5 Normal metabolism and disorders of carbohydrate metabolism THIERRY DE BARSY HENRI-GI~RY HERS

Carbohydrate metabolism has a primary role in muscle because of the unique function of glycolysis in providing ATP in anaerobic respiration. Indeed, muscle is the only tissue that can be severely deprived of oxygen under physiological conditions. Disorders of carbohydrate metabolism can therefore be classified into two main groups according to whether or not they result from insufficient glycolysis. Because glycogen is the most easily available substrate for glycolysis, the first group of disorders includes several of the known types of glycogenoses as well as a few specific defects of glycolytic enzymes. The second group of disorders is characterized by muscle degeneration resulting either from the lysosomal storage of glycogen (type II glycogenosis) or from the deposition of an abnormal polysaccharide (type IV glycogenosis and some ill-defined similar diseases). The field of glycogen storage diseases has recently been extensively covered by Hers et al (1989) in a review article in which additional information and references to original work can be found. BASIC ASPECTS OF GLUCOSE AND GLYCOGEN UTILIZATION BY MUSCLE Structure and function of glycogen Glycogen is a polymer of glucose present in most animal cells; it is a globular and very soluble structure, in which 10000-30000 glucose units are connected to each other by c~-1,4 (in 93%) or o~-1,6 (in 7%) glucosidic linkages in a tree-like structure, as depicted in Figure 1. Enzymatic analysis of glycogen has revealed an average length of four residues for the internal chains (between two branching points) and of nine residues for the external ones, which 'constitute about 60% of the molecular mass (see Manners, 1957). Figure 1 also suggests that each glycogen molecule should bear one reducing group. There is now a general belief that the so-called reducing end of the molecule is bound to a protein, called glycogenin, by an osyl tyrosine linkage (see Lomako et al, 1988). The major advantage of the structure of glycogen is that it allows the storage of glucose in a form that exerts a negligible 499 Copyright© 1990,byBailli6reTindall All rightsofreproductionin anyformreserved

Bailli&e's Clinical Endocrinology and Metabolism--

Vol. 4, No. 3, September1990 ISBN0-7020-1464-8







Figure 1. Model of a segment of a glycogen molecule. Open circles represent glucose residues in c~-l,4-1inkage; closed circles represent residues in a-l,6-1inkage. The broken line indicates the limit of degradation by phosphorylase (modified from Cori, 1954). The insert represents the degradation of the limit dextrin (L.D.) by amylo-l,6-glucosidase. Hatched circles represent the oligoglycan transferred from the side chain to the main chain of the polysaccharide during the first reaction catalysed by the bifunctional enzyme.

osmotic pressure but in which as much as 7-10% is terminal and directly exposed to the action of biosynthetic or degradative enzymes. The molecular weight of muscle glycogen ranges between 2 and 6 x 106. Muscle glycogen is a spherule of approximately 30 nm diameter and a molecular weight of 2.6 x 106. It is called the [3-particle. The concentration of glycogen in the muscle is close to 1%; its role is to serve as a reserve of glycolytic fuel to be used locally when oxygen or glucose are lacking. The sequences of reactions by which glycogen is synthesized from glucose and degraded to both glucose 1-phosphate and glucose are shown in Figure 2. The same figure also shows that the hexose phosphates formed by the phosphorolysis of muscle glycogen have no other fate than conversion to lactate by glycolysis, as illustrated in Figure 3. Different cytosolic enzymes are involved in both the synthesis (respectively glycogen synthase and branching enzyme) and the phosphorolytic degradation (phosphorylase and amylo-l,6-glucosidase) of the eL-l,4 and ~-1,6 glucosidic linkages. By contrast, acid o~-glucosidase alone allows the hydrolysis of both types of linkage and the complete degradation of glycogen to glucose in the lysosome. Properties of the enzymes involved in the conversion of glucose to glycogen in the muscle Hexokinases

The muscle cell contains several low-Km (10-7-10-6M) hexokinases, which













PhesPhorylaseA ;imylo°ilat e






UDPG pyrophosphorylase /



Ph°sph°gluc°mutase ¢/




""o=°"'"°°'='rase,l, t







Pi,ffr,~p FRUCTOSE6"P "~/,,,,,,.ATP Fructose-,.,- y bisphosphat a s ~ k

H20 -

(~ (glucose)n+l



Glucose 6-phosphate is a potent activator of the enzyme. It was on the basis of a different sensitivity to this activator that Larner and his co-workers (Friedman and Larner, 1963) recognized the existence of two forms of the enzyme, called I (glucose 6-phosphate independent) and D (glucose 6phosphate dependent), that are interconvertible by phosphorylation and dephosphorylation. The terms a (active) and b (less active) are often preferred to I and D. The greater activity of the a form of the muscle enzyme is related to a higher Vma×, when measured at physiological glucose 6-phosphate concentration. The two forms of enzyme have a great affinity for glycogen (Km close to 50 ~gm1-1) and remain associated with it during differential centrifugation of crude tissue extracts. They consist of two or four subunits of molecular weight close to 85 000 (reviewed by Stalmans and Hers, 1973). Several protein kinases can phosphorylate glycogen synthase (reviewed by Cohen, 1982). The predominant one is cyclic AMP-dependent protein kinase. The calcium-dependent enzymes include phosphorylase kinase and protein kinase C. Several cyclic AMP and calcium-independent kinases also act on glycogen synthase. The dephosphorylation of glycogen synthase b, which is simultaneous with its activation, is catalysed by synthase phosphatase. The main regulatory property of the muscle enzyme is inhibition by glycogen (VillarPalasi, 1969).

