Complication begets clarification in classification

As recently as 12 years ago, breakthroughs aided by laboratory neuroscience and modern neuroimaging had made differentiation and classification of malformations of cortical development seem straightforward (Barkovich et al. , 2001). Some resulted from abnormal neuronal proliferation (microcephalies, megalencephalies), others from abnormal neuronal migration (heterotopia and lissencephaly), and still others from abnormal cortical organization (mostly polymicrogyrias). The protein products of the few genes known to be associated with these disorders ( LIS1 and DCX with lissencephaly; FLNA with heterotopia) support these mechanistic concepts, as the lissencephaly genes are important in the migration of neurons (specifically in the extension of leading processes and nucleokinesis, the process by which the nucleus is able to follow the leading process); and the assumption that mutations of FLNA (which produces an actin cross-linking phosphoprotein important for cell locomotion) in neurons impair their migration is logical. Although details needed clarification, everything seemed to make sense.The discovery that tubulin mutations cause brain malformations was easily incorporated into existing malformation classifications. That some infants with lissencephaly had mutations of TUBA1A (Poirier et al. , 2007) did not dislodge existing concepts, as both LIS1 and DCX were known to be microtubule-associated proteins (MAPs), which complex with microtubules and/or microtubule motor proteins during cell migration. Reports that mutations of TUBB2B are associated with polymicrogyria (Jaglin et al. , 2009) posed more difficulties, but caused no great surprise, as polymicrogyria is hard to explain. This malformation of cortical development is associated with many different conditions, including prenatal injury (infection or ischaemia) and many mutations. The causative mechanisms are unknown, and the appearance on imaging varies greatly. Still, it was easy to accept that disruption of the complex (and poorly understood) processes of terminal neuronal migration and cortical organization could result from TUBB2B mutations. Similarly, the report that TUBB3 mutations are associated …