The hyperinsulinism-hyperammonemia syndrome (HI-HA) is the second most common form of congenital hyperinsulinism.

Etiology

 dominantly expressed missense mutations of the mitochondrial matrix enzyme, glutamate dehydrogenase (GDH) (MIM.602762)

GDH catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate plus ammonia, using NAD or NADP as co-factor.

HI/HA mutations impair GDH sensitivity to its allosteric inhibitor, GTP, resulting in a gain of enzyme function and increased sensitivity to its allosteric activator, leucine.

References

 Stanley CA. Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab. 2004 Apr;81 Suppl:45-51. PMID: #15050973#

 Kelly A, Li C, Gao Z, Stanley CA, Matschinsky FM. Glutaminolysis and insulin secretion: from bedside to bench and back. Diabetes. 2002 Dec;51 Suppl 3:S421-6. PMID: #12475785#

 Kelly A, Stanley CA. Disorders of glutamate metabolism. Ment Retard Dev Disabil Res Rev. 2001;7(4):287-95. PMID: #11754524#