Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase

Abstract

ObjectiveGenetic activation of the insulin signal-transducing kinase AKT2 causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction.MethodsThree patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no AKT2 mutation underwent further genetic, clinical and metabolic investigation. Signalling in dermal fibroblasts from one patient and efficacy of the mTOR inhibitor Sirolimus on pathway activation were examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was assessed.ResultsIn the first three patients, mosaic mutations in PIK3CA (p.Gly118Asp or p.Glu726Lys) or PIK3R2 (p.Gly373Arg) were found. In different tissue samples available from one patient, the PIK3CA p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in PIK3CA had neither clinical nor biochemical evidence of hypoglycaemia.ConclusionsMosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy.

The Effectiveness of Sirolimus Treatment in Two Rare Disorders with Nonketotic Hypoinsulinemic Hypoglycemia: The Role of mTOR Pathway

“…In human, mosaic activating mutations in PI3K are known to cause segmental overgrowth. In a study which evaluated the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, three patients were found to have early onset, severe, nonketotic hypoglycemia (11). With all of these findings, we concluded that dsyregulation of insuling signalling pathway affecting AKT2, PTEN, or PI3K could cause NkHH with syndromic features.…”

“…In recent times, NkHH cases which resulted from activation of insulin signaling pathway have started to be published. AKT2 mutation has been shown to be leading to this specific condition (1,8,11).…”

Hypoglycaemia represents a clinically significant manifestation of PIK3CA‐ and CCND2‐associated segmental overgrowth

“…Leiter et al recently described 3 patients with mosaic variants in PIK3CA or PIK3R2 who presented with severe non‐KH. The patients described in their cohort had a consistent endocrine phenotype which was hypothesised to be driven by an insulin‐independent activation of the PI3K‐AKT cascade.…”

“…Ubiquitous expression of the PIK3CA H1047R variant in mouse models causes profound hypoinsulinemic hypoglycaemia, only partially rescued by AKT2 knockout, suggesting that PIK3CA controls glucose homeostasis via several downstream mechanisms. 13 Leiter et al 14…”

CLAPO syndrome: identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype

“…14,17,18,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] P1 (CM: skin biopsy in right hemithorax) PIK3CA:NM_006218 2…”