Context: Childhood ketotic hypoglycemia (KH) is a disease characterized by fasting hypoglycemia and increased levels of ketone bodies. The cause is unknown.

Objective: To study a pair of homozygotic twin boys, one of whom had severe KH from the age of 14 months whereas the other boy was apparently healthy.

Design and Results: At the age of 6y the boys were thoroughly investigated. During a 24h fasting tolerance test the twin with KH showed hypoglycemia (B-glucose 2.0 mmol/L) after 18h. Three hours before the occurrence of hypoglycemia he had had ten times higher -hydroxybutyrate levels than his brother who showed no signs of hypoglycemia. Their glucose production rates were normal and similar (23.3 and 21.7 umol/kgbw/min in the healthy and KH twin, respectively) as well as their lipolysis rates (5.8 and 6.8 umol/kgbw/min, respectively). During repeated 60 min infusions of -hydroxybutyrate the plasma level of -hydroxybutyrate increased 5–10 times more in the twin with KH (mean 1.1 mmol/L in the healthy and 10.8mmol/L in the KH twin) indicating a disturbed clearance or metabolism of -hydroxybutyrate. No mutations were found in genes involved in ketone body metabolism or transport.

Conclusion: In the affected boy KH seems to be the result of a reduced capacity to utilize ketone bodies, leading to increased peripheral metabolism of glucose that cannot be met by hepatic glucose production. Since the boys are homozygotic twins and only one of them is affected, the ketotic hypoglycemia is most likely caused by an altered imprinting of gene(s) involved in regulating metabolic pathways.