No abstract

Increasing recognition of malformations of cortical development and continuing improvements in imaging techniques, molecular biologic techniques, and knowledge of mechanisms of brain development have resulted in continual improvement of the understanding of these disorders. The authors propose a revised classification based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories are based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In those cases in which the precise developmental and genetic features are uncertain, classification is based on known relationships among the genetics, pathologic features, and neuroimaging features. The major change since the prior classification has been a shift to using genotype, rather than phenotype, as the basis for classifying disorders wherever the genotype-phenotype relationship is adequately understood. Other substantial changes include more detailed classification of congenital microcephalies, particularly those in which the genes have been mapped or identified, and revised classification of congenital muscular dystrophies and polymicrogyrias. Information on genetic testing is also included. This classification allows a better conceptual understanding of the disorders, and the use of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple disease-causing missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C. We find a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus implicated in unexplained MCD. The mutations in KIF5C, KIF2A and DYNC1H1 drastically affect ATP hydrolysis, productive protein folding or microtubule binding, while suppression of Tubg1 expression in vivo interferes with proper neuronal migration and expression of Tubg1 mutations in S. cerevisiae results in disruption of normal microtubule behaviour. Our data reinforce the importance of centrosome- and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and post-mitotic processes are major contributors to the pathogenesis of MCD.