A 3-year-old boy from rural Maharashtra presents with recurrent episodes of muscle pain and weakness after playing for 2–3 hours. His mother reports dark-colored urine during these episodes. Physical examination reveals hepatomegaly. Serum lactate is elevated (8 mmol/L; normal <2), and venous blood gas shows metabolic acidosis. Muscle biopsy shows accumulation of glycogen with normal enzyme histochemistry. Which enzyme deficiency is most likely responsible for this clinical presentation?

Explanation

## Clinical Diagnosis: Glycogen Storage Disease Type VII (Tarui Disease) ### Pathophysiology of PFK Deficiency **Key Point:** Phosphofructokinase (PFK) catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate — the rate-limiting and committed step of glycolysis. Its deficiency causes glycolysis to stall proximal to the block. 1. **Glycogen accumulation** — glucose cannot be metabolized; it is shunted back to glycogen synthesis via glucose-6-phosphate → glucose-1-phosphate → UDP-glucose → glycogen. 2. **Lactate paradox** — despite glycolysis being blocked, lactate rises because: - Glucose-6-phosphate accumulates and is shunted to the pentose phosphate pathway and glycogen synthesis. - Anaerobic metabolism of residual glucose in muscle produces lactate. - Hepatic lactate uptake is impaired due to the systemic metabolic derangement. 3. **Muscle symptoms** — exercise-induced myalgia, cramps, and weakness occur because ATP production is severely compromised; muscles cannot sustain contraction. 4. **Dark urine** — myoglobinuria results from rhabdomyolysis triggered by ATP depletion and calcium dysregulation in muscle. ### Glycolytic Enzyme Defects: Comparative Table | Enzyme | GSD Type | Key Features | Lactate | Hepatomegaly | |--------|----------|--------------|---------|---------------| | **PFK** | **VII (Tarui)** | **Myalgia, rhabdomyolysis, ↑ lactate** | **↑↑** | **+** | | Pyruvate kinase | X | Hemolytic anemia, mild myalgia | ↑ | +/− | | Hexokinase | — | Severe hypoglycemia, no glycogen storage | Normal | − | | Aldolase | XII | Severe myopathy, hemolysis | ↑ | +/− | | Glycogen phosphorylase | V (McArdle) | Myalgia, **normal lactate response to exercise** | Normal | + | **High-Yield:** PFK deficiency is the **only glycolytic enzyme defect** that presents with both: - Severe exercise intolerance with myalgia and rhabdomyolysis, AND - **Paradoxically elevated lactate** (because glucose-6-phosphate backs up into alternative pathways). ### Clinical Pearl: The "Second Wind" Phenomenon Patients with PFK deficiency (and McArdle disease) may experience relief of symptoms 10–15 minutes into exercise — this is due to: - Increased blood glucose uptake from hepatic glycogenolysis. - Shift to fatty acid oxidation. - Improved ATP availability from non-glycolytic sources. This distinguishes glycolytic enzyme defects from mitochondrial myopathies. ### Diagnostic Clues in This Case - **Age 3 years** — GSD VII typically manifests in early childhood with exertional symptoms. - **Hepatomegaly** — glycogen accumulates in liver due to shunting of glucose-6-phosphate. - **Elevated lactate** — pathognomonic for PFK deficiency among glycolytic defects. - **Normal muscle enzyme histochemistry** — rules out mitochondrial myopathy; glycogen is structurally normal (not a branching enzyme defect). - **Myoglobinuria** — indicates severe muscle ATP depletion and rhabdomyolysis. [cite:Robbins 10e Ch 5] [cite:KD Tripathi 8e Ch 11]