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

Eur J Endocrinol 2017 Aug 31;177(2):175-186. Epub 2017 May 31.

Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Objective: Genetic activation of the insulin signal-transducing kinase 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.

Methods: Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no 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.

Results: In the first three patients, mosaic mutations in (p.Gly118Asp or p.Glu726Lys) or (p.Gly373Arg) were found. In different tissue samples available from one patient, the 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 had neither clinical nor biochemical evidence of hypoglycaemia.

Conclusions: Mosaic 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.

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-17-0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488397PMC
August 2017

Similar Publications

Polymicrogyria in association with hypoglycemia points to mutation in the mTOR pathway.

Eur J Med Genet 2018 Dec 5;61(12):738-740. Epub 2018 Jun 5.

Department of Neurology, Royal Children's Hospital, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.

We report a 16-month-old male with congenital megalencephaly, polymicrogyria and persistent hypoglycemia caused by a mosaic PIK3CA pathogenic variant. Hypoinsulinaemic, hypoketotic hypoglycaemia is a rare complication of pathogenic variants in the PI3K-AKT-mTOR pathway genes including AKT2, AKT3, CCND2, PIK3R2 and PIK3CA, and has been identified in a PIK3CA mutant mouse model. Our case highlights the importance of considering PI3K-AKT-mTOR pathway variants as a cause for megalencephaly and cortical malformation when the phenotype includes hypoglycaemia. Read More

View Article and Full-Text PDF
December 2018

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

Clin Genet 2018 03 5;93(3):687-692. Epub 2018 Feb 5.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals, NHS Foundation Trust Manchester Academic Health Sciences Centre, Manchester, UK.

The PI3K-AKT signalling cascade has a highly conserved role in a variety of processes including cell growth and glucose homoeostasis. Variants affecting this pathway can lead to one of several segmental overgrowth disorders. These conditions are genetically heterogeneous and require tailored, multidisciplinary involvement throughout life. Read More

View Article and Full-Text PDF
March 2018

The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS).

Oncotarget 2017 Jul;8(28):45470-45483

Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan.

The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is critical for cellular growth and metabolism. Recently, mosaic or segmental overgrowth, a clinical condition caused by heterozygous somatic activating mutations in PIK3CA, was established as PIK3CA-related overgrowth spectrum (PROS). In this study, we report a Japanese female diagnosed with PROS, who presented with hyperplasia of the lower extremities, macrodactyly, multiple lipomatosis, and sparse hair. Read More

View Article and Full-Text PDF
July 2017

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.

Nat Genet 2012 Jun 24;44(8):928-33. Epub 2012 Jun 24.

The National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p. Read More

View Article and Full-Text PDF
June 2012