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188 results on '"Ragona, F."'

1. 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

2. A novel KCNC1 gain-of-function variant causing developmental and epileptic encephalopathy: 'Precision medicine' approach with fluoxetine

Author: Ambrosino, P, Ragona, F, Mosca, I, Vannicola, C, Canafoglia, L, Solazzi, R, Rivolta, I, Freri, E, Granata, T, Messina, G, Castellotti, B, Gellera, C, Soldovieri, M, Difrancesco, J, Taglialatela, M, Ambrosino, Paolo, Ragona, Francesca, Mosca, Ilaria, Vannicola, Chiara, Canafoglia, Laura, Solazzi, Roberta, Rivolta, Ilaria, Freri, Elena, Granata, Tiziana, Messina, Giuliana, Castellotti, Barbara, Gellera, Cinzia, Soldovieri, Maria Virginia, DiFrancesco, Jacopo Cosimo, Taglialatela, Maurizio, Ambrosino, P, Ragona, F, Mosca, I, Vannicola, C, Canafoglia, L, Solazzi, R, Rivolta, I, Freri, E, Granata, T, Messina, G, Castellotti, B, Gellera, C, Soldovieri, M, Difrancesco, J, Taglialatela, M, Ambrosino, Paolo, Ragona, Francesca, Mosca, Ilaria, Vannicola, Chiara, Canafoglia, Laura, Solazzi, Roberta, Rivolta, Ilaria, Freri, Elena, Granata, Tiziana, Messina, Giuliana, Castellotti, Barbara, Gellera, Cinzia, Soldovieri, Maria Virginia, DiFrancesco, Jacopo Cosimo, and Taglialatela, Maurizio
Abstract: Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function features. Here, we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents (1) were larger, with membrane potentials between −40 and +40 mV; (2) displayed a hyperpolarizing shift in activation gating; (3) failed to inactivate; and (4) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills, and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs.
Published: 2023

3. A novel de novo HCN2 loss-of-function variant causing developmental and epileptic encephalopathy treated with a ketogenic diet

Author: Difrancesco, J, Ragona, F, Murano, C, Frosio, A, Melgari, D, Binda, A, Calamaio, S, Prevostini, R, Mauri, M, Canafoglia, L, Castellotti, B, Messina, G, Gellera, C, Previtali, R, Veggiotti, P, Milanesi, R, Barbuti, A, Solazzi, R, Freri, E, Granata, T, Rivolta, I, DiFrancesco, Jacopo C, Ragona, Francesca, Murano, Carmen, Frosio, Anthony, Melgari, Dario, Binda, Anna, Calamaio, Serena, Prevostini, Rachele, Mauri, Mario, Canafoglia, Laura, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Previtali, Roberto, Veggiotti, Pierangelo, Milanesi, Raffaella, Barbuti, Andrea, Solazzi, Roberta, Freri, Elena, Granata, Tiziana, Rivolta, Ilaria, Difrancesco, J, Ragona, F, Murano, C, Frosio, A, Melgari, D, Binda, A, Calamaio, S, Prevostini, R, Mauri, M, Canafoglia, L, Castellotti, B, Messina, G, Gellera, C, Previtali, R, Veggiotti, P, Milanesi, R, Barbuti, A, Solazzi, R, Freri, E, Granata, T, Rivolta, I, DiFrancesco, Jacopo C, Ragona, Francesca, Murano, Carmen, Frosio, Anthony, Melgari, Dario, Binda, Anna, Calamaio, Serena, Prevostini, Rachele, Mauri, Mario, Canafoglia, Laura, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Previtali, Roberto, Veggiotti, Pierangelo, Milanesi, Raffaella, Barbuti, Andrea, Solazzi, Roberta, Freri, Elena, Granata, Tiziana, and Rivolta, Ilaria
Abstract: Missense variants of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels cause variable phenotypes, ranging from mild generalized epilepsy to developmental and epileptic encephalopathy (DEE). Although variants of HCN1 are an established cause of DEE, those of HCN2 have been reported in generalized epilepsies. Here we describe the first case of DEE caused by the novel de novo heterozygous missense variant c.1379G>A (p.G460D) of HCN2. Functional characterization in transfected HEK293 cells and neonatal rat cortical neurons revealed that HCN2 p.G460D currents were strongly reduced compared to wild-type, consistent with a dominant negative loss-of-function effect. Immunofluorescence staining showed that mutant channels are retained within the cell and do not reach the membrane. Moreover, mutant HCN2 also affect HCN1 channels, by reducing the Ih current expressed by the HCN1-HCN2 heteromers. Due to the persistence of frequent seizures despite pharmacological polytherapy, the patient was treated with a ketogenic diet, with a significant and long-lasting reduction of episodes. In vitro experiments conducted in a ketogenic environment demonstrated that the clinical improvement observed with this dietary regimen was not mediated by a direct action on HCN2 activity. These results expand the clinical spectrum related to HCN2 channelopathies, further broadening our understanding of the pathogenesis of DEE.
Published: 2023

4. Neuro-telehealth for fragile patients in a tertiary referral neurological institute during the COVID-19 pandemic in Milan, Lombardy

