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1. Refractory Crohn’s Disease: Perspectives, Unmet Needs and Innovations

Author

Bertin L, Crepaldi M, Zanconato M, Lorenzon G, Maniero D, De Barba C, Bonazzi E, Facchin S, Scarpa M, Ruffolo C, Angriman I, Buda A, Zingone F, Savarino EV, and Barberio B

Subjects
refractory crohn’s disease, mesenchymal stem cell therapy, medical therapy, combination therapy, fecal microbiota transplantation, biologic drugs, perianal crohn’s disease, small molecules, hyperbaric oxygen therapy, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Luisa Bertin,1 Martina Crepaldi,1 Miriana Zanconato,1 Greta Lorenzon,1 Daria Maniero,1 Caterina De Barba,1 Erica Bonazzi,1 Sonia Facchin,1 Marco Scarpa,2 Cesare Ruffolo,2 Imerio Angriman,2 Andrea Buda,3 Fabiana Zingone,1 Edoardo Vincenzo Savarino,1 Brigida Barberio1 1Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; 2Chirurgia Generale 3 Unit, Azienda Ospedale Università di Padova, Padua, Italy; 3Gastroenterology Unit, Department of Oncological Gastrointestinal Surgery, Feltre, ItalyCorrespondence: Edoardo Vincenzo Savarino, Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy, Tel +39-049-8217749, Fax +39-049-8760820, Email edoardo.savarino@unipd.itAbstract: Crohn’s disease (CD) is a complex, chronic inflammatory bowel disease characterized by unpredictable flare-ups and periods of remission. Despite advances in treatment, CD remains a significant health burden, leading to substantial direct healthcare costs and out-of-pocket expenses for patients, especially in the first-year post-diagnosis. The impact of CD on patients’ quality of life is profound, with significant reductions in physical, emotional, and social well-being. Despite advancements in therapeutic options, including biologics, immunomodulators, and small molecules, many patients struggle to achieve or maintain remission, leading to a considerable therapeutic ceiling. This has led to an increased focus on novel and emerging treatments. This context underscores the importance of exploring advanced and innovative treatment options for managing refractory CD. By examining the latest approaches, including immunomodulators, combination therapies, stem cell therapies, and emerging treatments like fecal microbiota transplantation and dietary interventions, there is an opportunity to gain a comprehensive understanding of how best to address and manage refractory cases of CD. Keywords: refractory Crohn’s disease, mesenchymal stem cell therapy, medical therapy, combination therapy, fecal microbiota transplantation, biologic drugs, perianal Crohn’s disease, small molecules, hyperbaric oxygen therapy

Published
2024

7. P908 Real-life effectiveness and safety of tofacitinib and vedolizumab as a second-line therapy in anti-TNFs experienced patients ulcerative colitis: preliminary results of an IGIBD study (VE2TO-UC)

Author

Noviello, D, primary, Savarino, E, additional, Fries, W, additional, Fantini, M C, additional, Conforti, F, additional, Orlando, A, additional, Ribaldone, D G, additional, Mocci, G, additional, Viganò, C, additional, Festa, S, additional, Spagnuolo, R, additional, Campigotto, M, additional, Grossi, L, additional, Gravina, A G, additional, Principi, M, additional, Imperatore, N, additional, Carvalhas, A, additional, Scardino, G, additional, Scaldaferri, F, additional, Ceccarelli, L, additional, Biancone, L, additional, Di Sario, A, additional, De Barba, C, additional, De Francesco, C, additional, Calderone, S, additional, Onali, S, additional, Vecchi, M, additional, Ventimiglia, M, additional, and Caprioli, F, additional

Published
2024
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8. Ultra-High-Field MR Imaging in Polymicrogyria and Epilepsy

Author

De Ciantis, A, Barkovich, AJ, Cosottini, M, Barba, C, Montanaro, D, Costagli, M, Tosetti, M, Biagi, L, Dobyns, WB, and Guerrini, R

Subjects
Neurodegenerative, Clinical Research, Brain Disorders, Epilepsy, Neurosciences, Biomedical Imaging, Adolescent, Adult, Cerebral Angiography, Cerebral Cortex, Child, Child, Preschool, Female, Humans, Imaging, Three-Dimensional, Infant, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Polymicrogyria, Clinical Sciences, Nuclear Medicine & Medical Imaging
Abstract

