Activating AKT2 mutation: hypoinsulinemic hypoketotic hypoglycemia.

Background: Hyperinsulinemic hypoglycemia (HH), characterized by unregulated insulin secretion, is an important cause of persistent and severe hypoglycemia. The biochemical picture of HH is hypoketotic hypo-fatty-acidemic hypoglycemia along with elevated serum insulin. Not infrequently, serum insulin might be undetectable in HH despite the presence of evidence of insulin action (suppressed ketogenesis and lipolysis). However, autonomous activity of the downstream insulin signaling pathway without the presence of the ligand (insulin) will give rise to the same clinical and biochemical picture, apart from undetectable serum insulin/C-peptide. AKT2, a serine/threonine protein kinase, is involved downstream to the insulin receptor in mediating the physiological effects of insulin.

Aim: We describe the second report of an activating AKT2 mutation leading to hypoinsulinemic hypoketotic hypoglycemia.

Patients And Methods: The proband presented with hemihypertrophy and symptomatic hypoglycemia. Investigations confirmed evidence of insulin action, despite absence of detectable serum insulin on multiple occasions. Molecular genetic testing for common causes of HH (ABCC8, KCNJ11, and GLUD1) was negative. Sequencing of AKT2 identified a de novo mosaic c.49G→A (p.E17K) mutation, consistent with the clinical and biochemical phenotype.

Conclusions: This is the second report of an activating AKT2 mutation leading to hypoinsulinemic hypoketotic hypo-fatty-acidemic hypoglycemia. In patients presenting a clinical and biochemical picture of HH with undetectable serum insulin, consideration of autonomous activation of the downstream insulin signaling pathway should be made.