Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations

Background: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism-hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion. Objectives: To study the genotype-phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods: Twenty patients with HI from 16 families had mutational analysis of the GLUM gone in view of HA (n = 19) or leucine sensitivity (n = 1). Patients negative for a GLUD1 Mutation had sequence analysis of the SIRT4. gene. Functional analysis of the novel P436L GLUD1 mutation was performed. Results: Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D45IV). In addition, it patient with it normal serum ammonia concentration (21 mu mol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with it GLUD1 mutation. No mutations in the SIRT4 gene were identified. Conclusion: Patients with HI due to Mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity: even in the absence of HA. A high frequency of epilepsy (43%,) was observed in our patients with GLUD1 mutations.