Author: Pareyson, D, Pantaleoni, C, Eleopra, R, De Filippis, G, Moroni, I, Freri, E, Zibordi, F, Bulgheroni, S, Pagliano, E, Sarti, D, Silvani, A, Grazzi, L, Tiraboschi, P, Didato, G, Anghileri, E, Bersano, A, Valentini, L, Piacentini, S, Muscio, C, Leonardi, M, Mariotti, C, Eoli, M, Nuzzo, S, Tagliavini, F, Confalonieri, P, De Giorgi, F, Antozzi, C, Ardissone, A, Bersano, E, Boncoraglio, G, Bonvegna, S, Botturi, A, Brambilla, L, Canafoglia, L, Caputi, L, Caroppo, P, Carriero, M, Casali, C, Casazza, M, Catania, A, Ciaccio, C, Cilia, R, Dallabella, E, D'Amico, D, Danti, F, D'Arrigo, S, Decurtis, M, Deleo, F, Devigili, G, Difede, G, Digiacomo, R, Elia, A, Esposito, S, Estienne, M, Fenu, S, Fichera, M, Finocchiaro, G, Frangiamore, R, Gatti, M, Gaviani, P, Giaccone, G, Giani, L, Giovagnoli, A, Andreasi, N, Granata, T, Granocchio, E, Lamperti, C, Lamperti, E, Leone, M, Masson, R, Nanetti, L, Nardocci, N, Pastori, C, Pisciotta, C, Cecchini, A, Ragona, F, Redaelli, V, Saletti, V, Salsano, E, Scelzo, E, Solazzi, R, Tozzo, A, Usai, S, Zorzi, G, Arnoldi, M, Foscan, M, Marchi, A, Pedrinelli, I, Zanin, R, Gazzola, S, Magazu, S, Scopelliti, M, Casalino, T, Desalvatore, M, Mazzanti, S, Taddei, M, Fedeli, A, Sattin, D, Galimberti, L, Zagari, R, Bombonato, M, Fonte, L, Floridia, S, Pareyson D., Pantaleoni C., Eleopra R., De Filippis G., Moroni I., Freri E., Zibordi F., Bulgheroni S., Pagliano E., Sarti D., Silvani A., Grazzi L., Tiraboschi P., Didato G., Anghileri E., Bersano A., Valentini L., Piacentini S., Muscio C., Leonardi M., Mariotti C., Eoli M., Nuzzo S., Tagliavini F., Confalonieri P., De Giorgi F., Antozzi C., Ardissone A., Bersano E., Boncoraglio G., Bonvegna S., Botturi A., Brambilla L., Canafoglia L., Caputi L., Caroppo P., Carriero M. R., Casali C., Casazza M., Catania A., Ciaccio C., Cilia R., DallaBella E., D'Amico D., Danti F. R., D'Arrigo S., DeCurtis M., Deleo F., Devigili G., DiFede G., DiGiacomo R., Elia A., Esposito S., Estienne M., Fenu S., Fichera M., Finocchiaro G., Frangiamore R., Gatti M., Gaviani P., Giaccone G., Giani L., Giovagnoli A. R., Andreasi N. G., Granata T., Granocchio E., Lamperti C., Lamperti E., Leone M., Masson R., Nanetti L., Nardocci N., Pastori C., Pisciotta C., Cecchini A. P., Ragona F., Redaelli V., Saletti V., Salsano E., Scelzo E., Solazzi R., Tozzo A., Usai S., Zorzi G., Arnoldi M. T., Foscan M., Marchi A., Pedrinelli I., Zanin R., Gazzola S., Magazu S., Scopelliti M. R., Casalino T., DeSalvatore M., Mazzanti S., Taddei M., Fedeli A., Sattin D., Galimberti L., Zagari R., Bombonato M., Fonte L., Floridia S., Pareyson, D, Pantaleoni, C, Eleopra, R, De Filippis, G, Moroni, I, Freri, E, Zibordi, F, Bulgheroni, S, Pagliano, E, Sarti, D, Silvani, A, Grazzi, L, Tiraboschi, P, Didato, G, Anghileri, E, Bersano, A, Valentini, L, Piacentini, S, Muscio, C, Leonardi, M, Mariotti, C, Eoli, M, Nuzzo, S, Tagliavini, F, Confalonieri, P, De Giorgi, F, Antozzi, C, Ardissone, A, Bersano, E, Boncoraglio, G, Bonvegna, S, Botturi, A, Brambilla, L, Canafoglia, L, Caputi, L, Caroppo, P, Carriero, M, Casali, C, Casazza, M, Catania, A, Ciaccio, C, Cilia, R, Dallabella, E, D'Amico, D, Danti, F, D'Arrigo, S, Decurtis, M, Deleo, F, Devigili, G, Difede, G, Digiacomo, R, Elia, A, Esposito, S, Estienne, M, Fenu, S, Fichera, M, Finocchiaro, G, Frangiamore, R, Gatti, M, Gaviani, P, Giaccone, G, Giani, L, Giovagnoli, A, Andreasi, N, Granata, T, Granocchio, E, Lamperti, C, Lamperti, E, Leone, M, Masson, R, Nanetti, L, Nardocci, N, Pastori, C, Pisciotta, C, Cecchini, A, Ragona, F, Redaelli, V, Saletti, V, Salsano, E, Scelzo, E, Solazzi, R, Tozzo, A, Usai, S, Zorzi, G, Arnoldi, M, Foscan, M, Marchi, A, Pedrinelli, I, Zanin, R, Gazzola, S, Magazu, S, Scopelliti, M, Casalino, T, Desalvatore, M, Mazzanti, S, Taddei, M, Fedeli, A, Sattin, D, Galimberti, L, Zagari, R, Bombonato, M, Fonte, L, Floridia, S, Pareyson D., Pantaleoni C., Eleopra R., De Filippis G., Moroni I., Freri E., Zibordi F., Bulgheroni S., Pagliano E., Sarti D., Silvani A., Grazzi L., Tiraboschi P., Didato G., Anghileri E., Bersano A., Valentini L., Piacentini S., Muscio C., Leonardi M., Mariotti C., Eoli M., Nuzzo S., Tagliavini F., Confalonieri P., De Giorgi F., Antozzi C., Ardissone A., Bersano E., Boncoraglio G., Bonvegna S., Botturi A., Brambilla L., Canafoglia L., Caputi L., Caroppo P., Carriero M. R., Casali C., Casazza M., Catania A., Ciaccio C., Cilia R., DallaBella E., D'Amico D., Danti F. R., D'Arrigo S., DeCurtis M., Deleo F., Devigili G., DiFede G., DiGiacomo R., Elia A., Esposito S., Estienne M., Fenu S., Fichera M., Finocchiaro G., Frangiamore R., Gatti M., Gaviani P., Giaccone G., Giani L., Giovagnoli A. R., Andreasi N. G., Granata T., Granocchio E., Lamperti C., Lamperti E., Leone M., Masson R., Nanetti L., Nardocci N., Pastori C., Pisciotta C., Cecchini A. P., Ragona F., Redaelli V., Saletti V., Salsano E., Scelzo E., Solazzi R., Tozzo A., Usai S., Zorzi G., Arnoldi M. T., Foscan M., Marchi A., Pedrinelli I., Zanin R., Gazzola S., Magazu S., Scopelliti M. R., Casalino T., DeSalvatore M., Mazzanti S., Taddei M., Fedeli A., Sattin D., Galimberti L., Zagari R., Bombonato M., Fonte L., and Floridia S.
Abstract: Background: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced. Methods: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children. Results: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March–September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high. Conclusions: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.
Published: 2021

5. Neuro-telehealth for fragile patients in a tertiary referral neurological institute during the COVID-19 pandemic in Milan, Lombardy

Author: Pareyson D., Pantaleoni C., Eleopra R., De Filippis G., Moroni I., Freri E., Zibordi F., Bulgheroni S., Pagliano E., Sarti D., Silvani A., Grazzi L., Tiraboschi P., Didato G., Anghileri E., Bersano A., Valentini L., Piacentini S., Muscio C., Leonardi M., Mariotti C., Eoli M., Nuzzo S., Tagliavini F., Confalonieri P., De Giorgi F., Antozzi C., Ardissone A., Bersano E., Boncoraglio G., Bonvegna S., Botturi A., Brambilla L., Canafoglia L., Caputi L., Caroppo P., Carriero M. R., Casali C., Casazza M., Catania A., Ciaccio C., Cilia R., DallaBella E., D'Amico D., Danti F. R., D'Arrigo S., DeCurtis M., Deleo F., Devigili G., DiFede G., DiGiacomo R., Elia A., Esposito S., Estienne M., Fenu S., Fichera M., Finocchiaro G., Frangiamore R., Gatti M., Gaviani P., Giaccone G., Giani L., Giovagnoli A. R., Andreasi N. G., Granata T., Granocchio E., Lamperti C., Lamperti E., Leone M., Masson R., Nanetti L., Nardocci N., Pastori C., Pisciotta C., Cecchini A. P., Ragona F., Redaelli V., Saletti V., Salsano E., Scelzo E., Solazzi R., Tozzo A., Usai S., Zorzi G., Arnoldi M. T., Foscan M., Marchi A., Pedrinelli I., Zanin R., Gazzola S., Magazu S., Scopelliti M. R., Casalino T., DeSalvatore M., Mazzanti S., Taddei M., Fedeli A., Sattin D., Galimberti L., Zagari R., Bombonato M., Fonte L., Floridia S., Pareyson, D, Pantaleoni, C, Eleopra, R, De Filippis, G, Moroni, I, Freri, E, Zibordi, F, Bulgheroni, S, Pagliano, E, Sarti, D, Silvani, A, Grazzi, L, Tiraboschi, P, Didato, G, Anghileri, E, Bersano, A, Valentini, L, Piacentini, S, Muscio, C, Leonardi, M, Mariotti, C, Eoli, M, Nuzzo, S, Tagliavini, F, Confalonieri, P, De Giorgi, F, Antozzi, C, Ardissone, A, Bersano, E, Boncoraglio, G, Bonvegna, S, Botturi, A, Brambilla, L, Canafoglia, L, Caputi, L, Caroppo, P, Carriero, M, Casali, C, Casazza, M, Catania, A, Ciaccio, C, Cilia, R, Dallabella, E, D'Amico, D, Danti, F, D'Arrigo, S, Decurtis, M, Deleo, F, Devigili, G, Difede, G, Digiacomo, R, Elia, A, Esposito, S, Estienne, M, Fenu, S, Fichera, M, Finocchiaro, G, Frangiamore, R, Gatti, M, Gaviani, P, Giaccone, G, Giani, L, Giovagnoli, A, Andreasi, N, Granata, T, Granocchio, E, Lamperti, C, Lamperti, E, Leone, M, Masson, R, Nanetti, L, Nardocci, N, Pastori, C, Pisciotta, C, Cecchini, A, Ragona, F, Redaelli, V, Saletti, V, Salsano, E, Scelzo, E, Solazzi, R, Tozzo, A, Usai, S, Zorzi, G, Arnoldi, M, Foscan, M, Marchi, A, Pedrinelli, I, Zanin, R, Gazzola, S, Magazu, S, Scopelliti, M, Casalino, T, Desalvatore, M, Mazzanti, S, Taddei, M, Fedeli, A, Sattin, D, Galimberti, L, Zagari, R, Bombonato, M, Fonte, L, and Floridia, S
Subjects: Adult, medicine.medical_specialty, Telemedicine, Neurology, Referral, Dermatology, Telehealth, 03 medical and health sciences, 0302 clinical medicine, Pandemic, medicine, Humans, Outpatient clinic, 030212 general & internal medicine, Medical prescription, Child, Pandemics, Referral and Consultation, SARS-CoV-2, business.industry, Teleneurorehabilitation, COVID-19, General Medicine, medicine.disease, Televisit, Psychiatry and Mental health, Italy, Neuro-telehealth, Neurology (clinical), Neurosurgery, Medical emergency, business, 030217 neurology & neurosurgery
Abstract: Background: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced. Methods: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children. Results: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March–September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high. Conclusions: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.
Published: 2021

