6 The Glycogen Storage Diseases and Related Disorders G. Peter A. Smit, Jan Peter Rake, Hasan O. Akman, Salvatore DiMauro 6.1 The Liver Glycogenoses – 103 6.1.1 Glycogen Storage Disease Type I (Glucose-6-Phosphatase or Translocase Deficiency) – 103 6.1.2 Glycogen Storage Disease Type III (Debranching Enzyme Deficiency) – 108 6.1.3 Glycogen Storage Disease Type IV (Branching Enzyme Deficiency) – 109 6.1.4 Glycogen Storage Disease Type VI (Glycogen Phosphorylase Deficiency) – 111 6.1.5 Glycogen Storage Disease Type IX (Phosphorylase Kinase Deficiency) – 111 6.1.6 Glycogen Storage Disease Type 0 (Glycogen Synthase Deficiency) – 112 6.2 The Muscle Glycogenoses – 112 6.2.1 Glycogen Storage Disease Type V (Myophosphorylase Deficiency) – 113 6.2.2 Glycogen Storage Disease Type VII (Phosphofructokinase Deficiency) – 113 6.2.3 Phosphoglycerate Kinase Deficiency – 114 6.2.4 Glycogen Storage Disease Type X (Phosphoglycerate Mutase Deficiency) – 114 6.2.5 Glycogen Storage Disease Type XII (Aldolase A Deficiency) – 114 6.2.6 Glycogen Storage Disease Type XIII (E-Enolase Deficiency) – 115 6.2.7 Glycogen Storage Disease Type XI (Lactate Dehydrogenase Deficiency) – 115 6.2.8 Muscle Glycogen Storage Disease Type 0 (Glycogen Synthase Deficiency) – 115 6.3 The Generalized Glycogenoses and Related Disorders – 115 6.3.1 Glycogen Storage Disease Type II (Acid Maltase Deficiency) – 115 6.3.2 Danon Disease – 116 6.3.3 Lafora Disease – 116 References – 116 102 Chapter 6 · The Glycogen Storage Diseases and Related Disorders Glycogen Metabolism Glycogen is a macromolecule composed of glucose viding glucose and glycolytic intermediates (. Fig. 6.1). units. It is found in all tissues but is most abundant in Numerous enzymes intervene in the synthesis and deg- II liver and muscle where it serves as an energy store, pro- radation of glycogen which is regulated by hormones. Fig. 6.1. Scheme of glycogen metabolism and glycolysis. PGK, II, acid maltase (D-glucosidase); III, debranching enzyme; phosphoglycerate kinase; P, phosphate; PLD, phosphorylase limit IV, branching enzyme; V, myophosphorylase; VI, liver phosphory- dextrin; UDPG, uridine diphosphate glucose. Roman numerals lase; VII, phosphofructokinase; IX, phosphorylase-b-kinase; indicate enzymes whose deficiencies cause liver (italics) and/or X, phosphoglycerate mutase; XI, lactate dehydrogenase; XII, fruc- muscle glycogenoses: 0 glycogen synthase, I, glucose-6-phos- tose-1,6-bisphosphate aldolase A; XIII, E-enolase phatase; 103 6 6.1 · The Liver Glycogenoses Glycogen, an important energy source, is found in most The liver glycogen storage disorders (GSDs) comprise tissues, but is especially abundant in liver and muscle. In GSD I, the hepatic presentations of GSD III, GSD IV, GSD VI, the liver, glycogen serves as a glucose reserve for the main- the liver forms of GSD IX, and GSD 0. GSD I, III, VI, and IX tenance of normoglycemia. In muscle, glycogen provides present similarly with hypoglycemia, marked hepato- energy for muscle contraction. megaly, and growth retardation. GSD I is the most Despite some overlap, the GSDs can be divided in three severe affecting both glycogen breakdown and gluco- main groups: those affecting liver, those affecting muscle, neogenesis. In GSD Ib there is additionally a disorder of and those which are generalized (. Table 6.1). GSDs are neutrophil function. Most patients with GSD III have a d enoted by a Roman numeral that reflects the historical syndrome that inc ludes hepatopathy, myopathy, and sequence of their discovery, by the deficient enzyme, or by often cardiomyo pathy. GSD VI and GSD IX are the least the name of the author of the first description. The Fanconi- severe: there is only a mild tendency to fasting hypo- Bickel syndrome is discussed in Chap. 11. glycemia, liver size normalises with age, and patients reach normal adult height. GSD IV manifests in most patients in infancy or childhood as hepatic failure with 6.1 The Liver Glycogenoses cirrhosis leading to end-stage liver disease. GSD 0 presents in infancy or early childhood with fasting The liver GSDs comprise GSD I, the hepatic presentations hypoglycemia and ketosis and, in contrast, with post- of GSD III, GSD IV, GSD VI, the liver forms of GSD IX, and prandial hyperglycemia and hyperlactatemia. Treat- GSD 0. GSD I, III, VI, and IX present with similar symp- ment is primarily dietary and aims to prevent hypoglyc- toms during infancy, with hypoglycemia, marked hepatome- emia and suppress secondary metabolic decompensa- galy, and retarded growth. GSD I is the most severe of these tion. This usually requires frequent feeds by day, and in four conditions because not only is glycogen breakdown GSD I and in some patients with GSD III, continuous impaired, but also gluconeogenesis. Most patients with