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Review
. 2019 Jul 2;8(7):669.
doi: 10.3390/cells8070669.

Epilepsy in Tubulinopathy: Personal Series and Literature Review

Romina Romaniello  1 , Claudio Zucca  2 , Filippo Arrigoni  3 , Paolo Bonanni  4 , Elena Panzeri  5 , Maria T Bassi  5 , Renato Borgatti  6
Affiliations
Review

Epilepsy in Tubulinopathy: Personal Series and Literature Review

Romina Romaniello et al. Cells. .

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.

Keywords: EEG; TUBA1A; TUBB2B; TUBB3; epilepsy; malformations cortical development; tubulin genes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
EEG findings in TUBA1A, TUBB2 and TUBB3 genes mutations. Patient A [P89815] (33 months) has a mutation in TUBA1A gene and at MRI multifocal PMG. During drowsiness: asymmetric background activity (square: a). Paroxysmal slow abnormalities over right posterior regions (square: b). Asynchronous epileptiform abnormalities over left central areas (square: c). Patient B [P76712] (8 years) has a mutation in TUBB2B gene. B1 EEG during wakefulness: asymmetry of the background activity and paroxysmal slow abnormalities over left centro-temporal areas (square: d). B2 EEG during drowsiness: epileptiform abnormalities over left centro-temporal areas (square e). Patient’s MRI showed a schizencephaly in left centro-temporal areas consistent to EEG abnormalities. Patient C [P105814] (15 months) has a mutation in TUBB3 gene. EEG during 2-3 non-REM sleep: asymmetric and asynchronous background activity (square f). Diphasic slow abnormalities over right parietal and occipital areas (square g). In this patient, no epileptiform abnormalities were recorded according with the absence of MCDs on MRI.
Figure 2
Figure 2
MR imaging findings in three patients. Patient A [P109418] has a mutation in TUBB3 gene. T1-weighted images show a thin and short corpus callosum, perisylvian polymicrogyria (black arrow), a severe thinning/agenesis of the ALIC (white arrow) and brainstem asymmetry (arrowhead pointing at enlarged pons). Patient B [P45617] carries a mutation in TUBA1A gene. Thin corpus callosum, dysgyric cortex in perisylvian areas (black arrows), bilaterally thinned ALIC (white arrows) and pons asymmetry (arrowhead pointing at enlarged pons) are shown on T2-weighted images Patient C [P76712] carries a mutation in TUBB2B gene. He has a malformed corpus callosum and brainstem, with a thickened ponto-medullary junction and brainstem asymmetry (arrowhead pointing at enlarged medulla). He has also a complex cortical malformation with diffuse bilateral polymicrogyria and schizencephaly in the left hemisphere (arrows).
Figure 3
Figure 3
Schematic representations of the functional domains of TUBA1A, TUBB2B and TUBB3. The numbers in the boxes show how many mutations are described for each tubulin domain by distinguishing literature and our series, while above the protein schemes are reported the number of mutations associated with epilepsy and the corresponding percentage.
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