Integrative classification of morphology and molecular genetics in central nervous system malformations.

We propose a scheme to classify central nervous system (CNS) malformations that integrates morphology and genetics by using patterns of genetic expression as its basis. The precise genetic mutations are not necessary to know in all cases. The premises of this classification are (1) genetic expression in the neural tube follows gradients in the axes that are established at the time of gastrulation: vertical (dorsoventral and ventrodorsal); rostrocaudal; mediolateral. (2) Overexpression in one of these gradients generally results in duplication or hyperplasia of structures, or ectopic segmental (i.e., neuromeric) expression. (3) Underexpression in a gradient generally results in hypoplasia, noncleavage in the midline of paired structures or segmental deletion of neuromeres. These gradients may also affect the formation and migration of neural crest tissue, affecting non-neural structures such as the face in the case of the mesencephalic neural crest, or induction of paraxial mesodermal in the posterior fossa. Additional criteria of the new classification allow for other genetic influences on developmental processes, such as cellular lineage, exemplified by tuberous sclerosis, and hemimegalencephaly. It is essential that the CNS be considered as a whole and classification not be regionalized, as to the cerebral cortex, because the limit of the rostrocaudal gradient may account for variability in clinical manifestations. Copyright 2004 Wiley-Liss, Inc.