Hyperinsulinemic Hypoglycemia in Three Generations of a Family with Glucokinase Activating Mutation, c.295T>C (p.Trp99Arg)

Abstract

Familial Hyperinsulinemic Hypoglycemia (FHH) is a very rare disease with heterogeneous clinical manifestations. There are only a few reports of heterozygous activating mutations of glucokinase (GCK) attributable to FHH, with no reports describing effects in the course in pregnancy with affected mother/affected child. A large kindred with FHH and GCK:c.295T>C (p.Trp99Arg) pathogenic variant was identified in which four family members from three generations were affected. The clinical follow up in one clinical center lasted up to 30 years, with different times of diagnosis ranging from neonate period to adulthood. The severity of hypoglycemia was mild/severe and fasting was the trigger for hypoglycemia. Response to diazoxide varied from good, in the neonate, to moderate/poor, in childhood/adulthood; however, this was biased by poor compliance. Treatment with somatostatin analogues was discontinued due to side effects. Over time, patients developed clinical adaptation to very low glucose levels. During pregnancy, episodes of severe hypoglycemia in the first trimester were observed, which responded very well to steroids. The clinical course of the GCK:c.295T>C (p.Trp99Arg) mutation varied in the same family, with the development of clinical adaptation to very low glucose levels over time. Treatment with steroids might prevent hypoglycemia during pregnancy in an affected mother.

Ghost interactions: revealing missing protein-ligand interactions using AlphaFold predictions

“…The AF2 structure allows us to observe a ghost interaction of W99 with this ligand (Figure 7a) that contributes to the stabilisation of the ligand in the binding site and has the potential to influence the observed active conformation. Interestingly, this key position was previously identified as the site of a novel activating GK mutation (p.Trp99Arg) associated with familial hyperinsulinemic hypoglycemia 40 . Understanding the activation mechanism of GK and the interactions involved in it will aid in the design of GKAs with improved safety profiles for the treatment of conditions arising from activating mutations.…”

Case Report: Hypoglycemia Due to a Novel Activating Glucokinase Variant in an Adult – a Molecular Approach

“…Despite carrying the same GCK variant, the clinical presentation in this family varied significantly between affected relatives. Several studies have noted variation in clinical presentation within families with activating glucokinase variants ( 5 , 19 ). Although speculative, one possible explanation for this phenomenon is individual differences in the way liver-specific glucokinase regulatory protein (GKRP), the regulator of GCK activity in the liver, mediates GCK inhibition in individuals.…”

Hyperinsulinemic Hypoglycemia in Childhood

“…However, since the severity of the disease may be different in affected individuals, the picture may be quieter in previous individuals. Affected individuals may even become ill without being aware of it [27]. Although most GCK mutations lead to HH that responds to diazoxide therapy, some patients may need octreotide administration or pancreatectomy [26].…”