New Insight in Hyperinsulinism/Hyperammonemia Syndrome by Magnetic Resonance Imaging and Spectroscopy

Abstract

Hyperinsulinism/hyperammonemia syndrome (HI/HA) is an autosomal dominant disorder caused by monoallelic activating mutations in the glutamate dehydrogenase 1 (GLUD1) gene. While hyperinsulinism may be explained by a reduction in the allosteric inhibition of GLUD1, the pathogenesis of HA in HI/HA remains uncertain; interestingly, HA in the HI/HA syndrome is not associated with acute hyperammonemic intoxication events. We obtained a brain magnetic resonance (MR) in a woman with HI/HA syndrome with chronic asymptomatic HA. On MR spectroscopy, choline and myoinositol were decreased as in other HA disorders. In contrast, distinct from other HA disorders, combined glutamate and glutamine levels were normal (not increased). This observation suggests that brain biochemistry in HI/HA may differ from that of other HA disorders. In HI/HA, ammonia overproduction may come to the expense of glutamate levels, and this seems to prevent the condensation of ammonia with glutamate to produce glutamine that is typical of the other HA disorders. The absence of combined glutamate and glutamine elevation might be correlated to the absence of acute cerebral ammonia toxicity.

Novel compound heterozygote variants: c.4193_4206delinsG (p.Leu1398Argfs*25), c.793C > A (p.Pro265Thr), in the CPS1 gene (NM_001875.4) causing late onset carbamoyl phosphate synthetase 1 deficiency—Lessons learned

“…These concepts can be visualized by Fig. 4 [ [36] , [37] , [38] ]. Even though glutamine formation from alpha-ketoglutarate helps detoxify ammonia, elevated glutamine has also been shown to have neurotoxic effects and should therefore be appropriately monitored and controlled [ [36] , [37] , [38] , [39] ].…”

“…4 [ [36] , [37] , [38] ]. Even though glutamine formation from alpha-ketoglutarate helps detoxify ammonia, elevated glutamine has also been shown to have neurotoxic effects and should therefore be appropriately monitored and controlled [ [36] , [37] , [38] , [39] ]. Also, once the patient has any illness, the balance could be immediately disrupted and result in hyperammonemia.…”

“…Alanine also serves as a reservoir of ammonia as the amino group of glutamate is transferred to pyruvate by alanine aminotransferase which generates alanine and alpha-ketoglutarate [ [36] , [37] , [38] , [39] ]. Therefore, alanine production allows the body to carry and store ammonia in a non-toxic form.…”