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2. Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR

Author

Boßelmann, Christian M., Leu, Costin, Brünger, Tobias, Hoffmann, Lucas, Baldassari, Sara, Chipaux, Mathilde, Coras, Roland, Kobow, Katja, Hamer, Hajo, Delev, Daniel, Rössler, Karl, Bien, Christian G., Kalbhenn, Thilo, Pieper, Tom, Hartlieb, Till, Becker, Kerstin, Ferguson, Lisa, Busch, Robyn M., Baulac, Stéphanie, Nürnberg, Peter, Najm, Imad, Blümcke, Ingmar, and Lal, Dennis

Published
2024
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3. D-galactose Supplementation for the Treatment of Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE): A Pilot Trial of Precision Medicine After Epilepsy Surgery

Author

Aledo-Serrano, Ángel, Valls-Carbó, Adrián, Fenger, Christina D., Groeppel, Gudrun, Hartlieb, Till, Pascual, Irene, Herraez, Erika, Cabal, Borja, García-Morales, Irene, Toledano, Rafael, Budke, Marcelo, Beltran-Corbellini, Álvaro, Baldassari, Sara, Coras, Roland, Kobow, Katja, Herrera, David M., del Barrio, Antonio, Dahl, Hans Atli, del Pino, Isabel, Baulac, Stéphanie, Blumcke, Ingmar, Møller, Rikke S., and Gil-Nagel, Antonio

Published
2023
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4. Correction to: Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

Author

Hoffmann, Lucas, Coras, Roland, Kobow, Katja, López-Rivera, Javier A., Lal, Dennis, Leu, Costin, Najm, Imad, Nürnberg, Peter, Herms, Jochen, Harter, Patrick N., Bien, Christian G., Kalbhenn, Thilo, Müller, Markus, Pieper, Tom, Hartlieb, Till, Kudernatsch, Manfred, Hamer, Hajo, Brandner, Sebastian, Rössler, Karl, Blümcke, Ingmar, and Jabari, Samir

Published
2023
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5. Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

Author

Hoffmann, Lucas, Coras, Roland, Kobow, Katja, López-Rivera, Javier A., Lal, Dennis, Leu, Costin, Najm, Imad, Nürnberg, Peter, Herms, Jochen, Harter, Patrick N., Bien, Christian G., Kalbhenn, Thilo, Müller, Markus, Pieper, Tom, Hartlieb, Till, Kudernatsch, Manfred, Hamer, Hajo, Brandner, Sebastian, Rössler, Karl, Blümcke, Ingmar, and Jabari, Samir

Published
2023
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6. A deep learning-based histopathology classifier for Focal Cortical Dysplasia

Author

Vorndran, Jörg, Neuner, Christoph, Coras, Roland, Hoffmann, Lucas, Geffers, Simon, Honke, Jonas, Herms, Jochen, Roeber, Sigrun, Hamer, Hajo, Brandner, Sebastian, Hartlieb, Till, Pieper, Tom, Kudernatsch, Manfred, Bien, Christian G., Kalbhenn, Thilo, Simon, Matthias, Adle-Biassette, Homa, Cienfuegos, Jesús, Di Giacomo, Roberta, Garbelli, Rita, Miyata, Hajime, Mühlebner, Angelika, Raicevic, Savo, Rauramaa, Tuomas, Rogerio, Fabio, Blümcke, Ingmar, and Jabari, Samir

Published
2023
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7. Brain expression profiles of two SCN1A antisense RNAs in children and adolescents with epilepsy

Author

Schneider Marius Frederik, Vogt Miriam, Scheuermann Johanna, Müller Veronika, Fischer-Hentrich Antje H. L., Kremer Thomas, Lugert Sebastian, Metzger Friedrich, Kudernatsch Manfred, Kluger Gerhard, Hartlieb Till, Noachtar Soheyl, Vollmar Christian, Kunz Mathias, Tonn Jörg Christian, Coras Roland, Blümcke Ingmar, Pace Claudia, Heinen Florian, Klein Christoph, Potschka Heidrun, and Borggraefe Ingo

Subjects
dravet syndrome, long non coding rna, regulatory rna, precision medicine, epilepsy, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Heterozygous mutations within the voltage-gated sodium channel α subunit (SCN1A) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches.

Published
2024
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8. Deep histopathology genotype–phenotype analysis of focal cortical dysplasia type II differentiates between the GATOR1-altered autophagocytic subtype IIa and MTOR-altered migration deficient subtype IIb

Author

Honke, Jonas, Hoffmann, Lucas, Coras, Roland, Kobow, Katja, Leu, Costin, Pieper, Tom, Hartlieb, Till, Bien, Christian G., Woermann, Friedrich, Cloppenborg, Thomas, Kalbhenn, Thilo, Gaballa, Ahmed, Hamer, Hajo, Brandner, Sebastian, Rössler, Karl, Dörfler, Arnd, Rampp, Stefan, Lemke, Johannes R., Baldassari, Sara, Baulac, Stéphanie, Lal, Dennis, Nürnberg, Peter, and Blümcke, Ingmar

Published
2023
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9. Anti-convulsant Agents: Rufinamide

Author

Hartlieb, Till, Kluger, Gerhard, Elger, Christian E., Section editor, Riederer, Peter, editor, Laux, Gerd, editor, Nagatsu, Toshiharu, editor, Le, Weidong, editor, and Riederer, Christian, editor

