hyperinsulinism-hyperammonemia syndrome
MIM.606762
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