Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly

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.

Disorders of Microtubule Function in Neurons: Imaging Correlates

“…However, the MRI appearance of the cortex in the patients in our study and those described in the literature does not resemble true polymicrogyria. Pathologic analysis of the brains tubulin mutations showed migration of neurons through gaps in the pial limiting membrane into the subarachnoid space 32 , which is not found in polymicrogyria. Moreover, the appearance of smooth cortical surface with radially oriented sulci, even on high-resolution images, is not consistent with polymicrogyria.…”

“…MTs play a key role in mitosis ; therefore, cell proliferation is diminished in patients who have mutations of MT genes and patients with tubulin mutations ( TUBA1A, TUBB2B, TUBB3, TUBG , etc.) are almost universally microcephalic 6,8–10 ; the most severely affected do not survive gestation 32 . A review of the recent literature indicates that patients with MT mutations are very commonly severely microcephalic, some profoundly so, and the severity of the microcephaly seems to be directly related to the severity of the brain malformation; most severe in microlissencephaly followed by lissencephaly and pachygyria, and least severe with dysgyria (60% of which are normocephalic) 9 .…”

Lissencephaly: Expanded imaging and clinical classification

“…MLIS with cerebellar hypoplasia and other non-cortical malformations represents the most severe end of the tubulinopathy spectrum. Among those tested, several have had mutations of TUBA1A or TUBB2B [Fallet-Bianco et al, 2014]. Biallelic NDE1 mutations cause severe congenital microcephaly with cortical malformation resembling a tubulinopathy-associated dysgyria, although the cortex is not completely agyric.…”

“…We excluded patients with cobblestone cortical malformations, the malformation associated with Walker-Warburg syndrome, muscle-eye-brain disease and GPR56-associated dysgyria, as the pathological changes are different from LIS and other classifications have been proposed [Brun et al, 2017; Devisme et al, 2012]. The only exception is that we have included rare patients with severe tubulinopathies who have features overlapping with cobblestone malformations [Fallet-Bianco et al, 2014]. …”

The histopathology of polymicrogyria: a series of 71 brain autopsy studies

“…This has been illustrated for mutations in GPR56 and the tubulin genes. 44,45 However, despite advances in imaging and genetic techniques, defining aetiology for PMG may still represent a major challenge in clinical practice. …”