 95% of the total activity. The only other tissues containing substantial amounts of the M subunit are heart and sperm, but there is no evidence of cardiopathy or male infertility in PGAM deficiency (DiMauro et al., 2004). The M subunit of PGAM is encoded by a gene (PGAMM) on chromosome 7. About a dozen patients with muscle PGAM deficiency have been described: the first six patients were AfricanAmerican (DiMauro et al., 1981, 1982; Bresolin et al., 1983; Kissel et al., 1985; Tsujino et al., 1993b) but subsequent cases have included Italians (Toscano et al., 1996), Japanese (Hadjigeorgiou et al., 1999), and Pakistani (Vissing et al., 1999) patients. The clinical picture is stereotypical: exercise intolerance and cramps after vigorous exercise, often followed by myoglobinuria. Manifesting heterozygotes have been identified in several families. The muscle biopsy shows inconsistent and mild glycogen accumulation, accompanied in one case by tubular aggregates (Vissing et al., 1999). Four different mutations in the PGAMM gene have been identified (DiMauro et al., 2004). 7.2.1.7. Aldolase deficiency (GSD XII) There are three isoforms of aldolase (A, B and C); skeletal muscle and erythrocytes contain predominantly the A isoform, which is encoded by a gene (ALDOA) on chromosome 16. The only reported patient with aldolase deficiency was a 4.5-year-old boy, who had episodes of exercise intolerance and weakness following febrile illnesses (Kreuder et al., 1996). Rhabdomyolysis was described, but there was no pigmenturia and the highest serum CK value reported was 6480 u/l (normal: <60 u/l). Muscle biopsy showed no glycogen accumulation. Biochemical analysis showed markedly decreased levels of aldolase

in both muscle and erythrocytes. A missense mutation was identified in ALDOA. 7.2.1.8. b-enolase deficiency (GSD XIII) b-enolase is a dimeric enzyme present in different isoforms, which result from various combinations of three subunits, a, b and g. Skeletal muscle contains predominantly the bb homodimer and — in lesser amount — the ab heterodimer. The b subunit is encoded by a gene (ENO3) on chromosome 17. This new glycogenosis is still represented by a single patient, a 47-year-old Italian man with adult-onset but rapidly progressive exercise intolerance and myalgia, and chronically elevated serum CK (Comi et al., 2001). The muscle biopsy was normal by light microscopy and showed subsarcolemmal deposits of glycogen by electron microscopy. Sequence analysis of ENO3 showed that the patient was a compound heterozygote for two missense mutations. 7.2.1.9. Lactate dehydrogenase (LDH) deficiency (GSD XI) Lactate dehydrogenase is a tetrameric enzyme composed of two subunits, M (or A) and H (or B) forming five isozymes, the two homotetramers M4 and H4 and three heterodimers. Skeletal muscle contains LDH isozymes composed predominantly by M subunits, whereas heart and other tissues contain isozymes composed predominantly by H subunits. The gene for LDH-M (LDHA) is encoded by a gene on chromosome 11. The discovery of this glycogenosis was due to the astute observation that a patient with myoglobinuria had predictably sky-high values of serum CK but extremely low values of LDH (Kanno et al., 1980). Several Japanese patients and two Caucasian patients with LDH-M deficiency have been reported. All have had exercise intolerance and cramps, with or without myoglobinuria. Skin lesions and dystocia have been described in Japanese patients (Kanno and Maekawa, 1995). Several mutations in LDHA have been reported.

7.3. Glycogenoses causing progressive weakness These include a defect in the glycogenosynthetic pathway (branching enzyme deficiency), one in the cytosolic glycogenolytic pathway (debranching enzyme deficiency), and another in the lysosomal glycogenolytic pathway (acid a-glucosidase, or acid maltase; Fig. 7.1). In addition, recent work on myoclonus epilepsy with Lafora bodies (Lafora disease) suggests that this is a glycogenosis, probably due to abnormal glycogen synthesis.

