A 4-year-old boy from Delhi presents with severe fasting hypoglycemia and hepatomegaly. His parents report that he becomes irritable and sweaty within 3–4 hours of fasting. On examination, he has a doll-like face with fat cheeks and a protuberant abdomen. Serum glucose is 35 mg/dL after a 4-hour fast, lactate is 8 mM (normal <2), and uric acid is 9 mg/dL. A liver biopsy shows accumulation of glycogen with a normal outer branch pattern. Which enzyme deficiency is most likely responsible for this clinical picture?

Explanation

## Diagnosis: Glycogen Storage Disease Type I (Von Gierke Disease) **Key Point:** Glucose-6-phosphatase deficiency (GSD Type I) is the most severe glycogen storage disorder and presents with profound fasting hypoglycemia, hepatomegaly, and lactic acidosis. ### Clinical Features Explained | Feature | Mechanism | Relevance | |---------|-----------|----------| | **Severe fasting hypoglycemia** | G6Pase is the final step in both glycogenolysis and gluconeogenesis; its absence blocks glucose release into blood | Symptoms appear within 3–4 hours of fasting | | **Hepatomegaly** | Glucose-6-phosphate accumulates and is shunted into glycogen synthesis and glycolysis | Liver can become massively enlarged (up to 2–3× normal size) | | **Lactic acidosis** | Excess G6P drives anaerobic glycolysis → pyruvate → lactate | Lactate 8 mM (normal <2 mM) is pathognomonic | | **Hyperuricemia** | Increased ATP breakdown and purine degradation from futile cycling | Uric acid 9 mg/dL; gout can develop in childhood | | **Doll-like facies** | Fat deposition in cheeks and chin from chronic lipogenesis | Characteristic appearance | | **Normal outer branch pattern on biopsy** | Debranching enzyme is intact; only outer chains accumulate | Distinguishes from Type III (abnormal branching) | ### Pathophysiology ```mermaid flowchart TD A[Glucose-6-phosphatase deficiency]:::urgent --> B[G6P cannot be converted to free glucose] B --> C[Glucose unavailable for blood release] C --> D[Severe fasting hypoglycemia]:::outcome B --> E[G6P shunted to glycolysis] E --> F[Excess pyruvate → lactate]:::outcome B --> G[G6P shunted to glycogen synthesis] G --> H[Massive hepatomegaly]:::outcome E --> I[Increased ATP breakdown] I --> J[Hyperuricemia & gout risk]:::outcome ``` **High-Yield:** GSD Type I is the only glycogen storage disorder that presents with **severe fasting hypoglycemia within hours** and **lactic acidosis**. These two findings together are virtually pathognomonic. **Clinical Pearl:** Patients require frequent feeding (every 2–3 hours) or continuous nocturnal nasogastric feeding with glucose polymers to prevent hypoglycemic seizures and maintain growth. **Mnemonic: GSD Type I = "No Glucose Released"** - **G**lucose-6-phosphatase deficiency - **S**evere hypoglycemia (fasting) - **D**oll-like facies + hepatomegaly - Type **I** = most severe ### Why Other Enzymes Don't Fit - **Lysosomal acid α-glucosidase (Type II, Pompe):** Presents in infancy with cardiomegaly and muscle weakness; no fasting hypoglycemia or lactic acidosis. - **Glycogen phosphorylase (Type V, McArdle):** Presents in adolescence/adulthood with exercise-induced myalgia and myoglobinuria; normal fasting glucose. - **Debranching enzyme (Type III, Cori):** Mild hypoglycemia; abnormal glycogen structure on biopsy (short outer branches); no lactic acidosis. [cite:Robbins 10e Ch 5]