Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBAIA

Lissencephalies are congenital malformations responsible for epilepsy and mental retardation in children. A number of distinct lissencephaly syndromes have been characterized, according to the aspect and the topography of the cortical malformation, the involvement of other cerebral structures and the identified genetic defect. A mutation in TUBA1A, coding for alpha 1 tubulin, was recently identified in a mutant mouse associated with a behavioural disorder and a disturbance of the laminar cytoarchitectony of the isocortex and the hippocampus. Mutations of TUBA1A were subsequently found in children with mental retardation and brain malformations showing a wide spectrum of severities. Here we describe four fetuses with TUBA1A mutations and a prenatal diagnosis of major cerebral dysgeneses leading to a termination of pregnancy due to the severity of the prognosis. The study of these fetuses at 23, 25, 26 and 35 gestational weeks shows that mutations of TUBA1A are associated with a neuropathological phenotypic spectrum which consistently encompasses five brain structures, including the neocortex, hippocampus, corpus callosum, cerebellum and brainstem. Less constantly, abnormalities were also identified in basal ganglia, olfactory bulbs and germinal zones. At the microscopical level, migration abnormalities are suggested by abnormal cortical and hippocampal lamination, and heterotopic neurons in the cortex, cerebellum and brainstem. There are also numerous neuronal differentiation defects, such as the presence of immature, randomly oriented neurons and abnormal axon tracts and fascicles. Thus, the TUBA1A phenotype is distinct from LIS1, DCX, RELN and ARX lissencephalies. Compared with the phenotypes of children mutated for TUBA1A, these prenatally diagnosed fetal cases occur at the severe end of the TUBA1A lissencephaly spectrum. This study emphasizes the importance of neuropathological examinations in cases of lissencephaly for improving our knowledge of the distinct pathogenetic and pathophysiological mechanisms.