Activating AKT2 mutation: hypoinsulinemic hypoketotic hypoglycemia

Area of Science:

• Endocrinology
• Molecular Genetics
• Biochemistry

Background:

• Hyperinsulinemic hypoglycemia (HH) is a severe condition of unregulated insulin secretion causing persistent hypoglycemia.
• HH is biochemically characterized by hypoketotic hypo-fatty-acidemic hypoglycemia with elevated insulin, though insulin may be undetectable.
• Autonomous activation of the insulin signaling pathway can mimic HH biochemically without detectable insulin or C-peptide.

Observation:

• The proband presented with hemihypertrophy and symptomatic hypoglycemia.
• Investigations revealed evidence of insulin action despite undetectable serum insulin on multiple occasions.
• Genetic testing excluded common causes of HH, but AKT2 sequencing identified a de novo mosaic mutation.

Findings:

• A de novo mosaic activating mutation in AKT2 (c.49G→A, p.E17K) was identified in the proband.
• This mutation is consistent with the observed clinical and biochemical phenotype of HH.
• This represents the second reported case of an activating AKT2 mutation causing hypoinsulinemic hypoketotic hypoglycemia.

Implications:

• This case highlights the importance of considering the insulin signaling pathway in HH diagnosis.
• In patients with HH and undetectable insulin, autonomous pathway activation is a potential diagnosis.
• Further research into AKT2 mutations can improve understanding and diagnosis of rare hypoglycemia causes.