A 3-year-old boy from Mumbai presents with severe fasting hypoglycemia (blood glucose 35 mg/dL after 4 hours of fasting) and hepatomegaly. His parents report recurrent episodes of seizures during sleep and developmental delay. On examination, he has a doll-like face with full cheeks, short stature, and a protuberant abdomen. Serum lactate is markedly elevated at 8 mmol/L (normal <2). Liver biopsy shows excessive glycogen accumulation with normal structure. Which glycogen storage disorder is most likely?

Explanation

## Diagnosis: Glycogen Storage Disease Type I (Von Gierke Disease) ### Clinical Presentation Match The vignette presents the classic triad of GSD Type I: 1. **Severe fasting hypoglycemia** — occurs within 3–4 hours of fasting (pathognomonic) 2. **Hepatomegaly** — massive, can reach 2–3 times normal size 3. **Lactic acidosis** — markedly elevated serum lactate due to shunting of glucose-6-phosphate into lactate pathway ### Biochemical Defect **Key Point:** GSD Type I is caused by deficiency of **glucose-6-phosphatase**, the enzyme that catalyzes the final step of both gluconeogenesis and glycogenolysis: glucose-6-phosphate → glucose. Without this enzyme: - Glucose cannot be released from liver into bloodstream - Glucose-6-phosphate accumulates and is shunted into lactate, alanine, and fatty acid synthesis - Results in lactic acidosis, hyperuricemia, and hyperlipidemia ### Distinguishing Features | Feature | GSD Type I | GSD Type III | GSD Type V | GSD Type II | |---------|-----------|-------------|-----------|------------| | **Enzyme defect** | Glucose-6-phosphatase | Debranching enzyme | Muscle phosphorylase | Acid maltase (lysosomal) | | **Fasting hypoglycemia** | Severe, within 3–4 hrs | Mild to moderate | Absent | Absent | | **Lactate elevation** | Marked ↑↑↑ | Mild | Normal | Normal | | **Hepatomegaly** | Massive | Moderate | Absent | Absent | | **Muscle involvement** | None | None | Prominent | Prominent (infantile form) | | **Liver biopsy** | Normal structure | Normal structure | Normal structure | Vacuoles with glycogen | ### Clinical Pearl **High-Yield:** The combination of **severe fasting hypoglycemia + lactic acidosis + normal liver glycogen structure** is virtually diagnostic of GSD Type I. The "doll-like face" with full cheeks and short stature are classic anthropometric findings due to chronic metabolic derangement. ### Mnemonic **GLUT1** — **G**lucose-6-phosphatase deficiency, **L**actic acidosis, **U**ricemia, **T**riglyceridemia, **I**ncreased liver glycogen. ### Management Implications - Frequent feeds (every 2–3 hours) or continuous nasogastric feeding at night - Uncooked cornstarch (provides slow glucose release) - Avoid fasting - Monitor for complications: gout, kidney disease, hepatic adenomas [cite:Robbins 10e Ch 5]