6. Cannabidiol in Pharmacoresistant Epilepsy: Clinical Pharmacokinetic Data From an Expanded Access Program

Author: Contin M., Mohamed S., Santucci M., Lodi M. A. M., Russo E., Mecarelli O., Bisulli F., Boni A., Cantalupo G., Cesaroni E., Coppola A., Di Bonaventura C., Fetta A., La Neve A., Matricardi S., Michelucci R., Papa A., Pilolli N., Pulitano P., Ragona F., Russo P., Striano P., Volpi L., Zucca C., Contin, M., Mohamed, S., Santucci, M., Lodi, M. A. M., Russo, E., Mecarelli, O., Bisulli, F., Boni, A., Cantalupo, G., Cesaroni, E., Coppola, A., Di Bonaventura, C., Fetta, A., La Neve, A., Matricardi, S., Michelucci, R., Papa, A., Pilolli, N., Pulitano, P., Ragona, F., Russo, P., Striano, P., Volpi, L., and Zucca, C.
Subjects: 0301 basic medicine, medicine.medical_specialty, Evening, Gastroenterology, 03 medical and health sciences, cannabidiol, 0302 clinical medicine, Dravet syndrome, Pharmacokinetics, Internal medicine, medicine, Pharmacology (medical), antiseizure medication, Pharmacology, business.industry, epilepsy, Lennox–Gastaut syndrome, pharmacokinetics, lcsh:RM1-950, Venous blood, Brief Research Report, medicine.disease, digestive system diseases, 030104 developmental biology, lcsh:Therapeutics. Pharmacology, Concomitant, Expanded access, business, Cannabidiol, 030217 neurology & neurosurgery, medicine.drug
Abstract: Background and Aim: Data on the clinical pharmacokinetics of cannabidiol (CBD) are scanty. We explored the effect of demographic and clinical variables on plasma concentrations of purified CBD in patients with Dravet (DS) and Lennox–Gastaut syndrome (LGS).Methods: The study design was an open, prospective, multicenter expanded access program (EAP). Venous blood samples were drawn from patients between 8 and 9 am, before the CBD morning dose, 12 h apart from the last evening dose, and then 2.5 h after their usual morning dose.Results: We collected 127 plasma samples (67-morning pre-dosing and 60 post-dosing) from 43 patients (24 females, 19 males), 27 with LGS and 16 with DS. Mean ± standard deviation age was 26 ± 15 years. Duration of CBD treatment averaged 4.2 ± 2.9 months at 13.2 ± 4.6 mg/kg/day. CBD median trough plasma concentration was 91 ng/ml; it doubled to 190 ng/ml 2.5 h post-dosing (p < 0.001). Cannabidiol trough plasma concentrations were linearly related to daily doses (r = 0.564, p < 0.001). Median trough CBD plasma concentration-to-weight-adjusted dose ratio (C/D) was 32% higher (p < 0.02) in plasma samples from subjects aged 18 and over than in those under 18. Sex and concomitant antiseizure medications (ASMs) were not associated with significant variations in CBD C/D, but caution is required due to the potential influence of confounders.Conclusion: These are the first data on CBD pharmacokinetics in children and adults with LGS or DS in a real-world setting. The most relevant finding was the higher CBD C/D in adults. In practice, reduced weight-normalized doses might be required with aging to achieve the same CBD plasma levels.
Published: 2021

7. Clinical dissection of childhood occipital epilepsy of Gastaut and prognostic implication

Author: Verrotti, A., Laino, D., Rinaldi, V. E., Suppiej, A., Giordano, L., Toldo, I., Margari, L., Parisi, P., Rizzo, R., Matricardi, S., Cusmai, R., Grosso, S., Gaggero, R., Zamponi, N., Pavone, P., Capovilla, G., Rauchenzauner, M., Cerminara, C., Di Gennaro, G., Esposito, M., Striano, P., Savasta, S., Coppola, G., Siliquini, S., Operto, F., Belcastro, V., Ragona, F., Marseglia, G. L., and Spalice, A.
Published: 2016
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8. Progressive epileptic encephalopathy associated with a novel HCN2 mutation

Author: Binda, A, Murano, C, DI FRANCESCO, J, Castellotti, B, Milanesi, R, Ragona, F, Freri, E, Canafoglia, L, Franceschetti, S, Solazzi, R, Granata, T, Gellera, C, Rivolta, I, Binda A, MURANO, CARMEN, Di Francesco JC, Castellotti B, Milanesi R, Ragona F, Freri E, Canafoglia L, Franceschetti S, Solazzi R, Granata T, Gellera C, Rivolta I, Binda, A, Murano, C, DI FRANCESCO, J, Castellotti, B, Milanesi, R, Ragona, F, Freri, E, Canafoglia, L, Franceschetti, S, Solazzi, R, Granata, T, Gellera, C, Rivolta, I, Binda A, MURANO, CARMEN, Di Francesco JC, Castellotti B, Milanesi R, Ragona F, Freri E, Canafoglia L, Franceschetti S, Solazzi R, Granata T, Gellera C, and Rivolta I
Abstract: So far mutations in HCN2 gene, encoding for the hyperpolarization-activated cyclic nucleotide-gated channel 2, have been related to mild epileptic clinical phenotypes. In this study, a novel HCN2 mutation was found in a proband, now aged 7 years old, with a congenital encephalopathy characterized by drug resistant epilepsy, severe developmental delay, ataxia, dystonia and cerebral visual impairment. A convulsive status epilepticus at 5 months of age marked the onset of epilepsy. The HCN2 mutation affects an aminoacid located in the S6 transmembrane helix (p.Gly460Asp) and is carried in heterozygosis. To describe the functional consequences of the mutant channel, whole-cell patch-clamp experiments were performed in HEK293 cells expressing HCN2 wild type (WT) or p.Gly460Asp channel. A coexpression of the same amount of plasmid encoding for the wt or the mutant form of the channel mimed the heterozygous condition. A complete abolishment of the current was observed considering the mutant compared to the WT channel (-9.9±1.2 pA/pF, n=20 vs -31.2±8.4 pA/pF, n=44 respectively; p<0.05) and the heterozygous condition led to a significant reduction of the current density (-20.1±5.1 pA/pF n=35; p<0.05). WT and heterozygotic channels shared overlapping activation curves (V1/2 and k -92.9±0.3 mV and 5.6±0.3, n=29 vs -91.6±0.2 mV and 5.6±0.2, n=16 respectively) and no significant differences were present in their kinetics of both activation and deactivation. In conclusion, this is the first study linking HCN2 to progressive epileptic encephalopathy. The Gly460Asp mutation seems to act as a loss-of-function that could potentially affect the control of neuronal excitability and therefore explain the proband pathological condition.
Published: 2019