Branching enzyme Branching of glycogen is effected by the transfer of a segment of at least six ~-l,4-1inked glucosyl units from the outer chains of glycogen into an ~-l,6position (Verhue and Hers, 1966). Rabbit liver branching enzyme is a monomeric protein of molecular weight close to 70 000 (Zimmerman and Gold, 1983). Properties of some of the enzymes involved in the conversion of glycogen to lactate

Glycogen phosphorylase and its converter enzymes Glycogen phosphorylase catalyses the transfer of a glucose unit present at the non-reducing end of the polysaccharide onto inorganic phosphate (reviewed by Graves and Wang, 1972). The reaction is easily reversible in vitro, but not in vivo as the concentration of inorganic phosphate in cells is usually 100-fold that of glucose 1-phosphate. The reaction proceeds from


T. DE BARSY A N D H . - G . H E R S

the non-reducing ends until about four glucose residues remain on each external chain. The resulting polysaccharide is called a phosphorylase limit dextrin; it can be further degraded by phosphorolysis only after the removal of the branching point by amylo-l,6-glucosidase. The activity of glycogen phosphorylase is modified by the phosphorylation and dephosphorylation of a serine residue in position 14. The phosphoenzyme is called phosphorylase a because it is active under the ionic conditions prevailing in the cell. Phosphorylase b is the inactive dephosphoenzyme, which may be activated by non-physiological concentrations of AMP. Muscle phosphorylase is immunologically different from its liver counterpart and is therefore under different genetic control. The enzyme is a dimer or a tetramer of a subunit with a molecular weight close to 100 000, to which one essential pyridoxal phosphate is bound as a Schiff base to a lysine residue close to the active site. The gene of muscle phosphorylase has been isolated, sequenced and localized in the long arm of chromosome 11 (Lebo et al, 1986). The conversion of phosphorylase b into phosphorylase a occurs by transfer of the terminal phosphate of ATP catalysed by phosphorylase b kinase. This latter enzyme itself exists as a phosphorylated active and a nonphosphorylated less-active form. The latter is only active in the presence of calcium (/Ca = 1 0 - 6 M), a property which allows the initiation of glycogenolysis in muscle simultaneously with contraction. The phosphorylation of phosphorylase b kinase is catalysed by cyclic AMP-dependent protein kinase. It activates the enzyme 15-20-fold at saturating calcium concentrations and decreases the/Ca for calcium 15-fold (Cohen, 1982). Phosphorylase b kinase is a large protein of molecular weight 1.3 x 10 6 with the structure (o/.[3'~)4. The o~ and [3 subunits are the components phosphorylated by cyclic AMPdependent protein kinase and the ~/-peptide appears to be the catalytic subunit. The 8-subunit is identical to the calcium-binding protein calmodulin. The dephosphorylation and resulting inactivation of phosphorylase occurs by hydrolysis of the ester linkage by phosphorylase phosphatase. Despite a considerable amount of work devoted to that subject (Ingebritsen and Cohen, 1983), the precise identity and specificity of the various protein phosphatases involved in glycogen and other areas of intermediary metabolism remain a controversial subject.

Amylo-1,6-glucosidase Amylo-l,6-glucosidase is a bifunctional enzyme that converts the phosphorylase limit dextrin into a glycogen with external chains of normal length and liberates free glucose by hydrolysis of the a-l,6-glucosidic linkage (reviewed by Smith et al, 1968). The first step of this conversion is the ~-1,4/~-1,4 transfer of an oligoglucan of 3-4 glucose units from the side chain to the main chain of the phosphorylase limit dextrin, thereby exposing the a-l,6-1inked glucose unit of the branching point. The second step is the hydrolysis of the a-1,6 linkage and the liberation of glucose. The low level of reversibility of this reaction allows a simple assay of the enzyme in crude tissue preparations



following the incorporation of 14C-labelled glucose into glycogen (Hers et al, 1967). The combined action of phosphorylase and of amylo-l,6glucosidase causes the complete degradation of glycogen into glucose 1phosphate (93%) and glucose (7%).

6-Phosphofructokinases The name phosphofructokinase is currently used to designate the enzyme of glycolysis that phosphorylates fructose 6-phosphate into fructose 1,6bisphosphate at the expense of ATP. Another phosphofructokinase that forms fructose 2,6-bisphosphate by a similar reaction has now been discovered (reviewed by Van Schaftingen, 1986). It has been called phosphofructokinase-2, the classic phosphofructokinase then becoming phosphofructokinase-1. This nomenclature indicates both the carbon of fructose 6-phosphate that is phosphorylated and the order of discovery of the two enzymes. The control of phosphofructokinase-1 can be summarized by saying that one of its substrates, ATP, acts as a negative allosteric effector that induces marked co-operativity for the second substrate, fructose 6-phosphate. The latter acts as a positive effector that relieves the inhibition by ATP. Numerous other substances have an allosteric effect similar to, and usually synergistic with, those of ATP or fructose 6-phosphate. The most important positive effectors are AMP and fructose 2,6-bisphosphate. Numerous isoenzymes of phosphofructokinase-1 have been isolated from various types of cells (reviewed by Uyeda, 1979). Their catalytic and physicochemical properties are usually similar. Phosphofructokinase-2 is part of a bifunctional protein with two active sites, one allowing the formation of fructose 2,6-bisphosphate from fructose 6-phosphate and ATP, the other causing its hydrolysis to fructose 6phosphate and Pi (fructose-2,6-bisphosphatase). Contrary to the liver enzyme, muscle phosphofructokinase-2/fructose-2,6-bisphosphatase is not interconvertible by phosphorylation and dephosphorylation.