Published
2022
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11. DNA methylation-based classification of malformations of cortical development in the human brain

Author

Jabari, Samir, Kobow, Katja, Pieper, Tom, Hartlieb, Till, Kudernatsch, Manfred, Polster, Tilman, Bien, Christian G., Kalbhenn, Thilo, Simon, Matthias, Hamer, Hajo, Rössler, Karl, Feucht, Martha, Mühlebner, Angelika, Najm, Imad, Peixoto-Santos, José Eduardo, Gil-Nagel, Antonio, Delgado, Rafael Toledano, Aledo-Serrano, Angel, Hou, Yanghao, Coras, Roland, von Deimling, Andreas, and Blümcke, Ingmar

Published
2022
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13. Characterization of the Epileptogenic Phenotype and Response to Antiseizure Medications in Lissencephaly Patients.

Author

Proepper, Christiane R., Schuetz, Sofia M., Schwarz, Lisa-Maria, Au, Katja von, Bast, Thomas, Beaud, Nathalie, Borggraefe, Ingo, Bosch, Friedrich, Budde, Joerg, Busse, Melanie, Chung, Jena, Debus, Otfried, Diepold, Katharina, Fries, Thomas, Gersdorff, Gero von, Haeussler, Martin, Hahn, Andreas, Hartlieb, Till, Heiming, Ralf, and Herkenrath, Peter

Subjects
VALPROIC acid, SPASMS, INFANTILE spasms, MEDICAL protocols, AGE of onset
Abstract

Background Patients with lissencephaly typically present with severe psychomotor retardation and drug-resistant seizures. The aim of this study was to characterize the epileptic phenotype in a genotypically and radiologically well-defined patient cohort and to evaluate the response to antiseizure medication (ASM). Therefore, we retrospectively evaluated 47 patients of five genetic forms (LIS1/PAFAH1B1 , DCX , DYNC1H1 , TUBA1A , TUBG1) using family questionnaires, standardized neuropediatric assessments, and patients' medical reports. Results All but two patients were diagnosed with epilepsy. Median age at seizure onset was 6 months (range: 2.1–42.0), starting with epileptic spasms in 70%. Standard treatment protocols with hormonal therapy (ACTH or corticosteroids) and/or vigabatrin were the most effective approach for epileptic spasms, leading to seizure control in 47%. Seizures later in the disease course were most effectively treated with valproic acid and lamotrigine, followed by vigabatrin and phenobarbital, resulting in seizure freedom in 20%. Regarding psychomotor development, lissencephaly patients presenting without epileptic spasms were significantly more likely to reach various developmental milestones compared to patients with spasms. Conclusion Classic lissencephaly is highly associated with drug-resistant epilepsy starting with epileptic spasms in most patients. The standard treatment protocols for infantile epileptic spasms syndrome lead to freedom from seizures in around half of the patients. Due to the association of epileptic spasms with an unfavorable course of psychomotor development, early and reliable diagnosis and treatment of spasms should be pursued. For epilepsies occurring later in childhood, ASM with valproic acid and lamotrigine, followed by vigabatrin and phenobarbital, appears to be most effective. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study

