Abstract

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as “Tubulinopathies”. To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2–3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-69) contains supplementary material, which is available to authorized users.

Highlights

  • Disorders of cerebral cortical development are generally classified according to the developmental stage the lesions are observed

  • We report for the first time a large cohort of foetuses with various malformations of cortical development due to mutations in 3 different tubulin genes (TUBA1A, TUBB2B and TUBB3), underlining the relatively high frequency of tubulinopathies among the causes of severe complex cortical malformations ranging from polymicrogyria-like cortical dysplasia to microlissencephaly with corpus callosum agenesis and ponto-cerebellar hypoplasia

  • Our study clearly demonstrates that tubulin mutations may represent a significant cause of sporadic microlissencephaly with corpus callosum agenesis

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Summary

Introduction

Disorders of cerebral cortical development are generally classified according to the developmental stage the lesions are observed. An updated classification that takes into account genetic abnormalities as well as disrupted process and stage of brain development has been proposed. This classification system divides brain malformations into disorders of neuronal and glial proliferation, neuronal migration, and post-migrational development [1]. MRI and ultrasound investigations have led to major advances in the classification of these disorders [4,5,6,7,8] These advances need to be completed by studies focused on malformation-associated tissue architecture, and more importantly, definition of genetic causes and specific developmental pathways involved in the constitution of the lesions

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