Etiological classification of CNS malformations: integration of molecular genetic and morphological criteria

Classification is a creative activity that helps us understand relationships. The traditional classifications of central nervous system malformations was based exclusively upon descriptive morphology, but these criteria must now be integrated with molecular genetic data to enable an etiological classification that also remains useful to the clinician, radiologist and pathologist, who rely upon imaging and tissue examination for diagnosis. Many cerebral malformations previously thought to be a single disorder are now known to be common end-results of several independent genetic mutations. Examples are holoprosencephaly and lissencephaly. Gradients of genetic expression along the axes of the neural tube, established at the time of gastrulation, may explain many varieties or anatomical and clinical manifestations of cerebral malformations, including the involvement of non-neural tissues such as in midfacial hypoplasia, that may be attributed to abnormal neural crest migration. Genes of cellular lineage and of symmetry may explain some hamartomatous malformations, such as tuberous sclerosis and hemimegalencephaly. Modern classification should be applicable to the entire CNS as well as regions; schemes that attempt to artificially isolate the cerebral cortex for a "regional classification" may be erroneous even though the genetic defect primarily affects cortical structures because genetic gradients in the neuraxis are excluded and some involve a more subtle but still important expression in subcortical structures.