Author

Aichholzer, Martin, Amorim, Isabel, Aparicio, Javier, Aronica, Eleonora, Arzimanoglou, Alexis, Barba, Carmen, Beck, Jürgen, Becker, Albert, Beckervordersandforth, Jan C, Bien, Christian G, Blümcke, Ingmar, Bodi, Istvan, Braun, Kees PJ, Catenoix, Helene, Chassoux, Francine, Chipaux, Mathilde, Cloppenborg, Thomas, Coras, Roland, Cross, J Helen, De Palma, Luca, De Tisi, Jane, Deleo, Francesco, Devaux, Bertrand, Di Gennaro, Giancarlo, Dorfmüller, Georg, Duncan, John S, Elger, Christian, Ernst, Katharina, Esposito, Vincenzo, Feucht, Martha, Gadze, Zeljka Petelin, Garbelli, Rita, Geleijns, Karin, Gil-Nagel, Antonio, Grote, Alexander, Grunwald, Thomas, Guerrini, Renzo, Hamer, Hajo, Honavar, Mrinalini, Jacques, Thomas S, Jakovcevic, Antonia, Jutila, Leena, Kalina, Adam, Kälviäinen, Reetta, Klein, Karl Martin, Koenig, Kristina, Krsek, Pavel, Kudernatsch, Manfred, Kudr, Martin, Lamberink, Herm J, Malmgren, Kristina, Marusic, Petr, Melikyan, Armen, Menzler, Katja, Noachtar, Soheyl, Otte, Willem M, Özkara, Çiğdem, Pieper, Tom, Pimentel, Jose, Raicevic, Savo, Rheims, Sylvain, Ribeiro, Joana, Rosenow, Felix, Rössler, Karl, Rydenhag, Bertil, Sales, Francisco, San Antonio-Arce, Victoria, Schaller, Karl Lothar, Schijns, Olaf, Scholl, Theresa, Schramm, Johannes, Schulze-Bonhage, Andreas, Sciot, Raf, Seeck, Margitta, Shishkina, Lyudmila, Sokic, Dragoslav, Specchio, Nicola, Theys, Tom, Thom, Maria, Delgado, Rafael Toledano, Toulouse, Joseph, Uzan, Mustafa, van Loon, Johannes, Van Paesschen, Wim, von Oertzen, Tim J, Jansen, Floor, Leijten, Frans, van Rijen, Peter, Spliet, Wim GM, Mühlebner, Angelika, Kasper, Burkhard S, Fauser, Susanne, Polster, Tilman, Kalbhenn, Thilo, Delev, Daniel, McEvoy, Andrew, Miserocchi, Anna, Landré, Elisabeth, Turak, Bares, Varlet, Pascale, Ferrand-Sorbets, Sarah, Fohlen, Martine, Bulteau, Christine, Edelvik, Anna, Shah, Mukesch J, Scheiwe, Christian, Delicado, Eva Gutierrez, Tisdall, Martin, Eltze, Christin, Akkol, Serdar, Deniz, Kaancan, Oz, Buge, Holthausen, Hans, Hartlieb, Till, Staudt, Martin, Casciato, Sara, Quarato, Pier P, Giangaspero, Felice, Streichenberger, Nathalie, Guenot, Marc, Isnard, Jean, Valentijn, Antonio, Chang, Amanda, Mullatti, Nandini, Zamecnik, Josef, Zarubova, Jana, Tomasek, Martin, Immonen, Arto, Saarela, Anni, Rauramaa, Tuomas, Lobrinus, Johannes A, Egervari, Kristof, Momjian, Shahan, Harti, Elisabeth, Lohr, Hannah, Kroell, Judith, Vermeulen, Lynn, Cleeren, Evy, Vlasov, Pavel, Kozlova, Antonia, Vorobyev, Alexey, Goeppel, Gudrun, Samueli, Sharon, Czech, Thomas, Hainfellner, Johannes, Puttinger, Gertraud, Schwarz, Gabriele, Stefanits, Harald, Weis, Serge, Spreafico, Roberto, Villani, Flavio, Rossini, Laura, Hermsen, Anke, Knake, Susanne, Nimsky, Christopher, Carl, Barbara, Belohlavkova, Anezka, Benova, Barbora, Bisschop, Jeroen, Colon, Albert, van Kranen-Mastenbroek, Vivianne, Rouhl, Rob PW, Hoogland, Govert, Rumiá, Jordi, Ramírez-Camacho, Alia, Candela-Cantó, Santiago, Ostrowsky-Coste, Karine, Panagiotakaki, Eleni, Montavont, Alexandra, Kosal, Pascale Keo, Gokce-Samar, Zeynep, Milleret, Clara, Buccoliero, Anna M, Giordano, Flavio, Sulentic, Vlatko, Mrak, Goran, Desnica, Andrej, CarfíPavia, Giusy, De Benedictis, Alessandro, Marras, Carlo E, Bascarevic, Vladimir, Vojvodic, Nikola, Ristic, Aleksandar, Rebelo, Olinda, Aledo-Serrano, Angel, Garcia-Morales, Irene, Anciones, Carla, and Braun, Kees P J

Published
2020
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17. Chewing induced reflex seizures (“eating epilepsy”) and eye closure sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: Review of literature and report of 8 cases

Author

von Stülpnagel, Celina, Hartlieb, Till, Borggräfe, Ingo, Coppola, Antonietta, Gennaro, Elena, Eschermann, Kirsten, Kiwull, Lorenz, Kluger, Felicitas, Krois, Ilona, Møller, Rikke S., Rössler, Franziska, Santulli, Lia, Schwermer, Constanze, Wallacher-Scholz, Barbara, Zara, Federico, Wolf, Peter, and Kluger, Gerhard

Published
2019
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20. Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease

Author

Zagaglia, Sara, Selch, Christina, Nisevic, Jelena Radic, Mei, Davide, Michalak, Zuzanna, Hernandez-Hernandez, Laura, Krithika, S., Vezyroglou, Katharina, Varadkar, Sophia M., Pepler, Alexander, Biskup, Saskia, Leão, Miguel, Gärtner, Jutta, Merkenschlager, Andreas, Jaksch, Michaela, Møller, Rikke S., Gardella, Elena, Kristiansen, Britta Schlott, Hansen, Lars Kjærsgaard, Vari, Maria Stella, Helbig, Katherine L., Desai, Sonal, Smith-Hicks, Constance L., Hino-Fukuyo, Naomi, Talvik, Tiina, Laugesaar, Rael, Ilves, Pilvi, Õunap, Katrin, Körber, Ingrid, Hartlieb, Till, Kudernatsch, Manfred, Winkler, Peter, Schimmel, Mareike, Hasse, Anette, Knuf, Markus, Heinemeyer, Jan, Makowski, Christine, Ghedia, Sondhya, Subramanian, Gopinath M., Striano, Pasquale, Thomas, Rhys H., Micallef, Caroline, Thom, Maria, Werring, David J., Kluger, Gerhard Josef, Cross, J. Helen, Guerrini, Renzo, Balestrini, Simona, and Sisodiya, Sanjay M.

