Romina Romaniello and Renato Borgatti
Mutations in α- and β-tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation, and axon guidance and maintenance. Motor and language developmental disorders, cognitive impairment and epilepsy are the main clinical associated symptoms. Frequency and severity of these disorders are largely related with the involvement of specific tubulin genes and their functions.
The present study summarizes all the published data on tubulin family gene mutations and the associated clinical phenotype in order to define epilepsy recurrence and its characteristics.
Mutations disrupting the stability of microtubules, mainly mechanisms involving neuronal migration and organization, may play an important role in epileptogenicity. Moreover, since mutations in the α- and β- tubulin genes are responsible for a large spectrum of cortical and brain malformations, they do not show a high specificity and correlation with an epileptic phenotype unlike other MCDs-related genes. Usually seizures start early (in the first year of life) and they are more often generalized (infantile spasms, tonic, tonic-clonic) as expression of a diffuse cortical maldevelopment.
Mutations in the TUBA1A gene, causing various degrees of agyria-pachigyria spectrum, classical lissencephaly or polymicrogyria, represent among tubulin genes, the major responsible of epilepsy (about 50% of the cases).
Disorders of cortical development as polymicrogyria, various types of gyral disorganization and schizencephaly were also described in cases carrying TUBB2B gene mutations showing epilepsy in the 40%.
As far as mutations in the TUBB4A gene are concerned, despite the brain phenotype is represented by a form of leukoencephalopathy characterized by hypomielination with atrophy of the basal ganglia and cerebellum and not by MCDs, epilepsy is present in about 40% of the mutated subjects.
On the contrary, mutations in the TUBB3 gene cause epilepsy only in 15% of cases, while seizures have never been described in association with TUBB gene.