A 3-year-old boy from Mumbai is brought to the paediatric clinic with a 6-month history of progressive abdominal distension and hepatomegaly. His parents report that he becomes irritable and sweaty after 3–4 hours of fasting. On examination, he has marked hepatomegaly (liver edge 8 cm below costal margin), but no splenomegaly. His growth is normal. Blood glucose during a fasting episode is 35 mg/dL. Serum transaminases are mildly elevated (ALT 65 U/L). Liver biopsy shows glycogen accumulation predominantly in hepatocytes with normal glycogen structure. Which glycogen storage disorder is most likely?

Explanation

## Diagnosis: Glycogen Storage Disease Type I (Von Gierke Disease) ### Clinical Presentation Match The vignette describes a child with: - **Severe fasting hypoglycemia** (35 mg/dL after 3–4 hours) - **Marked hepatomegaly** with normal growth - **Absence of muscle involvement** (no weakness, normal motor milestones) - **Normal glycogen structure** on biopsy These findings are pathognomonic for GSD Type I. ### Pathophysiology **Key Point:** GSD Type I results from deficiency of **glucose-6-phosphatase**, the enzyme that catalyzes the final step of both gluconeogenesis and glycogenolysis — the conversion of glucose-6-phosphate to free glucose in the liver. Without this enzyme: 1. Glucose-6-phosphate accumulates → shunted into glycogen synthesis 2. Free glucose cannot be released into blood → severe hypoglycemia 3. Glucose-6-phosphate → glycolysis → lactate → lactic acidosis 4. Glucose-6-phosphate → pentose phosphate pathway → increased purine synthesis → hyperuricemia ### Distinguishing Features of GSD Type I | Feature | GSD I | GSD III | GSD II | GSD IV | |---------|-------|---------|--------|--------| | **Enzyme defect** | Glucose-6-phosphatase | Debranching enzyme | Acid maltase | Branching enzyme | | **Fasting hypoglycemia** | Severe (< 40 mg/dL) | Mild–moderate | None | None | | **Hepatomegaly** | Massive | Moderate | Absent | Moderate | | **Muscle involvement** | None | Mild myopathy | Severe (infantile form) | Progressive cirrhosis | | **Glycogen structure** | Normal | Normal | Normal | Abnormal (few branches) | | **Lactic acidosis** | Present | Absent | Absent | Absent | | **Hyperuricemia** | Yes (gout risk) | No | No | No | ### High-Yield Clinical Correlates **High-Yield:** The **doll-like face** (full cheeks, prominent lips) and **growth retardation** are classic features of GSD I, though this patient has normal growth — likely due to early diagnosis and dietary management. **Clinical Pearl:** Patients with GSD I require frequent feeding (every 2–3 hours) or continuous nasogastric feeds at night to prevent hypoglycemia and its neurological sequelae. Cornstarch is the mainstay of dietary management. **Warning:** GSD Type I carries a high risk of **hepatic adenomas** (30–50% by adulthood) and **renal disease** (glomerulosclerosis, chronic kidney disease). Regular ultrasound screening is essential. ### Why This Is NOT the Others - **GSD III (Cori disease):** Hypoglycemia is mild–moderate (not severe), and patients have some ability to mobilize glucose from outer branches of glycogen. Muscle involvement is common. - **GSD II (Pompe disease):** Infantile form presents with cardiomegaly and muscle weakness; no hypoglycemia. Glycogen accumulates in all tissues, not just liver. - **GSD IV (Andersen disease):** Abnormal glycogen structure (few branch points) leads to hepatic cirrhosis and failure in infancy; no hypoglycemia.