Background and purposePolymicrogyria is a malformation of cortical development that is often identified in children with epilepsy or delayed development. We investigated in vivo the potential of 7T imaging in characterizing polymicrogyria to determine whether additional features could be identified.Materials and methodsTen adult patients with polymicrogyria previously diagnosed by using 3T MR imaging underwent additional imaging at 7T. We assessed polymicrogyria according to topographic pattern, extent, symmetry, and morphology. Additional imaging sequences at 7T included 3D T2* susceptibility-weighted angiography and 2D tissue border enhancement FSE inversion recovery. Minimum intensity projections were used to assess the potential of the susceptibility-weighted angiography sequence for depiction of cerebral veins.ResultsAt 7T, we observed perisylvian polymicrogyria that was bilateral in 6 patients, unilateral in 3, and diffuse in 1. Four of the 6 bilateral abnormalities had been considered unilateral at 3T. While 3T imaging revealed 2 morphologic categories (coarse, delicate), 7T susceptibility-weighted angiography images disclosed a uniform ribbonlike pattern. Susceptibility-weighted angiography revealed numerous dilated superficial veins in all polymicrogyric areas. Tissue border enhancement imaging depicted a hypointense line corresponding to the gray-white interface, providing a high definition of the borders and, thereby, improving detection of the polymicrogyric cortex.Conclusions7T imaging reveals more anatomic details of polymicrogyria compared with 3T conventional sequences, with potential implications for diagnosis, genetic studies, and surgical treatment of associated epilepsy. Abnormalities of cortical veins may suggest a role for vascular dysgenesis in pathogenesis.

Published
2015

9. Aneuploidy identification in pre-B acute lymphoblastic leukemia patients at diagnosis by Multiplex Ligation-dependent Probe Amplification (MLPA)

Author

Vázquez-Reyes, A., Bobadilla-Morales, L., Barba-Barba, C., Macías-Salcedo, G., Serafín-Saucedo, G., Velázquez-Rivera, M.E., Almodóvar-Cuevas, M.C., Márquez-Mora, A., Pimentel-Gutiérrez, H.J., Ortega-de-la-Torre, C., Cruz-Osorio, R.M., Nava-Gervasio, S., Rivera-Vargas, J., Sánchez-Zubieta, F., Corona-Rivera, J.R., and Corona-Rivera, A.

Published
2017
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11. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Author

Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, Ali, QZ, Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, and Ali, QZ

Abstract

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Published
2023

16. Tregs and GvHD prevention by extracorporeal photopheresis: observations from a clinical trial

Author

Crocchiolo, R, Cesana, C, Girgenti, D, Bertani, G, Barba, C, Liga, G, Ferri, U, Crucitti, L, Grillo, G, Rossini, S, Cairoli, R, Crocchiolo R, Cesana C, Girgenti D, Bertani G, Barba C, Liga G, Ferri U, Crucitti L, Grillo G, Rossini S, Cairoli R, Crocchiolo, R, Cesana, C, Girgenti, D, Bertani, G, Barba, C, Liga, G, Ferri, U, Crucitti, L, Grillo, G, Rossini, S, Cairoli, R, Crocchiolo R, Cesana C, Girgenti D, Bertani G, Barba C, Liga G, Ferri U, Crucitti L, Grillo G, Rossini S, and Cairoli R

Abstract

The aim of the present study was to evaluate the circulating T regulatory cells (Tregs) in patients undergoing extracorporeal photopheresis (ECP) for the prevention of chronic graft-versus-host disease (GvHD) and to search for any correlation between Tregs counts and chronic GvHD occurrence. Among n = 12 patients with complete longitudinal data, the median cumulative values of absolute peripheral Tregs counts were 21.64 and 63.49 cells/µL for patients who developed chronic GvHD and those who did not develop it, respectively (p = 0.05). The analysis of the median absolute counts of peripheral HLA-DR + Tregs provided similar results, showing that 20% (1 out of 5) and 100% (7 out of 7) of patients with HLA-DR + Tregs values of > 5 cells/µL were in the GvHD and non-GvHD groups, respectively (p = 0.01). In conclusion, the present results support the involvement of Tregs in the prevention of chronic GvHD in patients receiving ECP and suggest Tregs count as a potential biomarker of ECP effectiveness. Future strategies are needed to enhance Tregs expansion and/or activity in conjunction with ECP for an effective chronic GvHD prevention.