Phosphoglycerate kinase Phosphoglycerate kinase catalyses the transfer of the energy-rich phosphate from the acid anhydride bond of 1,3-diphosphoglycerate to the terminal phosphate of ADP, forming ATP and 3-phosphoglycerate. Mg 2+ is required for the reaction (reviewed by Scopes, 1973). The equilibrium favours ATP formation (K = 3.2 × 103), but the reaction is tightly coupled to that catalysed by the glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase. Thus, the overall transformation by which the oxidation of the triose phosphate to 3-phosphoglycerate is coupled to the generation of ATP is nearly in balance. Phosphoglycerate kinase is a monomeric protein with a molecular weight of 45 000. Its activity in skeletal muscle is at least 25 times higher than necessary to cope with the highest glycolytic rates in that tissue. There is good genetic evidence that the corresponding gene is located on the X chromosome.


x . DE BARSY A N D H . - G .


Phosphoglycerate mutase Phosphoglycerate mutase catalyses the reversible conversion of glycerate 2-phosphate to glycerate 3-phosphate. The thermodynamic equilibrium favours glycerate 2-phosphate (6 : 1). Glycerate 2,3-bisphosphate is a cofactor of the mammalian enzyme and participates in the reaction as a phosphate donor. Highly purified preparations of muscle or yeast phosphoglycerate mutase also act as a bisphosphoglycerate phosphatase, but at a rate at least 1000-fold less than that of the mutase activity (reviewed by Ray and Peck, 1972; Rose, 1980). Phosphoglycerate mutase is a dimer of subunits of molecular weight 30 000. Two isoenzymes called B (brain) and M (muscle) can be distinguished by electrophoresis. The B enzyme migrates faster and is also much more thermolabile than the M enzyme; it is present in brain, fetal muscle and also in several other tissues (Omenn and Cheung, 1974). The muscle enzyme is also characterized by its high sensitivity to inhibition by Hg 2+ (Grisolia et al, 1970). Only in heart are the two isoenzymes present in substantial amounts.

Lactate dehydrogenase Lactate dehydrogenase catalyses the reaction: Lactate + NAD + ~ pyruvate + NADH + H + The equilibrium favours lactate formation, the concentration of which is normally 10 times that of pyruvate in the blood. The reaction is inhibited by pyruvate at high concentrations. Lactate dehydrogenase is a hetero-tetramer of molecular weight 140 000, containing two major types of subunits, called M and H, in various proportions from tissue to tissue. The H4 isoenzyme is more inhibited than M4 by pyruvate and migrates faster to the anode during electrophoresis (reviewed by Holbrook et al, 1975).

The hydrolytic degradation of glycogen The discovery that type II glycogenosis is caused by a deficiency of a lysosomal acid o~-glucosidase (Hers, 1963), and is accompanied by a striking accumulation of glycogen inside lysosomes (Baudhuin et al, 1964), led to the discovery that, in nearly all animal cells, some glycogen is continuously degraded hydrolytically in the lysosomes. Acid a-glucosidase was described by Lejeune et al (1963) who also demonstrated its lysosomal localization. It also catalyses transglucosylation from maltose into glycogen. As the enzyme is an exoglucosidase, freely diffusible glucose is the only reaction product and glycogen degradation can be completed without an increase in the intralysosomal osmotic pressure. The role of acid ot-glucosidase is obviously to degrade glycogen that has penetrated into the lysosomal system by autophagy.



Regulation of glycogen metabolism in the muscle In the muscle, insulin favours glycogen synthesis by facilitating glucose transport through the membrane (Levine et al, 1949). It causes also a moderate activation of glycogen synthase even in the absence of glucose (Villar-Palasi and Lamer, 1960). Cyclic AMP concentration is increased by adrenaline and other catecholamines, subsequently causing the activation of phosphorylase b kinase and the inactivation of glycogen synthase. Two most important local regulators are calcium, which stimulates the dephosphorylated form of phosphorylase b kinase, and glycogen itself, which, by inhibiting synthase phosphatase, prevents excessive synthesis of the polysaccharide. The lysosomal degradation of glycogen appears to be a continuous, non-regulated process. DISEASES RELATED TO INSUFFICIENT GLYCOLYSIS

