title: The wide spectrum of tubulinopathies: what are the key features for the diagnosis?
abstract: Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.
authors.affiliation: 1 Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France2 Inserm, U1016, Paris, France3 Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France4 INSERM UMR-1163, Embryology and genetics of congenital malformations, Paris, France5 Service de Neurologie pédiatrique, Assistance Publique-Hôpitaux de Paris (AP-HP), hôpital Necker, Paris, France nadia.bahi-buisson@nck.aphp.fr.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.affiliation: 1 Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France2 Inserm, U1016, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.affiliation: 6 CRUK London Research Institute, London, UK.
authors.forename: Franck
authors.initials: F
authors.lastname: Fourniol
authors.affiliation: 1 Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France2 Inserm, U1016, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Saillour
authors.affiliation: 1 Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France2 Inserm, U1016, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Valence
authors.affiliation: 1 Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France2 Inserm, U1016, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebrun
authors.affiliation: 5 Service de Neurologie pédiatrique, Assistance Publique-Hôpitaux de Paris (AP-HP), hôpital Necker, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Hully
authors.affiliation: 7 Université de Montreal-CHU Sainte Justine, Montreal (QC), Canada.
authors.forename: Catherine Fallet
authors.initials: CF
authors.lastname: Bianco
authors.affiliation: 8 Service de Radiologie Pédiatrique, AP-HP, hôpital Necker, Paris, France9 Inserm, U797-INSERM-CEA, Service Hospitalier Frédéric Joliot, CEA, 4, place du General Leclerc, 91406, Orsay, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: 10 BioInformatic Department-AP-HP, hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Elie
authors.affiliation: 11 Evelina Children's Hospital, St Thomas Hospital, London, UK.
authors.forename: Karine
authors.initials: K
authors.lastname: Lascelles
authors.affiliation: 12 Service de Biologie Moleculaire et Genetique, Pavillon Cassini AP-HP, Hôpital Cochin, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Souville
authors.affiliation: 12 Service de Biologie Moleculaire et Genetique, Pavillon Cassini AP-HP, Hôpital Cochin, Paris, France.
authors.forename: Cherif
authors.initials: C
authors.lastname: Beldjord
authors.affiliation: 1 Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France2 Inserm, U1016, Paris, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
mesh_terms: D000293:Adolescent; D000328:Adult; D061085:Agenesis of Corpus Callosum / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D054082:Lissencephaly / Q000175:diagnosis* / Q000453:epidemiology; D008297:Male; D054220:Malformations of Cortical Development / Q000175:diagnosis* / Q000453:epidemiology; D008831:Microcephaly / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009421:Nervous System Malformations / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D010641:Phenotype; D014404:Tubulin / Q000235:genetics*; D055815:Young Adult
chemical_list: D014404:Tubulin
keywords: lissencephaly; microcephaly; microlissencephaly; pachygyria; polymicrogyria; tubulin