De novo TUBB2B mutation causes fetal akinesia deformation sequence with microlissencephaly: an unusual presentation of tubulinopathy

Annie Laquerrière (1, 2) , Marie Gonzales (3) , Yoann Saillour (4) , Mara Cavallin (5, 6) , Nicole Joyē (3) , Chloé Quēlin (7) , Laurent Bidat (8) , Marc Dommergues (9) , Ghislaine Plessis (10) , Ferechte Encha-Razavi (11, 5, 6) , Jamel Chelly (12, 13) , Nadia Bahi-Buisson (5, 6) , Karine Poirier (4, 6)

1 Néovasc - Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement
2 Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
3 CHU Trousseau [APHP]
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 Service de Neuropédiatrie
6 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
7 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
8 Centre Hospitalier René Dubos [Pontoise]
9 CHU Pitié-Salpêtrière [AP-HP]
10 Service de Génétique [CHU Caen]
11 Service de Cytogénétique et Embryologie
12 HUS - Les Hôpitaux Universitaires de Strasbourg
13 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

Tubulinopathies are increasingly emerging major causes underlying complex cerebral malformations, particularly in case of microlissencephaly often associated with hypoplastic or absent corticospinal tracts. Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. We report on an early foetal case with FADS and microlissencephaly due to TUBB2B mutation. Neuropathological examination disclosed virtually absent cortical lamination, foci of neuronal overmigration into the leptomeningeal spaces, corpus callosum agenesis, cerebellar and brainstem hypoplasia and extremely severe hypoplasia of the spinal cord with no anterior and posterior horns and almost no motoneurons. At the cellular level, the p.Cys239Phe TUBB2B mutant leads to tubulin heterodimerization impairment, decreased ability to incorporate into the cytoskeleton, microtubule dynamics alteration, with an accelerated rate of depolymerization. To our knowledge, this is the first case of microlissencephaly to be reported presenting with a so severe and early form of FADS, highlighting the importance of tubulin mutation screening in the context of FADS with microlissencephaly.

Mots clés: Fetal akinesia deformation sequence; microcephaly; microlissencephaly; migration disorder; TUBB2B

Domaines: Génétique

Annie Laquerrière, Marie Gonzales, Yoann Saillour, Mara Cavallin, Nicole Joyē, et al.. De novo TUBB2B mutation causes fetal akinesia deformation sequence with microlissencephaly: an unusual presentation of tubulinopathy. European Journal of Medical Genetics, 2015, 59 (4), pp.249-256. ⟨10.1016/j.ejmg.2015.12.007⟩. ⟨hal-01259440⟩