Introduction
Insulin’s crucial role in energy metabolism is coordinated by a post-receptor signaling cascade resulting in activation of Akt2, a serine-threonine kinase. Expressed predominantly in insulin-sensitive tissue, Akt2 promotes glucose uptake by regulating translocation of the glucose transporter-4 (GLUT4) from cytoplasm to the cell membrane.1 Further, Akt2 mediates insulin’s metabolic effects by suppressing gluconeogenesis1 and lipolysis2, and stimulating lipogenesis.3
A growing body of evidence supports the clinical relevance of AKT2. Although rare, gain-of-function mutations in AKT2 have been described in eight individuals with hypoketotic hypoglycemia.4-8 Despite undetectable insulin levels, their biochemical profiles closely resemble hyperinsulinemic hypoglycemia due to constitutive activation of the insulin signaling cascade. Additional reported features include accelerated linear growth, hemihypertrophy, and polyhydramnios.4,6 Other features have been variably reported including characteristic facies, acanthosis nigricans, developmental delay and intellectual disability.5,6
Given the detrimental neurodevelopmental impact of hypoglycemia in infancy and childhood, achieving euglycemia is critical. Management consists of frequent carbohydrate-rich feedings, often including uncooked cornstarch.5 However, with this approach, euglycemia is achieved at the expense of excess weight gain and impaired quality of life.7 Due to the anticipated lifelong duration of treatment, alternate therapeutic approaches are needed. An encouraging option is modified waxy maize heat modified starch (WMHMS) which demonstrates improved tolerability and longer duration of action than uncooked cornstarch.9
We report a patient with an activating AKT2 mutation managed with WMHMS, providing additional insight into the phenotypic spectrum.