Clinical and Genetic Spectrum of Tubulinopathy: A Single-Center Study

Clinical and Genetic Spectrum of Tubulinopathy: A Single-Center Study

Purpose: Tubulinopathy represents a group of disorders caused by variants in tubulin genes, which present with a wide spectrum of brain malformations. This study was conducted to provide insight into the phenotypic and genetic spectra of tubulinopathy within the Korean pediatric population. Methods: Among individuals who underwent genetic testing at a pediatric neurology clinic between June 2011 and December 2021, 15 patients with tubulin gene variants were retrospectively recruited. Clinical features, genetic information, and brain imaging findings were retrospectively reviewed. Results: The genetic spectra of the patients included TUBA1A (n=5, 33.3%), TUBB4A (n=6, 40.0%), TUBB3 (n=2, 13.3%), TUBB (n=1, 6.7%), and TUBB2A (n=1, 6.7%) variants. Two novel mutations were identified: a c.497A>G; p.(Lys166Arg) variant in TUBA1A and a c.907G>C; p.(Ala303Pro) variant in TUBB. All 15 patients exhibited developmental delays, with a broad spectrum of severity. Other common manifestations included microcephaly (n=10; 66.7%) and seizures (n=9; 60%). A review of the neuroimaging data revealed a range of findings that were both genotype-specific and overlapping across genotypes. In cases of TUBA1A mutation (n=5), four patients (80%) presented with pachygyria and polymicrogyria, while three (60%) displayed cerebellar hypoplasia and dysplasia. All patients with TUBB4A variants (n=6) exhibited hypomyelination, and three (50%) had cerebellar dysplasia. Conclusion: This study represents the first cohort analysis of tubulin gene mutations associated with tubulinopathy in a Korean pediatric population. It suggests that these mutations can produce a broad spectrum of neurodevelopmental and neuroimaging findings and should be considered within the differential diagnosis in relevant clinical scenarios.