A 3-year-old boy from rural Maharashtra presents with hepatomegaly, failure to thrive, and recurrent hypoglycaemic episodes. Serum lactate is elevated at 8 mmol/L (normal <2). On examination, he has a doll-like face with fat cheeks and short stature. Which investigation is most specific for confirming glycogen storage disease type I (Von Gierke disease)?

Explanation

## Diagnostic Approach to GSD Type I **Key Point:** Glucose-6-phosphatase deficiency is the enzymatic defect in GSD Type I (Von Gierke disease). Enzyme assay on liver biopsy is the gold standard confirmatory test. ### Why Liver Biopsy with Enzyme Assay? 1. **Direct enzyme measurement** — Glucose-6-phosphatase activity can only be reliably measured in liver tissue (the enzyme is located in the endoplasmic reticulum of hepatocytes) 2. **Pathognomonic finding** — Absent or severely reduced enzyme activity confirms GSD Type I 3. **Allows histology** — Simultaneously visualizes excessive glycogen accumulation and hepatic architecture ### Differential Considerations | Investigation | Utility | Limitation | |---|---|---| | Serum lactate & glucose | Screening; shows metabolic derangement | Non-specific; seen in all GSDs | | Liver ultrasound | Shows hepatomegaly, fatty infiltration | Morphological only; no diagnosis | | PYGL gene testing | Identifies GSD Type III mutations | PYGL encodes glycogen phosphorylase; not involved in Type I | | Liver biopsy + enzyme assay | **Confirms glucose-6-phosphatase deficiency** | **Gold standard** | **High-Yield:** GSD Type I is the only GSD where the enzyme defect is in the final step of glucose release—hence the severe fasting hypoglycemia and lactic acidosis. **Clinical Pearl:** The "doll-like face" (round face with fat cheeks) and short stature are clinical hallmarks of GSD Type I due to chronic metabolic derangement and growth hormone resistance.