Hyperinsulinism-hyperammonemia syndrome is caused by mutations on the GLUD1 gene that result in an increase in glutamate dehydrogenase 1 activity by impairing allosteric inhibition by GTP. In general, it is first recognized in children at the age of 6 to 12 month, but some patients are not diagnosed until adulthood. In about 30% of the cases, the disease is inherited in an autosomal dominant way, whereas the other 70% occur de novo. (PMID:26962538).
A distinct syndrome of hyperinsulinism and hyperammonemia in 3 unrelated children was described by Zammarchi et al. (1996) and Weinzimer et al. (1997). In addition, Zammarchi et al. (1996) suggested that the defect involved leucine hypersensitivity. Hsu et ... A distinct syndrome of hyperinsulinism and hyperammonemia in 3 unrelated children was described by Zammarchi et al. (1996) and Weinzimer et al. (1997). In addition, Zammarchi et al. (1996) suggested that the defect involved leucine hypersensitivity. Hsu et al. (2001) studied 8 children and 6 adults with hypoglycemia due to congenital hyperinsulinism combined with persistent unexplained hyperammonemia. In each of these cases, known metabolic disorders were ruled out. All had dominantly expressed mutations of glutamine dehydrogenase and plasma concentrations of ammonium that were 2 to 5 times normal. The median age at onset of hypoglycemia in the 14 patients was 9 months; diagnosis was delayed beyond age 2 years in 6 patients, and 4 were not given a diagnosis until adulthood. Fasting tests revealed unequivocal evidence of hyperinsulinism in only 1 of 7 patients. Three did not develop hypoglycemia until 12 to 24 hours of fasting; however, all 7 demonstrated inappropriate glycemic responses to glucagon that were characteristic of hyperinsulinism. In response to oral protein, all 12 patients with hyperinsulinism/hyperammonemia showed a fall in blood glucose compared with none of 5 control subjects. Insulin responses to protein loading were similar in the patients with hyperinsulinism/hyperammonemia and control subjects. Hsu et al. (2001) concluded that the postprandial blood glucose response to a protein meal is more sensitive than prolonged fasting for detecting hypoglycemia in the hyperinsulinism/hyperammonemia syndrome. Kelly et al. (2001) postulated that children with hyperinsulinism/hyperammonemia syndrome would have exaggerated acute insulin responses to leucine in the postabsorptive state. As hyperglycemia increases beta-cell guanosine triphosphate (GTP), they also postulated that high glucose concentrations would extinguish abnormal responsiveness to leucine in hyperinsulinism/hyperammonemia syndrome patients. After an overnight fast, 7 patients had acute insulin response to leucine administered intravenously. Four patients then had acute insulin responses to leucine repeated at hyperglycemia. High blood glucose suppressed their abnormal baseline acute insulin responses to leucine. The authors concluded that protein-induced hypoglycemia in hyperinsulinism/hyperammonemia syndrome patients may be prevented by carbohydrate loading before protein consumption. De Lonlay et al. (2001) studied 12 unrelated patients with hyperinsulinism and hyperammonemia and observed clinically heterogeneous phenotypes, with neonatal- and infancy-onset hypoglycemia and variable responsiveness to medical (diazoxide) and dietary (leucine-restricted diet) treatment. Hyperammonemia was constant and not influenced by oral protein, by protein- and leucine-restricted diet, or by sodium benzoate or N-carbamylglutamate administration. Mean basal GDH activity in cultured lymphocytes did not differ between patients and controls, but the sensitivity of GDH activity to inhibition by GTP was reduced in all patient lymphoblast cultures. The activating effect of leucine on GDH activity varied among the patients; 4 patients had a significant decrease of sensitivity that correlated with a negative clinical response to dietary leucine. Ihara et al. (2005) reported a Japanese girl who presented in infancy with delayed growth and hyperammonemia. Liver biopsy showed decreased activity of carbamoyl phosphate synthetase-1 (CPS1; 608307), and she was given a diagnosis of CPS1 deficiency (237300) based on enzymatic studies. Her blood glucose was relatively low on retrospective analysis. Treatment with protein restriction, sodium benzoate, and arginine failed to reduce the ammonia throughout childhood. At age 15 years, she showed borderline intelligence, and biochemical studies showed low serum glucose and inappropriately high insulin. The correct diagnosis of hyperinsulinism-hyperammonemia syndrome due to a de novo heterozygous GLUD1 mutation was confirmed by genetic analysis (S445L; 138130.0002). Ihara et al. (2005) could not explain the secondary CPS1 enzymatic deficiency in this patient, but suggested that the urea cycle may not have been functioning sufficiently in this patient.
