Abstract
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. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. 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. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations.
Highlights
Microtubules play a pivotal role during brain development being indispensable for mitosis, neuronal migration, synaptic connectivity, and axonal transport [1]
Tubulinopathies are predominantly caused by variants in tubulin alpha 1A (TUBA1A), encoding the major CNS α-tubulin isotype, which accounts for a rapidly growing number of more than 170 cases [8]
TUBA1A tubulinopathy shows a more severe clinical and neuroradiological phenotype than β-tubulinopathies comprising a combination of MCDs and changes of extra-cortical structures such as cerebellum, corpus callosum (CC), basal ganglia, brainstem, and ventricles
Summary
Microtubules play a pivotal role during brain development being indispensable for mitosis, neuronal migration, synaptic connectivity, and axonal transport [1]. Tubulinopathies show a broad spectrum of malformations of cortical (MCDs) and extra-cortical development and are increasingly recognized as a cause of early-onset epilepsies [5, 6]. Their anti-epileptic treatment is challenging as epilepsy predominantly shows an infantile onset and treatment-resistant course with various semiologies [7]. Tubulinopathies are predominantly caused by variants in TUBA1A, encoding the major CNS α-tubulin isotype, which accounts for a rapidly growing number of more than 170 cases [8]. MCDs encompass subtypes of lissencephaly and cortical irregularities with simplified gyration in combination with atypical polymicrogyria [5].
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