Published
2018
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21. D-galactose supplementation for the treatment of mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE): A pilot trial of precision medicine after epilepsy surgery

Author

German Research Foundation, Aledo-Serrano, Ángel, Valls-Carbó, Adrián, Fenger, Christina D., Groeppel, Gudrun, Hartlieb, Till, Pascual, Irene, Herraez, Erika, Cabal, Borja, García-Morales, Irene, Toledano, Rafael, Budke, Marcelo, Beltran-Corbellini, Álvaro, Baldassari, Sara, Coras, Roland, Kobow, Katja, Herrera, David M., Barrio, Antonio del, Dahl, Hans Atli, Pino, Isabel del, Baulac, Stéphanie, Gil-Nagel, Antonio, German Research Foundation, Aledo-Serrano, Ángel, Valls-Carbó, Adrián, Fenger, Christina D., Groeppel, Gudrun, Hartlieb, Till, Pascual, Irene, Herraez, Erika, Cabal, Borja, García-Morales, Irene, Toledano, Rafael, Budke, Marcelo, Beltran-Corbellini, Álvaro, Baldassari, Sara, Coras, Roland, Kobow, Katja, Herrera, David M., Barrio, Antonio del, Dahl, Hans Atli, Pino, Isabel del, Baulac, Stéphanie, and Gil-Nagel, Antonio

Abstract

MOGHE is defined as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Approximately half of the patients with histopathologically confirmed MOGHE carry a brain somatic variant in the SLC35A2 gene encoding a UDP-galactose transporter. Previous research showed that D-galactose supplementation results in clinical improvement in patients with a congenital disorder of glycosylation due to germline variants in SLC35A2. We aimed to evaluate the effects of D-galactose supplementation in patients with histopathologically confirmed MOGHE, with uncontrolled seizures or cognitive impairment and epileptiform activity at the EEG after epilepsy surgery (NCT04833322). Patients were orally supplemented with D-galactose for 6 months in doses up to 1.5 g/kg/day and monitored for seizure frequency including 24-h video-EEG recording, cognition and behavioral scores, i.e., WISC, BRIEF-2, SNAP-IV, and SCQ, and quality of life measures, before and 6 months after treatment. Global response was defined by > 50% improvement of seizure frequency and/or cognition and behavior (clinical global impression of “much improved” or better). Twelve patients (aged 5–28 years) were included from three different centers. Neurosurgical tissue samples were available in all patients and revealed a brain somatic variant in SLC35A2 in six patients (non-present in the blood). After 6 months of supplementation, D-galactose was well tolerated with just two patients presenting abdominal discomfort, solved after dose spacing or reduction. There was a 50% reduction or higher of seizure frequency in 3/6 patients, with an improvement at EEG in 2/5 patients. One patient became seizure-free. An improvement of cognitive/behavioral features encompassing impulsivity (mean SNAP-IV − 3.19 [− 0.84; − 5.6]), social communication (mean SCQ − 2.08 [− 0.63; − 4.90]), and executive function (BRIEF-2 inhibit − 5.2 [− 1.23; − 9.2]) was observed. Global responder rate was 9/12 (6/6 in SLC35A2-po

Published
2023

23. D-galactose supplementation for the treatment of mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE): a trial of precision medicine after epilepsy surgery

Author

Aledo-Serrano, Angel, primary, Valls-Carbó, Adrián, additional, Fenger, Christina D., additional, Groeppel, Gudrun, additional, Hartlieb, Till, additional, Pascual, Irene, additional, Herraez, Erika, additional, Cabal, Borja, additional, García-Morales, Irene, additional, Toledano, Rafael, additional, Budke, Marcelo, additional, Beltran-Corbellini, Álvaro, additional, Baldassari, Sara, additional, Coras, Roland, additional, Kobow, Katja, additional, Herrera, David M., additional, Barrio, Antonio del, additional, Dahl, Hans Atli, additional, Pino, Isabel del, additional, Baulac, Stéphanie, additional, Blumcke, Ingmar, additional, Møller, Rikke S., additional, and Gil-Nagel, Antonio, additional

Published
2023
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24. Alterations inPTPN11and other RAS-/MAP-Kinase pathway genes define ganglioglioma with adverse clinical outcome and atypic histopathological features

Author

Hoffmann, Lucas, primary, Coras, Roland, additional, Kobow, Katja, additional, López-Rivera, Javier A., additional, Lal, Dennis, additional, Leu, Costin, additional, Najm, Imad, additional, Nürnberg, Peter, additional, Herms, Jochen, additional, Harter, Patrick N., additional, Bien, Christian G., additional, Kalbhenn, Thilo, additional, Müller, Markus, additional, Pieper, Tom, additional, Hartlieb, Till, additional, Kudernatsch, Manfred, additional, Hamer, Hajo, additional, Brandner, Sebastian, additional, Rössler, Karl, additional, Blümcke, Ingmar, additional, and Jabari, Samir, additional

Published
2022
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25. The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

Author

López-Rivera, Javier A, primary, Leu, Costin, additional, Macnee, Marie, additional, Khoury, Jean, additional, Hoffmann, Lucas, additional, Coras, Roland, additional, Kobow, Katja, additional, Bhattarai, Nisha, additional, Pérez-Palma, Eduardo, additional, Hamer, Hajo, additional, Brandner, Sebastian, additional, Rössler, Karl, additional, Bien, Christian G, additional, Kalbhenn, Thilo, additional, Pieper, Tom, additional, Hartlieb, Till, additional, Butler, Elizabeth, additional, Genovese, Giulio, additional, Becker, Kerstin, additional, Altmüller, Janine, additional, Niestroj, Lisa-Marie, additional, Ferguson, Lisa, additional, Busch, Robyn M, additional, Nürnberg, Peter, additional, Najm, Imad, additional, Blümcke, Ingmar, additional, and Lal, Dennis, additional

Published
2022
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28. genomic landscape across 474 surgically accessible epileptogenic human brain lesions.