nocturnal gastric feeding. GSD III have a syndrome that includes hepatopathy, myo- The muscle glycogenoses fall into two clinical pathy, and often cardiomyopathy. GSD IV manifests in groups. The first comprises GSD V, GSD VII, the muscle most patients in infancy or childhood as hepatic failure with forms of GSD IX (VIII according to McKusick), phospho- cirrhosis leading to end-stage liver disease. GSD VI and glycerate kinase deficiency (IX according to McKusick), the hepatic forms of GSD IX are the mildest forms: there is GSD X, GSD XI, GSD XII and GSD XIII, and is character- only a mild tendency to fasting hypoglycemia, liver size ised by exercise intolerance with exercise-induced normalises with age, and patients reach normal adult height. myalgia and cramps, which are often followed by rhab- GSD 0 presents in infancy or early childhood with fasting domyolysis and myoglobinuria; all symptoms are hypoglycemia and ketosis contrasting with postprandial reversible with rest. Disorders in the second group, hyperglycemia and hyperlactatemia. The muscle forms of consisting of the myopathic form of GSD III, and rare GSD III and IX are also discussed in this section. neuromuscular forms of GSD IV, manifest as sub-acute or chronic myopathies, with weakness of trunk, limb, and respiratory muscles. Involvement of other organs 6.1.1 Glycogen Storage Disease Type I (erythrocytes, central or peripheral nervous system, (Glucose-6-Phosphatase of Translo- heart, liver) is possible, as most of these enzymes de- case Deficiency) fects are not confined to skeletal muscle. Generalized glycogenoses comprise GSD II, caused GSD I, first described by von Gierke, comprises GSD Ia by the deficiency of a lysosomal enzyme, and Danon caused by deficiency of the catalytic subunit of glucose-6- disease due to the deficiency of a lysosomal membrane phosphatase (G6Pase), and GSD Ib, due to deficiency of the protein. Recent work on myoclonus epilepsy with endoplasmic reticulum (ER) glucose-6-phosphate (G6P) Lafora bodies ( Lafora disease) suggests that this is translocase. There is controversy about the existence of ER a glycogenosis, probab ly due to abnormal glycogen phosphate translocase deficiency (GSD Ic) and ER glucose synthesis. GSD II can be treated by enzyme replace- transporter deficiency (GSD Id) as distinct entities. In this ment therapy, but there is no specific treatment for chapter, the term GSD Ib includes all GSD I non-a forms. Danon and Lafora disease. Clinical Presentation A protruded abdomen, truncal obesity, rounded doll face, The glycogen storage diseases (GSDs) and related disorders hypotrophic muscles, and growth delay are conspicuous are caused by defects of glycogen degradation, glycolysis clinical findings. Profound hypoglycemia and lactic acidosis and, paradoxically, glycogen synthesis. They are all called occur readily and can be elicited by trivial events, such as glycogenoses, although not all affect glycogen breakdown. delayed meals or reduced food intake associated with inter- 104 Chapter 6 · The Glycogen Storage Diseases and Related Disorders . Table 6.1. Main features of glycogen storage diseases and related disorders Type or Defective enzyme or transporter Main tissue involved Main clinical symptoms II synonym Liver Ia Glucose-6-phosphatase Liver, kidney Hepatomegaly, short stature, hypoglycemia, lactatemia, Von hyperlipidemia Gierke Ib (non-a) Glucose-6-phosphate translocase Liver, kidney, leucocytes Same as Ia, neutropenia, infections III Debranching enzyme and sub- Liver, muscle Hepatomegaly, (cardio)myopathy, short stature, hypo- Cori, types glycemia Forbes IV Branching enzyme Liver Hepato(spleno)megaly, liver cirrhosis, rare neuromuscu- Andersen lar forms VI Liver phosphorylase Liver Hepatomegaly, short stature, Hers hypoglycemia IX Phosphorylase kinase Liver and/or muscle Hepatomegaly, short stature (myopathy), and subtypes hypoglycemia 0Glycogen synthase Liver Hypoglycemia Muscle V Myophosphorylase MuscleMyalgia, exercise intolerance, weakness Mc Ardle VII Phosphofructokinase Muscle, erythrocytes Myopathy, hemolytic anemia, Tarui and variants multisystem involvement (seizures, cardiopathy) – Phosphoglycerate kinase Muscle, erythrocytes, Exercise intolerance, hemolytic anemia central nervous system convulsions X Phosphoglycerate mutase Muscle Exercise intolerance, cramps XI Lactate dehydrogenase Muscle Exercise intolerance, cramps, skin lesions XII Aldolase A Muscle Exercise intolerance, cramps XIII E-Enolase Muscle Exercise intolerance, cramps Generalized II Lysosomal Generalized Hypotonia, cardio-myopathy Pompe D-glucosidase in lysosomes Infantile, juvenile, adult forms IIb Lysosomal-associated Heart, muscle Cardio-myopathy Pseudo membrane protein 2 Pompe Danon Lafora Enzyme defect not known Polyglucosan