Common properties In this group of diseases the symptoms are related to the inability of the muscle cell to obtain rapidly a glycolytic fuel for contraction. Indeed, glycolysis is the only metabolic conversion able to provide ATP in the absence of oxygen and the glucosyl units of glycogen are the most easily available substrate for this; the only alternative substrate is glucose itself, but the penetration of this sugar in the muscle requires insulin and is followed by a phosphorylation step at the expense of ATP. Similar symptoms are therefore observed in a series of disorders due to the deficiency of either a glycogenolytic enzyme (glycogenoses type III, type V and also some rare cases of phosphorylase b kinase deficiency affecting the muscle) or a glycolytic enzyme (glycogenosis type VII as well as a series of other rare diseases). In all these disorders, the symptomatology is usually mild, becoming apparent in the young adult and sometimes much later. The fact that several patients with such a defect were recognized only in their seventies indicates that others were presumably never detected. There is also a striking male preponderance of about 2: 1, probably explained by the fact that men usually exercise their muscles more intensively than do women, who more often escape clinical detection. The main manifestation of these diseases is the appearance of cramps and contracture during strenuous exercise. The inability of the muscle to perform glycolysis is easily recognized by using the forearm ischaemic exercise test, first described by McArdle in 1951. A sphygmomanometer cuff is placed about the upper arm and inflated above the systolic pressure. The subject is asked to squeeze the sphygmomanometer bulb once every second for 1 minute, after which the cuff is released. Normal subjects perform this test easily, but patients are usually obliged to stop the exercise after 30 to 40 seconds owing to pain and cramps. The evolution of lactate concentration in the venous blood of normal people and of patients is shown in Figure 4. A lack of increase in blood lactate is typical of a defect in the conversion of glycogen to lactate. It is also of interest to measure the concentration of



.3 5




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rr 2

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I 5

I 10

I 15

I 20

TIME ( m i n )

Figure 4. Effect of ischaemic work of the forearm muscles on the blood lactate in normal subjects (shaded area) and in a patient (o) with a defect of muscle glycolysis(From Hers et al, 1989). ammonia in the same blood samples, because normal or exaggerated values can be found, in contrast to what is observed in myoadenylate deaminase deficiency. In this latter condition there is a complete absence of ammonia and the rise in lactate is normal (Fishbein et al, 1978). Blood creatine kinase is variably increased, even at rest. Myoglobinuria occurs rarely and is usually benign. During cramps, the electromyography records an 'electrical silence'--that is no electrical activity. In general, there is no need for specific therapy in these conditions, other than avoidance of strenuous exercise.

Muscle phosphorylase deficiency (McArdle's disease or type V glycogenosis)

History and clinical features In 1951, McArdle reported the case of a 30-year-old man suffering from myalgia, weakness, stiffness and myoglobinuria, and displaying no rise in blood lactate after muscle exercise. The epinephrine-induced rise in blood lactate was less marked than in normal subjects. Exercise of a muscle that had been rendered ischaemic resulted in the development of swelling due to contracture. McArdle concluded that the muscle of his patient was not able to convert glycogen to lactate. Mommaerts et al (1959) demonstrated a


DISORDERS OF CARBOHYDRATE METABOLISM Table 1. Main clinical and laboratory features in 74 patients with type V glycogenosis.

Age of onset: < 20 years > 20 years Exercise intolerance Myoglobinuria Renal failure Seizures Permanent muscular weakness Affected sibs Creatine kinase elevated at rest Abnormal EMG at rest



68/74 6/74 71/74 38/74 5/74 4/74 16/74 39/74 31/33 10/25

92 8 96 51 7 5 22 53 94 40

This series includes 51 male and 23 female patients: 62 cases are from DiMauro (1978) and 12 cases from the authors' laboratory. From Hers et al (1989) with permission.

deficiency of the glycogenolytic pathway in a similar case and showed that muscle phosphorylase was inactive. The symptoms are essentially as described in the preceding section. Their frequencies are reported in Table 1. Most patients are free of clinical manifestation until the second or third decade, but they often remember fatiguability during childhood and adolescence. Usually, moderate exercise such as walking on level ground or intermittent more vigorous activities can easily be performed. Many patients experience a 'second wind' phenomenon characterized by the fact that the pain disappears progressively after a few minutes, even if the exercise is prolonged. Myoglobinuria is usually benign, but renal blockade has been reported exceptionally. Most patients have no complaint between the attacks but 22% suffer permanent muscular weakness. Siblings are affected in about 50% of cases. Serum creatine kinase is elevated at rest and increases manyfold during exercise. Ammonia, inosine and hypoxanthine are found at upper normal values, indicating an excessive degradation of the adenosine nucleotide pool. By contrast, 32p NMR measurements of ATP concentration in muscle indicate only a slight reduction under similar conditions (Duboc et al, 1987). Electromyography at rest shows a myogenic pattern in about half of the patients.

Diagnosis The absence of an increase in venous blood lactate during the forearm ischaemic exercise test indicates the existence of a defect in the conversion of glycogen to lactate. The precise diagnosis rests on the histochemical or biochemical demonstration of a complete deficiency of muscle phosphorylase.

Physiopathology The clinical symptoms observed in McArdle's disease can be encountered in normal people after sustained vigorous exercise (Pearson et al, 1961).