Published
2021

17. Correction to: Tregs and GvHD prevention by extracorporeal photopheresis: observations from a clinical trial (Experimental Hematology & Oncology, (2021), 10, 1, (14), 10.1186/s40164-021-00210-9)

Author

Crocchiolo R., Crocchiolo, R, Cesana, C, Girgenti, D, Bertani, G, Barba, C, Liga, G, Ferri, U, Crucitti, L, Grillo, G, Rossini, S, Cairoli, R, Crocchiolo R., Cesana C., Girgenti D., Bertani G., Barba C., Liga G., Ferri U., Crucitti L., Grillo G., Rossini S., Cairoli R., Crocchiolo R., Crocchiolo, R, Cesana, C, Girgenti, D, Bertani, G, Barba, C, Liga, G, Ferri, U, Crucitti, L, Grillo, G, Rossini, S, Cairoli, R, Crocchiolo R., Cesana C., Girgenti D., Bertani G., Barba C., Liga G., Ferri U., Crucitti L., Grillo G., Rossini S., and Cairoli R.

Published
2021

18. Individualized prediction of seizure relapse and outcomes following antiepileptic drug withdrawal after pediatric epilepsy surgery

Author

Lamberink, Herm J., Boshuisen, Kim, Otte, Willem M., Geleijns, Karin, Braun, Kees P. J., Feucht, M, Gröppel, G, Kahane, P, Minotti, L, Arzimanoglou, A, Ryvlin, P, Panagiotakaki, E, de Bellescize, J, Ostrowsky‐Coste, K, Hirsch, E, Valenti, M, Polster, T, Sassen, R, Hoppe, C, Kuczaty, S, Elger, C, Schubert, S, Strobl, K, Bast, T, Barba, C, Guerrini, R, Giordano, F, Francione, S, Caputo, D, Boshuisen, K, Braun, K P J, Uiterwaal, C S P M, van Nieuwenhuizen, O, Leijten, F S, van Rijen, P C, Seeck, M, Yalnizoglu, D, Turanli, G, Topcu, M, Özkara, C, Uzan, M, Cross, J H, DʼArgenzio, L, and Harkness, W

Published
2018
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19. Development of pharmacological tools to study the kv4.3 channelosome in atrial fibrillation

Author

Viedma-Barba, C., Sandin, P., Bonache de Marcos, María Ángeles, Martín-Martínez, Mercedes, Valenzuela, Carmen, Gutiérrez-Rodríguez, Marta, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), and Consejo Superior de Investigaciones Científicas (España)

Abstract

Resumen del trabajo presentado en el XX National Meeting of the Spanish Society of Medicinal Chemistry, celebrado en Santiago de Compostela (España) del 19 al 22 de junio de 2022., Ion channels are macromolecular complexes present in the plasma membrane and in intracellular organelles of the cells, where they play important functions, such as smooth muscle contraction or secretion of hormones. The dysfunction of these channels results in several disorders named channelopathies, which represent a challenge for study and treatment.[1] We are focused on voltage-gated potassium channels, specifically on KV4.3 and its role in atrial fibrillation (AF). KV4.3 channel is expressed in smooth muscle, heart and brain. Its activation generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current). KV4.3 plays a key role in AF, the most common cardiac arrhythmia, with an estimated prevalence in the general population of 1.5–2%. However, current antiarrhythmic drugs for AF prevention have limited efficacy and considerable potential for adverse effects.[2] To reproduce the ITO currents, KV4.3 channels need to assemble with other subunits, forming channelosome. KChIPs (Potassium Channel Interacting Proteins), which belong to the calcium binding protein superfamily, forms the KV4.3 channelosome, along with other proteins.[3] To study the complex interaction of KV4.3 channelosome and the development of modulators, the interplay of different techniques is central to advance knowledge. In this regard, the development of novel KChIPs modulators and fluorescent biosensors constitutes invaluable pharmacological tools to unravel the KV4 channelosome and its role in AF.[3] In this communication, we will describe preliminary results towards the identification of new pharmacological tools to study the KChIPs/KV4 interaction., This work was supported by the projects: PID2019-104366RB-C21, PID2019-104366RB-C22, PID2020-114256RB-I00 and PID2020-119805RB-I00 funded by MCIN/ AEI /10.13039/501100011033; and the projects PIE202180E073 and 2019AEP148 funded by CSIC. C. Viedma Barba holds the grant PRE2020-093542 and M. Valencia holds the grant PRE2020-093950, both funded by MCIN/AEI/10.13039/501100011033. A. Pérez-Lara holds the grant RYC2018-023837-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”.

