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

Publication date: Available online 5 December 2014 Source:Molecular Genetics and Metabolism Author(s): Mark Nellist , Rachel Schot , Marianne Hoogeveen-Westerveld , Rinze F. Neuteboom , Elles J.T.M. van der Louw , Maarten H. Lequin , Karen Bindels-de Heus , Barbara J. Sibbles , René de Coo , Alice Brooks , Grazia M.S. Mancini 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 43cm (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 6months of age the patient developed infantile spasms that were resistant to antiepileptic polytherapy. Recurrent hypoglycemia was noted during treatment with adrenocorticotropic hormone but stabilised 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 h...

Source: Molecular Genetics and Metabolism - December 6, 2014 Category: Genetics & Stem Cells Source Type: research