Epilepsy in Tubulinopathy: Personal Series and Literature Review.

Romina Romaniello,Elena Panzeri,Claudio Zucca,Maria T Bassi,Paolo Bonanni,Filippo Arrigoni,Renato Borgatti

doi:10.3390/cells8070669

Abstract

Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation and axon guidance and maintenance. Motor impairment, intellectual disability and epilepsy are the main clinical symptoms. In the present study 15 patients from a personal cohort and 75 from 21 published studies carrying mutations in TUBA1A, TUBB2B and TUBB3 tubulin genes were evaluated with the aim to define a clinical and electrophysiological associated pattern. Epilepsy shows a wide range of severity without a specific pattern. Mutations in TUBA1A (60%) and TUBB2B (74%) and TUBB3 (25%) genes are associated with epilepsy. The accurate analysis of the Electroencephalogram (EEG) pattern in wakefulness and sleep in our series allows us to detect significant abnormalities of the background activity in 100% of patients. The involvement of white matter and of the inter-hemispheric connection structures typically observed in tubulinopathies is evidenced by the high percentage of asynchronisms in the organization of sleep activity recorded. In addition to asymmetries of the background activity, excess of slowing, low amplitude and Magnetic Resonance (MR) imaging confirm the presence of extensive brain malformations involving subcortical and midline structures. In conclusion, epilepsy in tubulinopathies when present has a favorable evolution over time suggesting a not particularly aggressive therapeutic approach.

Highlights

In the last two decades, more evidence has been provided about the role of genes in determining epilepsy [1,2,3,4,5]
Tubulins represent the major constituents of microtubules; they are dimeric proteins consisting of two closely α and β related subunits [9] encoded by tubulin genes (i.e., TUBA1A, TUBB2B, TUBB3, TUBB4A, TUBB2A, TUBB, TUB8A)
The main role in causing epilepsy is played by mutations that disrupt stability of MTs, which are primarily involved in neuronal migration and organization, while perturbations of the microtubule dynamic, which have a crucial function in the axonal growth and guidance, are less frequently associated with epileptic phenotypes [43,44,45]

Summary

Introduction

In the last two decades, more evidence has been provided about the role of genes in determining epilepsy [1,2,3,4,5] Among these genes, some play a role in neuronal membrane electrical stabilization [1], while others are involved in or regulate neuronal proliferation, migration and postmigrational cortical organization during fetal brain development. Some play a role in neuronal membrane electrical stabilization [1], while others are involved in or regulate neuronal proliferation, migration and postmigrational cortical organization during fetal brain development Mutations in this last group of genes lead to major structural cortical abnormalities (malformations of cortical development, MCDs) which are associated with specific neuroradiological patterns [2,3]. The most frequent findings are cortical cerebellar dysplasia, brainstem asymmetries and brainstem clefts [40,41,42]

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Conclusion