Published
2022

24. New approaches for the identification of KChIP2 ligands to study the KV4.3 channelosome in atrial fibrillati

Author

Viedma-Barba, C., Martinez-Salas, P., Benito-Bueno, Ángela de, Socuéllamos, Paula G., Marín-Olivero, Irene, Daniel-Mozo, M., Pérez-Lara, Ángel, González-Vera, Juan A., Orte, Angel, Albert, Armando, Martín-Martínez, Mercedes, Valenzuela, Carmen, Gutiérrez-Rodríguez, Marta, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), and Consejo Superior de Investigaciones Científicas (España)

Abstract

Resumen del trabajo presentado en el VIII Congreso Red Española de Canales iónico, celebrado en Alicante (España) del 24 al 27 de mayo de 2022., Ion channels are macromolecular complexes present in the plasma membrane and in intracellular organelles of the cells, where they play important functions. The dysfunction of these channels results in several disorders named channelopathies, which represent a challenge for study and treatment.[1] We are focused on voltage-gated potassium channels, specifically on KV4.3. Kv4.3 is expressed in smooth muscle, heart and brain. Within the heart, Kv4.3 channels generate the transient outward potassium current (ITO). However, ITO characteristics are only observed when Kv4.3 assemble with accessory subunits as KChIP2 and DPP6. KV4.3 channelosome play a key role in atrial fibrillation (AF),the most common cardiac arrhythmia, with an estimated prevalence in the general population of 1.5–2%. However, current antiarrhythmic drugs for AF prevention have limited efficacy and considerable potential for adverse effects.[2] KChIP2 (Potassium Channel Interacting Protein 2) belongs to the calcium binding protein superfamily. It is the KChIP member predominantly expressed in heart and a key regulator of cardiac action potential duration. The identification of novel KChIP2 ligands could be useful to understand the role of KV4.3 channelosome in AF and it could help to discover new treatments for AF. [3] In this regard, structure-based virtual screening could be an important tool to accelerate the identification of novel KChIP2 ligands. In this communication, we will describe a multidisciplinary approach that, starting with a structurebased virtual screening, followed by an iterative process of synthesis/biological evaluation/docking studies, has led to the identification of new KChIP2 ligands., PID2019-104366RB-C21, PID2019-104366RB-C22, PID2020-114256RB-I00 and PID2020-119805RB-I00 grants funded by MCIN/AEI/10.13039/501100011033; and PIE202180E073 and 2019AEP148 funded by CSIC. C.V.B. holds PRE2020-093542 FPI grant funded by MCIN/AEI/10.13039/501100011033. PGS was recipient of an FPU grant (FPU17/02731). AB-B holds BES-2017-080184 FPI grant and A.P-L.holds RYC2018-023837-I grant both funded by MCIN/ AEI/ 10.13039/501100011033 and by “ESF Investing in your future”

Published
2022

25. Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study

Author

Wagstyl, K, Whitaker, K, Raznahan, A, Seidlitz, J, Vertes, PE, Foldes, S, Humphreys, Z, Hu, W, Mo, J, Likeman, M, Davies, S, Lenge, M, Cohen, NT, Tang, Y, Wang, S, Ripart, M, Chari, A, Tisdall, M, Bargallo, N, Conde-Blanco, E, Carlos Pariente, J, Pascual-Diaz, S, Delgado-Martinez, I, Perez-Enriquez, C, Lagorio, I, Abela, E, Mullatti, N, O'Muircheartaigh, J, Vecchiato, K, Liu, Y, Caligiuri, M, Sinclair, B, Vivash, L, Willard, A, Kandasamy, J, McLellan, A, Sokol, D, Semmelroch, M, Kloster, A, Opheim, G, Yasuda, C, Zhang, K, Hamandi, K, Barba, C, Guerrini, R, Gaillard, WD, You, X, Wang, I, Gonzalez-Ortiz, S, Severino, M, Striano, P, Tortora, D, Kalviainen, R, Gambardella, A, Labate, A, Desmond, P, Lui, E, O'Brien, T, Shetty, J, Jackson, G, Duncan, JS, Winston, GP, Pinborg, L, Cendes, F, Cross, JH, Baldeweg, T, Adler, S, Wagstyl, K, Whitaker, K, Raznahan, A, Seidlitz, J, Vertes, PE, Foldes, S, Humphreys, Z, Hu, W, Mo, J, Likeman, M, Davies, S, Lenge, M, Cohen, NT, Tang, Y, Wang, S, Ripart, M, Chari, A, Tisdall, M, Bargallo, N, Conde-Blanco, E, Carlos Pariente, J, Pascual-Diaz, S, Delgado-Martinez, I, Perez-Enriquez, C, Lagorio, I, Abela, E, Mullatti, N, O'Muircheartaigh, J, Vecchiato, K, Liu, Y, Caligiuri, M, Sinclair, B, Vivash, L, Willard, A, Kandasamy, J, McLellan, A, Sokol, D, Semmelroch, M, Kloster, A, Opheim, G, Yasuda, C, Zhang, K, Hamandi, K, Barba, C, Guerrini, R, Gaillard, WD, You, X, Wang, I, Gonzalez-Ortiz, S, Severino, M, Striano, P, Tortora, D, Kalviainen, R, Gambardella, A, Labate, A, Desmond, P, Lui, E, O'Brien, T, Shetty, J, Jackson, G, Duncan, JS, Winston, GP, Pinborg, L, Cendes, F, Cross, JH, Baldeweg, T, and Adler, S

