Inborn Errors of Carbohydrate Metabolism

Inborn Errors of Carbohydrate Metabolism

Overview of Carbohydrate Metabolism

• Key Components:

  • Hexosemonophosphate Shunt - A metabolic pathway that generates NADPH and ribose-5-phosphate, essential for fatty acid synthesis and nucleotide production.

  • Glycolysis

  • Gluconeogenesis

  • Glycogenesis

  • Glycogenolysis

  • Krebs Cycle

  • Lactic Acid Production

  • Influence of Noncarbohydrate Sources

Glycogen Storage Diseases (GSD) Overview

• Definition:

  • Inherited metabolic disorders caused by enzyme deficiencies affecting glycogen breakdown or synthesis.

  • A cannot go to B

    • Accumulation of A and deficiency in B

Types of Glycogen Storage Diseases

1. GSD Type I - Von Gierke’s

   • Affected Organs: Liver/Kidneys

2. GSD Type II - Pompe’s

   • Affected Organs: Skeletal/Cardiac Muscle

3. GSD Type III - Cori’s

   • Affected Organs: Liver/Muscle

4. GSD Type IV - Andersen’s

   • Affected Organs: Liver/Muscle

5. GSD Type V - McArdle’s

   • Affected Organs: Muscle

6. GSD Type VI - Her's

   • Affected Organs: Liver

7. GSD Type VII - Tarui’s

   • Affected Organs: Muscle, RBCs

Glycogenolysis

GSD Type I - Von Gierke's Disease

• Enzyme Deficiency: Glucose-6-phosphatase

• Affects liver and kidneys

• Metabolic Consequences:

  • Accumulation of Glycogen

  • Impaired conversion of Glycogen to Glucose

• Symptoms:

  • Hypoglycemia

  • Hepatomegaly - an enlargement of the liver due to excessive glycogen accumulation, often seen in conditions affecting glycogen metabolism.

  • Lactic acidosis - a condition characterized by an accumulation of lactic acid in the body, often resulting from reduced oxygen levels or increased production such as during hypoglycemic episodes in certain metabolic disorders.

  • Hyperlipidemia

  • Hyperuricemia

  • Stunted growth

• Treatment Strategies:

  • Frequent glucose/starch intake every 3-4 hours

  • Nocturnal nasogastric glucose administration

GSD Type III - Cori’s Disease

• Enzyme Deficiency: α-1,6 glucosidase (debranching enzyme)

• Symptoms:

  • Milder version than Von Gierke

  • Hepatomegaly

  • Hypoglycemia

  • Muscle weakness (myopathy)

  • Cardiomyopathy

• Treatment Strategies:

  • Continuous glucose source

GSD Type IV - Andersen’s Disease

• Enzyme Deficiency: α-1,6 branching enzyme

• Symptoms:

  • Enlarged liver & spleen

  • Liver cirrhosis

  • High mortality rate generally before age 5

GSD Type V - McArdle’s Disease

• Enzyme Deficiency: Muscle glycogen phosphorylase

• Clinical Symptoms:

  • Exercise intolerance

  • Muscle fatigue

  • Muscle pain

  • Red-brown urine

    • Myoglobinuria

      • Myoglobin in urine

    • Rhabomyolysis: A condition characterized by the breakdown of muscle tissue, resulting in the release of myoglobin into the bloodstream, which can cause myoglobinuria. Death of muscle fibers → release of myoglobin

  • Possible renal failure

• Treatment Strategies:

  • No definitive treatment;

  • Avoid strenuous exercise

  • Administration of sucrose

  • Consideration of creatine supplements

    • Phosphocreatine - a high-energy compound that plays a critical role in energy metabolism and is often used to replenish ATP levels during short bursts of intense activity.

  • High-protein diet

For all of those, treatment is introducing glucose or substitute for glucose

GSD Type VI - Her's Disease

• Enzyme Deficiency: Liver glycogen phosphorylase

• Clinical Symptoms:

  • Milder than GSD Type I with less severe hypoglycemia

GSD Type VII - Tarui’s Disease

• Enzyme Deficiency: Phosphofructokinase-1 in muscle and RBCs

• Clinical Symptoms:

  • Similar to McArdle’s disease

  • Hemolytic anemia

  • Jaundice

• Treatment Strategies:

  • Avoid strenuous exercise

Pyruvate Kinase Deficiency

• Affected Cells: Red blood cells

• Clinical Symptoms:

  • Hemolytic anemia

  • Fatigue

  • Liver failure

  • Jaundice

  • Gallstones

• Treatment Strategies:

  • Blood transfusion

  • Splenectomy (removal of the spleen)

    • Spleen acts as blood filter

Summary of Glycogen Storage Diseases

• Common Symptoms Across GSDs:

• Overview of Enzyme Deficiencies by GSD Type:

  • I - Glucose-6-Phosphatase

  • II - Lysosomal α-Glucosidase

  • III - Debranching enzyme

  • IV - Branching enzyme

  • V - Muscle phosphorylase

  • VI - Liver phosphorylase

Disorders of Other Monosaccharides**

Galactose Metabolism Disorders

• Pathway Components:

  • Galactose

  • Galactose-1-phosphate

  • UDP-galactose

  • UDP-glucose

GALK - Galactose kinase def., an enzyme that catalyzes the phosphorylation of galactose to galactose-1-phosphate.

GALT - Galactose-1-phosphate uridylyltransferase def., an enzyme that converts galactose-1-phosphate to glucose-1-phosphate.

GALE - UDP-galactose-4-epimerase def.

• Galactosemia Types:

  1. Galactokinase deficiency

  2. Deficiency of Galactose-1-phosphate uridyl transferase

  • Classically severe, Duarte is milder

3. UDP-galactose-4-epimerase deficiency

• Classic Galactosemia Treatment:

  • Lifelong lactose-free diet to avoid milk and milk products; consider alternatives like soy, oat, almond milk.

Fructose Metabolism Disorders

• Types of Disorders:

  1. Essential fructosuria

     1. Fructose in the urine

  2. Fructosemia (hereditary fructose intolerance)

     1. A more severe disorder caused by a deficiency in the enzyme aldolase B, leading to the accumulation of fructose-1-phosphate in the liver, which can cause severe hypoglycemia, vomiting, and liver damage if fructose is ingested.

• Fructose Metabolism Pathway:

  • Fructose is phosphorylated by fructokinase to produce fructose-1-phosphate (F1-P)

Clinical Symptoms of Hereditary Fructose Intolerance

• Symptoms:

  • Strong aversion to sweet foods

  • Abdominal pain

  • Vomiting

  • Hypoglycemia caused by prolonged ingestion leading to hepatic and/or renal failure

• Treatment Strategies:

  • Lifelong fructose-free diet; avoidance of sucrose and sweeteners.