DISORDERS OF CARBOHYDRATE METABOLISM 7.3.1. Acid maltase deficiency (AMD, GSD II) Acid maltase (a-1,4 and a-1,6 glucosidase) is a lysosomal enzyme encoded by a gene (GAA) on chromosome 17. The predicted frequency of this disease is 1 in 40 000 (Ausems et al., 1999). The defect of this single ubiquitous protein causes three different clinical phenotypes distinguished by clinical features and age at onset (Engel et al., 2004). The first variant (infantile AMD or Pompe disease) is a generalized infantile form dominated by massive cardiomegaly and invariably fatal before 2 years of age. The second variant (juvenile AMD) starts either in infancy or in childhood, affects exclusively muscle, and causes severe proximal, truncal and respiratory muscle weakness. Calf hypertrophy is occasionally present and, in boys, can raise the suspicion of Duchenne muscular dystrophy. Death usually occurs in the second or third decade, due to respiratory failure. The third variant is also confined to muscle, but onset is in adult and even late life, simulating limb-girdle muscular dystrophy or polymyositis. However, a recent survey of 255 patients older than 2 years performed through a questionnaire showed more of a continuum for the muscular variant, where disease severity correlated best with duration of the disease rather than age at onset (Hagemans et al., 2005). Nevertheless, a subgroup of patients under 15 years of age had earlier onset and more rapid and severe clinical course, similar to the “non-typical infantile” patients described by Slonim et al. (2000). The diagnosis of Pompe disease is suggested by the association of profound weakness (floppy infant syndrome) and massive cardiomegaly, but must be confirmed by muscle biopsy, which shows severe vacuolar myopathy with accumulation of both intralysosomal and free glycogen. The diagnosis is more difficult in the myopathic forms of AMD, especially in the adult variant, where glycogen storage in muscle can be minimal in some biopsies. One useful clinical clue is the early and preferential involvement of truncal and respiratory muscles. A study on the quality of life of a large cohort of adult-onset AMD patients confirmed that this disorder causes severe physical limitations while not impairing mental health (Hagemans et al., 2004). Characteristically, the EMG shows — besides myopathic features — fibrillation potentials, positive waves, and myotonic discharges, more easily seen in paraspinal muscles (Engel et al., 2004). Muscle biopsy shows massive accumulation of glycogen in both infantile and childhood variants (Fig. 7.4), but may be unimpressive in adult cases, with variable involvement of different muscles. The histochemical stain for acid phosphatase, another lysosomal enzyme, is virtually absent in normal muscle but very prominent

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in the lysosome-rich muscle of AMD patients. Over 80 pathogenic mutations in GAA are known (Engel et al., 2004). Some degree of genotype–phenotype correlation is becoming apparent, with “severe” mutations associated with the infantile form and “leaky” mutations associated with the myopathic variant (Engel et al., 2004). However, the biochemical bases for the different phenotypes remain largely unclear. Palliative therapy includes respiratory support, dietary regimens (e.g., high-protein diet), and aerobic exercise. Gene therapy is being actively pursued in vitro and in animal models but is not yet applicable to patients. However, great strides were achieved with enzyme-replacement therapy using recombinant human a-glucosidase, although this therapeutic modality is invasive and expensive. Four infants with Pompe disease were treated with impressive results; although one patient died of an intercurrent infection at 4 years of age (typically, patients with Pompe disease die before 1 year of age), all four patients showed remarkable clinical improvement in motor and cardiac function and parallel improvement in muscle morphology (Van den Hout et al., 2000; 2004). The same therapeutic approach was applied with success in three children with the muscular variant (Winkel et al., 2004). Before starting enzyme replacement, all three were wheelchair-bound and two were respirator-dependent. After 3 years of treatment, their pulmonary function had stabilized and their exercise tolerance had improved, and the youngest patient resumed walking independently. It is important to start enzyme replacement therapy as soon as possible.

7.3.2. Debrancher deficiency (glycogenosis type III) The debrancher is a “double-duty” enzyme, with two catalytic functions, oligo-1,4-1,4-glucantransferase and amylo-1,6-glucosidase. After the peripheral chains of glycogen have been shortened by phosphorylase to about four glycosyl units, these stumps are removed by the debrancher in two steps. First, a maltotriosyl unit is transferred from a donor to an acceptor chain (transferase activity), leaving behind a single glucosyl unit, which is then hydrolyzed by the amylo-1,6-glucosidase. The enzyme is encoded by a single-copy gene (AGL) on chromosome 1p21. There are different clinical presentations of debrancher deficiency, depending on which tissues are affected and which enzymatic function is deficient (Shen and Chen, 2002). In the most common clinical variant (IIIa), the enzyme defect is generalized but liver and muscle are predominantly affected. In the rare variant IIIb, only liver is affected. The even less frequent variants IIIc and IIId are characterized by the selective defect of the

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A

B

C Fig. 7.4. Acid maltase deficiency. (A) A transverse semithin plastic sections of muscle demonstrates PAS-positive aggregates of glycogen (dark) in virtually every muscle fiber of a patient with the infantile form of acid maltase deficiency (Pompe disease). Much of the glycogen accumulates within lysosomes of the subsarcolemmal zone (arrow) as well as the intermyofibrillar spaces (arrowhead). Toluidine blue–PAS, bar ¼ 20 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com. (B) A histochemical stain for acid phosphatase, a lysosomal enzyme, shows greatly increased enzyme activity of lysosomes within muscle fibers of a patient with the childhood form of the disorder. Normally, myofibers contain sparse very small lysosomes. Marked activity of lysosomes in glycogen storage diseases provides a pathological clue that the disorder is caused by acid maltase deficiency. Cryosection, bar ¼ 45 mm. (C) An electron micrograph demonstrates excessive glycogen particles that are often enclosed by a lysosomal membrane (arrows). Bar ¼ 0.5 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com.

