Molecular characterization of hemimegalencephaly Abstract Somatic mutations, in which a fraction of the cells in the body have a deleterious mutation, is well recognized in cancer but only recently appreciated in neurological disease. In the setting of a somatic mutation in a population of progenitor cells, all daughter cells inherit te mutation and are able to express the resultant phenotype as a function of the differentiation program. We recently identified the first de novo somatic mutations in the developing brain in the condition "hemimegalencephaly", (HME) a catastrophic focal epilepsy condition associated with a malformation of cerebral cortical development (MCD). HME is one of the most severe MCD syndromes, characterized by massive hamartomatous overgrowth of either of the two cerebral hemispheres. Cerebral hemispherectomy is a frequent treatment for the refractory epilepsy, allowing sampling of diseased tissue. By comparing DNA from diseased brain with DNA from blood/saliva, we identified de novo somatic mutations in PIK3CA, AKT3 or MTOR, part of the mTOR pathway. Mutations were present in 8-40% of sequenced alleles in various brain regions sampled during surgery, and some in codons known to activate the protein. However, the pilot study was based on a limited sample size. The goal of this application is to expand upon our initial findings, and elucidate the genetic, developmental, signaling and cell biological mechanisms of HME, particularly in the context of mammalian cortex development. We will combine next-generation sequencing of diseased brain from HME patients with advanced bioinformatics, complete clinical correlated neuroanatomy, and mouse modeling to help advance our understanding of the mechanism of this important disease. We will: 1] Test for de novo somatic mutations in a larger retrospectively and prospectively collected cohort of HME patients. 2] Correlate genetic disease burden with clinical, imaging, and histopathological findings (phenotype). 3] Test how these de novo mutations alter progenitor cell functions in the developing cerebral cortex. The goal of the experiments is to determine how mutations in these genes lead to disrupted cortical development, why these lesions are epileptogenic, and whether repurposing approved medications might benefit patients, with relevance to other focal dysplasias and focal epilepsies.

Public Health Relevance

Hemimegalencephaly is a devastating childhood neurodevelopmental disorder in which one hemisphere is massively overgrown, leading to intractable epilepsy and intellectual disability, with the only known treatment hemispherectomy to remove the affected half of the brain. Our recent work identified somatic mutations in the mTOR pathway in a significant number of patients with HME. We will expand our mutation analysis, and study the developmental and signaling mechanism to understand the basis of this condition, with the goal of improved therapy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Riddle, Robert D
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Rockefeller University
Other Domestic Higher Education
New York
United States
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Marin-Valencia, Isaac; Guerrini, Renzo; Gleeson, Joseph G (2014) Pathogenetic mechanisms of focal cortical dysplasia. Epilepsia 55:970-8