Disorders of glycolytic enzymes

Glycolytic Defects - RBC Energy Crisis

• Red blood cells (RBCs) lack mitochondria and depend exclusively on anaerobic glycolysis for ATP production.
• Enzyme deficiencies disrupt this pathway, leading to an energy crisis (↓ ATP).
• Failure of the Na⁺/K⁺-ATPase pump causes membrane instability, dehydration, and RBC lysis.

Key Deficiencies & Features:

• Pyruvate Kinase (PK) Deficiency:
  • Most common cause. Autosomal recessive.
  • Causes chronic hemolytic anemia, jaundice, and splenomegaly.
  • Peripheral smear shows echinocytes (burr cells).
• Glucose-Phosphate Isomerase (GPI) Deficiency: Second most common.

⭐ Despite the ATP deficit, levels of 2,3-BPG are increased, causing a rightward shift in the oxygen-hemoglobin dissociation curve, which improves oxygen delivery to tissues.

Pyruvate Kinase Deficiency - The Main Culprit

• Pathophysiology: Autosomal recessive defect in the final step of glycolysis. ↓ ATP production leads to rigid RBC membranes and subsequent extravascular hemolysis.
• Key Consequence: ↓ ATP & ↑ 2,3-bisphosphoglycerate (2,3-BPG).

• Clinical Presentation: Presents in infancy/childhood with hemolytic anemia, jaundice, and splenomegaly. Severity varies.
• Lab Findings: Normocytic anemia, reticulocytosis, and ↑ unconjugated bilirubin. ↑ 2,3-BPG levels are characteristic.

⭐ High-Yield Pearl: The accumulation of 2,3-BPG shifts the oxygen-dissociation curve to the right, facilitating O₂ delivery to tissues. This often makes the anemia less symptomatic than expected for the degree of hemolysis.

PFK-1 Deficiency - Tarui's Muscle Trouble

• Glycogen Storage Disease Type VII: An autosomal recessive disorder caused by a defect in the PFKM gene, which affects muscle and RBCs.
• Pathophysiology: Severely reduced PFK-1 activity impairs glycolysis. Muscles cannot effectively use glucose for energy, leading to glycogen accumulation.
• Clinical Features:
  • Exercise intolerance: Presents as early fatigue, muscle pain, and cramps.
  • Rhabdomyolysis: Can be triggered by intense exercise, leading to myoglobinuria (dark urine).
  • Hemolysis: A compensated hemolytic anemia is common as RBCs depend on glycolysis.
• Diagnosis:
  • Failure of blood lactate to rise after ischemic exercise.
  • Elevated serum Creatine Kinase (CK).

⭐ A high-carbohydrate meal paradoxically worsens exercise intolerance by increasing the concentration of upstream glycolytic intermediates that cannot be processed.

High‑Yield Points - ⚡ Biggest Takeaways

• Pyruvate kinase deficiency, the most common defect, causes autosomal recessive hemolytic anemia as RBCs rely solely on glycolysis for ATP.
• This leads to extravascular hemolysis and splenomegaly; labs show ↑ 2,3-BPG, which shifts the O₂-dissociation curve to the right.
• Glucokinase deficiency impairs pancreatic β-cell glucose sensing, causing a stable, mild hyperglycemia known as MODY 2.
• Phosphofructokinase-1 (PFK-1) deficiency (Tarui disease) causes exercise intolerance, muscle pain, and hemolytic anemia.