Abstract

AKT2 is a serine/threonine kinase that plays a key role in regulating insulin signalling. The gain-of-function alteration in the AKT2 gene (c.49G>A, p.Glu17Lys) has been described in 9 patients with clinical findings consisting in severe persistent hypoketotic, hypofattyacidaemic, hypoinsulinaemic fasting hypoglycaemia, hemihypertrophy and obesity.

A new patient with the same activating AKT2 alteration leading to autonomous activation of the insulin signalling pathway and dysmorphic features is reported. Moreover, to our knowledge, this is the first report using continuous glucose monitoring (CGM) for diagnoses and follow-up in this condition. 12-year-old boy who started follow-up by neuropaediatric clinic for long-term history of seizures started at 8 months old, having been diagnosed with epilepsy in his country of origin. Physical examination revealed proptosis and abnormal fat distribution with lipomastia. Intellectual disability was confirmed. Due to the phenotype and the intellectual impairment, a whole-exome sequencing was done identifying a heterozygous missense variant in AKT2 NM 001626:c.49G>A:p.(Glu17Lys). With this finding, CGM was started revealing severe hypoglycaemia below 40 mg/dl (2.2 mmol/L) with dawn predominance, coinciding with nocturnal focal seizures. To achieve euglycaemia, a high carbohydrate intake (milk with cereals and cocoa powder) with short fasting periods (maximum 3-4 hours) was indicated, with an improvement of hypoglycaemia episodes and resolution of symptomatic seizures. This report reinforces the phenotypic variability of gain-of-function change in AKT2, as our patient exhibits symmetric overgrowth. The reported patient was diagnosed later than those previously reported, already displaying abnormal fat distribution suggesting a dependence on genetic alteration rather than caloric excess. Responding favourably to reduced fasting time, our patient's management has been aided by continuous glucose monitoring (CGM), proving useful for both diagnosis and follow-up.