Although there are many causes of hypoglycemia, a new syndrome associating hyperinsulinism with hyperammonemia was recently described (Zammarachi, et al. Metabolism 1996:45:957; Weinzimer, et al. J Pediatr 1997:130:661; Stanley, et al. N Eng J Med 1998:338:1352).  This syndrome is identical or closely related to the leucine-sensitive hypoglycemia syndrome and is congenital in origin.  Clinical manifestations are usually observed in neonates and/or infants.  The diagnosis of patients with HSS is crucial as therapy differs radically, medical and not surgical, from that of other hyperinsulinemic patients.  A positive response to diazoxide- and/or leucine-free diet is usually observed.  All but one of the 12 patients in the article by De Lonlay had at least a partial response to diazoxide.

Genetically all 12 cases studied seem to be new mutations, as they occurred sporadically without family histories.  This mutation results in a gain of function in the glutamate dehydrogenase gene (GLUD1).  It also results in a decreased inhibitory effect of guanosine triphosphate on the enzyme.  It has been suggested that the elevated oxidation of glutamate to α-ketoglutarate stimulates insulin secretion by increasing the ATP/ADP ratio in the pancreatic Beta cell, although this is unproven.  All 12 patients studied had mutations located within or outside the GTP binding site, without any correlation between phenotype and genotype.  The mutations in the GLUD1 gene are found in exons 6, 10, 11, and 12, which includes the antenna region of the enzyme and the GDP binding domain.

In a review of hyperinsulinemic patients by the authors in their institution over the past 20 years, plasma ammonia concentrations were measured in 71 (45 neonates and 26 infants) and hyperammonemia was found in 12 of the 71.  The incidence of this type of hypoglycemia is significant.  The authors conclude that ammonia concentrations should be measured in every patient investigated for hyperinsulinism and that, conversely, hypoglycemia should be looked for in all patients with unexplained hyperammonemia.

Editor’s Comment:  Heterogeneity is the name of the game, and molecular techniques allow us to recognize many of the reasons for heterogeneity.  Within heterogeneity, many new biochemical pathways and mechanisms of disease are being identified.  As in the case of this syndrome, different types of therapy become most appropriate.   

Judith G. Hall, OC, MD