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

Annie Laquerriere; Marie Gonzales; Yoann Saillour; Mara Cavallin; Nicole Joyē; Chloé Quēlin; Laurent Bidat; Marc Dommergues; Ghislaine Plessis; Ferechte Encha-Razavi; Jamel Chelly; Nadia Bahi-Buisson; Karine Poirier

doi:10.1016/j.ejmg.2015.12.007

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

Eur J Med Genet. 2016 Apr;59(4):249-56. doi: 10.1016/j.ejmg.2015.12.007. Epub 2015 Dec 28.

Authors

Affiliations

¹ Pathology Laboratory, Rouen University Hospital, France; Region-Inserm Team NeoVasc ERI28, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Institute of Research Innovation in Biomedecine, Normandy University, Rouen, France.
² Department of Medical Genetics, Armand Trousseau Hospital, APHP, Paris, France; Sorbonne Universities, UPMC, Paris, France.
³ Inserm, U1016, Institut Cochin, Paris, France; CNRS, UMR8104, Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
⁴ Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology, Necker Enfants Malades University Hospital, Paris, France; INSERM UMR-1163, Embryology and Genetics of Congenital Malformation Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, France.
⁵ Department of Clinical Genetics, South University Hospital, Rennes, France.
⁶ Department of Prenatal Diagnosis, Department of Obstetrics and Gynecology, René Dubos Hospital, Pontoise, France.
⁷ Sorbonne Universities, UPMC, Paris, France; Department of Obstetrics and Gynecology, Groupe Hospitalier Pitié Salpêtrière, APHP, Paris, France.
⁸ Department of Genetics, Clinical Genetics, Caen University Hospital, Caen, France.
⁹ Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology, Necker Enfants Malades University Hospital, Paris, France; Département de Génétique, Necker-Enfants Malades University Hospital, Paris, France.
¹⁰ Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut de Génétique et Biologie Moléculaire et Cellulaire - IGBMC, INSERM, CNRS, Université de Strasbourg, Strasbourg, France.
¹¹ Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology, Necker Enfants Malades University Hospital, Paris, France; INSERM UMR-1163, Embryology and Genetics of Congenital Malformation Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, France. Electronic address: [email protected].

PMID: 26732629
DOI: 10.1016/j.ejmg.2015.12.007

Abstract

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.

Keywords: Fetal akinesia deformation sequence; Microcephaly; Microlissencephaly; Migration disorder; TUBB2B.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Arthrogryposis / genetics*
Arthrogryposis / physiopathology
Cerebellum / physiopathology
Female
Fetus
Humans
Malformations of Cortical Development / genetics*
Malformations of Cortical Development / physiopathology
Microcephaly / genetics*
Microcephaly / physiopathology
Motor Neurons / pathology
Mutation
Spinal Cord / physiopathology
Tubulin / deficiency
Tubulin / genetics*

Substances

TUBB2B protein, human
Tubulin

Supplementary concepts

Pena Shokeir syndrome, type 1