9. 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

10. Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox–Gastaut Syndrome

Author: Iannone, L. F., Arena, G., Battaglia, Domenica Immacolata, Bisulli, F., Bonanni, P., Boni, A., Canevini, M. P., Cantalupo, G., Cesaroni, E., Contin, M., Coppola, A., Cordelli, D. M., Cricchiuti, G., De Giorgis, V., De Leva, M. F., De Rinaldis, M., D'Orsi, Giovanni Maria, Elia, M., Galimberti, C. A., Morano, A., Granata, T., Guerrini, R., Lodi, M. A. M., La Neve, A., Marchese, F., Masnada, S., Michelucci, R., Nosadini, M., Pilolli, N., Pruna, D., Ragona, F., Rosati, A., Santucci, M., Spalice, A., Pietrafusa, N., Striano, P., Tartara, E., Tassi, L., Papa, A., Zucca, C., Russo, Elisa, Mecarelli, O., Battaglia D. (ORCID:0000-0003-0491-4021), d'Orsi G., Russo E., Iannone, L. F., Arena, G., Battaglia, Domenica Immacolata, Bisulli, F., Bonanni, P., Boni, A., Canevini, M. P., Cantalupo, G., Cesaroni, E., Contin, M., Coppola, A., Cordelli, D. M., Cricchiuti, G., De Giorgis, V., De Leva, M. F., De Rinaldis, M., D'Orsi, Giovanni Maria, Elia, M., Galimberti, C. A., Morano, A., Granata, T., Guerrini, R., Lodi, M. A. M., La Neve, A., Marchese, F., Masnada, S., Michelucci, R., Nosadini, M., Pilolli, N., Pruna, D., Ragona, F., Rosati, A., Santucci, M., Spalice, A., Pietrafusa, N., Striano, P., Tartara, E., Tassi, L., Papa, A., Zucca, C., Russo, Elisa, Mecarelli, O., Battaglia D. (ORCID:0000-0003-0491-4021), d'Orsi G., and Russo E.
Abstract: Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox–Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.
Published: 2021

11. Multicenter prospective longitudinal study in 34 patients with Dravet syndrome: Neuropsychological development in the first six years of life

Author: Battaglia, Domenica Immacolata, Chieffo, Daniela Pia Rosaria, Lucibello, Simona, Marini, C., Sibilia, V., Mei, D., Darra, F., Offredi, F., Fontana, Elisa, Specchio, N., Cappelletti, S., Granata, T., Ragona, F., Patrini, Massimiliano, Baglietto, M. G., Prato, G., Ferrari, A., Vigevano, F., Mercuri, Eugenio Maria, Bernardina, B. D., Guerrini, R., Dravet, C., Guzzetta, F., Battaglia D. (ORCID:0000-0003-0491-4021), Chieffo D., Lucibello S., Fontana E., Patrini M., Mercuri E. (ORCID:0000-0002-9851-5365), Battaglia, Domenica Immacolata, Chieffo, Daniela Pia Rosaria, Lucibello, Simona, Marini, C., Sibilia, V., Mei, D., Darra, F., Offredi, F., Fontana, Elisa, Specchio, N., Cappelletti, S., Granata, T., Ragona, F., Patrini, Massimiliano, Baglietto, M. G., Prato, G., Ferrari, A., Vigevano, F., Mercuri, Eugenio Maria, Bernardina, B. D., Guerrini, R., Dravet, C., Guzzetta, F., Battaglia D. (ORCID:0000-0003-0491-4021), Chieffo D., Lucibello S., Fontana E., Patrini M., and Mercuri E. (ORCID:0000-0002-9851-5365)
Abstract: The objective of this study was to identify developmental trajectories of developmental/behavioral phenotypes and possibly their relationship to epilepsy and genotype by analyzing developmental and behavioral features collected prospectively and longitudinally in a cohort of patients with Dravet syndrome (DS). Thirty-four patients from seven Italian tertiary pediatric neurology centers were enrolled in the study. All patients were examined for the SCN1A gene mutation and prospectively assessed from the first years of life with repeated full clinical observations including neurological and developmental examinations. Subjects were found to follow three neurodevelopmental trajectories. In the first group (16 patients), an initial and usually mild decline was observed between the second and the third year of life, specifically concerning visuomotor abilities, later progressing towards global involvement of all abilities. The second group (12 patients) showed an earlier onset of global developmental impairment, progressing towards a generally worse outcome. The third group of only two patients ended up with a normal neurodevelopmental quotient, but with behavioral and linguistic problems. The remaining four patients were not classifiable due to a lack of critical assessments just before developmental decline. The neurodevelopmental trajectories described in this study suggest a differential contribution of neurobiological and genetic factors. The profile of the first group, which included the largest fraction of patients, suggests that in the initial phase of the disease, visuomotor defects might play a major role in determining developmental decline. Early diagnosis of milder cases with initial visuomotor impairment may therefore provide new tools for a more accurate habilitation strategy.
Published: 2021

12. Cardiac phenotype in ATP1A3-related syndromes A multicenter cohort study

Author: Balestrini, S, Mikati, MA, Alvarez-Garcia-Roves, R, Carboni, M, Hunanyan, AS, Kherallah, B, McLean, M, Prange, L, De Grandis, E, Gagliardi, A, Pisciotta, L, Stagnaro, M, Veneselli, E, Campistol, J, Fons, C, Pias-Peleteiro, L, Brashear, A, Miller, C, Samoes, R, Brankovic, V, Padiath, QS, Potic, A, Pilch, J, Vezyroglou, A, Bye, AME, Davis, AM, Ryan, MM, Semsarian, C, Hollingsworth, G, Scheffer, IE, Granata, T, Nardocci, N, Ragona, F, Arzimanoglou, A, Panagiotakaki, E, Carrilho, I, Zucca, C, Novy, J, Parowicz, M, Weckhuysen, S, Pons, R, Groppa, S, Sinden, DS, Pitt, GS, Tinker, A, Ashworth, M, Michalak, Z, Thom, M, Cross, JH, Vavassori, R, Kaski, JP, Sisodiya, SM, Dzieiyc, K, Mazurkiewicz-Beldzinska, M, Balestrini, S, Mikati, MA, Alvarez-Garcia-Roves, R, Carboni, M, Hunanyan, AS, Kherallah, B, McLean, M, Prange, L, De Grandis, E, Gagliardi, A, Pisciotta, L, Stagnaro, M, Veneselli, E, Campistol, J, Fons, C, Pias-Peleteiro, L, Brashear, A, Miller, C, Samoes, R, Brankovic, V, Padiath, QS, Potic, A, Pilch, J, Vezyroglou, A, Bye, AME, Davis, AM, Ryan, MM, Semsarian, C, Hollingsworth, G, Scheffer, IE, Granata, T, Nardocci, N, Ragona, F, Arzimanoglou, A, Panagiotakaki, E, Carrilho, I, Zucca, C, Novy, J, Parowicz, M, Weckhuysen, S, Pons, R, Groppa, S, Sinden, DS, Pitt, GS, Tinker, A, Ashworth, M, Michalak, Z, Thom, M, Cross, JH, Vavassori, R, Kaski, JP, Sisodiya, SM, Dzieiyc, K, and Mazurkiewicz-Beldzinska, M
Abstract: OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
Published: 2020

