Malformations of the human cerebral cortex represent clinically important birth defects, resulting in mental retardation, epilepsy, and cerebral palsy. Cortical malformations can range anywhere from grossly visible derangements of the cerebral hemispheres, to subtle, focal defects of cortical architecture. Consequently, the wide range of phenotypes includes profoundly crippled children as well as adults with normal intelligence who present with mild epilepsy or no symptoms at all. It is increasingly clear that many malformations of the human cortex result from the action of defective genes. We propose to map and clone genes for several autosomal recessive disorders of human cerebral cortical development that are associated with abnormal neuronal migration. Although recessively inherited human cortical malformations are clinically and genetically heterogenous, our preliminary data suggest that they can be subdivided into less heterogenous categories by careful pedigree ascertainment. Through collaborations with clinicians, pedigrees with recessive cortical malformations will be ascertained and studied by performing medical review and MRI brain imaging. Attention will particularly focus on pedigrees that show consanguinity for mapping rare recessive disease genes. For well-characterized pedigrees that show evidence for simply inherited, highly penetrant recessive traits, DNA samples will be collected and subjected to genome wide screens to find areas of genetic linkage. Linkage will be tested with standard statistical methods, and multiple distinct pedigrees with the same disorder from genetically isolated populations will be analyzed because of the likelihood of founder mutations that allow genetic fine mapping and eventual gene identification. Identifying the genes that cause recessive neuronal migration disorders of the cerebral cortex would be important for understanding normal human brain development and evolution, as well as epilepsy pathogenesis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Walsh, Christopher A (2018) Rainer W. Guillery and the genetic analysis of brain development. Eur J Neurosci :
Smith, Richard S; Kenny, Connor J; Ganesh, Vijay et al. (2018) Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development. Neuron 99:905-913.e7
Jamuar, Saumya S; Lam, Anh-Thu N; Kircher, Martin et al. (2014) Somatic mutations in cerebral cortical malformations. N Engl J Med 371:733-43
Jamuar, Saumya S; Walsh, Christopher A (2014) Somatic mutations in cerebral cortical malformations. N Engl J Med 371:2038
Dies, Kira A; Bodell, Adria; Hisama, Fuki M et al. (2013) Schizencephaly: association with young maternal age, alcohol use, and lack of prenatal care. J Child Neurol 28:198-203
Barkovich, James (2013) Complication begets clarification in classification. Brain 136:368-73
Poduri, Annapurna; Heinzen, Erin L; Chitsazzadeh, Vida et al. (2013) SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol 74:873-82
Poduri, Annapurna; Evrony, Gilad D; Cai, Xuyu et al. (2013) Somatic mutation, genomic variation, and neurological disease. Science 341:1237758
Lehtinen, Maria K; Zappaterra, Mauro W; Chen, Xi et al. (2011) The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69:893-905
Chang, Edward F; Wang, Doris D; Barkovich, A James et al. (2011) Predictors of seizure freedom after surgery for malformations of cortical development. Ann Neurol 70:151-62

Showing the most recent 10 out of 52 publications