Abstract

OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual l

Published
2022

26. Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study

Author

Spitzer, H, Ripart, M, Whitaker, K, D'Arco, F, Mankad, K, Chen, AA, Napolitano, A, De Palma, L, De Benedictis, A, Foldes, S, Humphreys, Z, Zhang, K, Hu, W, Mo, J, Likeman, M, Davies, S, Guttler, C, Lenge, M, Cohen, NT, Tang, Y, Wang, S, Chari, A, Tisdall, M, Bargallo, N, Conde-Blanco, E, Pariente, JC, Pascual-Diaz, S, Delgado-Martinez, I, Perez-Enriquez, C, Lagorio, I, Abela, E, Mullatti, N, O'Muircheartaigh, J, Vecchiato, K, Liu, Y, Caligiuri, ME, Sinclair, B, Vivash, L, Willard, A, Kandasamy, J, McLellan, A, Sokol, D, Semmelroch, M, Kloster, AG, Opheim, G, Ribeiro, L, Yasuda, C, Rossi-Espagnet, C, Hamandi, K, Tietze, A, Barba, C, Guerrini, R, Gaillard, WD, You, X, Wang, I, Gonzalez-Ortiz, S, Severino, M, Striano, P, Tortora, D, Kalviainen, R, Gambardella, A, Labate, A, Desmond, P, Lui, E, O'Brien, T, Shetty, J, Jackson, G, Duncan, JS, Winston, GP, Pinborg, LH, Cendes, F, Theis, FJ, Shinohara, RT, Cross, JH, Baldeweg, T, Adler, S, Wagstyl, K, Spitzer, H, Ripart, M, Whitaker, K, D'Arco, F, Mankad, K, Chen, AA, Napolitano, A, De Palma, L, De Benedictis, A, Foldes, S, Humphreys, Z, Zhang, K, Hu, W, Mo, J, Likeman, M, Davies, S, Guttler, C, Lenge, M, Cohen, NT, Tang, Y, Wang, S, Chari, A, Tisdall, M, Bargallo, N, Conde-Blanco, E, Pariente, JC, Pascual-Diaz, S, Delgado-Martinez, I, Perez-Enriquez, C, Lagorio, I, Abela, E, Mullatti, N, O'Muircheartaigh, J, Vecchiato, K, Liu, Y, Caligiuri, ME, Sinclair, B, Vivash, L, Willard, A, Kandasamy, J, McLellan, A, Sokol, D, Semmelroch, M, Kloster, AG, Opheim, G, Ribeiro, L, Yasuda, C, Rossi-Espagnet, C, Hamandi, K, Tietze, A, Barba, C, Guerrini, R, Gaillard, WD, You, X, Wang, I, Gonzalez-Ortiz, S, Severino, M, Striano, P, Tortora, D, Kalviainen, R, Gambardella, A, Labate, A, Desmond, P, Lui, E, O'Brien, T, Shetty, J, Jackson, G, Duncan, JS, Winston, GP, Pinborg, LH, Cendes, F, Theis, FJ, Shinohara, RT, Cross, JH, Baldeweg, T, Adler, S, and Wagstyl, K

Abstract

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in

Published
2022

27. New approaches for the identification of KChIP2 ligands to study the KV4.3 channelosome in atrial fibrillati

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Viedma-Barba, C., Martinez-Salas, P., Benito-Bueno, Ángela de, Socuéllamos, Paula G., Marín-Olivero, Irene, Daniel-Mozo, M., Pérez-Lara, Ángel, González-Vera, Juan A., Orte, Angel, Albert, Armando, Martín-Martínez, Mercedes, Valenzuela, Carmen, Gutiérrez-Rodríguez, Marta, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Viedma-Barba, C., Martinez-Salas, P., Benito-Bueno, Ángela de, Socuéllamos, Paula G., Marín-Olivero, Irene, Daniel-Mozo, M., Pérez-Lara, Ángel, González-Vera, Juan A., Orte, Angel, Albert, Armando, Martín-Martínez, Mercedes, Valenzuela, Carmen, and Gutiérrez-Rodríguez, Marta