13. Gabapentin treatment in a patient with KCNQ2 developmental epileptic encephalopathy

Author: Soldovieri, M, Freri, E, Ambrosino, P, Rivolta, I, Mosca, I, Binda, A, Murano, C, Ragona, F, Canafoglia, L, Vannicola, C, Solazzi, R, Granata, T, Castellotti, B, Messina, G, Gellera, C, Labalme, A, Lesca, G, Difrancesco, J, Taglialatela, M, Soldovieri, Maria Virginia, Freri, Elena, Ambrosino, Paolo, Rivolta, Ilaria, Mosca, Ilaria, Binda, Anna, Murano, Carmen, Ragona, Francesca, Canafoglia, Laura, Vannicola, Chiara, Solazzi, Roberta, Granata, Tiziana, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Labalme, Audrey, Lesca, Gaetan, DiFrancesco, Jacopo C., Taglialatela, Maurizio, Soldovieri, M, Freri, E, Ambrosino, P, Rivolta, I, Mosca, I, Binda, A, Murano, C, Ragona, F, Canafoglia, L, Vannicola, C, Solazzi, R, Granata, T, Castellotti, B, Messina, G, Gellera, C, Labalme, A, Lesca, G, Difrancesco, J, Taglialatela, M, Soldovieri, Maria Virginia, Freri, Elena, Ambrosino, Paolo, Rivolta, Ilaria, Mosca, Ilaria, Binda, Anna, Murano, Carmen, Ragona, Francesca, Canafoglia, Laura, Vannicola, Chiara, Solazzi, Roberta, Granata, Tiziana, Castellotti, Barbara, Messina, Giuliana, Gellera, Cinzia, Labalme, Audrey, Lesca, Gaetan, DiFrancesco, Jacopo C., and Taglialatela, Maurizio
Abstract: De novo variants in KCNQ2 encoding for Kv7.2 voltage-dependent neuronal potassium (K+) channel subunits are associated with developmental epileptic encephalopathy (DEE). We herein describe a the clinical and electroencephalographic (EEG) features of a child with early-onset DEE caused by the novel KCNQ2 p.G310S variant. In vitro experiments demonstrated that the mutation induces loss-of-function effects on the currents produced by channels incorporating mutant subunits; these effects were counteracted by the selective Kv7 opener retigabine and by gabapentin, a recently described Kv7 activator. Given these data, the patient started treatment with gabapentin, showing a rapid and sustained clinical and EEG improvement over the following months. Overall, these results suggest that gabapentin can be regarded as a precision therapy for DEEs due to KCNQ2 loss-of-function mutations.
Published: 2020

14. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study

Author: Specchio, N., Pietrafusa, N., Doccini, V., Trivisano, M., Darra, F., Ragona, F., Cossu, A., Spolverato, S., Battaglia, Domenica Immacolata, Quintiliani, Michela, Luigia Gambardella, M., Rosati, Andrea, Mei, D., Granata, T., Dalla Bernardina, B., Vigevano, F., Guerrini, R., Battaglia D. (ORCID:0000-0003-0491-4021), Quintiliani M., Rosati A., Specchio, N., Pietrafusa, N., Doccini, V., Trivisano, M., Darra, F., Ragona, F., Cossu, A., Spolverato, S., Battaglia, Domenica Immacolata, Quintiliani, Michela, Luigia Gambardella, M., Rosati, Andrea, Mei, D., Granata, T., Dalla Bernardina, B., Vigevano, F., Guerrini, R., Battaglia D. (ORCID:0000-0003-0491-4021), Quintiliani M., and Rosati A.
Abstract: Objective: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. Methods: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. Results: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. Significance: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.
Published: 2020

15. Diagnostic imaging in 13 cases of Rasmussen's encephalitis: can early MRI suggest the diagnosis?

Author: Chiapparini, L., Granata, T., Farina, L., Ciceri, E., Erbetta, A., Ragona, F., Freri, E., Fusco, L., Gobbi, G., Capovilla, G., Tassi, L., Giordano, L., Viri, M., Dalla Bernardina, B., Spreafico, R., and Savoiardo, M.
Published: 2003
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16. DISTRIBUTION OF PROGRESSIVE MYOCLONUS EPILEPSIES IN ITALY; POSITIVELY DIAGNOSED AND UNCLASSIFIED PATIENTS: p827

Author: Canafoglia, L., Franceschetti, S., Michelucci, R., Magaudda, A., Rubboli, G., Tinuper, P., Striano, P., Striano, S., Gambardella, A., Neve, La A., Francavilla, T., Ferlazzo, E., Italiano, D., Gobbi, G., Villani, F., Nardocci, N., Granata, T., Veggiotti, P., Pareyson, D., Coppola, G., Uziel, G., Belcastro, V., Bisulli, F., Spreafico, R., Guerrini, R., Viri, M., Zucca, C., Capovilla, G., Giovagnoli, A. R., Canevini, M. P., Binelli, S., Casazza, M., Cantisani, A. T., Filla, A., Pezzella, M., Santucci, M., Parmeggiani, A., Posar, A., De Maria, G., Marini, C., Bianchi, A., Ragona, F., Freri, E., Mariotti, C., and Costa, P.
Published: 2012

17. HCN1 novel mutations in familiar generalized epilepsy

Author: Binda, A, Murano, C, Granata, T, Ragona, F, Freri, E, Franceschetti, S, Canafoglia, L, Castellotti, B, Gellere, C, Milanesi, r, DiFrancesco, JC, Rivolta, I, Binda, A, Murano, C, Granata, T, Ragona, F, Freri, E, Franceschetti, S, Canafoglia, L, Castellotti, B, Gellere, C, Milanesi, R, Difrancesco, J, and Rivolta, I
Subjects: Epilepsy, HCN1, patch-clamp
Published: 2018

18. White matter and cerebellar involvement in alternating hemiplegia of childhood

Author: Severino, M., Pisciotta, L., Tortora, D., Toselli, B., Stagnaro, M., Cordani, R., Morana, G., Zicca, A., Kotzeva, S., Zanaboni, C., Montobbio, G., Rossi, A., De Grandis, E., Bassi, M. T., Zucca, C., Veneselli, E., Franchini, F., Vavassori, M. R., Giannotta, M., Gobbi, G., Granata, T., Nardocci, N., Ragona, F., Gurrieri, F., Neri, G., Tiziano, F. D., Vigevano, F., Capuano, A., and Sartori, S.
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Hemiplegia, Grey matter, Corpus callosum, Tract-based spatial statistics, Severity of Illness Index, White matter, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Cerebellum, medicine, Humans, Alternating hemiplegia of childhood, Brain MRI, Voxel-based morphometry, Case-Control Studies, Child, Diffusion Tensor Imaging, Female, Gray Matter, Middle Aged, Prospective Studies, White Matter, Magnetic Resonance Imaging, 030212 general & internal medicine, Dystonia, business.industry, medicine.disease, medicine.anatomical_structure, Neurology, Brain size, Cardiology, International Cooperative Ataxia Rating Scale, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: To determine whether brain volumetric and white matter microstructural changes are present and correlate with neurological impairment in subjects with alternating hemiplegia of childhood (AHC). In this prospective single-center study, 12 AHC subjects (mean age 22.9 years) and 24 controls were studied with 3DT1-weighted MR imaging and high angular resolution diffusion imaging at 3T. Data obtained with voxel-based morphometry and tract-based spatial statistics were correlated with motor impairment using the International Cooperative Ataxia Rating Scale (ICARS) and Movement and Disability sub-scales of Burke-Fahn-Marsden Dystonia Rating Scale (BFMMS and BFMDS). Compared to healthy controls, AHC subjects showed lower total brain volume (P
Published: 2019

19. HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature

Author: Difrancesco, J, Castellotti, B, Milanesi, R, Ragona, F, Freri, E, Canafoglia, L, Franceschetti, S, Ferrarese, C, Magri, S, Taroni, F, Costa, C, Labate, A, Gambardella, A, Solazzi, R, Binda, A, Rivolta, I, Di Gennaro, G, Casciato, S, D'Incerti, L, Barbuti, A, Difrancesco, D, Granata, T, Gellera, C, DiFrancesco, Jacopo C., Castellotti, Barbara, Milanesi, Raffaella, Ragona, Francesca, Freri, Elena, Canafoglia, Laura, Franceschetti, Silvana, Ferrarese, Carlo, Magri, Stefania, Taroni, Franco, Costa, Cinzia, Labate, Angelo, Gambardella, Antonio, Solazzi, Roberta, Binda, Anna, Rivolta, Ilaria, Di Gennaro, Giancarlo, Casciato, Sara, D'Incerti, Ludovico, Barbuti, Andrea, DiFrancesco, Dario, Granata, Tiziana, Gellera, Cinzia, Difrancesco, J, Castellotti, B, Milanesi, R, Ragona, F, Freri, E, Canafoglia, L, Franceschetti, S, Ferrarese, C, Magri, S, Taroni, F, Costa, C, Labate, A, Gambardella, A, Solazzi, R, Binda, A, Rivolta, I, Di Gennaro, G, Casciato, S, D'Incerti, L, Barbuti, A, Difrancesco, D, Granata, T, Gellera, C, DiFrancesco, Jacopo C., Castellotti, Barbara, Milanesi, Raffaella, Ragona, Francesca, Freri, Elena, Canafoglia, Laura, Franceschetti, Silvana, Ferrarese, Carlo, Magri, Stefania, Taroni, Franco, Costa, Cinzia, Labate, Angelo, Gambardella, Antonio, Solazzi, Roberta, Binda, Anna, Rivolta, Ilaria, Di Gennaro, Giancarlo, Casciato, Sara, D'Incerti, Ludovico, Barbuti, Andrea, DiFrancesco, Dario, Granata, Tiziana, and Gellera, Cinzia
Abstract: The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are highly expressed in the Central Nervous Systems, where they are responsible for the I h current. Together with specific accessory proteins, these channels finely regulate neuronal excitability and discharge activity. In the last few years, a substantial body of evidence has been gathered showing that modifications of I h can play an important role in the pathogenesis of epilepsy. However, the extent to which HCN dysfunction is spread among the epileptic population is still unknown. The aim of this work is to evaluate the impact of genetic mutations potentially affecting the HCN channels’ activity, using a NGS approach. We screened a large cohort of patients with epilepsy of unknown etiology for mutations in HCN1, HCN2 and HCN4 and in genes coding for accessory proteins (MiRP1, Filamin A, Caveolin-3, TRIP8b, Tamalin, S-SCAM and Mint2). We confirmed the presence of specific mutations of HCN genes affecting channel function and predisposing to the development of the disease. We also found several previously unreported additional genetic variants, whose contribution to the phenotype remains to be clarified. According to these results and data from literature, alteration of HCN1 channel function seems to play a major role in epilepsy, but also dysfunctional HCN2 and HCN4 channels can predispose to the development of the disease. Our findings suggest that inclusion of the genetic screening of HCN channels in diagnostic procedures of epileptic patients should be recommended. This would help pave the way for a better understanding of the role played by I h dysfunction in the pathogenesis of epilepsy.
Published: 2019

20. Screening of SLC2A1 in a large cohort of patients suspected for Glut1 deficiency syndrome: identification of novel variants and associated phenotypes

Author: Castellotti, B, Ragona, F, Freri, E, Solazzi, R, Ciardullo, S, Tricomi, G, Venerando, A, Salis, B, Canafoglia, L, Villani, F, Franceschetti, S, Nardocci, N, Gellera, C, Difrancesco, J, Granata, T, Castellotti, Barbara, Ragona, Francesca, Freri, Elena, Solazzi, Roberta, CIARDULLO, STEFANO, Tricomi, Giovanni, Venerando, Anna, Salis, Barbara, Canafoglia, Laura, Villani, Flavio, Franceschetti, Silvana, Nardocci, Nardo, Gellera, Cinzia, DiFrancesco, Jacopo C., Granata, Tiziana, Castellotti, B, Ragona, F, Freri, E, Solazzi, R, Ciardullo, S, Tricomi, G, Venerando, A, Salis, B, Canafoglia, L, Villani, F, Franceschetti, S, Nardocci, N, Gellera, C, Difrancesco, J, Granata, T, Castellotti, Barbara, Ragona, Francesca, Freri, Elena, Solazzi, Roberta, CIARDULLO, STEFANO, Tricomi, Giovanni, Venerando, Anna, Salis, Barbara, Canafoglia, Laura, Villani, Flavio, Franceschetti, Silvana, Nardocci, Nardo, Gellera, Cinzia, DiFrancesco, Jacopo C., and Granata, Tiziana
Abstract: Glucose transporter type 1 deficiency syndrome (Glut1 DS) is a rare neurological disorder caused by impaired glucose delivery to the brain. The clinical spectrum of Glut1 DS mainly includes epilepsy, paroxysmal dyskinesia (PD), developmental delay and microcephaly. Glut1 DS diagnosis is based on the identification of hypoglycorrhachia and pathogenic mutations of the SLC2A1 gene. Here, we report the molecular screening of SLC2A1 in 354 patients clinically suspected for Glut1 DS. From this cohort, we selected 245 patients for whom comprehensive clinical and laboratory data were available. Among them, we identified 19 patients carrying nucleotide variants of pathological significance, 5 of which were novel. The symptoms of onset, which varied from neonatal to adult age, included epilepsy, PD or non-epileptic paroxysmal manifestations. The comparison of the clinical features between the 19 SLC2A1 mutated and the 226 non-mutated patients revealed that the onset of epilepsy within the first year of life (when associated with developmental delay or other neurological manifestations), the association of epilepsy with PD and acquired microcephaly are more common in mutated subjects. Taken together, these data confirm the variability of expression of the phenotypes associated with mutation of SLC2A1 and provide useful clinical tools for the early identification of subjects highly suspected for the disease
Published: 2019

