Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

Julian Schröter; Bernt Popp; Heiko Brennenstuhl; Jan H. Döring; Stephany H. Donze; Emilia K. Bijlsma; Arie van Haeringen; Dagmar Huhle; Leonie Jestaedt; Andreas Merkenschlager; Maria Arelin; Daniel Gräfe; Sonja Neuser; Stephanie Oates; Deb K. Pal; Michael J. Parker; Johannes R. Lemke; Georg F. Hoffmann; Stefan Kölker; Inga Harting; Steffen Syrbe

doi:10.1038/s41431-021-01027-0

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

Julian Schröter, Bernt Popp, Heiko Brennenstuhl, Jan H. Döring, Stephany H. Donze, Emilia K. Bijlsma, Arie van Haeringen, Dagmar Huhle, Leonie Jestaedt, Andreas Merkenschlager, Maria Arelin, Daniel Gräfe, Sonja Neuser, Stephanie Oates, Deb K. Pal, Michael J. Parker, Johannes R. Lemke, Georg F. Hoffmann, Stefan Kölker, Inga HartingSteffen Syrbe^*

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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.

Original language	English
Pages (from-to)	298-306
Number of pages	9
Journal	European Journal of Human Genetics
Volume	30
Issue number	3
DOIs	https://doi.org/10.1038/s41431-021-01027-0
Publication status	Published - Mar 2022

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Schröter, J., Popp, B., Brennenstuhl, H., Döring, J. H., Donze, S. H., Bijlsma, E. K., van Haeringen, A., Huhle, D., Jestaedt, L., Merkenschlager, A., Arelin, M., Gräfe, D., Neuser, S., Oates, S., Pal, D. K., Parker, M. J., Lemke, J. R., Hoffmann, G. F., Kölker, S., ... Syrbe, S. (2022). Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies. European Journal of Human Genetics, 30(3), 298-306. https://doi.org/10.1038/s41431-021-01027-0

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title = "Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies",

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.",

author = "Julian Schr{\"o}ter and Bernt Popp and Heiko Brennenstuhl and D{\"o}ring, {Jan H.} and Donze, {Stephany H.} and Bijlsma, {Emilia K.} and {van Haeringen}, Arie and Dagmar Huhle and Leonie Jestaedt and Andreas Merkenschlager and Maria Arelin and Daniel Gr{\"a}fe and Sonja Neuser and Stephanie Oates and Pal, {Deb K.} and Parker, {Michael J.} and Lemke, {Johannes R.} and Hoffmann, {Georg F.} and Stefan K{\"o}lker and Inga Harting and Steffen Syrbe",

note = "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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = mar,

doi = "10.1038/s41431-021-01027-0",

language = "English",

volume = "30",

pages = "298--306",

journal = "European journal of human genetics : EJHG",

issn = "1018-4813",

publisher = "Springer Nature [academic journals on nature.com]",

number = "3",

}

Schröter, J, Popp, B, Brennenstuhl, H, Döring, JH, Donze, SH, Bijlsma, EK, van Haeringen, A, Huhle, D, Jestaedt, L, Merkenschlager, A, Arelin, M, Gräfe, D, Neuser, S, Oates, S, Pal, DK, Parker, MJ, Lemke, JR, Hoffmann, GF, Kölker, S, Harting, I & Syrbe, S 2022, 'Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies', European Journal of Human Genetics, vol. 30, no. 3, pp. 298-306. https://doi.org/10.1038/s41431-021-01027-0

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 : EJHG

JF - European journal of human genetics : EJHG

IS - 3

ER -

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

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