Complementing the Phenotypical Spectrum of TUBA1A Tubulinopathy and Its Role in Early-Onset Epilepsies

Background/Purpose: TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early onset and intractable epilepsy. As pathomechanisms and genotype–phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum.

Methods: We present a multicenter case series of 10 individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling.

Results: The phenotypic range showed various severity. 63% had global developmental delay and 50% showed severe motor impairment with tetraparesis. Epilepsy was observed in 75% and mostly showed an infantile onset (50%) and refractory course (60%). One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. In two cases, pregnancy was terminated due to severe brain malformations. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation.

Conclusion: We extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations.

Publication History

Article published online:
28 October 2021