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Glycogen Storage Diseases ROBERT MAHLER J Clin Pathol: first published as 10.1136/jcp.s1-2.1.32 on 1 January 1969. Downloaded from J. clin. Path., 22, suppl. (Ass. clin. Path.), 2, 32-41 Glycogen storage diseases ROBERT MAHLER From the Department ofMetabolic Medicine, Welsh National School of Medicine, Cardiff The glycogen storage diseases are disorders of glycogen metabolism in which an excessive amountof glycogen accumulates in several tissues. The presence of an excessive amount of glycogen may physically interfere with the function of the tissue but many REDUC2NG END Ar 0z/z of the clinical features of the various of types CHO -R N How glycogen storage diseases are due directly or in- directly to the impairment of carbohydrate metab- olism. :c0 c Claude Bernard first isolated glycogen from the liver in 1857 and described its chemical and physio- FIG. 1. Formation ofbranched glycogen molecule. logical properties. A little over 70 years later, two assumes a tree-like appearance with relatively forms of glycogen storage disease were recognized: long inner chains, consisting of up to 20 glucosyl in one form, glycogen was present in large amounts moieties, and shorter outer chains of eight to 12 in almost all the tissues of the body, including the glucosyl groups branching off from the inner chains heart and tongue, while in the other the excess of (Fig. 1). The glycogen molecule is large enough to be glycogen was restricted to the liver and kidney. In visualized under the electron it is microscope: roughly copyright. spite of much ingenious speculation, no headway spherical in shape with a molecular weight of was made in the understanding of these disorders 20 x 106 and a volume of 200 cubic Angstroms but, until 1952 when Cori and Cori demonstrated the depending upon the nutritional state, it may aggre- absence of the enzyme glucose 6-phosphatase in the gate with other glycogen molecules into even larger liver of children suffering from the hepatorenal particles. Glycogen particles are usually present in type of glycogen storage disease. Since then, at the cytoplasm, but they also occur in the lysosomes, least five other types of glycogen storage disease and in certain pathological conditions may be seen have been reliably recognized and classified on the in the nucleus and the mitochondria. http://jcp.bmj.com/ basis of specific enzyme defects related to glycogen metabolism (Table I). GLYCOGEN SYNTHESIS AND DEGRADATION THE GLYCOGEN MOLECULE These occur by different pathways. The initial step is the conversion of glucose by The glycogen molecule is composed of over 120,000 hexokinase to glucose 6-phosphate, which is then glucosyl units linked together in such a way that it re-arranged to form glucose 1-phosphate. The first on September 23, 2021 by guest. Protected ILE I CLASSIFICATION OF MAJOR GLYCOGEN STORAGE DISEASES Type Enzyme Defect Tissue Affected Clinical Features I (von Gierke) Glucose-6-phosphatase Liver, kidney, gut Hepatomegaly, hypoglycaemia, ketosis, acidosis II (Pompe) Acid maltase Generalized, particularly heart, Cardiomegaly, heart failure, tongue, brain, WBC enlarged tongue, muscle weakness death in infancy [II (limit dextrinosis) 'Debrancher' Liver, heart, muscle, RBC, WBC Hepatomegaly, moderate fasting hypoglycaemia, muscle weakness, and wasting IV (amylopectinosis) 'Brancher' Liver, spleen, heart, muscle, Cirrhosis, hepatic failure RBC, WBC V (McArdle) Muscle phosphorylase Skeletal muscle only Pain, stiffness, weakness on exercise only; occasionally myoglobinuria VI (Hers Liver phosphorylase Liver, WBC Hepatomegaly, moderate fasting hypoglycaemia 32 J Clin Pathol: first published as 10.1136/jcp.s1-2.1.32 on 1 January 1969. Downloaded from Glycogen storage diseases 33 step of glycogen synthesis proper is the formation of disease, and in 1952 Cori and Cori demonstrated uridine diphosphoglucose (UDPG) from glucose 1- that there was no glucose 6-phosphatase activity in phosphate. This reaction is reversible, but the next the liver of affected cases. In the absence of the step is the irreversible reaction of UDPG with enzyme, the liver cannot produce glucose by either 'glycogen synthetase', which results in the formation glycogenolysis or gluconeogenesis (Fig. 2) so that of a chain in which glucose molecules are joined patients are liable to have attacks of profound to one another in a 1: 4-linkage (Fig. 1). This reac- hypoglycaemia. Prolonged severe hypoglycaemia tion is stimulated by glucose 6-phosphate and by results in secondary disturbances of lipid metabolism insulin. When the chains reach a length of about with increased mobilization of fat from adipose 12 glucosyl units, three or four of the units are tissue and overproduction of cholesterol and ketone transferred from the end of that chain to another bodies in the liver. Normally the liver clears the chain but there they are attached in a 1: 6-linkage in blood of the lactic acid which has been produced by such a way that a branch point is formed (Fig. 1). muscles and other tissues with a high