TY - JOUR
T1 - Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies
AU - Schröter, Julian
AU - Popp, Bernt
AU - Brennenstuhl, Heiko
AU - Döring, Jan H.
AU - Donze, Stephany H.
AU - Bijlsma, Emilia K.
AU - van Haeringen, Arie
AU - Huhle, Dagmar
AU - Jestaedt, Leonie
AU - Merkenschlager, Andreas
AU - Arelin, Maria
AU - Gräfe, Daniel
AU - Neuser, Sonja
AU - Oates, Stephanie
AU - Pal, Deb K.
AU - Parker, Michael J.
AU - Lemke, Johannes R.
AU - Hoffmann, Georg F.
AU - Kölker, Stefan
AU - Harting, Inga
AU - Syrbe, Steffen
N1 - Funding Information:
BP obtains funding by the Deutsche Forschungsgemeinschaft (grant PO2366/2-1). SS and JS are supported by the Dietmar Hopp Foundation (grant 1DH1813319 to SS). JS is additionally supported by the Physician-Scientist-Program (University of Heidelberg). Open Access funding enabled and organized by Projekt DEAL.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122682459&partnerID=8YFLogxK
U2 - 10.1038/s41431-021-01027-0
DO - 10.1038/s41431-021-01027-0
M3 - Article
C2 - 35017693
AN - SCOPUS:85122682459
SN - 1018-4813
VL - 30
SP - 298
EP - 306
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
ER -