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