TY - JOUR
T1 - GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity?
AU - Benova, Barbora
AU - Sanders, Maurits W. C. B.
AU - Uhrova-Meszarosova, Anna
AU - Belohlavkova, Anezka
AU - Hermanovska, Barbora
AU - Novak, Vilem
AU - Stanek, David
AU - Vlckova, Marketa
AU - Zamecnik, Josef
AU - Aronica, Eleonora
AU - Braun, Kees P. J.
AU - Koeleman, Bobby P. C.
AU - Jansen, Floor E.
AU - Krsek, Pavel
N1 - Funding Information: Supported by Ministry of Health of the Czech Republic , grant nr. NV19-04-00369 . All rights reserved. The funding source had no role in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. The authors have no conflict of interests to report. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Publisher Copyright: © 2021 European Paediatric Neurology Society
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Background: Variants of GATOR1-genes represent a recognised cause of focal cortical dysplasia (FCD), the most common structural aetiology in paediatric drug-resistant focal epilepsy. Reports on familial cases of GATOR1-associated FCD are limited, especially with respect to epilepsy surgery outcomes. Methods: We present phenotypical manifestations of four unrelated patients with drug-resistant focal epilepsy, FCD and a first-degree relative with epilepsy. All patients underwent targeted gene panel sequencing as a part of the presurgical work up. Literature search was performed to compare our findings to previously published cases. Results: The children (probands) had a more severe phenotype than their parents, including drug-resistant epilepsy and developmental delay, and they failed to achieve seizure freedom post-surgically. All patients had histopathologically confirmed FCD (types IIa, IIb, Ia). In Patient 1 and her affected father, we detected a known pathogenic NPRL2 variant. In patients 2 and 3 and their affected parents, we found novel likely pathogenic germline DEPDC5 variants. In family 4, we detected a novel variant in NPRL3. We identified 15 additional cases who underwent epilepsy surgery for GATOR1-associated FCD, with a positive family history of epilepsy in the literature; in 8/13 tested, the variant was inherited from an asymptomatic parent. Conclusion: The presented cases displayed a severity gradient in phenotype with children more severely affected than the parents. Although patients with GATOR1-associated FCD are considered good surgical candidates, post-surgical seizure outcome was poor in our familial cases, suggesting that accurate identification of the epileptogenic zone may be more challenging in this subgroup of patients.
AB - Background: Variants of GATOR1-genes represent a recognised cause of focal cortical dysplasia (FCD), the most common structural aetiology in paediatric drug-resistant focal epilepsy. Reports on familial cases of GATOR1-associated FCD are limited, especially with respect to epilepsy surgery outcomes. Methods: We present phenotypical manifestations of four unrelated patients with drug-resistant focal epilepsy, FCD and a first-degree relative with epilepsy. All patients underwent targeted gene panel sequencing as a part of the presurgical work up. Literature search was performed to compare our findings to previously published cases. Results: The children (probands) had a more severe phenotype than their parents, including drug-resistant epilepsy and developmental delay, and they failed to achieve seizure freedom post-surgically. All patients had histopathologically confirmed FCD (types IIa, IIb, Ia). In Patient 1 and her affected father, we detected a known pathogenic NPRL2 variant. In patients 2 and 3 and their affected parents, we found novel likely pathogenic germline DEPDC5 variants. In family 4, we detected a novel variant in NPRL3. We identified 15 additional cases who underwent epilepsy surgery for GATOR1-associated FCD, with a positive family history of epilepsy in the literature; in 8/13 tested, the variant was inherited from an asymptomatic parent. Conclusion: The presented cases displayed a severity gradient in phenotype with children more severely affected than the parents. Although patients with GATOR1-associated FCD are considered good surgical candidates, post-surgical seizure outcome was poor in our familial cases, suggesting that accurate identification of the epileptogenic zone may be more challenging in this subgroup of patients.
KW - Epilepsy surgery
KW - Focal cortical dysplasia
KW - Focal epilepsy
KW - GATOR1
KW - Malformations of cortical development
KW - Targeted gene panel sequencing
UR - http://www.scopus.com/inward/record.url?scp=85099388217&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ejpn.2020.12.001
DO - https://doi.org/10.1016/j.ejpn.2020.12.001
M3 - Article
C2 - 33461085
SN - 1090-3798
VL - 30
SP - 88
EP - 96
JO - European journal of paediatric neurology : EJPN
JF - European journal of paediatric neurology : EJPN
ER -