Author

López-Rivera, Javier A, Leu, Costin, Macnee, Marie, Khoury, Jean, Hoffmann, Lucas, Coras, Roland, Kobow, Katja, Bhattarai, Nisha, Pérez-Palma, Eduardo, Hamer, Hajo, Brandner, Sebastian, Rössler, Karl, Bien, Christian G, Kalbhenn, Thilo, Pieper, Tom, Hartlieb, Till, Butler, Elizabeth, Genovese, Giulio, Becker, Kerstin, and Altmüller, Janine

Subjects
EPILEPSY, FOCAL cortical dysplasia, BRAIN damage, HIPPOCAMPAL sclerosis, CHROMOSOME duplication, PARTIAL epilepsy
Abstract

Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2 , DEPDC5 and PTEN , germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed 'second hit' disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21–q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics. [ABSTRACT FROM AUTHOR]

Published
2023
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29. The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

Author

López-Rivera, Javier A., primary, Leu, Costin, additional, Macnee, Marie, additional, Khoury, Jean, additional, Hoffmann, Lucas, additional, Coras, Roland, additional, Kobow, Katja, additional, Bhattarai, Nisha, additional, Pérez-Palma, Eduardo, additional, Hamer, Hajo, additional, Brandner, Sebastian, additional, Rössler, Karl, additional, Bien, Christian G., additional, Kalbhenn, Thilo, additional, Pieper, Tom, additional, Hartlieb, Till, additional, Butler, Elizabeth, additional, Genovese, Giulio, additional, Becker, Kerstin, additional, Altmüller, Janine, additional, Niestroj, Lisa-Marie, additional, Ferguson, Lisa, additional, Busch, Robyn M., additional, Nürnberg, Peter, additional, Najm, Imad, additional, Blümcke, Ingmar, additional, and Lal, Dennis, additional

Published
2022
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30. Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.

Author

Barba, Carmen, Blumcke, Ingmar, Winawer, Melodie R., Hartlieb, Till, Kang, Hoon-Chul, Grisotto, Laura, Chipaux, Mathilde, Bien, Christian G., Heřmanovská, Barbora, Porter, Brenda E., Lidov, Hart G.W., Cetica, Valentina, Woermann, Friedrich G., Lopez-Rivera, Javier A., Canoll, Peter D., Mader, Irina, D'Incerti, Ludovico, Baldassari, Sara, Yang, Edward, and Gaballa, Ahmed

Published
2023
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31. DNA methylation-based classification of malformations of cortical development in the human brain

Author

Jabari, Samir, primary, Kobow, Katja, additional, Pieper, Tom, additional, Hartlieb, Till, additional, Kudernatsch, Manfred, additional, Polster, Tilman, additional, Bien, Christian G., additional, Kalbhenn, Thilo, additional, Simon, Matthias, additional, Hamer, Hajo, additional, Rössler, Karl, additional, Feucht, Martha, additional, Mühlebner, Angelika, additional, Najm, Imad, additional, Peixoto-Santos, José Eduardo, additional, Gil-Nagel, Antonio, additional, Delgado, Rafael Toledano, additional, Aledo-Serrano, Angel, additional, Hou, Yanghao, additional, Coras, Roland, additional, von Deimling, Andreas, additional, and Blümcke, Ingmar, additional

Published
2021
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32. Multilobar unilateral hypoplasia with emphasis on the posterior quadrant and severe epilepsy in children with FCD ILAE Type 1A

Author

Holthausen, Hans, primary, Coras, Roland, additional, Tang, Yingying, additional, Bai, Lily, additional, Wang, Irene, additional, Pieper, Tom, additional, Kudernatsch, Manfred, additional, Hartlieb, Till, additional, Staudt, Martin, additional, Winkler, Peter, additional, Hofer, Wiebke, additional, Jabari, Samir, additional, Kobow, Katja, additional, and Blumcke, Ingmar, additional

Published
2021
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36. Additional file 1 of Frequent SLC35A2 brain mosaicism in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)

Author

Bonduelle, Thomas, Hartlieb, Till, Baldassari, Sara, Sim, Nam Suk, Kim, Se Hoon, Hoon-Chul Kang, Kobow, Katja, Coras, Roland, Chipaux, Mathilde, Dorfmüller, Georg, Adle-Biassette, Homa, Aronica, Eleonora, Lee, Jeong Ho, Blumcke, Ingmar, and Baulac, Stéphanie

Abstract

Additional file: 1. Supplemental data. Full list of genes included in the panel. SupplementaryTable 1. Neuropathological reassessment of multicentric cohort of 43 MCD cases. Supplementary Table 2. Clinical comparisons between SLC35A2-mutated and panelnegative MOGHE cases.

