Brain Advance Access originally published online on July 18, 2008
Brain 2008 131(9):2304-2320; doi:10.1093/brain/awn155
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Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBA1A
1Department of Pathology and Neuropathology, Sainte-Anne Hospital, 75014 Paris, 2Department of Pathology, General Hospital of Poissy, 78300 Poissy, 3Cochin Institute, Paris-Descartes University, CNRS (UMR 8104), 4INSERM (U567), 75014 Paris, 5Department of Pathology, University Hospital of Rennes, 35000 Rennes, 6Department of Pathology, University Hospital of Caen-Cote-de-Nacre, 14300 Caen, 7Department of Genetics, University Hospital of Rennes, 35300 Rennes and 8Department of Molecular Genetics, Cochin-Port-Royal University Hospital, 75014 Paris, France
Correspondence to: Catherine Fallet-Bianco, Service d’ Anatomie Pathologique, Hôpital Sainte Anne, 1, rue Cabanis, 75014 Paris, France E-mail: c.fallet{at}ch-sainte-anne.fr
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.
Key Words: TUBA1A; lissencephaly; abnormal corpus callosum; abnormal hippocampus; brainstem and cerebellum hypoplasia
Abbreviations: GFAP, glial fibrillary acidic protein; PBA, protein blocking agent
Received January 5, 2008. Revised June 16, 2008. Accepted June 23, 2008.