During intense muscular contraction, aerobic oxidative metabolism suffers from a shortage in oxygen and the muscle shifts from aerobic to anaerobic metabolism. This transition is detectable by the formation of lactate, which rapidly diffuses in the bloodstream. The ATP content of the muscle does not decrease markedly, as the variation in energy-rich phosphate essentially concerns phosphocreatine. Alteration of the muscle membrane and muscle necrosis explains the elevation of circulating levels of muscle-specific enzymes and the appearance of myoglobin in the blood. In patients, these manifestations occur much more rapidly owing to their inability to mobilize muscle glycogen. If a large amount of myoglobin, a small-molecular-weight protein, is excreted by the kidney, renal blockage may occur. It is, however, surprising that patients display such a mild symptomatology for many years. The second wind phenomenon could be explained partially by increased blood flow after ischaemic exercise (McArdle, 1951) and by the fact that, at that time, plasma free fatty acids mobilized by the stimulation of adipocyte lipase by catecholamines, are used by the muscle (Porte et al, 1966).

The enzyme defect and the mode of transmission Phosphorylase exists as different tissue-specific isoenzymes. The M enzyme, which is the only one present in mature muscle, is completely inactive in patients. However, slight activity can be detected histochemically in regenerating fibres, which may be abundant in a biopsy taken after an episode of myoglobinuria. This low activity appears to be due to the presence of a small amount of both the fetal and the liver forms of phosphorylase (Sato et al, 1977). Furthermore, the presence in variable amounts (from 1 to 100% of the normal) of the inactive phosphorylase has been demonstrated in some patients by electrophoretic, immunological and molecular biological methods, thereby establishing the genetic heterogeneity of the disease. The fact that muscle phosphorylase is completely inactive in the patients indicates that they are homozygous for the abnormal gene. Autosomal recessive transmission is confirmed by parental consanguinity, affected siblings and decreased enzyme activity in muscle of asymptomatic heterozygotes. Apparent dominant transmission of the disease has, however, been reported in some families.

Amylo-l,6-glucosidase deficiency (type III glycogenosis) Type III glycogenosis or Cori-Forbes disease is a generalized disorder characterized by a deficiency of the debranching enzyme, amylo-l,6glucosidase. It is also called 'limit dextrinosis', because the polysaccharide that accumulates in all cells has an abnormal structure characterized by short external chains, as in a phosphorylase limit dextrin.

Clinical features During infancy and childhood, the condition is mainly characterized by a hepatic disorder but muscle involvement may be important and becomes


DISORDERS OF CARBOHYDRATE METABOLISM Table 2. Main clinical and laboratory features of amylo-l,6-glucosidase deficiency myopathy in 22 patients.

Incidence Onset of the disease Childhood Adulthood Exercise intolerance Weakness

Wasting Present Distal more than proximal Hepatomegaly Increased serum creatine kinase at rest Forearm ischaemic test No lactate found Partial lactate response Abnormal electrocardiogram Abnormal electromyogram

7/22 15/22 8/22 20/22

15/21 8/16 13/22 20/20 7/13 5/13 14/17 15/17

Modified from Cornelio et al (1984).

predominant in adulthood. The main symptoms are summarized in Table 2. In infancy, one observes a failure to thrive, hypoglycaemia and hepatomegaly, as in other forms of hepatomegalic glycogenosis. The prognosis is usually good and the symptoms tend to disappear around puberty. In adult patients, proximal muscular weakness can be the only complaint, with or without previous signs of liver dysfunction and hepatomegaly. Cramps and contractures during vigorous exercise have rarely been reported. Cardiac involvement has been found more frequently than previously suspected even during childhood. This can be the cause of sudden death. Serum creatine kinase is elevated at all ages. Serum lipids are frequently high in infancy and childhood but normalize after puberty. Electromyography shows a myopathic pattern with, in some cases, signs of irritability, myotonic discharge and sometimes fibrillation potentials. Functional tests and diagnosis Administration of glucagon or epinephrine to fasted patients is not followed by a hyperglycaemic response, but a small response is observed in normally fed patients. The forearm ischaemic exercise test gives an abnormal response with no, or a very small, increase in venous lactate. The deficiency in amylo-l,6-glucosidase can easily be demonstrated in muscle, liver, erythrocytes and leukocytes, where the accumulation of glycogen is also the most prominent (Van Hoof, 1967). Prenatal diagnosis is possible using chorionic trophoblasts (Maire et al, 1989) or cultured amniotic fluid cells (Ding et al, 1990), but this is not commonly performed because the evolution of the disease is usually benign. The abnormal structure of the polysaccharide present in all tissues can be determined by its iodine absorption spectrum.


T. DE BARSY A N D H . - G . H E R S

Mode of transmission and genetic heterogeneity Transmission is clearly autosomal recessive. Van Hoof and Hers (1967) were able to show that the condition has a genetic heterogeneity corresponding to the defect of one or of both activities of the enzyme present in muscle or in liver. In patients with an isolated transferase deficiency and retention of glucosidase activity (type IIID) a nearly normal amount of cross-reactive material was present, whereas in patients with both transferase and glucosidase deficiencies the corresponding protein was either absent or greatly reduced (Ding et al, 1990).

Treatment There is no treatment for the muscle disease. Frequent feeding may be useful in infancy and childhood to avoid hypoglycaemia (Fernandes et al, 1988).

