Brain Malformations

  • Férechté Encha-RazaviEmail author


Brain malformations causing various neurological deficits are being recognized as a significant public health concern and are the subject of growing etio-pathological interest. In isolation or associated with extracerebral anomalies, they belong to the vast spectrum of embryofetal disorders (birth defects), which are nowadays a prevalent cause of neonatal and pediatric mortality and morbidity in developed countries. However, most remain unexplained and treatments or preventive measures are scarce. Usually, brain malformations, resulting from chromosomal/genetic mutations or disruption, are only documented from a clinical and a radiological point of view and named by morphological descriptive terms.

To further refine the characterization of brain malformations, neurohistopathological studies have emerged as a powerful tool. Embryofetal and neuropathological studies performed after fetal death or termination of pregnancy have demonstrated a positive impact of such necropsy-based studies on the identification of the pathogenesis of brain malformations, in addition to illustrating their phenotypic diversity and revealing genetic heterogeneity (i.e., genocopies). Indeed, the new-generation DNA sequencing techniques permit identification of a growing number of genetic variations. Interestingly, functional studies reveal involvement of these genes in distinct biological processes and molecular pathways. Dissection of molecular cascades of signaling pathways using genotype/phenotype correlations demonstrates that mutations in different genes involved in a common signaling pathway may result in overlapping patterns of malformation. Furthermore, signaling pathways may be a possible target of exogenous agents, which will phenocopy genetic causes. Thus, signaling pathways have emerged as key modulators of phenotypic diversity. Integration of these important findings opens a new way in the evaluation of malformations, based on functional disorders, such as ciliopathies, tubulinopathies, dystroglycanopathies, mTOR pathway disorders, etc. This new approach ends the classical dogma of one gene/one disease and improves our understanding of the genetic and phenotypic heterogeneity of birth defects.


Brain Cerebrum Cerebellum Malformation Microcephaly Megalencephaly Holoprosencephaly Microgyria Pachygyria Agyria Lissencephaly Hydrocephaly Agenesis of the corpus callosum Neural tube defect Anencephaly Meningomyelocele Encephalocele 


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Copyright information

© Springer International Publishing 2015

Authors and Affiliations

  1. 1.Department of GeneticsNecker-Enfants MaladesParisFrance

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