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Refinement of cortical dysgeneses associated with TUBA1A mutations: perisylvian pachygyria and dysgenesis of the interal capsule are specific features of the TUBA1A lissencephaly spectrum
  1. Nadia Bahi-Buisson (nadia.bahi-buisson{at}
  1. Necker Enfants Malades, France
    1. Karine Poirier
    1. Institut Cochin, France
      1. Nathalie Boddaert
      1. Necker Enfants Malades, France
        1. Yoann Saillour
        1. Institut Cochin, France
          1. Laetitia Castelnau
          1. Institut Cochin, France
            1. Nicole Philip
            1. La Timone Marseille, France
              1. Gunnar Buyse
              1. Uz Kuleuven, Belgium
                1. Laurent Villard
                1. INSERM Marseille, France
                  1. Sylvie Joriot
                  1. CHU Lille, France
                    1. Stéphane Marret
                    1. CHU Rouen, France
                      1. Marie Bourgeois
                      1. Necker Enfants Malades, France
                        1. Hilde Van Esch
                        1. Uz Kuleuven, Belgium
                          1. Liven Lagae
                          1. Uz Kuleuven, Belgium
                            1. Jeanne Amiel
                            1. Necker Enfants Malades, France
                              1. Lucie Hertz Pannier
                              1. Necker Enfants Malades, France
                                1. Agathe Roubertie
                                1. CHU Montpellier, France
                                  1. François Rivier
                                  1. CHU Montpellier, France
                                    1. Jean Marc Pinard
                                    1. Raymond Poincaré-APHP, France
                                      1. Chérif Beldjord
                                      1. Institut Cochin, France
                                        1. Jamel Chelly
                                        1. Institut Cochin, France


                                          Objective: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to 5 previously described patients with TUBA1A mutations.

                                          Results: We detected de novo TUBA1A mutations in 6 patients and highlight the existence of a prominent form of TUBA1A-related lissencephaly. In 4 patients, the mutations identified c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R) have not been reported before and in 2 others, the mutation corresponds to a recurrent missense mutation c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific of TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia / tetraplegia.

                                          Conclusions: Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A-related lissencephalies from those related to LIS1, DCX and ARX genes.

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