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GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity

B. Benova, MWCB. Sanders, A. Uhrova-Meszarosova, A. Belohlavkova, B. Hermanovska, V. Novak, D. Stanek, M. Vlckova, J. Zamecnik, E. Aronica, KPJ. Braun, BPC. Koeleman, FE. Jansen, P. Krsek

. 2021 ; 30 (-) : 88-96. [pub] 20210106

Language English Country Great Britain

Document type Case Reports, Journal Article

Persistent link   https://www.medvik.cz/link/bmc21019527

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.

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$a Benova, Barbora $u Department of Paediatric Neurology, Motol Epilepsy Center, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 15006, Prague, Czech Republic; Neurogenetics Laboratory of the Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, Prague, 15006, Czech Republic. Electronic address: barbora.benova@fnmotol.cz
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$a GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity / $c B. Benova, MWCB. Sanders, A. Uhrova-Meszarosova, A. Belohlavkova, B. Hermanovska, V. Novak, D. Stanek, M. Vlckova, J. Zamecnik, E. Aronica, KPJ. Braun, BPC. Koeleman, FE. Jansen, P. Krsek
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$a 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.
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$a Sanders, Maurits W C B $u Department of Child Neurology, Brain Center University Medical Center Utrecht, the Netherlands. Electronic address: M.W.C.B.Sanders-5@umcutrecht.nl
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$a Uhrova-Meszarosova, Anna $u Department of Paediatric Neurology, Motol Epilepsy Center, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 15006, Prague, Czech Republic; Neurogenetics Laboratory of the Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, Prague, 15006, Czech Republic. Electronic address: anna.meszarosova@lfmotol.cuni.cz
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$a Belohlavkova, Anezka $u Department of Paediatric Neurology, Motol Epilepsy Center, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 15006, Prague, Czech Republic. Electronic address: anezka.belohlavkova@fnmotol.cz
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$a Hermanovska, Barbora $u Department of Paediatric Neurology, Motol Epilepsy Center, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 15006, Prague, Czech Republic. Electronic address: barbora.hermanovska@fnmotol.cz
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$a Novak, Vilem $u Department of Paediatric Neurology, Ostrava Faculty Hospital, 17. Listopadu 1790, 708 00, Ostrava-Poruba, Czech Republic. Electronic address: vilem.novak@fno.cz
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$a Stanek, David $u Neurogenetics Laboratory of the Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, Prague, 15006, Czech Republic. Electronic address: david.stanek@lfmotol.cuni.cz
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$a Vlckova, Marketa $u Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 15006, Prague, Czech Republic. Electronic address: marketa.vlckova@fnmotol.cz
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$a Zamecnik, Josef $u Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 15006, Prague, Czech Republic. Electronic address: josef.zamecnik@lfmotol.cuni.cz
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$a Aronica, Eleonora $u Amsterdam UMC, University of Amsterdam, Department of (Neuro)Pathology, Amsterdam, Meibergdreef 9, 1105, AZ Amsterdam, the Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN), Achterweg 2, 2103, SW, Heemstede, the Netherlands. Electronic address: e.aronica@amsterdamumc.nl
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$a Braun, Kees P J $u Department of Child Neurology, Brain Center University Medical Center Utrecht, the Netherlands. Electronic address: K.Braun@umcutrecht.nl
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$a Koeleman, Bobby P C $u Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: B.P.C.Koeleman@umcutrecht.nl
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$a Jansen, Floor E $u Department of Child Neurology, Brain Center University Medical Center Utrecht, the Netherlands. Electronic address: f.e.jansen@umcutrecht.nl
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$a Krsek, Pavel $u Department of Paediatric Neurology, Motol Epilepsy Center, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V Uvalu 84, 15006, Prague, Czech Republic. Electronic address: pavel.krsek@fnmotol.cz
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$w MED00149836 $t European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society $x 1532-2130 $g Roč. 30, č. - (2021), s. 88-96
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