Clinical and enzymatic phenotypes in congenital hyperinsulinemic hypoglycemia due to glucokinase‐activating mutations: A report of two cases and a brief overview of the literature

Abstract

Aims/IntroductionThe principal aim of this study was to investigate the clinical, genetic and functional characteristics of two cases of congenital hyperinsulinism (CHI) caused by glucokinase (GCK) mutations in young patients.Materials and MethodsNovel mutations were detected by CHI next‐generation sequencing, and the kinetic parameters and thermal stability of recombinant wild‐type and mutant glucokinase were determined in vitro. In addition, 18 naturally occurring GCK‐CHI mutations reported previously were also summarized.ResultsA de novo mutation (M197V) was found in a 17‐year‐old male with an epilepsy history, whereas an autosomal dominant mutation (K90R) was found in a 20‐year‐old female with inherited asymptomatic hypoglycemia. Kinetic analysis showed increased enzyme activity for both mutants (RAI 4.7 for M197V and 1.6 for K90R) and enhanced thermal stability for the M197V mutant. However, of all the GCK‐CHI mutants, the increase in enzyme activity (RAI between 1.6 and 130) did not correlate strongly with the severity of hypoglycemia. The de novo group (7/19) showed distinctive phenotypes from the autosomal dominant group (12/19), such as a higher proportion of diazoxide unresponsiveness (28.6% vs 0%), a higher incidence of macrosomia (85.7% vs 40%) and a rarer incidence of adulthood onset (0% vs 25%).ConclusionsThe clinical phenotypes of GCK‐CHIs were highly heterogeneous. We have identified two novel GCK‐CHI mutations in young patients and investigated their pathogenicity by enzyme kinetic analysis, which expanded the spectrum of this rare disease.

Glucokinase activating mutation causing hypoglycaemia diagnosed late in adult who fasts for Ramadhan

“…CHI, otherwise called hyperinsulinism in infancy or nesidioblastosis, is most often diagnosed at infancy because of the early symptoms of poor feeding, floppiness, and jitteriness ( 10 ). Among the 11 different genes associated with CHI, GCK-HH is less common than ABCC8 and KCNJ11 ( 11 ). About 20 GCK-HH mutations have been reported with the majority being missense mutations in 95% ( 11 ).…”

“…Among the 11 different genes associated with CHI, GCK-HH is less common than ABCC8 and KCNJ11 ( 11 ). About 20 GCK-HH mutations have been reported with the majority being missense mutations in 95% ( 11 ). GCK-HH presents with a wide spectrum of phenotypic features even within the same family with respect to presentation, age, severity, treatment response and hypoglycaemia awareness ( 2 , 6 , 12 , 13 ).…”

“…Whilst somatostatin analogue experience is limited and not effective for some patients ( 6 ), this patient presented herein had an excellent clinical response. The absence of family history does not exclude GCK-HH because mutations could be de novo and results in a variable spectrum of symptoms ( 11 , 13 ). Patients presenting with de novo mutation tend to be unresponsive to diazoxide, have macrosomia and less adult onset ( 11 ).…”

“…The absence of family history does not exclude GCK-HH because mutations could be de novo and results in a variable spectrum of symptoms ( 11 , 13 ). Patients presenting with de novo mutation tend to be unresponsive to diazoxide, have macrosomia and less adult onset ( 11 ).…”

Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research

“…Heterozygous loss-of-function mutations in the GCK gene induces a decrease of glucose phosphorylation into glucose-6-phosphate (G6P), which blocks the entry of G6P into the glycolytic pathway. Insulin secretion in response to glucose is reduced and this mechanism results in non-progressive fasting hyperglycaemia in patients ( 79 – 81 ).…”