Format

Send to

Choose Destination
Brain. 2014 Jun;137(Pt 6):1676-700. doi: 10.1093/brain/awu082.

The wide spectrum of tubulinopathies: what are the key features for the diagnosis?

Author information

1
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.
2
1 Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France2 Inserm, U1016, Paris, France.
3
6 CRUK London Research Institute, London, UK.
4
5 Service de Neurologie pédiatrique, Assistance Publique-Hôpitaux de Paris (AP-HP), hôpital Necker, Paris, France.
5
7 Université de Montreal-CHU Sainte Justine, Montreal (QC), Canada.
6
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.
7
10 BioInformatic Department-AP-HP, hôpital Necker-Enfants Malades, Paris, France.
8
11 Evelina Children's Hospital, St Thomas Hospital, London, UK.
9
12 Service de Biologie Moleculaire et Genetique, Pavillon Cassini AP-HP, Hôpital Cochin, Paris, France.

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.

KEYWORDS:

lissencephaly; microcephaly; microlissencephaly; pachygyria; polymicrogyria; tubulin

PMID:
24860126
DOI:
10.1093/brain/awu082
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center