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15 Disorders of Carbohydrate and Glycogen Metabolism Jan Peter Rake, Gepke Visser, G

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15 Disorders of Carbohydrate and Glycogen Metabolism Jan Peter Rake, Gepke Visser, G 15 Disorders of Carbohydrate and Glycogen Metabolism Jan Peter Rake, Gepke Visser, G. Peter A. Smit 15.1 Introduction The disorders described in this chapter have symptoms varying from mild to severe and life-threatening. The symptoms comprise failure to thrive, hep- atomegaly, jaundice and liver failure, hypoglycemia, metabolic acidosis, and (cardio-) myopathy, including muscle pain and exercise intolerance. Four groups of disorders can be distinguished: A. Disorders of galactose metabolism comprise galactokinase deficiency, gal- actose-1-P-uridyl transferase deficiency (classical galactosemia), and UDP- galactose-4-epimerase deficiency. The primary source of dietary galactose is lactose, the sugar in milk. It is present in human and cow’s milk and in most infant formulae. Individuals with one of these enzyme defects are unable to transform galactose into glucose and they accumulate metabolites of galactose after ingesting lactose and/or galactose. Galactitol accumulation accounts for cataract formation. Galactose-1-phosphate is considered to be responsible for the other clinical manifestations, especially liver and kidney failure. Cataracts are the only manifestations of galactose kinase deficiency. The clinical manifestations of classic galactosemia are vomiting, failure to thrive, liver failure with jaundice, kidney failure, cataract, and sepsis, occurring when galactose is introduced in the diet. The severe form of UDP galacose-4-epimerase deficiency resembles classic galactosemia. The main goal of treatment for galactokinase deficiency (more liberal) and classic galactosemia (strict) is the elimination of galactose from the diet. In severe forms of UDP galactose-4-epimerase deficiency, a narrow balance in dietary galactose requirements for biosynthesis (galactosylated compounds) and excess causing accumulation of galactose-1-phosphate should be aimed for. B. Disorders of fructose metabolism comprise hereditary fructose intolerance, d-glyceric acidemia together with defects in gluconeogenesis. The dietary sources of fructose are fruits, table sugar (sucrose), and sucrose-containing infant formulae. Affected infants with hereditary fructose intolerance (ac- cumulation of fructose-1-phosphate inhibits both hepatic glycogenolysis and gluconeogenesis and results also in depletion of adenosine triphos- phate) present with hypoglycemia, vomiting, other gastrointestinal com- 162 Disorders of Carbohydrate and Glycogen Metabolism plaints, hepatomegaly, and failure to thrive after ingestion of fructose. Older individuals avoid sweet foods. The main goal of treatment is the elimina- tion of fructose from the diet. Fructose-1,6-diphosphatase deficiency and pyruvate carboxylase deficiency are disorders of gluconeogenesis. Fructose- 1,6-diphosphatase deficiency, especially in younger children, presents with moderate hepatomegaly, fasting hypoglycemia, and lactic acidosis. Treat- ment is aimed at the maintenance of normoglycemia, and fructose ingestion is reduced especially in young children. Pyruvate carboxylase deficiency presentsinthefirstmonthsoflifewithmildlacticacidemiaanddelayed psychomotor development. A subgroup of patients with pyruvate carboxy- lase deficiency present shortly after birth with severe lactic acidemia and die before the age of 3 months. d-Glyceric acidemia, also to be regarded as a defect of serine metabolism, has a relatively large number of healthy unaffected individuals. Affected individuals show a variety of symptoms, mainly neurological. Essential fructosuria, a rare "non-disease" necessitat- ing no specific dietary treatment, and phosphoenolpyruvate carboxykinase deficiency, a very rare disorder of gluconeogenesis with severe psychomotor impairment, are not discussed in this chapter. C. Disorders of glycogen metabolism affecting mainly the liver comprise glyco- gen storage diseases (GSDs) 1, 3, 4, 6, 9, 0, and the Fanconi-Bickel form. GSDs 1, 3, 6, and 9 present similarly during infancy, with symptoms of hy- poglycemia, marked hepatomegaly, and retarded growth. In all these types, mental development is normal as long as hypoglycemic brain damage is prevented. GSD 1 is the most severe type of these four conditions because, besides impaired glycogen breakdown, also gluconeogenesis is blocked. Af- terashortperiodoffasting,anoverwhelminghypoglycemiaandseverelactic acidosis may develop. Two forms of GSD 1 can be distinguished: GSD 1a and GSD 1b. Patients with GSD 1b may also present with infections and symp- toms of inflammatory bowel disease related to neutropenia and neutrophil dysfunction. The majority of patients with GSD 3 have a hepatic-myogenic form: a generalized