The wide spectrum of alpha and beta-Tubulinopathies in foetus : From microlissencephaly to asymmetrical multifocal polymicrogyria. N. Bahi-Buisson1, K. Poirier2, C. Fallet-Bianco3, Y. Saillour2, S. Valence1, N. Lebrun2, M. Ossando4, F. Razavi4, T. Attie Bittach4, F. Guimot5, S. Blesson6, B. Doray7, B. Lhermitte7, E. Andrini8, P. S. Jouk8, C. Rouleau9, M. C. Addor9, F. Jossic10, P. Marcorelles11, L. Loeuillet12, A. Gelot13, A. Laquerriere14, L. Pinson15, P. Loget16, F. Chapon17, P. Dias18, N. Revencu19, F. J. Fourniol20, C. Beldjord21, J. Chelly2 1) INSERM U781, Institut IHU Imagine, Paris, France; 2) INSERM U1016 Institut Cochin, Paris France; 3) Neuropathologie et Foetopathologie GH Cochin Port Royal; 4) Foetopathologie GH Necker Enfants Malades; 5) Foetopathologie Hopital Robert Debré; 6) Clinical Genetics CHU Tours; 7) Clinical Genetics CHU Strasbourg; 8) Clinical Genetics CHU Grenoble; 9) Clinical Genetics, Lausanne, Switzerland; 10) Clinical Genetics CHU Nantes; 11) Clinical Genetics, CHU Brest; 12) Foetopathologie Hopital Poissy Saint Germain; 13) Foetopathologie Hopital Trousseau; 14) Foetopathologie, CHU Rouen; 15) Clinical Genetics, CHU Montpellier; 16) Clinical Genetics CHU Rennes; 17) CHU Caen; 18) Clinical Genetics, Lisboa, Portugal; 19) Clinical Genetics CHU Louvain, Belgium; 20) Institute of Structural Molecular Biology, Birkbeck College, London; 21) Molecular Biology, GH Cochin, Paris.
Complex cortical malformations associated with mutations in tubulin genes commonly referred to as Tubulinopathies are a heterogeneous group of conditions. Reported phenotypes range from microlissencephaly (MicroLIS) usually diagnosed antenatally to relatively milder with simplified gyral pattern. To further define the phenotypes of fetal tubulinopathies, we studied a cohort of 60 ftal cases. After sequencing the four tubulin genes, a causal mutation was found in 24/60 of cases interrupted between 16 and 37.8 weeks of gestation; TUBA1A mutations in 17 cases, TUBB2B in six and TUBB3 in a single case. On the basis of a ratio of severity, three subtypes clearly emerged. MicroLIS with corpus callosum agenesis and pontocerebellar hypoplasia represent the most important group (n=11). Cortical lamination is always abnormal either absent cortical plaque (3), reduced to 2-layered cortex (5) or poorly differentiated with 4-layered individualized (3). Neuronoglial overmigration over the pial membrane are occasional (4/11) in particular in the most severe forms and 7/11 showed ectopic neurons within the white matter. All cases demonstrated voluminous enlarged germinal zones. 8/11 had TUBA1A mutations, 2 had TUBB2B and one TUBB3 mutation. Lissencephaly either classic (6/8) or with cerebellar hypoplasia (2/8) are corpus callosum agenesis was the second group. None were microcephalic. Abnormal lamination consisted of either 4 layered cortex with large band of neurons that failed to migrated (3/6) or poorly differentiated cortex (3/6). Neuroglial overmigrations were never observed while ectopic neurons were constant. Brainstem and cerebellum were mildly hypoplasic for all cases except two cases. Polymicrogyria (5) was the third group consisting of focal or multifocal polymicrogyria. None were microcephalic. The majority (4/5) had corpus callosum agenesis and two cases showed pontocerebellar hypoplasia. Two cases had TUBA1A mutations and 3 had TUBB2B mutation. Compared with the phenotypes of children with tubulinopathies, these prenatally diagnosed fetal cases represent the severe end of the tubulinopathies spectrum. The TUBA1A tubulinopathies is mostly represented by microLIS or classic LIS. By contrast, the TUBB2B tubulinopathies is either a PMG usually asymetric or microLIS or LIS. This study emphasizes the importance of neuropathological examinations in diffuse cortical dysgenesis for improving our knowledge of the distinct pathogenetic mechanisms.
You may contact the first author (during and after the meeting) at