Stanley et al. (1997) studied GLUD activity and cDNA using cultured lymphoblasts from 2 infants with hyperinsulinism and hyperammonemia and their parents. In these patients, heterozygous mutations were found in the GLUD1 gene (138130.0001, 138130.0002). The C-terminal region ... Stanley et al. (1997) studied GLUD activity and cDNA using cultured lymphoblasts from 2 infants with hyperinsulinism and hyperammonemia and their parents. In these patients, heterozygous mutations were found in the GLUD1 gene (138130.0001, 138130.0002). The C-terminal region affected by the mutations was known to confer responsiveness to allosteric regulators of GLUD activity. These unusual mutations resulted in a gain rather than a loss of enzyme function. In their report of 4 sporadic and 2 familial cases, Stanley et al. (1998) found 5 missense mutations clustered within a range of 10 codons in exons 11 and 12 of the GLUD1 gene, which predicted an effect on the presumed allosteric domain of the enzyme (see, e.g., 138130.0003-138130.0005). All of these mutations were associated with a diminished inhibitory effect of GTP on glutamate dehydrogenase activity. In family 2 with hyperinsulinemic hypoglycemia studied by Thornton et al. (1998), Glaser et al. (1998) identified the S448P mutation in the GLUD1 gene. Miki et al. (2000) performed mutation analysis of 5 unrelated Japanese patients (3 girls and 2 boys) with hyperinsulinism-hyperammonemia syndrome. All had convulsions or loss of consciousness resulting from hypoglycemia before the age of 1 year and asymptomatic, minimally elevated plasma ammonia levels. Heterozygous missense mutations were found in all. Three patients had a previously identified mutation, ser445 to leu (138130.0002), located in the allosteric domain. Two others were heterozygous for missense mutations within the catalytic domain of the gene (138130.0006 and 138130.0007). The site of the mutations was not correlated with the severity of hypoglycemia. Santer et al. (2001) investigated 14 patients from 7 European families with mild hyperinsulinism. In 1 of the families, a novel heterozygous missense mutation in exon 6 (R221C; 138130.0008) was detected, and in all other cases from 6 unrelated families, the novel heterozygous missense mutation R269H (138130.0009) was found in exon 7. When glutamate dehydrogenase activity was measured in lymphocytes isolated from affected patients, both mutations were shown to result in a normal basal activity but a diminished sensitivity to GTP. The observation of the high prevalence of the exon 7 mutation both in familial and in sporadic cases of hyperinsulinism-hyperammonemia syndrome suggested a mutation hotspot and justified mutation screening for this mutation by mismatch PCR-based restriction enzyme digestion in patients with hyperinsulinism. In the 7 families with hyperinsulinism-hyperammonemia syndrome studied by Santer et al. (2001), 4 had more than 1 affected member. In 8 of 14 cases, hyperammonemia was documented, and 8 cases had signs of significant leucine sensitivity. In 65 hyperinsulinism/hyperammonemia probands screened for GDH mutations, MacMullen et al. (2001) identified 19 (29%) who had mutations in a domain encoded by exons 6 and 7. Six new mutations were found. In all 5 mutations tested, lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP, consistent with a gain of enzyme function. Studies of ATP allosteric effects on GDH showed a triphasic response with a decrease in high affinity inhibition of enzyme activity in hyperinsulinism/hyperammonemia lymphoblasts. All of the residues altered by exons 6 and 7 hyperinsulinism/hyperammonemia mutations lie in the GTP-binding domain of the enzyme. De Lonlay et al. (2001) analyzed the GLUD1 gene in 11 unrelated patients with hyperinsulinism/hyperammonemia and identified 6 different heterozygous missense mutations in 10 patients. Three mutations were located within and 3 outside the GTP-binding site, without any correlation between phenotype and genotype.