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.

Recent surveys of wind energy areas offshore of Massachusetts and Rhode Island (USA) have demonstrated that they encompass habitat used by the Endangered North Atlantic right whale Eubalaena glacialis. Prior to 2011, little systematic survey effort had been conducted in the area. The Bureau of Ocean Energy Management and the state of Massachusetts supported 3.5 yr of twice-monthly aerial surveys by the Northeast Large Pelagic Survey Collaborative (NLPSC). Additional survey teams including the Northeast Fisheries Science Center and the Center for Coastal Studies have collected sightings data in the region. Data systematically collected by the NLPSC allowed analyses of monthly sightings rates, sightings per unit effort, and hot spots which provided information on current temporal and spatial use patterns. Abundance estimates for each season-year (i.e. a 3 mo period within a given survey year) were calculated. Behaviors observed included feeding and surface active groups. Photo-identification of whales since 2010 yielded a minimum count of 196 unique individuals (annual average = 35), or over one-third of the current population estimate. Analyses of demographics of these individuals revealed that 34 known calving females (30% of the total currently presumed alive) visited the study area. These results demonstrate consistent annual use of this area by a significant portion of the E. glacialis population, with a strong correlation between season and presence. These findings can inform management activities and development planning, and be used as a baseline dataset for assessing long-term impacts to the species.