Phosphorylase b kinase deficiency Because it is composed of four subunits with different gene control, phosphorylase b kinase can be affected by various mutations, some of them concerning only the muscle enzyme. Lederer et al (1975) proposed that two different genetic defects affecting phosphorylase b kinase could be responsible for a hepatomegalic type of glycogenosis: (a) a sex-linked phosphorylase b kinase deficiency, first described by Huijing and Fernandes (1969), in which the muscle enzyme is unaffected; (b) an autosomal phosphosphorylase b kinase deficiency that affects both liver and muscle (Lederer et al, 1975; Bashan et al, 1981; Madlom et al, 1989). In the latter disease, hepatomegaly, mild muscular weakness and hypotonia are the prominent features; the enzyme deficiency was demonstrated in liver, muscle, erythrocytes and leukocytes. Other case reports have been published, in which either skeletal muscle alone (Ohtani et al, 1982; Abarbanel et al, 1986) or cardiac muscle alone was affected (Eishi et al, 1985; Mizuta et al, 1984; Servidei et al, 1988).

Muscle phosphofructokinase deficiency (Tarui's disease or glycogenosis type VII)

History and general description In 1965, Tarui et al described three siblings, a 13-year-old girl and 23- and 27-year-old men, presenting symptoms similar to but more severe than those of McArdle's disease, including an increased concentration of glycogen in the muscle (up to 4%). In contrast, the activity of muscle phosphorylase was in the normal range, but that of phosphofructokinase was almost undetectable and, accordingly, the concentration of glucose 6-phosphate was about 30 times the normal; furthermore, erythrocyte's phosphofructokinase was decreased by about 50%. Subsequently, similar cases were reported and the main features of the disease (including a male preponderance of 2:1)


DISORDERS OF CARBOHYDRATE METABOLISM Table 3. Main clinical and laboratory features in 26 patients with glycogenosis type VII.

Exercise intolerance Pigmenturia Recurrent jaundice Permanent weakness Onset in childhood Affected sibs Increased serum creatine kinase at rest Abnormal E M G at rest Increased reticulocyte count Increased serum bilirubin Gout Hyperuricaemia



20/20 8/20 6/14

100 40 43 36 95 35 88 54 100 83 31 64


21/22 7/20 14/16 7/I3 15/15 15/18 4/13 9/14

Courtesy of Dr S. Tarui, Osaka University, Medical School, Japan. This series includes 18 male and 8 female patients. From Hers et al, 1989, with permission.

together with their frequencies are shown in Table 3. Unlike McArdle's disease, the clinical symptoms appear more often during childhood, with a spectrum from a rapidly progressive myopathy in infancy to a progressive proximal muscular weakness with cramps and myoglobinuria in the case of late onset (Danon et al, 1983). 31p nuclear magnetic resonance studies in one patient revealed that the ATP level was low at rest and continued to decline during exercise (Argov et al, 1987). In two patients, the muscle contained both an excess of normal glycogen and an abnormal polysaccharide, revealed by periodic acid-Schiff staining and by its resistance to a-amylase. On electron microscopy, this abnormal polysaccharide was found to consist of filamentous material. A possible explanation for this finding could be that the high concentration of glucose 6-phosphate caused an increase in the activity of glycogen synthase relative to that of branching enzyme, favouring the synthesis of a poorly soluble amylopectin-like polysaccharide (Agamanolis et al, 1980; Hays et al, 1981).

Physiopathology The factors that differentiate type VII from type V are: (1) that the muscle is unable to utilize glucose; (2) that the erythrocytes are affected, causing a tendency to haemolysis and increased reticulocyte counts as well as an elevated serum bilirubin. The 50% decrease in activity of erythrocyte's phosphofructokinase is due to the fact that this enzyme is a tetrameric hybrid, of which two protomers are of the muscular type. Erythrocytes have no source of energy other than glycolysis, and phosphofructokinase catalyses the limiting step. The partial defect of phosphofructokinase activity is responsible for the shorter life-span of these cells and recurrent jaundice. Blood ammonia, inosine, hypoxanthine and uric acid increase as a result of an accelerated degradation of purine nucleotides, and may cause clinical gout (Mineo et al, 1987). For these reasons, phosphofructokinase deficiency is the most severe glycogen storage disease specific to muscle.



Diagnosis The diagnosis rests on the biochemical or histochemical determination of the enzymic defect in the muscle of patients who show no rise in venous lactate in the forearm ischaemic exercise test.

Phosphoglycerate kinase deficiency Phosphoglycerate kinase deficiency has been known, since 1968, essentially as an X-linked chronic haemolytic anaemia frequently complicated by neurological manifestations (reviewed by Valentine et al, 1989). About half of the 12 reported variants with reduced activity involved neurological and mental aberrations. However, the disease is clinically and biochemically polymorphic. Rosa et al (1982) reported the case of a patient with rhabdomyolysis and acute renal failure but with no sign of haemolysis. The symptomatology was similar to that of McArdle's disease, except that the ischaemic exercise test was only partially abnormal. The activity of phosphoglycerate kinase was as high as 25% of the normal value in muscle, but the enzyme displayed a greatly reduced affinity for ADP and ATP as well as a reduced thermostability. The absence of red-cell impairment is unexplained, as phosphoglycerate kinase activity was only 2% of the normal value in these cells. In a similar case, Bresolin et al (1984) measured 5% of residual activity in the muscle with, paradoxically, an increased affinity of the enzyme for both ATP and 3-phosphoglycerate. Affinity for ADP was not measured.

