A 3-year-old child presents with recurrent episodes of severe hypoglycemia, hepatomegaly, and lactic acidosis after fasting for 4 hours. Enzyme assays reveal deficiency of a key glycolytic enzyme. Which enzyme deficiency is the most common cause of symptomatic glycolytic enzyme deficiency presenting in childhood?

## Most Common Glycolytic Enzyme Deficiency **Key Point:** Pyruvate kinase (PK) deficiency is the most common symptomatic glycolytic enzyme deficiency, accounting for approximately 50% of all glycolytic enzyme disorders. ### Clinical Presentation of PK Deficiency **High-Yield:** PK deficiency presents with: - Hemolytic anemia (due to RBC ATP depletion) - Jaundice and splenomegaly - Hypoglycemia after fasting - Lactic acidosis (accumulation of pyruvate → lactate) - Symptoms typically appear in infancy or early childhood ### Why PK Deficiency is Most Common | Enzyme | Frequency | Key Clinical Feature | |--------|-----------|----------------------| | Pyruvate kinase | Most common (~50%) | Hemolytic anemia + hypoglycemia | | Phosphofructokinase | ~20% | Myopathy (muscle weakness) | | Aldolase | Rare | Hepatomegaly, neurological signs | | Hexokinase | Very rare | Mild fasting hypoglycemia | **Clinical Pearl:** In PK deficiency, RBCs are uniquely vulnerable because they lack mitochondria and depend entirely on glycolysis for ATP. ATP depletion leads to loss of RBC membrane integrity and hemolysis. **Mnemonic:** **PK = RBC Problem** — Pyruvate Kinase deficiency causes hemolytic anemia because RBCs cannot generate ATP via glycolysis. ### Pathophysiology Pyruvate kinase catalyzes the final step of glycolysis: $$\text{Phosphoenolpyruvate (PEP)} + \text{ADP} \xrightarrow{PK} \text{Pyruvate} + \text{ATP}$$ Deficiency leads to: 1. Accumulation of PEP and upstream glycolytic intermediates 2. Shunting to 2,3-DPG pathway → increased RBC 2,3-DPG 3. ATP depletion in RBCs → hemolysis 4. Impaired hepatic gluconeogenesis → hypoglycemia 5. Pyruvate → lactate conversion → lactic acidosis [cite:Robbins 10e Ch 7]