PEDIATRICS Vol. 106 No. 3 September 2000, pp. 596-600

EXPERIENCE AND REASON:
Functional Hyperactivity of Hepatic Glutamate Dehydrogenase as a Cause of the Hyperinsulinism/Hyperammonemia Syndrome: Effect of Treatment

Received Nov 10, 1999; accepted Jan 19, 2000.

Jan G. M. Huijmans^*, Marinus Duran^*, , and Johannis B. C. de Klerk^{*, §}

^* Erasmus University Department of Clinical Genetics Rotterdam, The Netherlands  University Medical Center Het Wilhelmina Kinderziekenhuis Utrecht, The Netherlands ^§ University Children's Hospital Sophia Kinderziekenhuis Rotterdam, The Netherlands

Marinus J. Rovers

Hospital Zeeuws-Vlaanderen Department of Pediatrics Terneuzen, The Netherlands

Hans R. Scholte

Erasmus University Department of Biochemistry Rotterdam, The Netherlands

Objective.  The combination of persistent hyperammonemia and hypoketotic hypoglycemia in infancy presents a diagnostic challenge. Investigation of the possible causes and regulators of the ammonia and glucose disposal may result in a true diagnosis and predict an optimum treatment.

Patient.  Since the neonatal period, a white girl had been treated for hyperammonemia and postprandial hypoglycemia with intermittent hyperinsulinism. Her blood level of ammonia varied from 100 to 300 µmol/L and was independent of the protein intake.

Methods.  Enzymes of the urea cycle as well as glutamine synthetase and glutamate dehydrogenase (GDH) were assayed in liver tissue and/or lymphocytes.

Results.  The activity of hepatic GDH was 874 nmol/(min·mg protein) (controls: 472-938). Half-maximum inhibition by guanosine triphosphate was reached at a concentration of 3.9 µmol/L (mean control values: .32). The ratio of plasma glutamine/blood ammonia was unusually low. Oral supplements with N-carbamylglutamate resulted in a moderate decrease of the blood level of ammonia. The hyperinsulinism was successfully treated with diazoxide.

Conclusion.  A continuous conversion of glutamate to 2-oxoglutarate causes a depletion of glutamate needed for the synthesis of N-acetylglutamate, the catalyst of the urea synthesis starting with ammonia. In addition, the shortage of glutamate may lead to an insufficient formation of glutamine by glutamine synthetase. As GDH stimulates the release of insulin, the concomitant hyperinsulinism can be explained. This disorder should be considered in every patient with postprandial hypoglycemia and diet-independent hyperammonemia.  Key words:  hyperammonemia, hyperinsulinism, plasma glutamine, glutamate dehydrogenase.

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