Published
2021
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37. Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study

Author

Lamberink, Herm J, primary, Otte, Willem M, additional, Blümcke, Ingmar, additional, Braun, Kees P J, additional, Aichholzer, Martin, additional, Amorim, Isabel, additional, Aparicio, Javier, additional, Aronica, Eleonora, additional, Arzimanoglou, Alexis, additional, Barba, Carmen, additional, Beck, Jürgen, additional, Becker, Albert, additional, Beckervordersandforth, Jan C, additional, Bien, Christian G, additional, Bodi, Istvan, additional, Braun, Kees PJ, additional, Catenoix, Helene, additional, Chassoux, Francine, additional, Chipaux, Mathilde, additional, Cloppenborg, Thomas, additional, Coras, Roland, additional, Cross, J Helen, additional, De Palma, Luca, additional, De Tisi, Jane, additional, Deleo, Francesco, additional, Devaux, Bertrand, additional, Di Gennaro, Giancarlo, additional, Dorfmüller, Georg, additional, Duncan, John S, additional, Elger, Christian, additional, Ernst, Katharina, additional, Esposito, Vincenzo, additional, Feucht, Martha, additional, Gadze, Zeljka Petelin, additional, Garbelli, Rita, additional, Geleijns, Karin, additional, Gil-Nagel, Antonio, additional, Grote, Alexander, additional, Grunwald, Thomas, additional, Guerrini, Renzo, additional, Hamer, Hajo, additional, Honavar, Mrinalini, additional, Jacques, Thomas S, additional, Jakovcevic, Antonia, additional, Jutila, Leena, additional, Kalina, Adam, additional, Kälviäinen, Reetta, additional, Klein, Karl Martin, additional, Koenig, Kristina, additional, Krsek, Pavel, additional, Kudernatsch, Manfred, additional, Kudr, Martin, additional, Lamberink, Herm J, additional, Malmgren, Kristina, additional, Marusic, Petr, additional, Melikyan, Armen, additional, Menzler, Katja, additional, Noachtar, Soheyl, additional, Özkara, Çiğdem, additional, Pieper, Tom, additional, Pimentel, Jose, additional, Raicevic, Savo, additional, Rheims, Sylvain, additional, Ribeiro, Joana, additional, Rosenow, Felix, additional, Rössler, Karl, additional, Rydenhag, Bertil, additional, Sales, Francisco, additional, San Antonio-Arce, Victoria, additional, Schaller, Karl Lothar, additional, Schijns, Olaf, additional, Scholl, Theresa, additional, Schramm, Johannes, additional, Schulze-Bonhage, Andreas, additional, Sciot, Raf, additional, Seeck, Margitta, additional, Shishkina, Lyudmila, additional, Sokic, Dragoslav, additional, Specchio, Nicola, additional, Theys, Tom, additional, Thom, Maria, additional, Delgado, Rafael Toledano, additional, Toulouse, Joseph, additional, Uzan, Mustafa, additional, van Loon, Johannes, additional, Van Paesschen, Wim, additional, von Oertzen, Tim J, additional, Jansen, Floor, additional, Leijten, Frans, additional, van Rijen, Peter, additional, Spliet, Wim GM, additional, Mühlebner, Angelika, additional, Kasper, Burkhard S, additional, Fauser, Susanne, additional, Polster, Tilman, additional, Kalbhenn, Thilo, additional, Delev, Daniel, additional, McEvoy, Andrew, additional, Miserocchi, Anna, additional, Landré, Elisabeth, additional, Turak, Bares, additional, Varlet, Pascale, additional, Ferrand-Sorbets, Sarah, additional, Fohlen, Martine, additional, Bulteau, Christine, additional, Edelvik, Anna, additional, Shah, Mukesch J, additional, Scheiwe, Christian, additional, Delicado, Eva Gutierrez, additional, Tisdall, Martin, additional, Eltze, Christin, additional, Akkol, Serdar, additional, Deniz, Kaancan, additional, Oz, Buge, additional, Holthausen, Hans, additional, Hartlieb, Till, additional, Staudt, Martin, additional, Casciato, Sara, additional, Quarato, Pier P, additional, Giangaspero, Felice, additional, Streichenberger, Nathalie, additional, Guenot, Marc, additional, Isnard, Jean, additional, Valentijn, Antonio, additional, Chang, Amanda, additional, Mullatti, Nandini, additional, Zamecnik, Josef, additional, Zarubova, Jana, additional, Tomasek, Martin, additional, Immonen, Arto, additional, Saarela, Anni, additional, Rauramaa, Tuomas, additional, Lobrinus, Johannes A, additional, Egervari, Kristof, additional, Momjian, Shahan, additional, Harti, Elisabeth, additional, Lohr, Hannah, additional, Kroell, Judith, additional, Vermeulen, Lynn, additional, Cleeren, Evy, additional, Vlasov, Pavel, additional, Kozlova, Antonia, additional, Vorobyev, Alexey, additional, Goeppel, Gudrun, additional, Samueli, Sharon, additional, Czech, Thomas, additional, Hainfellner, Johannes, additional, Puttinger, Gertraud, additional, Schwarz, Gabriele, additional, Stefanits, Harald, additional, Weis, Serge, additional, Spreafico, Roberto, additional, Villani, Flavio, additional, Rossini, Laura, additional, Hermsen, Anke, additional, Knake, Susanne, additional, Nimsky, Christopher, additional, Carl, Barbara, additional, Belohlavkova, Anezka, additional, Benova, Barbora, additional, Bisschop, Jeroen, additional, Colon, Albert, additional, van Kranen-Mastenbroek, Vivianne, additional, Rouhl, Rob PW, additional, Hoogland, Govert, additional, Rumiá, Jordi, additional, Ramírez-Camacho, Alia, additional, Candela-Cantó, Santiago, additional, Ostrowsky-Coste, Karine, additional, Panagiotakaki, Eleni, additional, Montavont, Alexandra, additional, Kosal, Pascale Keo, additional, Gokce-Samar, Zeynep, additional, Milleret, Clara, additional, Buccoliero, Anna M, additional, Giordano, Flavio, additional, Sulentic, Vlatko, additional, Mrak, Goran, additional, Desnica, Andrej, additional, CarfíPavia, Giusy, additional, De Benedictis, Alessandro, additional, Marras, Carlo E, additional, Bascarevic, Vladimir, additional, Vojvodic, Nikola, additional, Ristic, Aleksandar, additional, Rebelo, Olinda, additional, Aledo-Serrano, Angel, additional, Garcia-Morales, Irene, additional, and Anciones, Carla, additional

