Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype.

Neuronal migration disorders account for a substantial number of cortical malformations, the most severe forms being represented by lissencephalies. Classical lissencephaly has been shown to result from mutations in LIS1 (PAFAH1B1; MIM#601545), DCX (Doublecortin; MIM#300121), ARX (Aristaless-related homeobox gene; MIM#300382), RELN (Reelin; MIM#600514) and VLDLR (Very low density lipoprotein receptor; MIM#224050). More recently, de novo missense mutations in the alpha-tubulin 1a gene (TUBA1A) located on chromosome 12q13.12, have also been associated with more or less severe defects of cortical development, resulting in complete agyria in the most severe cases of lissencephaly. We report here the cerebral lesions in a 36 weeks' gestation female foetus with a novel de novo missense mutation in the TUBA1A gene, presenting the most severe antenatal phenotype reported so far. Using routine immunohistochemistry and confocal microscopy, we show evidence for defects in axonal transport in addition to defects in neuronal migration and differentiation, giving new insights to the pathophysiology of this form of lissencephaly.