Phosphoglycerate mutase deficiency DiMauro et al (1981) reported the case of a 52-year-old man with intolerance for strenuous exercise and recurrent pigmenturia since adolescence. Muscle phosphoglycerate mutase displayed only 6% of the control value, whereas other glycolytic enzymes had normal activities. Electrophoretic, heat lability, and mercury inhibition studies showed that the residual activity in the patient's muscle was represented by the brain (BB) isoenzyme, indicating a genetic defect of the M subunit, which predominates in normal muscle. Because phosphoglycerate mutase is the glycolytic enzyme with the highest activity in normal muscle, the small activity due to the BB enzyme was sufficient to explain a modest rise of venous lactate during ischaemic exercise as well as a normal concentration of glycogen.

Lactate dehydrogenase deficiency Kanno et al (1980) described the case of a 18-year-old Japanese man whose complaints suggested McArdle's disease. Lactate dehydrogenase activity in a muscle biopsy was only 5% of the normal value; it was also reduced by about 50% in erythrocytes. Electrophoretic analysis of the muscle, erythrocytes and leukocytes from the patient showed only an H4 band, indicating that the M subunit was genetically deficient. The same defect in the M



subunit was found in three asymptomatic siblings; intermediate values were observed in two other siblings and in the parents, indicating autosomal recessive transmission of the disease. Accordingly, the gene encoding the M subunit was located on chromosome 11 (Boone et al, 1972).


Acid oL-glucosidase deficiency (type II glycogenosis) Acid u-glucosidase, a lysosomal enzyme, is present in all cells, except erythrocytes. Its deficiency (Hers, 1963) causes a generalized disorder in which muscle symptoms are prominent. This disorder appears under different clinical forms characterized by their infantile, juvenile or adult age of onset.

Clinical features Clinical signs of 129 cases are summarized in Table 4. The infantile form (Pompe, 1932) starts in the first weeks or months of life, exhibiting a difficulty to thrive, generalized hypotonia and weakness. Cardiomyopathy, hepatomegaly and respiratory distress become progressively evident. Macroglossia, peribuccal cyanosis and an abnormal cry are frequently reported. Serum creatine kinase is elevated. Death usually occurs before 2 years of age by cardiorespiratory decompensation. Radiographs of the chest demonstrate enlargement of the heart and sometimes a complete opacity of the left hemithorax, secondary to lung atelectasia. The electrocardiographic pattern is characterized by a short P - R interval, huge QRS, inversion of the T wave and left deviation of the axis. On electromyography, the myopathic origin of the weakness is apparent. Sometimes pseudomyotonic discharges are observed; motor and sensory conduction velocities are normal. The patients are mentally well preserved. Dynamic mobilization of the glycogen by glucagon or epinephrine induces a normal hyperglycaemia. The children never suffer from hypoglycaemia. In late infantile and juvenile cases, proximal muscle weakness is usually the first symptom and walking difficulties are the first complaint; the visceromegaly is variable. The clinical evolution of the disorder depends on the degree of respiratory muscle involvement; cardiac muscle can be spared for a long time but death usually occurs as a result of cardiomyopathy, often during the second or third decade. In the adult form, the clinical picture is comparable with that of a limb girdle myopathy, starting in the second or third decade and evolving for a long time, in some cases up to the sixties. Visceromegaly is very rare. Cardiac failure may be the cause of death. Some patients experience respiratory difficulties secondary to the involvement of the respiratory muscles. Electromyography is very helpful in these cases by showing myopathic patterns, often with pseudomyotonic discharge in the absence of clinical myotonia.

78* 24t 27

No. of cases

77 14 0

1 10 0

0 0 27

71 0 0

1 7 0

0 2 5

75 24 27

Muscular weakness 74 1 0


64 7 1

48 2 1

Hepatomegaly Macroglossia

Table 4. Clinical features in 129 patients with type II glycogenosis.

Age of onset (years) Age at death (years) 2 2-15 15 2 2-15 15

This series includes 73 cases from DiMauro (1978) and 56 cases from the authors' laboratory. * 36 male, 42 female patients. t 16 male, 8 female patients. From Hers et al (1989) with permission.

Infantile Juvenile Adult


75 9 11

Involvement of respiratory muscles


> Z





Morbid anatomy On light microscopy, PAS-positive material is found in and between the myofibrils; this material disappears after amylase digestion, thus giving the classic appearance of 'vacuolar myopathy'. In the infantile form, an enormous amount of glycogen is stored; in the juvenile and adult forms, the overloading is more discrete and may even be absent in some muscles. Under the electron microscope, one part of the glycogen is found to be present in vacuoles surrounded by a unique membrane, and another part is freely dispersed in the cytoplasm, as was initially shown by Baudhuin et al (1964) for the liver. Lysosomes overloaded with glycogen can be seen in all tissues and cells, including muscle, liver, kidney, lymphocytes, epithelialperipheral cells of blood vessels, cultured skin fibroblasts, and the nervous system, mainly in the glial cells and the neurones of the brain stem. This lysosomal overloading is evident in Pompe's disease but less pronounced in the juvenile cases and discrete in the adult form, in which only muscle cells are overloaded (Martin et al, 1976).

