[A proposal for a molecular genetic classification of the malformations of the nervous system]

This proposal is a first attempt to incorporate the recent molecular genetic data that explains programming of development etiologically.

Traditional schemes of classifying nervous system malformations are based upon descriptive morphogenesis of anatomical processes of ontogeny, such as neurulation, neuroblast migration and axonal pathfinding; such anatomical schemes do not allow for the incorporation of multiple genetic etiologies that lead to the same anatomical result, such as holoprosencephaly or lissencephaly. A scheme based purely on genetic mutations also is impractical because several genes might be involved sequentially in a cascade, the same genes serve different functions at different stages and are involved in multiple organ systems. Some complex malformations result from several unrelated defective genes, again citing the example of holoprosencephaly. Finally, a pure genetic classification would be too inflexible to incorporate anatomical criteria and also acquired lesions of the fetal brain that lead to secondary focal dysgeneses. The basis for the proposed scheme is, therefore, disturbances in patterns of genetic expression: polarity gradients of the axes of the neural tube (e.g. upregulation or downregulation of genetic influences); segmentation (e.g. deletions of specific neuromeres; ectopic expression); mutations that cause change in cell lineage (e.g. dysplastic gangliocytoma of cerebellum; myofiber differentiation within brain); and specific genes or molecules that mediate neuroblast migration in its early (e.g. filamin 1), middle (e.g. LIS1; doublecortin) or late course (e.g. reelin; L1 CAM).

The classification schemes that served so well throughout the 20th century no longer are adequate for the 21st century. The proposed scheme undoubtedly will undergo many future revisions, but it provides a starting point using currently available data.