By Lucy Piper, Senior medwireNews Reporter
Researchers have identified the genetic basis for bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria.
They found a mosaic mutation (Gly373Arg) in phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2) – part of the PI3K-AKT-mTOR pathway – in two of eight children with BPP by exome sequencing blood and saliva samples.
The team then confirmed the same mutation’s presence in a further 18 children with BPP out of 118 with polymicrogyria, using targeted sequencing of the entire gene by single molecular inversion probes or amplicon sequencing of the recurrent mutation.
Seven of the 20 children with the gene mutation had isolated BPP and 13 had additional features such as megalencephaly and ventriculomegaly indicative of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.
Mutations of this gene are therefore associated with a range of cortical development malformations, write lead researcher Ghayda Mirzaa (University of Washington, Seattle, USA) and colleagues in The Lancet Neurology.
All the patients with PIK3R2 mutations had BPP, with or without megalencephaly, the team notes, and the most distinctive phenotypical characteristics of this group were polymicrogyria, megalencephaly, ventriculomegaly, epilepsy and oromotor weakness.
The mutations found were a mix of constitutional and mosaic. Constitutional malformations were found in 12 patients – arising de novo in 10 cases and inherited from an affected parent in two cases. Mosaic mutations were identified in eight patients, which the researchers say is a higher proportion than that reported for most malformations of cortical development.
Among the patients with mosaic mutations, mutant allele levels varied substantially, ranging from 5% to 73% of cells analysed, and may partly explain the variable severity of the condition.
The author of a related comment, Ingrid Scheffer (University of Melbourne, Victoria, Australia), believes that “[t]he next crucial step will be to interrogate the actual polymicrogyric tissue to look at the percentage mosaicism in the affected region where it may be higher than the low levels seen in the periphery.”
She concludes: “The implication of PIK3R2 in polymicrogyria emphasises the burgeoning importance of the mTOR pathway in malformations of cortical development with the promise that therapeutic convergence, targeting a pathway rather than a protein, might enable a precision medicine approach to be more widely and readily applicable in future.”
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