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Mol Genet Metab. 2015 Mar;114(3):467-73. doi: 10.1016/j.ymgme.2014.11.018. Epub 2014 Dec 5.

Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia.

Author information

1
Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
2
Department of Child Neurology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
3
Department of Dietetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
4
Department of Radiology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
5
Department of Pediatrics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
6
Department of Clinical Genetics, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands. Electronic address: g.mancini@erasmusmc.nl.

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.

KEYWORDS:

AKT3; Hypoglycemia; Ketogenic diet; MPPH/MCAP

PMID:
25523067
DOI:
10.1016/j.ymgme.2014.11.018
[Indexed for MEDLINE]

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