myopathy may include cardiomyopathy. GSD 6 and GSD 9 are the mildest forms: only a mild tendency to fasting hypoglycemia is observed, liver size normalises at adult age, and patients reach normal adult height. A rare hepatic-myogenic form of GSD 9 exists. The main goal of treatment for all these GSDs is to maint normoglycemia by dietary treat- ment. GSD 4 manifests in the majority of patients in infancy or childhood as hepatic failure with cirrhosis, leading to end-stage liver disease necessi- tating liver transplantation. In the other patients with GSD 4, all kinds of combinations of hepatic and (cardio-)myogenic forms occur. GSD 0 is in fact not a GSD but a glycogen-synthesis deficiency. It is seen in infancy or early childhood with fasting hypoglycemia and ketosis and postprandial with hy- perglycemia and hyperlactacidemia. The Fanconi-Bickel form of GSD has hepatomegaly, hypoglycemia, rickets, and tubulopathy. This type of GSD is discussed separately in Chap. 16. Introduction 163 D. Disorders of glycogen metabolism affecting mainly affecting muscle com- priseGSDs2,5,and7.TheinfantiletypeofGSD2(infactalysosomalstorage disease) results in cardiac failure, failure to thrive, and death during infancy. Adolescent and adult-onset forms of GSD 2 primarily involve skeletal mus- cle. GSD 5 (glycogenolytic defect) and 7 (glycolytic defect) involve skeletal muscle and are usually not diagnosed until adolescence or adulthood, when patients present with muscle weakness, exercise intolerance, and myoglobin- uria. Patients with GSD 5 may benefit from carbohydrate intake aiming at normoglycemia. In patients with GSD 7, the focus of dietary treatment is aimed at fat enrichment of the diet, since these patients may worsen after high doses of carbohydrates. Some subtypes of the GSDs mainly affecting the liver (GSD 3, GSD 4, and GSD 9) may also affect (heart) muscle. Manage- ment of these GSDs including the (cardio-)myogenic symptoms is discussed in the paragraph about liver-related GSDs. Other (very rare) GSDs affecting muscle-related glycogenolytic or glycolytic defects (phosphoglucomutase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and aldolase A deficiency) are not discussed in this chapter. 164 Disorders of Carbohydrate and Glycogen Metabolism 15.2 Nomenclature No. Disorder Definition/comment Gene OMIM symbol No. 15.1 Galactokinase deficiency Galactose (P,U) ↑, galactitol (U)↑ Cataract GALK 230200 15.2 Galactosemia Galactose-1-phosphate (P, RBC) ↑, galactose GALT 230400 (B,U) ↑ Vomiting, hepatomegaly, jaundice, renal failure, cataracts 15.3 UDPGal-4-epimerase defi- Galactose-1-phosphate (P, RBC) ↑ galactose (P) GALE 230350 ciency ↑ See galactosemia 15.4 Hereditary fructose intoler- Fructose ↑ (P), reducing substance (U) Vomiting, ALDOP 229600 ance liver/renal dysfunction, failure to thrive 15.5 Fructose-1,6-diphosphatase Glucose ↓(P), lactate ↑ (P) ketones ↑ (P) FDP 1 229700 deficiency 2-ketoglutaric acid (U) Seizures, acidosis, hepatomegaly 15.7 d-Glyceric acidemia May vary from mental/motor retardation to no 220120 symptoms 15.8 GSD 1a Glucose ↓ (P), lactate ↑ (P U), ketones ↓ (P), G6PC 232200 uric acid ↑ (P), cholesterol ↑ (P), triglycerides ↑ (P) Hepatorenomegaly, seizures, acidosis, short stature 15.8a GSD 1b As in GSD Ia and: neutropenia (B) neutrophil G6PT 232220 dysfunction; infections, inflammatory bowel disease 15.9 GSD 2 (Pompe) Infancy: severe cardiomyopathy, hypotonia GAA 232300 Juvenile/adult: myopathy 15.10 GSD 3 (Forbe, Cori) Glucose ↓ (P) ketones ↑↑(P, U), uric acid ↑ (P), AGL 232400 cholesterol ↑ (P), CK ↑ (P) 3A Hepatomegaly myopathy 3B Hepatomegaly 15.11 GSD 4 (Andersen) Hepatosplenomegaly, cirrhosis GBE 1 232500 15.12 GSD 5 (Mc Ardle) Muscle pain, exercise intolerance, CK ↑ (P) PGYm 232600 15.13 GSD 6 (Hers) Glucose ↓ (P) ketones ↑↑ (P, U), uric acid ↑ (P), PGYL 232700 cholesterol ↑ (P), triglycerides ↑ (P) Hepatomegaly 15.14 GSD 7 (Tauri) Muscle pain, exercise intolerance, CK ↑ (P) PFK-m 232800 15.15 GSD 9 (GSD 8 by McKusick) Glucose ↓ (P) ketones ↑↑ (P, U), uric acid ↑ (P), PHKA/B/G 306000 cholesterol ↑ (P), triglycerides ↑ (P) Hepatomegaly 15.16 GSD 0 Glucose ↓ (P) ketones ↑↑ (P, U), lactate ↑ (P, U) GYS 2 240600 No hepatomegaly 15.17 GSD Fanconi-Bickel type Glucose ↑ (P,U) galactose ↑ (P,U) GLUT 2 227810 Hepatorenomegaly, tubulopathy Disorders of Galactose Metabolism 165 15.3 Disorders of Galactose Metabolism I Emergency Treatment No. Symbol Therapy 15.2 GALT Immediate complete restriction of galactose intake, supportive care 15.3 GALE Immediate complete restriction of galactose intake, supportive care If GALT (disorder 15.2) or GALE (disorder 15.3) is suspected in a (newborn) child, dietary treatment consisting of a lactose-/galactose-free feeding regimen should be initiated without delay, even before the diagnosis has been confirmed enzymatically or by DNA analysis. Supportive
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