Genotypic and phenotypic heterogeneity in tubulinopathies: insights from a Turkish multicenter cohort

Tubulinopathies encompass a clinically and neuroradiologically diverse group of neurodevelopmental disorders caused by mutations in genes encoding tubulins and microtubule-associated proteins. This study aims to delineate the extensive phenotypic and genotypic spectrum within a pediatric cohort.

We conducted a multicenter retrospective analysis of 15 pediatric patients from 12 unrelated families with genetically confirmed tubulinopathies across five tertiary centers in Turkey. Clinical data, seizure profiles, and neuroradiological findings were systematically evaluated.

Genetic analysis identified 12 distinct pathogenic variants across seven genes (TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBG1, TUBGCP2), including four novel variants. The most prevalent clinical features included microcephaly (93.3%), global developmental delay (86.7%), and epilepsy (73.3%). Notably, one patient with TUBB2A-related tubulinopathy experienced a probable sudden unexpected death in epilepsy (SUDEP). Movement disorders were observed in 33.3% of the cohort, including dystonia and mirror movements. Neuroradiological assessment revealed corpus callosum anomalies (76.9%) and cortical malformations (76.9%) as the most frequent findings. Furthermore, we identified a rare case of TUBGCP2-related tubulinopathy presenting with cystic leukomalacia, expanding the known radiological spectrum.

Our findings underscore the profound genetic and phenotypic heterogeneity of tubulin-related disorders. The identification of rare variants and specific complications, such as SUDEP, highlights the necessity for comprehensive clinical monitoring and standardized management guidelines to optimize outcomes for this complex patient population.