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

Chloe Stutterd; George McGillivray; Zornitza Stark; Betty Messazos; Fergus Cameron; Sue White; Melbourne Genomics Health Alliance; Ghayda Mirzaa; Richard Leventer

doi:10.1016/j.ejmg.2018.06.002

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

Eur J Med Genet. 2018 Dec;61(12):738-740. doi: 10.1016/j.ejmg.2018.06.002. Epub 2018 Jun 5.

Authors

Chloe Stutterd¹, George McGillivray², Zornitza Stark³, Betty Messazos⁴, Fergus Cameron⁴, Sue White⁵; Melbourne Genomics Health Alliance; Ghayda Mirzaa⁶, Richard Leventer⁷

Affiliations

¹ Department of Neurology, Royal Children's Hospital, Melbourne, Australia; Victorian Clinical Genetics Service, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address: chloe.stutterd@mcri.edu.au.
² Victorian Clinical Genetics Service, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Royal Women's Hospital, Melbourne, Australia.
³ Victorian Clinical Genetics Service, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia.
⁴ Murdoch Children's Research Institute, Melbourne, Australia; Department of Endocrinology, Royal Children's Hospital, Melbourne, Australia.
⁵ Victorian Clinical Genetics Service, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.
⁶ Department of Pediatrics, University of Washington, Seattle, WA, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
⁷ Department of Neurology, Royal Children's Hospital, Melbourne, Australia; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.

PMID: 29883676
DOI: 10.1016/j.ejmg.2018.06.002

Abstract

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. Recognizing the association of hypoglycemia with PI3K-AKT-mTOR pathway variants can provide a clue to the genetic basis of the cortical malformation. Patients with megalencephaly and a cortical malformation may be considered at risk of hypoglycaemia and monitored accordingly, at least until a PI3K-AKT-mTOR pathway variant has been excluded.

Keywords: Hypoglycemia; Megalencephaly; Phosphatidylinositol 3-Kinases; Polymicrogyria.

Publication types

Case Reports

MeSH terms

Abnormalities, Multiple / genetics
Abnormalities, Multiple / pathology
Animals
Class I Phosphatidylinositol 3-Kinases / genetics
Humans
Hypoglycemia / genetics*
Hypoglycemia / pathology
Infant
Male
Megalencephaly / genetics*
Megalencephaly / pathology
Mice
Mutation
Polymicrogyria / genetics*
Polymicrogyria / pathology
Proto-Oncogene Proteins c-akt / genetics
Signal Transduction
TOR Serine-Threonine Kinases / genetics*

Substances

MTOR protein, human
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases