Discussion
In this case report, we describe a young female with hypoketotic hypoglycemia and dysmorphic features secondary to an activatingAKT2 mutation.
AKT2 is a serine/threonine kinase in the insulin signalling pathway. Insulin activates a transmembrane tyrosine kinase receptor, which phosphorylates insulin receptor substrate (IRS) proteins, leading to activation of phosphadtidylinositol-3-kinase (PI3K).11PI3K in turn generates phosphatidylinositol (3,4,5)-trisphosphate which activates AKT.12 Several AKT isoforms exist, of which AKT2 has been shown to mediate the metabolic actions of insulin.1 The AKT2 c.49G>A variant has been reported as de novo in patients with a similar clinical picture as our patient (Table 2). This gain of function AKT2variant leads to independent, constitutive activation of the insulin pathway in target tissues including liver, adipose, and skeletal muscle.7 Consequently, the biochemical profile resembles hyperinsulinism with suppressed free fatty acids and ketones.13 However, insulin levels are undetectable due to negative feedback from the constitutively active signaling cascade.14
Table 2: Summary of the clinical features of individuals with c.49G>A AKT2 mutations