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Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia.
- Source :
-
Molecular genetics and metabolism [Mol Genet Metab] 2015 Mar; Vol. 114 (3), pp. 467-73. Date of Electronic Publication: 2014 Dec 05. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Abnormalities, Multiple etiology
Abnormalities, Multiple genetics
Adrenocorticotropic Hormone therapeutic use
Capillaries abnormalities
Diet, Ketogenic
Epilepsy etiology
Humans
Hypoglycemia etiology
Hypoglycemia metabolism
Infant
Megalencephaly etiology
Muscle Hypotonia genetics
Mutation
Polymicrogyria etiology
Proto-Oncogene Proteins c-akt metabolism
Radiography
Skull diagnostic imaging
Spasms, Infantile therapy
Vascular Malformations etiology
Vascular Malformations genetics
Epilepsy genetics
Germ-Line Mutation
Hypoglycemia genetics
Megalencephaly genetics
Polymicrogyria genetics
Proto-Oncogene Proteins c-akt genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1096-7206
- Volume :
- 114
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular genetics and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 25523067
- Full Text :
- https://doi.org/10.1016/j.ymgme.2014.11.018