title: Activating AKT2 mutation: hypoinsulinemic hypoketotic hypoglycemia.
abstract: BACKGROUND
  Hyperinsulinemic hypoglycemia (HH), characterized by unregulated insulin secretion, is an important cause of persistent and severe hypoglycemia. The biochemical picture of HH is hypoketotic hypo-fatty-acidemic hypoglycemia along with elevated serum insulin. Not infrequently, serum insulin might be undetectable in HH despite the presence of evidence of insulin action (suppressed ketogenesis and lipolysis). However, autonomous activity of the downstream insulin signaling pathway without the presence of the ligand (insulin) will give rise to the same clinical and biochemical picture, apart from undetectable serum insulin/C-peptide. AKT2, a serine/threonine protein kinase, is involved downstream to the insulin receptor in mediating the physiological effects of insulin.
  
  
  OBJECTIVE
  We describe the second report of an activating AKT2 mutation leading to hypoinsulinemic hypoketotic hypoglycemia.
  
  
  METHODS
  The proband presented with hemihypertrophy and symptomatic hypoglycemia. Investigations confirmed evidence of insulin action, despite absence of detectable serum insulin on multiple occasions. Molecular genetic testing for common causes of HH (ABCC8, KCNJ11, and GLUD1) was negative. Sequencing of AKT2 identified a de novo mosaic c.49G→A (p.E17K) mutation, consistent with the clinical and biochemical phenotype.
  
  
  CONCLUSIONS
  This is the second report of an activating AKT2 mutation leading to hypoinsulinemic hypoketotic hypo-fatty-acidemic hypoglycemia. In patients presenting a clinical and biochemical picture of HH with undetectable serum insulin, consideration of autonomous activation of the downstream insulin signaling pathway should be made.
authors.affiliation: London Centre for Paediatric Endocrinology (V.B.A., K.H.), Great Ormond Street Hospital for Children National Health Service Foundation Trust, London WC1N 3JH, United Kingdom; The Institute of Child Health (V.B.A., K.H.), University College London, London WC1N 1EH, United Kingdom; Institute of Biomedical and Clinical Science (S.E.F., S.E.), University of Exeter Medical School, Exeter EX2 5DW, United Kingdom; and Department of Pediatrics (E.S., B.R.-M.), Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Ved Bhushan
authors.initials: VB
authors.lastname: Arya
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: Edith
authors.initials: E
authors.lastname: Schober
authors.forename: Birgit
authors.initials: B
authors.lastname: Rami-Merhar
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D001786:Blood Glucose / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000235:genetics*; D007223:Infant; D007328:Insulin / Q000097:blood*; D009154:Mutation; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt