A 4-year-old child presents with easy fatigability. The mother also complains that the child has increased hunger between meals, which is relieved after food. Liver examination revealed no glycogen. The enzyme most likely deficient is?

Explanation

## Correct Answer: C. Glycogen synthase The clinical presentation of easy fatigability, increased hunger between meals (relieved by food), and **absence of hepatic glycogen** is pathognomonic for glycogen synthase deficiency. This enzyme catalyzes the transfer of glucose from UDP-glucose to the growing glycogen chain, forming α-1,4-glycosidic bonds—the rate-limiting step of glycogen synthesis. Without functional glycogen synthase, the liver cannot store glucose as glycogen, leading to severe postprandial hyperglycemia (glucose cannot be stored) and fasting hypoglycemia (no glycogen reserve to mobilize). The "no glycogen on liver examination" is the discriminating clue: in other glycogenoses, glycogen accumulates abnormally; here it is absent because synthesis is blocked. The hunger between meals reflects reactive hypoglycemia when dietary glucose is exhausted and the liver cannot release glucose from non-existent glycogen stores. This is **Glycogen Storage Disease Type 0 (GSD-0)**, the only glycogenosis with hepatomegaly *absent* and glycogen stores *depleted*. Fasting triggers severe hypoglycemia and lactic acidosis. The child's symptoms (fatigue, hunger relief with food) fit the hypoglycemic pattern, not the hyperglycemic accumulation seen in other GSDs. Indian pediatric practice recognizes this as the rarest and most severe form requiring frequent feeding schedules and uncooked cornstarch therapy. ## Why the other options are wrong **A. Debranching enzyme** — Debranching enzyme deficiency (GSD-III, Cori disease) causes **glycogen accumulation** with abnormal branching pattern and hepatomegaly. The liver would be enlarged and contain excess glycogen, not absent glycogen. This is a common trap because GSD-III also presents with hypoglycemia and hepatomegaly, but the key differentiator is the presence of glycogen on biopsy. **B. Glucose 6 phosphatase** — Glucose 6 phosphatase deficiency (GSD-I, Von Gierke disease) causes **severe hepatomegaly with massive glycogen accumulation**, lactic acidosis, and fasting hypoglycemia. While hypoglycemia occurs, the liver is grossly enlarged with glycogen present—opposite of the clinical finding here. GSD-I is the most common glycogenosis in India; this question tests differentiation from GSD-0. **D. Glycogen phosphorylase** — Glycogen phosphorylase deficiency (GSD-V, McArdle disease) causes **glycogen accumulation** in muscle and liver with hepatomegaly. Patients present with muscle pain and myoglobinuria on exertion, not the fasting hypoglycemia and absent hepatic glycogen described here. The clinical phenotype is entirely different—exercise intolerance rather than postprandial hunger. ## High-Yield Facts - **GSD-0 (glycogen synthase deficiency)** is the only glycogenosis with absent hepatic glycogen and no hepatomegaly—all others accumulate glycogen. - **Fasting hypoglycemia + postprandial hyperglycemia** is the hallmark of GSD-0; glucose cannot be stored, so blood glucose swings wildly. - **Frequent feeding with uncooked cornstarch** is the Indian DOC for GSD-0 to prevent severe hypoglycemic episodes. - **Lactic acidosis during fasting** occurs in GSD-0 because glucose-6-phosphate is shunted into glycolysis and lactate production. - **Glycogen synthase** catalyzes the rate-limiting step of glycogen synthesis (UDP-glucose → α-1,4-glycosidic bonds); its deficiency is the only GSD with depleted, not accumulated, glycogen stores. ## Mnemonics **GSD-0 vs Others: The Absent Glycogen Rule** GSD-0 = **No glycogen** (synthase deficient → cannot build). All others = **Glycogen accumulates** (breakdown or branching defects). When you see 'no glycogen on liver exam,' think GSD-0 immediately. **Hypoglycemia Pattern Differentiator** **GSD-0**: Fasting hypoglycemia + postprandial hyperglycemia (glucose swings). **GSD-I**: Fasting hypoglycemia + lactic acidosis + massive hepatomegaly. **GSD-III**: Hypoglycemia + hepatomegaly + normal lactate. The 'no glycogen' finding locks in GSD-0. ## NBE Trap NBE pairs "easy fatigability + increased hunger" with hepatomegaly to lure students toward GSD-I (Von Gierke) or GSD-III (Cori), which are more common. The critical discriminator—**absent hepatic glycogen**—is the trap-breaker that points uniquely to GSD-0. ## Clinical Pearl In Indian pediatric practice, GSD-0 is rare but must be recognized early because untreated fasting hypoglycemia can cause seizures and permanent neurological damage. Mothers are counseled to provide frequent meals (every 2–3 hours) and uncooked cornstarch at bedtime to prevent nocturnal hypoglycemia—a simple intervention that transforms the prognosis. _Reference: Robbins Ch. 5 (Genetic Disorders); KD Tripathi Ch. 12 (Carbohydrate Metabolism); Harrison Ch. 356 (Glycogen Storage Diseases)_