Disorders of Carbohydrate Metabolism

Galactosemia & Fructose Intolerance - Toxic Treats

• Galactosemia: AR. Impaired galactose metabolism.
  • Classic (GALT deficiency): Most common/severe. Galactose-1-P & galactitol accumulate.
    • Features: Jaundice, hepatomegaly, vomiting, FTT, cataracts (oil-droplet), E. coli sepsis, developmental delay.
    • Dx: ↑Blood galactose, urine reducing substances (+ve, non-glucose), ↓GALT activity (RBCs).
    • Rx: Lifelong galactose-free (lactose-free) diet.
  • GALK deficiency: Cataracts.
  • GALE deficiency: Variable severity.
• Hereditary Fructose Intolerance (HFI): AR. Aldolase B deficiency.
  • Fructose-1-P accumulates → inhibits gluconeogenesis/glycogenolysis.
  • Features (post fructose/sucrose/sorbitol): Severe hypoglycemia, vomiting, hepatomegaly, jaundice, FTT.
  • Aversion to sweets.
  • Dx: History, enzyme assay (liver), DNA. Urine reducing substances (+ve post-fructose).
  • Rx: Avoid fructose, sucrose, sorbitol.

  ⭐ Classic Galactosemia: Despite diet, long-term risks include ovarian failure (females) & developmental delays.

Key GSDs (Von Gierke, Pompe) - Stash & Crash

Impaired glycogen metabolism leads to glycogen "stash" (accumulation) and systemic "crash" (dysfunction).

• Von Gierke (GSD Type Ia): Liver Stash, Glucose Crash

  • Enzyme: ↓Glucose-6-phosphatase (liver, kidney).
  • Stash: Glycogen in liver & kidney → massive hepatomegaly, renomegaly.
  • Crash: Severe fasting hypoglycemia (seizures), lactic acidosis, hyperuricemia, hyperlipidemia.
  • Features: Doll-like facies, protuberant abdomen.
  • Rx: Frequent feeds, uncooked cornstarch. Avoid fructose/galactose.

• Pompe (GSD Type II): Lysosomal Stash, Muscle/Heart Crash

  • Enzyme: ↓Lysosomal acid $\alpha$-1,4-glucosidase (acid maltase).
  • Stash: Glycogen in lysosomes (all tissues, esp. heart, muscle).
  • Crash:
    • Infantile: Cardiomyopathy (massive cardiomegaly), profound hypotonia ("floppy baby"), respiratory failure. Death <2 yrs if untreated.
    • Late-onset: Progressive muscle weakness, respiratory insufficiency.
  • Rx: Enzyme Replacement Therapy (ERT).

⭐ In Von Gierke disease, uncooked cornstarch provides a slow-release form of glucose, crucial for preventing nocturnal hypoglycemia.

📌 Mnemonic:

• Von Gierke: Very low Glucose.
• Pompe: Problems with the Pump (heart) & Posture (muscles).

Other GSDs (Cori, McArdle) & Dx - Fuel Failures

• Cori Disease (GSD Type III; Forbes Disease; Debrancher Deficiency)

  • Enzyme: Amylo-1,6-glucosidase (debranching enzyme).
  • Clinical Features:
    • Hepatomegaly, ketotic hypoglycemia (milder vs GSD I).
    • Muscle weakness, hypotonia, growth retardation.
    • Cardiomyopathy (type IIIa).
    • Accumulation of limit dextrin (abnormally structured glycogen).
  • Labs: ↑CK, AST, ALT. Normal lactate & uric acid.
  • Rx: Frequent high-protein meals, uncooked cornstarch.

• McArdle Disease (GSD Type V; Myophosphorylase Deficiency)

  • Enzyme: Muscle glycogen phosphorylase (myophosphorylase).
  • Clinical Features:
    • Exercise intolerance, muscle cramps/pain, fatigue with intense exercise.
    • "Second wind" phenomenon.
    • Myoglobinuria (rhabdomyolysis risk).
  • Labs: ↑CK (baseline & post-exercise). Ischemic exercise test: Venous lactate fails to rise >1.5x baseline.
  • Rx: Oral sucrose before exercise. Avoid intense exercise. 📌 McArdle = Muscle.

⭐ In McArdle's (GSD V), the ischemic forearm exercise test shows a characteristic failure of blood lactate to rise, contrasting with a normal exaggerated rise in ammonia.

• General GSD Diagnostic Approach
  • Suspect if: Hypoglycemia, hepatomegaly, muscle symptoms (weakness, cramps).
  • Initial tests: Blood glucose, lactate, uric acid, lipids, LFTs, CK.
  • Confirmatory:
    • Specific enzyme assays (leukocytes, fibroblasts, tissue biopsy).
    • Genetic testing.
    • Biopsy (liver/muscle): Glycogen content & structure.

High‑Yield Points - ⚡ Biggest Takeaways

• Galactosemia (GALT deficiency): Cataracts, jaundice, hepatomegaly, E. coli sepsis; avoid galactose/lactose.
• Hereditary Fructose Intolerance (Aldolase B deficiency): Hypoglycemia, vomiting, jaundice after fructose/sucrose intake.
• Von Gierke's (GSD I): Severe fasting hypoglycemia, lactic acidosis, hepatomegaly, doll-like facies; Glucose-6-phosphatase defect.
• Pompe's (GSD II): Cardiomegaly, muscle weakness (hypotonia), macroglossia; lysosomal acid α-glucosidase defect.
• McArdle's (GSD V): Muscle cramps, myoglobinuria with exercise, "second wind"; muscle phosphorylase defect.
• Essential Fructosuria: Benign; fructokinase deficiency; fructose in urine.