Published
2020
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39. Multilobar unilateral hypoplasia with emphasis on the posterior quadrant and severe epilepsy in children with FCD ILAE Type 1A.

Author

Holthausen, Hans, Coras, Roland, Tang, Yingying, Bai, Lily, Wang, Irene, Pieper, Tom, Kudernatsch, Manfred, Hartlieb, Till, Staudt, Martin, Winkler, Peter, Hofer, Wiebke, Jabari, Samir, Kobow, Katja, and Blumcke, Ingmar

Subjects
EPILEPSY, CHILDHOOD epilepsy, MAGNETIC resonance imaging, EPILEPTIFORM discharges, STATUS epilepticus, DNA methylation, VAGUS nerve
Abstract

Objective: Focal cortical dysplasia (FCD) Type 1 and its three subtypes have yet not been fully characterized at the clinical, anatomopathological, and molecular level (International League Against Epilepsy [ILAE] FCD classification from 2011). We aimed to describe the clinical phenotype of patients with histopathologically confirmed FCD1A obtained from a single epilepsy center between 2002 and 2016. Methods: Medical records were retrieved from the hospital's archive. Results from electroencephalography (EEG) video recordings, neuroimaging, and histopathology were reevaluated. Magnetic resonance imaging (MRI) post‐processing was retrospectively performed in nine patients. DNA methylation studies were carried out from archival surgical brain tissue in 11 patients. Results: Nineteen children with a histopathological diagnosis of FCD1A were included. The average onset of epilepsy was 0.9 years (range 0.2–10 years). All children had severe cognitive impairment and one third had mild motor deficits, yet fine finger movements were preserved in all patients. All patients had daily seizures, being drug resistant from disease onset. Interictal electroencephalography revealed bilateral multi‐regional epileptiform discharges. Interictal status epilepticus was observed in 8 and countless subclinical seizures in 11 patients. Regional continuous irregular slow waves were of higher lateralizing and localizing yield than spikes. Posterior background rhythms were normal in 16 of 19 children. Neuroimaging showed unilateral multilobar hypoplasia and increased T2‐FLAIR signals of the white matter in 18 of 19 patients. All children underwent tailored multilobar resections, with seizure freedom achieved in 47% (Engel class I). There was no case with frontal involvement without involvement of the posterior quadrant by MRI and histopathology. DNA methylation profiling distinguished FCD1A samples from all other epilepsy specimens and controls. Significance: We identified a cohort of young children with drug resistance from seizure onset, bad EEG with posterior emphasis, lack of any focal neurological deficits but severe cognitive impairment, subtle hypoplasia of the epileptogenic area on MRI, and histopathologically defined and molecularly confirmed by DNA methylation analysis as FCD ILAE Type 1A. [ABSTRACT FROM AUTHOR]

Published
2022
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40. Neurologic phenotypes associated with COL4A1 / 2 mutations

Author

Zagaglia, Sara, Selch, Christina, Radić Nišević, Jelena, Mei, Davide, Michalak, Zuzanna, Hernandez-Hernandez, Laura, Krithika, S., Vezyroglou, Katharina, Varadkar, Sophia M., Pepler, Alexander, Biskup, Saskia, Leão, Miguel, Gärtner, Jutta, Merkenschlager, Andreas, Jaksch, Michaela, Møller, Rikke S., Gardella, Elena, Kristiansen, Britta Schlott, Hansen, Lars Kjærsgaard, Vari, Maria Stella, Helbig, Katherine L., Desai, Sonal, Smith-Hicks, Constance L., Hino-Fukuyo, Naomi, Talvik, Tiina, Laugesaar, Rael, Ilves, Pilvi, Õunap, Katrin, Körber, Ingrid, Hartlieb, Till, Kudernatsch, Manfred, Winkler, Peter, Schimmel, Mareike, Hasse, Anette, Knuf, Markus, Heinemeyer, Jan, Makowski, Christine, Ghedia, Sondhya, Subramanian, Gopinath M., Striano, Pasquale, Thomas, Rhys H., Micallef, Caroline, Thom, Maria, Werring, David J., Kluger, Gerhard Josef, Cross, J. Helen, Guerrini, Renzo, Balestrini, Simona, and Sisodiya, Sanjay M.

Subjects
Adult, Collagen Type IV, Male, Epilepsy, Adolescent, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Neurologija, Young Adult, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Neurology, Child, Preschool, Mutation, Humans, Female, Nervous System Diseases, Child, Genetic Association Studies
Abstract

Objective To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge. Conclusion COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Published
2018
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41. Corpus callosotomy in pediatricdrug resistent lesionalepilepsies - diagnostic approach or therapeutic option?

