Heterogeneity in disease severity in a family with a novel G68V GCK activating mutation causing persistent hyperinsulinaemic hypoglycaemia of infancy

Background/aim Glucokinase (GCK)-activating mutations cause persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI). GCK-PHHI patients have regulated insulin secretion and can usually be treated with diazoxide. The six reported cases suggest that the severity of the mutation predicts the clinical phenotype. The aim of this study was to relate genotype to phenotype [clinical phenotype, glucose-stimulated insulin release (GSIR) and GCK functional analysis] in a large pedigree with eight affected individuals. Methods The genes encoding B-cell GCK and the K-ATP channel subunits (ABCC8 and KCNJ11) were sequenced to identify mutations for functional analysis. Genetic variants influencing B-cell function were genotyped in affected individuals. Islet secretory capacity was determined by oral glucose tolerance test Results A novel GCK mutation (G68V) co-segregating with hypoglycaemia was identified in eight family members. Kinetic analysis revealed that G68V-GCK activity is similar to 16 times more than wild-type-GCK with an increased affinity for glucose [concentration at half maximal activation (S-0.5) 1.94 +/- 0.16 vs. 7.43 +/- 0.12, mutant vs. wild type, mean +/- SEM]. Mathematical modelling predicted a threshold for GSIR of 1.9 mmol/l in the mutant. Oral glucose tolerance tests showed regulated insulin secretion. The severity of hypoglycaemia and related symptoms in affected subjects were heterogeneous. Clinical presentations were asymptomatic (n = 1), extreme hunger (n = 3), seizures (n = 2) and loss of consciousness (n = 2); 7/8 were managed with diet but the proband was treated with diazoxide and octreotide. Phenotypic modification by a second mutation in the K-ATP channel genes (ABCC8, KCNJ11) or by common genetic variants in KCNJ11, GCK and TCF7L2 was excluded. Conclusion The novel activating GCK mutation G68V is associated with variable phenotypic severity, supporting modification of GSIR by genetic and/or environmental factors.