Neuropathological phenotype of a new type of lissencephaly associated with mutations of TUBA1A

In 2007, Keays et al identified in an ENU‐induced mutant mouse, a mutation in Tuba1a, a gene coding for alpha 1 tubulin protein, associated with behavioral disorders and a disturbance of the cortical cytoarchitectony. Subsequently, mutations of TUBA1A were found in children with mental retardation and lissencephaly with abnormalities of the corpus callosum and cerebellum, on MRI. Recently, mutations of TUBA1A were found in 4 fetuses, with a prenatal diagnosis of cerebral dysgenesis leading to a medical termination of pregnancy according to French laws. These fetuses, not mutated for LIS1 , DCX and ARX, were studied at 23, 25, 26 and 35 gestational weeks respectively. The neuropathological study demonstrated a phenotype including abnormalities affecting constantly the neocortex, hippocampus, corpus callosum, cerebellum and brainstem, and inconstantly, basal ganglia, olfactory bulbs and subventricular germinal zones. This phenotype was different from that of LIS1 , DCX , ARX lissencephalies, and in agreement with the pattern of expression of TubA1A studied in the mouse embryo. Compared with children mutated for TUBA1A , fetal cases are located at the most severe end of the spectrum, suggesting that prenatally diagnosed cases are probably the most severe forms of TUBA1A lissencephaly.