The enzymic defect In Pompe's disease, the capacity of acid a-glucosidase to hydrolyse glycogen and maltose is close to zero in liver and muscle (Hers, 1963). Juvenile and adult cases often show some residual acid a-glucosidase activity, but there are exceptions to this rule. The genetic heterogeneity of the defect has been investigated in cultured fibroblasts from patients. At least four different mutations were found to affect the biosynthesis of the enzyme, but no clear correlation between mutation and the clinical expression of the disease could be established (Reuser et al, 1985, 1987; Martiniuk et al, 1986; Hirschhorn et al, 1989).

Diagnosis and treatment The diagnosis rests on the demonstration of a deficiency of acid a-glucosidase in muscle or other tissues. Fibroblasts and leukocytes can be used if special precautions are taken. Prenatal diagnosis on amniotic and/or (better) on chorionic villi is feasible. Attempts at replacement therapy with purified human placental a-glucosidase were unsuccessful (de Barsy and Van Hoof, 1974).

Physiopathology Acid oL-glucosidase deficiency was the first inborn lysosomal disease to be clearly defined and has been used as a model to establish the pathogenesis of a large number of storage diseases (Hers, 1965). The deficiency of the lysosomal glucosidase is believed to be responsible for the intravacuolar accumulation of glycogen that has penetrated into the lysosomal system through the process of autophagy. The presence of a normal amount of cytosolic glycogen in the liver and its normal availability for phosphorolytic degradation explain why the patients never become hypoglycaemic and



respond normally to hyperglycaemic stimulation by glucagon. In all cells, the glycogen in excess is, at least initially, in the vacuolar system. The high content of apparently extralysosomal glycogen in muscle has been discussed by Hers and de Barsy (1973). The discrepancy between a generalized enzymatic defect and a morphologically normal aspect of some muscles in the adult patients is not understood.

Atypical cases Several juvenile or adult cases presenting the typical symptomatology of type II glycogenosis, as well as an intralysosomal accumulation of glycogen in their liver and muscle, but with a demonstrable acid a-glucosidase activity, have also been observed (de Barsy et al, 1979; Danon et al, 1983; Riggs et al, 1983; Byrne et al, 1986; Bru et al, 1988). This condition is presumably due to an inhibition of a-glucosidase in vivo by a still unknown mechanism and emphasizes the importance of electron microscopy in the diagnosis of a myopathy. Diseases related to an abnormal structure of glycogen

Branching enzyme deficiency (type IV glycogenosis) Type IV glycogenosis is a very rare disease, characterized by the accumulation in moderate amounts of an abnormal polysaccharide resembling amylopectin in that it stains blue with iodine and is poorly soluble. Under the electron microscope, cytoplasmic deposits are seen to consist of three components--glycogen particles, fibrils and finely granular material. The disease is attributable to a deficiency of branching enzyme (Brown and Brown, 1966), which is presumably incomplete because normal glycogen is present and the patients are not hypoglycaemic. The condition starts during the first months of life with non-specific gastrointestinal symptoms and progressive hepa~osplenomegaly. Cirrhosis with portal hypertension is the usual cause of death after two or three years of evolution. Neuromuscular abnormalities include hypotonia, muscular atrophy and decrease or absence of tendon reflex. Exceptionally, cardiopathy and exercise intolerance have predominated over the liver symptoms (Servidei et al, 1987). Recently, Greene et al (1988) reported a new variant of branching enzyme deficiency without apparent progressive liver disease. The poor solubility of the amylopectin-like glycogen is probably the cause of the cellular injury, including the deposition of this polysaccharide in the lysosomes of the reticuloendothelial system. The diagnosis rests on the abnormal structure of the polysaccharide and on the measurement of branching enzyme activity in various types of cells. Prenatal diagnosis appears feasible (Brown, 1985).

Other amyloid-like storage myopathies Besides the glycogen storage myopathies with well-defined enzymatic



defects, some cases are reported in the literature with overloading of the muscle cells and, rarely, of the peripheral nervous system with amyloid-like substance, but without demonstrated glycolytic enzyme deficiency. The clinical picture is heterogeneous but in some ways is reminiscent of a proximal myopathy, starting between 13 and 50 years, with extension to the distal muscles and cardiomyopathy in some cases. Serum creatine kinase is moderately elevated and electromyography shows a myopathic pattern. Most cases are sporadic. In some respects, the storage material resembles that seen in type IV glycogenosis, with Lafora bodies, corpora amylacea and the basophilic degeneration of the myocardium. The material is positive with PAS staining and iodine and is partially degraded by amylase. On electron microscopy, the material appears filamentous and surrounded by glycogen particles and mitochondria, without a unit membrane. These rare conditions have been classified as 'polyglucosan body disease', 'polysaccharide storage myopathy' or 'polyglucosan body myopathy' (for reviews see Thompson et al, 1988; Weiss and Schr6der, 1988).

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Normal metabolism and disorders of carbohydrate metabolism.

5 Normal metabolism and disorders of carbohydrate metabolism THIERRY DE BARSY HENRI-GI~RY HERS Carbohydrate metabolism has a primary role in muscle b...
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