title: Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia.
abstract: Activating germ-line and somatic mutations in AKT3 (OMIM 611223) are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH; OMIM # 615937) and megalencephaly-capillary malformation (MCAP; OMIM # 602501). Here we report an individual with megalencephaly, polymicrogyria, refractory epilepsy, hypoglycemia and a germline AKT3 mutation. At birth, head circumference was 43 cm (5 standard deviations above the mean). No organomegaly was present, but there was generalized hypotonia, joint and skin laxity, developmental delay and failure to thrive. At 6 months of age the patient developed infantile spasms that were resistant to antiepileptic polytherapy. Recurrent hypoglycemia was noted during treatment with adrenocorticotropic hormone but stabilized upon introduction of continuous, enriched feeding. The infantile spasms responded to the introduction of a ketogenic diet, but the hypoglycemia recurred until the diet was adjusted for increased resting energy expenditure. A novel, de novo AKT3 missense variant (exon 5; c.548T>A, p.(V183D)) was identified and shown to activate AKT3 by in vitro functional testing. We hypothesize that the sustained hypoglycemia in this patient is caused by increased glucose utilization due to activation of AKT3 signaling. This might explain the efficacy of the ketogenic diet in this individual.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schot
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.affiliation: Department of Child Neurology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Rinze F
authors.initials: RF
authors.lastname: Neuteboom
authors.affiliation: Department of Dietetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Elles J T M
authors.initials: EJ
authors.lastname: van der Louw
authors.affiliation: Department of Radiology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Lequin
authors.affiliation: Department of Pediatrics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: Bindels-de Heus
authors.affiliation: Department of Pediatrics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sibbles
authors.affiliation: Department of Child Neurology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: de Coo
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Alice
authors.initials: A
authors.lastname: Brooks
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands. Electronic address: g.mancini@erasmusmc.nl.
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
mesh_terms: D000015:Abnormalities, Multiple / Q000209:etiology / Q000235:genetics; D000324:Adrenocorticotropic Hormone / Q000627:therapeutic use; D002196:Capillaries / Q000002:abnormalities; D055423:Diet, Ketogenic; D004827:Epilepsy / Q000209:etiology / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D058627:Megalencephaly / Q000209:etiology / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D065706:Polymicrogyria / Q000209:etiology / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D012886:Skull / Q000000981:diagnostic imaging; D013036:Spasms, Infantile / Q000628:therapy; D054079:Vascular Malformations / Q000209:etiology / Q000235:genetics
chemical_list: D000324:Adrenocorticotropic Hormone; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT3; Hypoglycemia; Ketogenic diet; MPPH/MCAP