glucosidase activity (IIIc) or of the transferase activity (IIId). Patients with the IIIa variant typically present in childhood with hepatomegaly, growth retardation,

hypoglycemia and occasional seizures related to hypoglycemia. Symptoms tend to resolve spontaneously around puberty. Clinical myopathy may not be apparent in infants or children, although some of them show

DISORDERS OF CARBOHYDRATE METABOLISM hypotonia and delayed motor milestones. Myopathy often appears in adult life, long after liver symptoms have subsided. Adult-onset myopathies have been distinguished into two groups, distal and generalized (Kiechl et al., 1999a). Patients with distal myopathy develop atrophy of leg and intrinsic hand muscles, often suggesting the diagnosis of motor neuron disease or peripheral neuropathy (DiMauro et al., 1979). The course is slowly progressive and the myopathy is rarely crippling. Patients with generalized myopathy are more severely affected and often suffer from respiratory distress (Kiechl et al., 1999a, 1999b). Although debrancher works in parallel with myophosphorylase, the symptoms of debrancher deficiency are very different from those of McArdle disease and cramps and myoglobinuria are exceedingly rare. In agreement with the notion that the enzyme defect is generalized, peripheral neuropathy has been documented both electrophysiologically and by nerve biopsy and may contribute to the weakness and the neurogenic features of some patients. Similarly, while clinical cardiopathy is uncommon (Miller et al., 1972; Rossignol et al., 1979; Lee et al., 1997), cardiac involvement is demonstrable by laboratory tests in virtually all patients with myopathy (Moses et al., 1989). In the EMG, myopathic features are mixed with “irritative features” (fibrillations, positive sharp waves, myotonic discharges), a pattern that may reinforce the diagnosis of motor neuron disease in patients with distal muscle atrophy. As mentioned above, nerve conduction velocities are often decreased (DiMauro et al., 2004). Muscle biopsy typically shows a vacuolar myopathy. The vacuoles contain PAS-positive material and — in the electron microscope — correspond to large pools of normal-looking glycogen, most of which is free in the cytoplasm (Fig. 7.5). However, some of the glycogen is present within lysosomes. Biochemical analysis shows greatly increased concentration of glycogen, which — by iodine spectrum — has unusually short peripheral chains, as expected. Over 30 mutations in the AGL gene have been reported (Horinishi et al., 2002; Lucchiari et al., 2003; Lam et al., 2004). While there is no specific therapy, young patients should be protected from fasting hypoglycemia with frequent feedings and nocturnal gastric infusions of glucose and uncooked cornstarches. Liver transplantation should be considered in children with cirrhosis or hepatocellular carcinoma (Matern et al., 1999). 7.3.3. Branching enzyme deficiency (GSD IV) Glycogen branching enzyme (GBE) is encoded by a gene (GBE1) on chromosome 3p14, but alternative splicing

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Fig. 7.5. Debrancher enzyme deficiency. This semithin plastic section demonstrates deposits of PAS-positive (dark) glycogen within myofibers (arrows). The glycogen predominates in the subsarcolemmal zone. This location resembles the pattern of glycogen accumulation caused by defects of phosphorylase and glycolytic enzymes but is greater in quantity. A ring fiber (arrowhead) is included in the section. Toluidine blue–PAS, bar ¼ 20 mm. Reproduced from DiMauro et al. (1984) with permission from Taylor & Francis, Inc., http://www.taylorandfrancis.com.

may generate different isozymes, some of which may be tissue-specific (Moses and Parvari, 2002). Glycogen branching enzyme deficiency can be silent or variably affect liver, heart, skeletal muscle and brain (Moses and Parvari, 2002; DiMauro et al., 2004). The presentation described as “typical” until recently includes hepatoslenomegaly in infancy, progressing to liver cirrhosis and death from liver failure or gastrointestinal bleeding, usually before 4 years of age. However, nonprogressive hepatopathy was also reported in some children (McConkie-Rosell et al., 1996), while cardiomyopathy dominated the clinical picture in a few older children (Farrans et al., 1966; Nase et al., 1995; Ewert et al., 1999). Myopathy is a common manifestation of GBE deficiency, either alone or associated with hepatopathy or cardiopathy. Recent experience suggests that congenital myopathy was probably underdiagnosed (Tang et al., 1994; Nambu et al., 2003; Bruno et al., 2004; Tay et al., 2004). Even within this group, clinical presentations vary from perinatal fetal akinesia deformation sequence (FADS), characterized by arthrogryposis multiplex congenita, hydrops fetalis, and perinatal death (Bruno et al., 2004), to isolated myopathy (Bruno et al., 2004), to congenital myopathy and cardiomyopathy (Tang et al., 1994; Nambu et al., 2003; Tay et al., 2004), to Werdnig–Hoffmann-like syndrome (Tay et al., 2004). Muscle biopsy in these children shows the typical foci of polyglucosan, intensely PAS-positive and diastase-resistant (Fig. 7.6). Similar deposits are seen in the cardiomyocytes of

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A

B

Fig. 7.6. Brancher enzyme deficiency. (A) The defect of this enzyme causes formation of an abnormal glycogen composed of poorly branched polymeric glucose with long peripheral glucose chains. This material appears as strongly PAS-positive polyglucosan bodies within the cytoplasm of muscle fibers (arrows), liver cells and other organs. The staining properties and ultrastructural features of the bodies closely resemble those of phosphofructokinase deficiency (see Figure 7.3). Paraffin section, PAS, bar ¼ 25 mm. (B) The histochemical reaction for acid phosphatase may show excessive activity in muscle fibers in brancher enzyme deficiency, most pronounced around the polyglucosan bodies. This markedly increased lysosomal enzyme activity is an exception to other non-lysosomal glycogen storage diseases. Cryosection, bar ¼ 25 mm.

children with cardiopathy and in motor neurons of infants with Werdnig–Hoffmann-like presentation (Tang et al., 1994; Tay et al., 2004). Myopathy has also been described in a few adults (Ferguson et al., 1983; Bornemann et al., 1996). A neurological variant of GBE deficiency presenting late in life is known as adult polyglucosan body disease (APBD); it is characterized by progressive upper and lower motor neuron dysfunction (sometimes simulating amyotrophic lateral sclerosis), sensory loss, sphincter problems and, inconsistently, dementia. In APBD, polyglucosan bodies have been described in the axons and axon hillocks of neurons in both gray and white matter. Numerous mutations in the GBE1 gene have been identified (Bao et al., 1996; Nambu et al., 2003; Bruno et al., 2004; Tay et al., 2004), suggesting some genotype–phenotype correlation (Bruno et al., 2004). Interestingly, the mutation found in patients with APBD (Lossos et al., 1998) appears to be relatively mild (Bao et al., 1996), which may explain the late onset of this disorder. There is no specific therapy, but liver transplantation is an option for children with liver cirrhosis or portal hypertension (Matern et al., 1999). 7.3.4. Lafora disease Clinically, Lafora disease (myoclonus epilepsy with Lafora bodies) is characterized by seizures, myoclonus and dementia. Onset is in adolescence, the course is rapidly progressive, and death occurs almost always

before 25 years of age. The pathologic signature of the disease are the bodies described by Gonzalo Rodriguez Lafora in 1911 (Lafora, 1911); these are round, basophilic, strongly PAS-positive intracellular inclusions seen in neuronal dendrites of the cerebral cortex, substantia nigra, thalamus, globus pallidus, and dentate nucleus. Polyglucosan bodies are also seen in muscle, liver, heart, skin, and retina, indicating that Lafora disease is a generalized glycogenosis. However, the obvious biochemical suspect, branching enzyme, is normal (Gambetti et al., 1971; Ponzetto Zimmerman and Gold, 1982). Linkage analysis localized the gene responsible for Lafora disease (EPM2A) to chromosome 6q24 and about 30 pathogenic mutations have been identified in patients (Minassian et al., 2000) The protein encoded by EPM2A, dubbed “laforin”, contains a carbohydratebinding module in the N-terminus and a dual-specificity phosphatase domain in the C-terminus, whose substrate remains unknown (Wang et al., 2002; Chan et al., 2005). It was suggested that laforin may play a role in the cascade of phosphorylation/dephosphorylation reactions controlling glycogen synthesis and degradation and that mutations in laforin may alter the ratio of glycogen synthetase/GBE in favor of the synthetase, but this mechanism remains to be proven. Mutations in EPM2A accounted for 48% of a large cohort of patients with Lafora disease (Chan et al., 2004), and pathogenic mutations were identified in a second gene (called NHLRC1 or EPMD2B), accounting for another 40% of patients. NHLRC1 encodes a protein

DISORDERS OF CARBOHYDRATE METABOLISM called malin, a putative E3 ubiquitin ligase. Both laforin and malin localize to the endoplasmic reticulum (ER) and it has been suggested that they operate in a related pathway protecting against polyglucosan accumulation (Chan et al., 2003).

Acknowledgements Part of this work was supported by a grant from the Muscular Dystrophy Association.

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