Author

Kudernatsch, Manfred, Hartlieb, Till, Pieper, Tom, Staudt, Martin, Holthausen, Hans, Winkler, Peter A., and Blümcke, Ingmar

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Objective: CC in our 12 pts led to postoperative EEG lateralization and recommendation to 2nd surgery in 6 cases. In 3 cases 2nd resective surgery was performed with seizure freedom in one and favorable outcome in 2 patients. Quality of life was improved in 9 cases after CC, therefore 3 pts still waiting[for full text, please go to the a.m. URL], 69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie

Published
2018

45. Neurologic phenotypes associated with COL4A1/2 mutations

Author

Zagaglia, Sara, Selch, Christina, Nisevic, Jelena Radic, Mei, Davide, Michalak, Zuzanna, Hernandez-Hernandez, Laura, Krithika, S., Vezyroglou, Katharina, Varadkar, Sophia M., Pepler, Alexander, Biskup, Saskia, Leão, Miguel, Gärtner, Jutta, Merkenschlager, Andreas, Jaksch, Michaela, Møller, Rikke S., Gardella, Elena, Kristiansen, Britta Schlott, Hansen, Lars Kjærsgaard, Vari, Maria Stella, Helbig, Katherine L., Desai, Sonal, Smith-Hicks, Constance L., Hino-Fukuyo, Naomi, Talvik, Tiina, Laugesaar, Rael, Ilves, Pilvi, Õunap, Katrin, Körber, Ingrid, Hartlieb, Till, Kudernatsch, Manfred, Winkler, Peter, Schimmel, Mareike, Hasse, Anette, Knuf, Markus, Heinemeyer, Jan, Makowski, Christine, Ghedia, Sondhya, Subramanian, Gopinath M., Striano, Pasquale, Thomas, Rhys H., Micallef, Caroline, Thom, Maria, Werring, David J., Kluger, Gerhard Josef, Cross, J. Helen, Guerrini, Renzo, Balestrini, Simona, and Sisodiya, Sanjay M.

Subjects
ddc
Published
2018

48. Network for Therapy in Rare Epilepsies (NETRE): Lessons From the Past 15 Years.

Author

von Stülpnagel, Celina, van Baalen, Andreas, Borggraefe, Ingo, Eschermann, Kirsten, Hartlieb, Till, Kiwull, Lorenz, Pringsheim, Milka, Wolff, Markus, Kudernatsch, Manfred, Wiegand, Gert, Striano, Pasquale, and Kluger, Gerhard

Subjects
BRUGADA syndrome, EPILEPSY, SODIUM channel blockers, DATA entry
Abstract

Background: In 2005, Ne twork for T herapy in R are E pilepsies (NETRE)—was initiated in order to share treatment experiences among clinicians in patients with rare epilepsies. Here we describe the structure of the rapidly growing NETRE and summarize some of the findings of the last 15 years. Methodology/Structure of NETRE: NETRE is organized in distinct groups (currently >270). Starting point is always a patient with a rare epilepsy/ epileptic disorder. This creates a new group, and next, a medical coordinator is appointed. The exchange of experiences is established using a data entry form, which the coordinator sends to colleagues. The primary aim is to exchange experiences (retrospectively, anonymously, MRI results also non-anonymously) of the epilepsy treatment as well as on clinical presentation and comorbidities NETRE is neither financed nor sponsored. Results: Some of the relevant results: (1) first description of FIRES as a new epilepsy syndrome and its further investigation, (2) in SCN2A , the assignment to gain- vs. loss-of-function mutations has a major impact on clinical decisions to use or avoid treatment with sodium channel blockers, (3) the important aspect of avoiding overtreatment in CDKL5 patients, due to loss of effects of anticonvulsants after 12 months, (4) pathognomonic MRI findings in FOXG1 patients, (5) the first description of pathognomonic chewing-induced seizures in SYNGAP1 patients, and the therapeutic effect of statins as anticonvulsant in these patients, (6) the phenomenon of another reflex epilepsy—bathing epilepsy associated with a SYN1 mutation. Of special interest is also a NETRE group following twins with genetic and/or structural epilepsies [including vanishing-twin-syndrome and twin-twin-transfusion syndrome) [= "Early Neuroimpaired Twin Entity" (ENITE)]. Discussion and Perspective: NETRE enables clinicians to quickly exchange information on therapeutic experiences in rare diseases with colleagues at an international level. For both parents and clinicians/scientist this international exchange is both reassuring and helpful. In collaboration with other groups, personalized therapeutic approaches are sought, but the present limitations of currently available therapies are also highlighted. Presently, the PATRE Project (PATient based phenotyping and evaluation of therapy for Rare Epilepsies) is commencing, in which information on therapies will be obtained directly from patients and their caregivers. [ABSTRACT FROM AUTHOR]

Published
2021
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49. Mesial Temporal Sclerosis inSCN1A-Related Epilepsy: Two Long-Term EEG Case Studies

Author

Tiefes, Anna M., primary, Hartlieb, Till, additional, Tacke, Moritz, additional, von Stülpnagel-Steinbeis, Celina, additional, Larsen, Line H. G., additional, Hao, Quin, additional, Dahl, Hans Atli, additional, Neubauer, Bernd A., additional, Gerstl, Lucia, additional, Kudernatsch, Manfred, additional, Kluger, Gerhard J., additional, and Borggraefe, Ingo, additional

Published
2018
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