Abstract

Ion channels are macromolecular complexes present in the plasma membrane and in intracellular organelles of the cells, where they play important functions. The dysfunction of these channels results in several disorders named channelopathies, which represent a challenge for study and treatment.[1] We are focused on voltage-gated potassium channels, specifically on KV4.3. Kv4.3 is expressed in smooth muscle, heart and brain. Within the heart, Kv4.3 channels generate the transient outward potassium current (ITO). However, ITO characteristics are only observed when Kv4.3 assemble with accessory subunits as KChIP2 and DPP6. KV4.3 channelosome play a key role in atrial fibrillation (AF),the most common cardiac arrhythmia, with an estimated prevalence in the general population of 1.5–2%. However, current antiarrhythmic drugs for AF prevention have limited efficacy and considerable potential for adverse effects.[2] KChIP2 (Potassium Channel Interacting Protein 2) belongs to the calcium binding protein superfamily. It is the KChIP member predominantly expressed in heart and a key regulator of cardiac action potential duration. The identification of novel KChIP2 ligands could be useful to understand the role of KV4.3 channelosome in AF and it could help to discover new treatments for AF. [3] In this regard, structure-based virtual screening could be an important tool to accelerate the identification of novel KChIP2 ligands. In this communication, we will describe a multidisciplinary approach that, starting with a structurebased virtual screening, followed by an iterative process of synthesis/biological evaluation/docking studies, has led to the identification of new KChIP2 ligands.

Published
2022

30. Phenotypic and genetic spectrum of ATP6V1A encephalopathy:a disorder of lysosomal homeostasis

Author

Guerrini, R. (Renzo), Mei, D. (Davide), Kerti-Szigeti, K. (Katalin), Pepe, S. (Sara), Koenig, M. K. (Mary Kay), Von Allmen, G. (Gretchen), Cho, M. T. (Megan T), McDonald, K. (Kimberly), Baker, J. (Janice), Bhambhani, V. (Vikas), Powis, Z. (Zöe), Rodan, L. (Lance), Nabbout, R. (Rima), Barcia, G. (Giulia), Rosenfeld, J. A. (Jill A), Bacino, C. A. (Carlos A), Mignot, C. (Cyril), Power, L. H. (Lillian H), Harris, C. J. (Catharine J), Marjanovic, D. (Dragan), Møller, R. S. (Rikke S), Hammer, T. B. (Trine B), T. D. (The DDD Study), Keski Filppula, R. (Riikka), Vieira, P. (Päivi), Hildebrandt, C. (Clara), Sacharow, S. (Stephanie), U. D. (Undiagnosed Diseases Network), Maragliano, L. (Luca), Benfenati, F. (Fabio), Lachlan, K. (Katherine), Benneche, A. (Andreas), Petit, F. (Florence), de Sainte Agathe, J. M. (Jean Madeleine), Hallinan, B. (Barbara), Si, Y. (Yue), Wentzensen, I. M. (Ingrid M), Zou, F. (Fanggeng), Narayanan, V. (Vinodh), Matsumoto, N. (Naomichi), Boncristiano, A. (Alessandra), la Marca, G. (Giancarlo), Kato, M. (Mitsuhiro), Anderson, K. (Kristin), Barba, C. (Carmen), Sturiale, L. (Luisa), Garozzo, D. (Domenico), Bei, R. (Roberto), A. c. (ATP6V1A collaborators), Masuelli, L. (Laura), Conti, V. (Valerio), Novarino, G. (Gaia), and Fassio, A. (Anna)

Subjects
developmental delay, epileptic encephalopathy, lysosomal disorder, ATP6V1A, progressive brain atrophy
Abstract

Vacuolar-type H⁺-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/β family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.

Published
2022

41. Razas caprinas autóctonas de fomento

Author

Gonzalo, C., Barba, C., and Gómez-Moya, J. D.

