Inborn Errors of Carbohydrate Metabolism Causing Hypoglycemia

1. Type I - von Gierke disease - glucose-6-phosphatase deficiency
2. Type III - Cori disease - amylo-1,6-glucosidase (debranching enzyme) deficiency
3. Type VI - Hers disease - liver phosphorylase deficiency
4. Type 0 - glycogen synthase deficiency (glycogen cannot even be made, so fasting hypoglycemia occurs despite low liver glycogen)

• Goldman-Cecil Medicine, Ch. 211 ("Hypoglycemia Due to Defects in Hepatic Glycogen Release/Storage" and "...Defects in Gluconeogenesis")

Detailed Account: Von Gierke Disease (Glycogen Storage Disease Type I)

Enzyme Defect

• Emery's Elements of Medical Genetics and Genomics, p. 287
• Goldman-Cecil Medicine, Ch. 211

Biochemical Basis of Clinical Features

• Severe fasting hypoglycemia: Neither glycogenolysis nor gluconeogenesis can deliver free glucose to the blood, so blood glucose falls within 3-4 hours of fasting - much more severe and rapid-onset than in Hers disease (liver phosphorylase deficiency), because in GSD I both glycogenolysis and gluconeogenesis are blocked at the terminal step, whereas in Hers disease gluconeogenesis remains intact.
• Hepatomegaly (and later hepatic adenomas): Glycogen (and some fat) accumulates massively in hepatocytes since it cannot be broken down to free glucose; the liver becomes enlarged but functional synthetic capacity (albumin, clotting factors) is often relatively preserved early on.
• Lactic acidosis: The accumulated glucose-6-phosphate is diverted into glycolysis, generating excess pyruvate and lactate. Hypoglycemia itself also drives peripheral tissues toward anaerobic glycolysis, worsening lactate production. The chronic lactic acidosis additionally raises the renal threshold for urate excretion.
• Hyperuricemia: Glucose-6-phosphate is shunted into the hexose monophosphate (pentose phosphate) pathway, increasing production of ribose-5-phosphate, the precursor of PRPP, which drives purine overproduction; this combined with reduced renal urate clearance (from lactic acidosis) produces hyperuricemia, sometimes leading to gout in later life.
• Hyperlipidemia (hypertriglyceridemia and hypercholesterolemia): Hypoglycemia stimulates counter-regulatory hormones (glucagon, cortisol, catecholamines), which mobilize peripheral fat, and the glucose-6-phosphate excess also fuels increased acetyl-CoA and glycerol-3-phosphate availability for hepatic triglyceride synthesis (lipogenesis), while lipoprotein lipase activity is reduced. The resulting hyperlipidemia contributes to eruptive xanthomas.
• Growth failure and "doll-like" facies: Chronic hypoglycemia and metabolic derangement impair growth; a rounded face with fat cheeks and relatively thin limbs (protuberant abdomen from hepatomegaly) is characteristic.
• Nephromegaly and progressive renal disease: Glycogen also accumulates in renal tubular cells, causing renomegaly, proximal tubular dysfunction (renal Fanconi-like picture), and eventually focal segmental glomerulosclerosis with progression to chronic kidney disease in some patients.
• Bleeding tendency: Chronic hypoglycemia and metabolic stress impair platelet aggregation, causing a functional platelet defect and easy bruising/epistaxis.
• (Type Ib only) Neutropenia and recurrent bacterial infections/inflammatory bowel disease-like colitis, because the translocase defect also impairs neutrophil glucose-6-phosphate handling and function.
• Harper's Illustrated Biochemistry, 32nd ed., "von Gierke Disease"
• Brenner and Rector's The Kidney, "Glycogenosis (von Gierke Disease)"
• Lippincott Illustrated Reviews: Biochemistry, 8th ed.

Management

1. Dietary therapy is the mainstay (under a metabolic dietitian):
   • Frequent, small feeds (every 2-4 hours in infants) to prevent fasting hypoglycemia.
   • Uncooked cornstarch given every 3-6 hours (including extended-release cornstarch preparations in older children/adults) provides a slow-release glucose source that maintains normoglycemia between feeds.
   • Continuous nocturnal nasogastric/gastrostomy glucose or cornstarch feeding may be needed in infancy to prevent overnight hypoglycemia.
   • Strict avoidance/restriction of fructose, sucrose, and galactose, since these sugars cannot be efficiently converted to blood glucose in this disorder and instead worsen lactic acidosis and hyperlipidemia.
   • Supplementation with multivitamins, calcium, and vitamin D.
   • Avoid over-treatment, which causes iatrogenic obesity and insulin resistance.
2. Monitoring and treatment of complications:
   • Regular monitoring of glucose, lactate, uric acid, and lipids; allopurinol or urate-lowering therapy for hyperuricemia/gout; lipid-lowering agents if hypertriglyceridemia is severe.
   • Surveillance imaging for hepatic adenomas (risk of hemorrhage or malignant transformation) - managed with ethanol injection, radiofrequency ablation, partial hepatectomy, or liver transplantation if adenomas are multiple, enlarging, or recurrent. Liver transplantation also markedly improves overall metabolic control.
   • Monitoring of renal function; kidney transplantation for advanced chronic kidney disease.
3. Type Ib specific: granulocyte colony-stimulating factor for neutropenia/recurrent infections; mesalamine for associated inflammatory bowel disease; empagliflozin (an SGLT2 inhibitor) has been used to reduce accumulation of a neutrophil-toxic metabolite (1,5-anhydroglucitol-6-phosphate) and improve neutrophil function.

• Goldman-Cecil Medicine, Ch. 191, "Glycogen Storage Disease I"

Summary Diagram of the Defect