Brain malformations and mutations in α‐ and β‐tubulin genes: a review of the literature and description of two new cases

Abstract

ABBREVIATIONS MCDsMalformations of cortical development PMG Polymicrogyria AIM The aim of this study was to determine the frequency of mutations in tubulin genes (TUBB2B, TUBA1A, and TUBB3) in patients with malformations of cortical development (MCDs) of unknown origin.METHOD In total, 79 out of 156 patients (41 males, 38 females; age range 8mo-55y (mean age 13y 3mo, SD 11y 2mo) with a neuroradiological diagnosis of MCDs were enrolled in the study. The 77 excluded patients were excluded for the following reasons: suspected or proven diagnosis of pre-or perinatal ischaemic insult (n=13); syndromic disease (n=10); congenital infection (n=14); pregnancy complicated by twin-to-twin transfusion syndrome (n=2); proven mutations in known genes (n=13); poor magnetic resonance imaging (MRI) quality, or lack of informed consent (n=25). A genetic analysis of the TUBA1A, TUBB2B and TUBB3 genes was carried out by direct sequencing of the coding regions of the relevant genes for each participant. Previously described patients with mutations in the TUBB2B and TUBA1A genes were reviewed; clinical and neuroradiological findings were compared and discussed.RESULTS Two novel heterozygous mutations were detected: a heterozygous mutation in exon 4 of the TUBA1A gene (c.1160C>T) in a 5-year-old female with microcephaly, severe intellectual disability, and absence of language, and a c.1080 _1084del CCTGAinsACATCTTC in exon 4 of the TUBB2B gene in a 31-year-old female with microcephaly, spastic tetraparesis, severe intellectual disability, and scoliosis. Different types of cortical abnormalities, cerebellar vermis hypoplasia, and optic nerve hypoplasia/atrophy were detected on MRI. Dysmorphisms of the basal ganglia and the hippocampi with abnormalities of the midline commissural structures were present in both cases. INTERPRETATIONThe consistent presence of hypoplastic and disorganized white matter tracts suggests that, in addition to defects in neuronal migration, disruption of axon growth and guidance is a peculiar feature of tubulin-related disorders.

Unilateral Opercular Polymicrogyria in a Girl with 22q13 Deletion Syndrome

“…Mutations in the tubulin genes mostly affect the formation of tubulin heterodimers and result in different disorders. The associated phenotypic spectrum encompasses a wide range of brain malformations, all reflecting axon guidance disturbances (abnormal fascicles and axon tracts, abnormalities of the internal capsule and corpus callosum, hypoplasia of the brainstem and corticospinal tracts), and migration or postmigration defects (abnormal cortex and hippocampal lamination) [25]. In particular disorders of microtubule complex represent one of the most known causes of polymicrogyria (TUBA8, TUBB2B, TUBA1A) [7].…”

Whole-exome sequencing identifies a de novo TUBA1A mutation in a patient with sporadic malformations of cortical development: a case report

“…Although there are at least 34 known TUBA1A mutations, and many of these mutations are located in the C-terminal half of the amino acid sequence [3,11,14-27], this report is the first to describe the E27Q mutation (Additional file 1: Figure S1). In contrast to most of the previously reported mutations, this mutation is located in the N-terminal region (Additional file 1: Figure S1).…”

Epilepsy in Multigene Tubulin Family Mutations

“…Subsequently, the spectrum of associated MCDs has broadened and various types of lissencephaly as well as more complex gyral disorganization and schizencephaly (SCH) were found [31][32][33][34][35]. In a recent study on mice models, Breuss et al analyzed the expression pattern of the tubulin isoform tubb2b, high in postmitotic regions dominated by migrating and differentiating neurons, which is restricted to macroglia in the 8-week-old cortex (corpus callosum, anterior commissure and internal capsule) [36].…”