rate of glyco- The sequential interactions of 'glycogen synthetase' lysis and converts it into glucose by the usual and 'branching enzymes' result in the typical pathways of gluconeogenesis. In type I glycogen branched glycogen molecule which has a character- storage disease the liver itselfproduces large amounts istic colour and light absorption at 460 m,u when of lactic acid from glycogen, because when glyco- stained with iodine. genolysis is stimulated, the glucose 6-phosphate is Glycogen breakdown is initiated by phosphoryl- diverted into the glycolytic pathway; the liver thus ase, which successively hydrolyzes all the 1: 4-link- accentuates an existing lactic acidosis and further ages in a chain, each time producing glucose I -phos- disturbs the acid-base balance of the body. Pro- phate, but is incapable of splitting the 1: 6-links at longed severe lactic acidaemia may also lead to branch points. To break through the 1: 6 link retention of uric acid by competition for transport another enzyme is required, the 'debranching at the renal tubule and may result in the appearance enzyme', which yields a molecule of glucose and of clinical manifestations of tophaceous gout. through its action exposes another chain of 1: 4-linked The accumulation of abnormal amounts of copyright. glucosyl units to the action of phosphorylase. Thus glycogen in this disease is confined to the liver, the degradation of glycogen, like its synthesis, kidney, and intestinal mucosa, ie, tissues which requires the sequential interaction of two distinct normally show glucose 6-phosphatase activity. enzymes and results in the formation of glucose and Although all these tissues can also metabolize of glucose 1-phosphate which can be used by the glycogen by other pathways, it would seem that the cells for their metabolic requirements. Not all the enzyme is of importance in the control of their glycogen is broken down by this mechanism: some glycogen content. In other tissues, such as muscle, of it finds its way into the intracellular lysosomes which normally possess no glucose 6-phosphatase, http://jcp.bmj.com/ where it is hydrolysed by a-glucosidases to form there is no excess ofglycogen. maltose and glucose. Absence of enzyme activity in this disorder has The identity and quantitative importance in been shown by direct assay of the enzyme in biopsies human metabolism of the separate pathways of glycogen synthesis and degradation were only clarified when the specific enzyme defects of the glycogen storage diseases were recognized. Their GLYCOGEN on September 23, 2021 by guest. Protected study emphasizes the contribution which clinical ---p g-)i-p - _|Glucagon medicine can make to basic biochemistry and the help which can be gained from an understanding _ ,- 9-11 -P of the biochemical processes in the management of patients suffering from metabolic disorders. A _-* Glucose g-4:6-P X measure of the wide interest which their study has Fructose -. aroused is the number of reviews of this subject which have appeared recently (Steinitz, 1967; Pyruvate Lactate Brown and Brown, 1968; Hers and van Hoof, 1968; Symposium, Amer J. clinPath., 1968; Mahler, 1969). 0o2 TYPE I GLYCOGEN STORAGE DISEASE (GLUCOSE 6-PHOSPHATE DEFICIENCY) In 1929 von Gierke described the excessive accumu- FIG. 2. Type I glycogen storage disease due to glucose lation of glycogen in the liver and kidney in this 6-phosphatase[nolor+^oodeficiencyII_ (X).~~~~~4_ J Clin Pathol: first published as 10.1136/jcp.s1-2.1.32 on 1 January 1969. Downloaded from 34 Robert Mahler from liver, kidney, and intestinal mucosa. Indirect TABLE II evidence for the absence of glucose 6-phosphatase SUMMARY OF THE CLINICAL AND FUNCTIONAL DIFFEREN- activity in the liver can be obtained from various TIATION BETWEEN THE SIX MAJOR TYPES OF GLYCOGEN functional tests: neither the administration of STORAGE DISEASE glucagon or adrenaline, both of which stimulate Tissue Response to Diagnostic Test Type of Glycogen glycogenolysis, nor the administration of galactose Affected Storage Disease or fructose, which are normally converted into glucose by the liver, result in a rise in the blood Liver (and kidney) glucose level, but they produce an abnormal rise in only i, VI blood lactate. Muscle only V Many The prognosis is poor in young children and tissues II, III, IV prevention of hypoglycaemia by frequent meals is Fasting Severe hypoglycaemia I important if damage to the brain is to be avoided. Moderate hypoglycaemia III, IV, VI Administration of diazoxide, which interferes with No hypoglycaemia II, V the release of insulin from islet cells, also helps to Glucagon maintain the blood sugar level within a clinically No increase in Vlt blood glucose Fasting I, III, IV, safe range, and rarely more heroic measures, such Normal increase in as the anastomosis of the portal vein to the inferior blood glucose f II, V vena cava so that glucose from the gut bypasses the No increase in Ptrd blood glucose I, Vit liver, have been used with some success for this Normal increase in purpose.
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