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Insufficient Ketone Body Use Is the Cause of Ketotic Hypoglycemia in One of a Pair of Homozygotic Twins

Department for Clinical Science, Intervention and Technology (Clintec), Division of Pediatrics, (C.M., J.A., J.E.), Karolinska University Hospital, Karolinska Institutet, Huddinge SE-141 86 Stockholm, Sweden; Department of Pediatrics (L.B.), University of Lund, SE-221 84 Lund, Sweden; and Department of Women’s and Children’s Health (J.G.), Uppsala University, SE-751 05 Uppsala, Sweden

Address all correspondence and requests for reprints to: Claude Marcus, M.D., Ph.D., Professor of Pediatrics, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. E-mail: claude.marcus{at}ki.se.

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

Objective: The objective of the study was 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 6 yr, the boys were thoroughly investigated. During a 24-h fasting tolerance test, the twin with KH showed hypoglycemia (blood glucose 2.0 mmol/liter) after 18 h. Three h before the occurrence of hypoglycemia, he had had 10 times higher ß-hydroxybutyrate levels than his brother, who showed no signs of hypoglycemia. Their glucose production rates were normal and similar (23.3 and 21.7 µmol/kg body weight per minute in the healthy and KH twin, respectively) as well as their lipolysis rates (5.8 and 6.8 µmol/kg body weight per minute, respectively). During repeated 60-min infusions of ß-hydroxybutyrate, the plasma level of ß-hydroxybutyrate increased 5–10 times more in the twin with KH (mean 1.1 mmol/liter in the healthy and 10.8 mmol/liter in the KH twin), indicating a disturbed clearance or metabolism of ß-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 use ketone bodies, leading to increased peripheral metabolism of glucose that cannot be met by hepatic glucose production. Because 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.