A 3-year-old presents with fasting hypoglycemia, ketosis, and elevated plasma lactate. Glucagon fails to raise blood glucose. Electron microscopy of liver shows depleted glycogen stores. Which enzyme defect is most consistent?

• A Glycogen synthase deficiency ✓
• B Phosphorylase kinase deficiency
• C Pyruvate carboxylase deficiency
• D Liver glycogen phosphorylase deficiency (GSD VI)

Explanation

Glycogen synthase deficiency (GSD 0) impairs glycogen synthesis, so post-absorptive glycogen stores are markedly reduced. During fasting, the child relies entirely on gluconeogenesis, but if gluconeogenic substrates are limited or the pathway is somewhat stressed, ketosis and hypoglycemia result. Glucagon cannot mobilise what is not there, so the glucagon test is flat. Unlike classic GSDs with glycogen accumulation, EM shows depleted stores in GSD 0.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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