Subjects
Cabres, Veterinària
Abstract

Las razas Murciana-Granadina, Malagueña, Agrupación Caprina Canaria (Majorera, Palmera y Tinerfeña) y Verata constituyen claros ejemplos de subpoblaciones bien diferenciadas y adaptadas al clima seco y árido de sus regiones de origen. Poseen una gran importancia censal y una aptitud lechera mayoritaria, cuya mejora selectiva está siendo desarrollada por Asociaciones de Criadores bien consolidadas y en expansión. La mayoría de ellas presentan una elevada aptitud para el ordeño mecánico con elevados caudales medios y máximos de leche, soportando muy bien la realización de un único ordeño diario sin pérdidas importantes de producción y composición de leche. Adicionalmente, su leche es de muy elevada calidad grasa y proteica, en comparación con otras razas especializadas como la Alpina y la Saanen, siendo destinada a la elaboración de quesos amparados por diferentes Denominaciones de Origen (Queso de Murcia, Majorero, Palmero, Queso de Ibores) que gozan de un excelente mercado. Los rendimientos productivos son claramente tributarios de la intensificación del sistema de producción, sobrepasando los 500 litros de leche por lactación en los rebaños más especializados. Desde el punto de vista cárnico, todas ellas presentan una elevada prolificidad, que oscila entre 140% y 200%, si bien las canales que poseen un mayor índice de compacidad son las de los cabritos de raza Verata, haciendo, así, honor a su doble aptitud carne-leche.

Published
2021

42. Productos porcinos tradicionales de la región de Murcia

Author

Poto, A., Peinado, B., Barba, C., and Marín, M.

Subjects
Porcs, Veterinària
Abstract

Murcia es una de las regiones españolas que más tradición atesora en la elaboración de productos porcinos tradicionales. La competitividad de estos productos derivados del cerdo Chato Murciano como raza porcina autóctona obedece a cuestiones tecnológicas debido a su proceso artesanal, de tipo económico al encontrarse mayor valor añadido relativo en aquellos productos elaborados a partir de las partes menos nobles del animal, y finalmente a sus características organolépticas que contribuyen a su definitiva diferenciación en el mercado. Dichos productos se clasifican en tres tipos. Por un lado, aquellos obtenidos por técnicas de salazón y secado de los que el lomo curado es uno de los derivados más importantes obtenidos a partir de las piezas nobles. Por otra parte, en su segundo apartado destacamos los productos crudos curados como es el caso del chorizo, la longaniza y la sobrasada, haciendo especial referencia a la imperial lorquina como elaborado más genuino del grupo. Finalmente, se exponen los productos típicos elaborados mediante cocción siendo éste el caso del morcón de Lorca, el chiquillo, la morcilla, la butifarra lorquina y otros productos menos conocidos como la rejila, el buche o botija y el envuelto. Estos productos se consideran como los más locales y específicos entre todos los descritos.

Published
2021

43. Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy

Author

Spinelli, E, Christensen, KR, Bryant, E, Schneider, A, Rakotomamonjy, J, Muir, AM, Giannelli, J, Littlejohn, RO, Roeder, ER, Schmidt, B, Wilson, WG, Marco, EJ, Iwama, K, Kumada, S, Pisano, T, Barba, C, Vetro, A, Brilstra, EH, Jaarsveld, RH, Matsumoto, N, Goldberg-Stern, H, Carney, PW, Andrews, PI, El Achkar, CM, Berkovic, S, Rodan, LH, McWalter, K, Guerrini, R, Scheffer, IE, Mefford, HC, Mandelstam, S, Laux, L, Millichap, JJ, Guemez-Gamboa, A, Nairn, AC, Carvill, GL, Spinelli, E, Christensen, KR, Bryant, E, Schneider, A, Rakotomamonjy, J, Muir, AM, Giannelli, J, Littlejohn, RO, Roeder, ER, Schmidt, B, Wilson, WG, Marco, EJ, Iwama, K, Kumada, S, Pisano, T, Barba, C, Vetro, A, Brilstra, EH, Jaarsveld, RH, Matsumoto, N, Goldberg-Stern, H, Carney, PW, Andrews, PI, El Achkar, CM, Berkovic, S, Rodan, LH, McWalter, K, Guerrini, R, Scheffer, IE, Mefford, HC, Mandelstam, S, Laux, L, Millichap, JJ, Guemez-Gamboa, A, Nairn, AC, and Carvill, GL

Abstract

OBJECTIVE: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum. METHODS: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells. RESULTS: We identify de novo missense variants in the STK domain in 11 individuals, including 2 recurrent variants p.G510S (n = 5) and p.G515S (n = 3). All 11 individuals had developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at <2 years of age. All patients developed multiple seizure types, 9 of 11 patients had seizures triggered by fever and 9 of 11 patients had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wild-type. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally. INTERPRETATION: In summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex. ANN NEUROL 2021;90:274-284.

Published
2021

44. Phenotypic Spectrum of Seizure Disorders in MBD5-Associated Neurodevelopmental Disorder

Author

Myers, KA, Marini, C, Carvill, GL, McTague, A, Panetta, J, Stutterd, C, Stanley, T, Marin, S, Nguyen, J, Barba, C, Rosati, A, Scott, RH, Mefford, HC, Guerrini, R, Scheffer, IE, Myers, KA, Marini, C, Carvill, GL, McTague, A, Panetta, J, Stutterd, C, Stanley, T, Marin, S, Nguyen, J, Barba, C, Rosati, A, Scott, RH, Mefford, HC, Guerrini, R, and Scheffer, IE

Abstract

OBJECTIVE: To describe the phenotypic spectrum in patients with MBD5-associated neurodevelopmental disorder (MAND) and seizures; features of MAND include intellectual disability, epilepsy, psychiatric features of aggression and hyperactivity, and dysmorphic features including short stature and microcephaly, sleep disturbance, and ataxia. METHODS: We performed phenotyping on patients with MBD5 deletions, duplications, or point mutations and a history of seizures. RESULTS: Twenty-three patients with MAND and seizures were included. Median seizure onset age was 2.9 years (range 3 days-13 years). The most common seizure type was generalized tonic-clonic; focal, atypical absence, tonic, drop attacks, and myoclonic seizures occurred frequently. Seven children had convulsive status epilepticus and 3 nonconvulsive status epilepticus. Fever, viral illnesses, and hot weather provoked seizures. EEG studies in 17/21 patients were abnormal, typically showing slow generalized spike-wave and background slowing. Nine had drug-resistant epilepsy, although 3 eventually became seizure-free. All but one had moderate-to-severe developmental impairment. Epilepsy syndromes included Lennox-Gastaut syndrome, myoclonic-atonic epilepsy, and infantile spasms syndrome. Behavioral problems in 20/23 included aggression, self-injurious behavior, and sleep disturbance. CONCLUSIONS: MBD5 disruption may be associated with severe early childhood-onset developmental and epileptic encephalopathy. Because neuropsychiatric dysfunction is common and severe, it should be an important focus of clinical management.

Published
2021

45. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB

Abstract

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

46. Temporal lobe epilepsy surgery in children and adults: A multicenter study

Author

Barba, C., Cossu, M., Guerrini, R., Di Gennaro, G., Villani, F., De Palma, L., Grisotto, L., Consales, A., Battaglia, Domenica Immacolata, Zamponi, N., D'Orio, P., Revay, M., Rizzi, M., Casciato, S., Esposito, V., Quarato, P. P., Di Giacomo, R., Didato, G., Pastori, C., Pavia, G. C., Pellacani, S., Matta, G., Pacetti, M., Tamburrini, Gianpiero, Cesaroni, E., Colicchio, G., Vatti, G., Asioli, S., Caulo, M., Marras, C. E., Tassi, L., D'Aniello, Aleandra, Morace, R., De Curtis, M., Deleo, F., Giordano, F., De Benedictis, Anna, Prato, G., Perulli, Marco, Battaglia D. (ORCID:0000-0003-0491-4021), Tamburrini G. (ORCID:0000-0002-7139-5711), D'Aniello A., De Benedictis A., Perulli M., Barba, C., Cossu, M., Guerrini, R., Di Gennaro, G., Villani, F., De Palma, L., Grisotto, L., Consales, A., Battaglia, Domenica Immacolata, Zamponi, N., D'Orio, P., Revay, M., Rizzi, M., Casciato, S., Esposito, V., Quarato, P. P., Di Giacomo, R., Didato, G., Pastori, C., Pavia, G. C., Pellacani, S., Matta, G., Pacetti, M., Tamburrini, Gianpiero, Cesaroni, E., Colicchio, G., Vatti, G., Asioli, S., Caulo, M., Marras, C. E., Tassi, L., D'Aniello, Aleandra, Morace, R., De Curtis, M., Deleo, F., Giordano, F., De Benedictis, Anna, Prato, G., Perulli, Marco, Battaglia D. (ORCID:0000-0003-0491-4021), Tamburrini G. (ORCID:0000-0002-7139-5711), D'Aniello A., De Benedictis A., and Perulli M.

Abstract

Objective: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers. Methods: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons. Results: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P =.006 and <.0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P =.023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P =.001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P =.001, Q = 0.003, at 2-year FU and OR = 45.03, P <.0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group. Significance: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. E

Published
2021

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