21. Dravet syndrome: Early electroclinical findings and long-term outcome in adolescents and adults

Author: Darra, F., Battaglia, Domenica Immacolata, Dravet, C., Patrini, Massimiliano, Offredi, F., Chieffo, Daniela Pia Rosaria, Piazza, E., Fontana, Elisa, Olivieri, Giorgia, Turrini, Ida, Dalla Bernardina, B., Granata, T., Ragona, F., Battaglia D. (ORCID:0000-0003-0491-4021), Patrini M., Chieffo D., Fontana E., Olivieri G., Turrini I., Darra, F., Battaglia, Domenica Immacolata, Dravet, C., Patrini, Massimiliano, Offredi, F., Chieffo, Daniela Pia Rosaria, Piazza, E., Fontana, Elisa, Olivieri, Giorgia, Turrini, Ida, Dalla Bernardina, B., Granata, T., Ragona, F., Battaglia D. (ORCID:0000-0003-0491-4021), Patrini M., Chieffo D., Fontana E., Olivieri G., and Turrini I.
Abstract: To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course. At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders. Moreover, in both cohorts, we performed a correlation analysis between early characteristics of the disease and the outcome of DS with regard to seizure persistence, ID, behavioral disorder, and neurologic impairment at last evaluation. Group 1 includes 22 adolescents with complete form of DS and 12 with incomplete form; group 2 includes 35 adults with complete form and 15 with incomplete form. The seizures persisted in 73.6% of adolescents and in 80% of adults, but epilepsy severity progressively decreased through age. Seizure persistence correlated with the complete phenotype and with the occurrence of reflex seizures. At last evaluation, ID was moderate or severe in 70.5% of adolescents and in 80% of adults. The most severe cognitive and motor impairment was observed in patients with persisting seizures. The severity of cognition, language, and neurologic impairment at last evaluation correlated statistically with the complete phenotype. The study confirms that the global outcome of DS is poor in most cases, albeit epilepsy severity decreases throughout adulthood. The improvement of epilepsy throughout ages is not associated with improvement in intellectual abilities and motor skills; this confirms that the unfavorable outcome is not a pure consequence of epilepsy.
Published: 2019

22. A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability

Author: Campostrini, G, Difrancesco, J, Castellotti, B, Milanesi, R, Gnecchi-Ruscone, T, Bonzanni, M, Bucchi, A, Baruscotti, M, Ferrarese, C, Franceschetti, S, Canafoglia, L, Ragona, F, Freri, E, Labate, A, Gambardella, A, Costa, C, Gellera, C, Granata, T, Barbuti, A, Difrancesco, D, Difrancesco, JC, Freri, Elena, Labate, Angelo, Campostrini, G, Difrancesco, J, Castellotti, B, Milanesi, R, Gnecchi-Ruscone, T, Bonzanni, M, Bucchi, A, Baruscotti, M, Ferrarese, C, Franceschetti, S, Canafoglia, L, Ragona, F, Freri, E, Labate, A, Gambardella, A, Costa, C, Gellera, C, Granata, T, Barbuti, A, Difrancesco, D, Difrancesco, JC, Freri, Elena, and Labate, Angelo
Abstract: HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies.
Published: 2018

23. HCN1 mutation spectrum: From neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Author: Marini, C, Porro, A, Rastetter, A, Dalle, C, Rivolta, I, Bauer, D, Oegema, R, Nava, C, Parrini, E, Mei, D, Mercer, C, Dhamija, R, Chambers, C, Coubes, C, Thévenon, J, Kuentz, P, Julia, S, Pasquier, L, Dubourg, C, Carré, W, Rosati, A, Melani, F, Pisano, T, Giardino, M, Innes, A, Alembik, Y, Scheidecker, S, Santos, M, Figueiroa, S, Garrido, C, Fusco, C, Frattini, D, Spagnoli, C, Binda, A, Granata, T, Ragona, F, Freri, E, Franceschetti, S, Canafoglia, L, Castellotti, B, Gellera, C, Milanesi, R, Mancardi, M, Clark, D, Kok, F, Helbig, K, Ichikawa, S, Sadler, L, Neupauerová, J, Laššuthova, P, Šterbová, K, Laridon, A, Brilstra, E, Koeleman, B, Lemke, J, Zara, F, Striano, P, Soblet, J, Smits, G, Deconinck, N, Barbuti, A, Difrancesco, D, Leguern, E, Guerrini, R, Santoro, B, Hamacher, K, Thiel, G, Moroni, A, Di Francesco, J, Depienne, C, Innes, AM, Mancardi, MM, Clark, DR, Helbig, KL, Lemke, JR, DiFrancesco, D, LeGuern, E, Di Francesco, JC, Marini, C, Porro, A, Rastetter, A, Dalle, C, Rivolta, I, Bauer, D, Oegema, R, Nava, C, Parrini, E, Mei, D, Mercer, C, Dhamija, R, Chambers, C, Coubes, C, Thévenon, J, Kuentz, P, Julia, S, Pasquier, L, Dubourg, C, Carré, W, Rosati, A, Melani, F, Pisano, T, Giardino, M, Innes, A, Alembik, Y, Scheidecker, S, Santos, M, Figueiroa, S, Garrido, C, Fusco, C, Frattini, D, Spagnoli, C, Binda, A, Granata, T, Ragona, F, Freri, E, Franceschetti, S, Canafoglia, L, Castellotti, B, Gellera, C, Milanesi, R, Mancardi, M, Clark, D, Kok, F, Helbig, K, Ichikawa, S, Sadler, L, Neupauerová, J, Laššuthova, P, Šterbová, K, Laridon, A, Brilstra, E, Koeleman, B, Lemke, J, Zara, F, Striano, P, Soblet, J, Smits, G, Deconinck, N, Barbuti, A, Difrancesco, D, Leguern, E, Guerrini, R, Santoro, B, Hamacher, K, Thiel, G, Moroni, A, Di Francesco, J, Depienne, C, Innes, AM, Mancardi, MM, Clark, DR, Helbig, KL, Lemke, JR, DiFrancesco, D, LeGuern, E, and Di Francesco, JC
Abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: One adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or volta
Published: 2018

24. A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability

Author: Bonzanni, M, Difrancesco, J, Milanesi, R, Campostrini, G, Castellotti, B, Bucchi, A, Baruscotti, M, Ferrarese, C, Franceschetti, S, Canafoglia, L, Ragona, F, Freri, E, Labate, A, Gambardella, A, Costa, C, Rivolta, I, Gellera, C, Granata, T, Barbuti, A, Difrancesco, D, Bonzanni, Mattia, DiFrancesco, Jacopo C., Milanesi, Raffaella, Campostrini, Giulia, Castellotti, Barbara, Bucchi, Annalisa, Baruscotti, Mirko, Ferrarese, Carlo, Franceschetti, Silvana, Canafoglia, Laura, Ragona, Francesca, Freri, Elena, Labate, Angelo, Gambardella, Antonio, Costa, Cinzia, RIVOLTA, ILARIA, Gellera, Cinzia, Granata, Tiziana, Barbuti, Andrea, DiFrancesco, Dario, Bonzanni, M, Difrancesco, J, Milanesi, R, Campostrini, G, Castellotti, B, Bucchi, A, Baruscotti, M, Ferrarese, C, Franceschetti, S, Canafoglia, L, Ragona, F, Freri, E, Labate, A, Gambardella, A, Costa, C, Rivolta, I, Gellera, C, Granata, T, Barbuti, A, Difrancesco, D, Bonzanni, Mattia, DiFrancesco, Jacopo C., Milanesi, Raffaella, Campostrini, Giulia, Castellotti, Barbara, Bucchi, Annalisa, Baruscotti, Mirko, Ferrarese, Carlo, Franceschetti, Silvana, Canafoglia, Laura, Ragona, Francesca, Freri, Elena, Labate, Angelo, Gambardella, Antonio, Costa, Cinzia, RIVOLTA, ILARIA, Gellera, Cinzia, Granata, Tiziana, Barbuti, Andrea, and DiFrancesco, Dario
Abstract: The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C > G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.
Published: 2018

25. Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study

Author: Trivisano, M., Pietrafusa, N., Terracciano, A., Marini, C., Mei, D., Darra, F., Accorsi, P., Battaglia, Domenica Immacolata, Caffi, L., Canevini, M. P., Cappelletti, S., Cesaroni, E., de Palma, L., Costa, Paolo, Cusmai, R., Giordano, Liliana, Ferrari, A., Freri, E., Fusco, L., Granata, T., Martino, T., Mastrangelo, Marica, Bova, S. M., Parmeggiani, L., Ragona, F., Sicca, F., Striano, P., Specchio, L. M., Tondo, I., Zambrelli, E., Zamponi, N., Zanus, C., Boniver, C., Vecchi, M., Avolio, C., Dalla Bernardina, B., Bertini, Enrico Silvio, Guerrini, R., Vigevano, F., Specchio, N., Battaglia D. (ORCID:0000-0003-0491-4021), Costa P., Giordano L., Mastrangelo M., Bertini E., Trivisano, M., Pietrafusa, N., Terracciano, A., Marini, C., Mei, D., Darra, F., Accorsi, P., Battaglia, Domenica Immacolata, Caffi, L., Canevini, M. P., Cappelletti, S., Cesaroni, E., de Palma, L., Costa, Paolo, Cusmai, R., Giordano, Liliana, Ferrari, A., Freri, E., Fusco, L., Granata, T., Martino, T., Mastrangelo, Marica, Bova, S. M., Parmeggiani, L., Ragona, F., Sicca, F., Striano, P., Specchio, L. M., Tondo, I., Zambrelli, E., Zamponi, N., Zanus, C., Boniver, C., Vecchi, M., Avolio, C., Dalla Bernardina, B., Bertini, Enrico Silvio, Guerrini, R., Vigevano, F., Specchio, N., Battaglia D. (ORCID:0000-0003-0491-4021), Costa P., Giordano L., Mastrangelo M., and Bertini E.
Abstract: Objective: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. Methods: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. Results: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). Significance: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizur
Published: 2018

26. Stabilometry in patients with Dravet Syndrome to quantitatively assess ataxia: A preliminary study

Author: Di Marco, R., primary, Duso, M., additional, Cesaletti, R., additional, Nieves, L., additional, Boniver, C., additional, Darra, F., additional, Ragona, F., additional, Masiero, S., additional, and Del Felice, A., additional
Published: 2018
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27. Electroclinical findings and long-term outcomes in epileptic patients with inv dup (15)

Author: Matricardi, S., primary, Darra, F., additional, Spalice, A., additional, Basti, C., additional, Fontana, E., additional, Dalla Bernardina, B., additional, Elia, M., additional, Giordano, L., additional, Accorsi, P., additional, Cusmai, R., additional, De Liso, P., additional, Romeo, A., additional, Ragona, F., additional, Granata, T., additional, Concolino, D., additional, Carotenuto, M., additional, Pavone, P., additional, Pruna, D., additional, Striano, P., additional, Savasta, S., additional, and Verrotti, A., additional
Published: 2018
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28. Myoclonus Epilepsy and Ataxia due to KCNC1 Mutation: Analysis of 20 Cases and K plus Channel Properties

Author: Oliver, KL, Franceschetti, S, Milligan, CJ, Muona, M, Mandelstam, SA, Canafoglia, L, Boguszewska-Chachulska, AM, Korczyn, AD, Bisulli, F, Di Bonaventura, C, Ragona, F, Michelucci, R, Ben-Zeev, B, Straussberg, R, Panzica, F, Massano, J, Friedman, D, Crespel, A, Engelsen, BA, Andermann, F, Andermann, E, Spodar, K, Lasek-Bal, A, Riguzzi, P, Pasini, E, Tinuper, P, Licchetta, L, Gardella, E, Lindenau, M, Wulf, A, Moller, RS, Benninger, F, Afawi, Z, Rubboli, G, Reid, CA, Maljevic, S, Lerche, H, Lehesjoki, A-E, Petrou, S, Berkovic, SF, Oliver, KL, Franceschetti, S, Milligan, CJ, Muona, M, Mandelstam, SA, Canafoglia, L, Boguszewska-Chachulska, AM, Korczyn, AD, Bisulli, F, Di Bonaventura, C, Ragona, F, Michelucci, R, Ben-Zeev, B, Straussberg, R, Panzica, F, Massano, J, Friedman, D, Crespel, A, Engelsen, BA, Andermann, F, Andermann, E, Spodar, K, Lasek-Bal, A, Riguzzi, P, Pasini, E, Tinuper, P, Licchetta, L, Gardella, E, Lindenau, M, Wulf, A, Moller, RS, Benninger, F, Afawi, Z, Rubboli, G, Reid, CA, Maljevic, S, Lerche, H, Lehesjoki, A-E, Petrou, S, and Berkovic, SF
Abstract: OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. METHODS: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant KV 3.1 channels. RESULTS: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type KV 3.1, increasing channel availability. INTERPRETATION: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type KV 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for pre
Published: 2017

29. Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

Author: Parrini, E., Marini, C., Mei, D., Galuppi, A., Cellini, E., Pucatti, D., Chiti, L., Rutigliano, D., Bianchini, C., Virdo, S., De Vita, D., Bigoni, S., Barba, C., Mari, F., Montomoli, M., Pisano, T., Rosati, A., Guerrini, R., Accorsi, P., Ardissone, A., Battaglia, Domenica Immacolata, Bertani, G., Borgarello, G., Cesaroni, E., Chiari, S., Cordelli, D. M., Doccini, V., Donati, I., Fontana, E., Fusco, C., Gentile, M., Giordano, L., Jacinto, S., Leuzzi, V., Mangano, S., Mastrangelo, M., Melani, F., Obino, L., Offer, C., Pruna, D., Ragona, F., Ricciardelli, P., Salandin, M., Saporoso, A., Sicca, F., Specchio, N., Sterebova, K., Battaglia D. (ORCID:0000-0003-0491-4021), Parrini, E., Marini, C., Mei, D., Galuppi, A., Cellini, E., Pucatti, D., Chiti, L., Rutigliano, D., Bianchini, C., Virdo, S., De Vita, D., Bigoni, S., Barba, C., Mari, F., Montomoli, M., Pisano, T., Rosati, A., Guerrini, R., Accorsi, P., Ardissone, A., Battaglia, Domenica Immacolata, Bertani, G., Borgarello, G., Cesaroni, E., Chiari, S., Cordelli, D. M., Doccini, V., Donati, I., Fontana, E., Fusco, C., Gentile, M., Giordano, L., Jacinto, S., Leuzzi, V., Mangano, S., Mastrangelo, M., Melani, F., Obino, L., Offer, C., Pruna, D., Ragona, F., Ricciardelli, P., Salandin, M., Saporoso, A., Sicca, F., Specchio, N., Sterebova, K., and Battaglia D. (ORCID:0000-0003-0491-4021)
Abstract: Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients, epilepsy onset occurred before the age of 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5, and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype–genotype correlations. Molecular diagnosis might influence patients' management and translate into better and specific treatment recommendations in some conditions.
Published: 2017

30. Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations

Author: Cetica, V., Chiari, S., Mei, D., Parrini, E., Grisotto, L., Marini, C., Pucatti, D., Ferrari, A., Sicca, F., Specchio, N., Trivisano, M., Battaglia, Domenica Immacolata, Contaldo, Ilaria, Zamponi, N., Petrelli, Cecilia, Granata, T., Ragona, F., Avanzini, G., Guerrini, R., Battaglia D. (ORCID:0000-0003-0491-4021), Contaldo I., Petrelli C., Cetica, V., Chiari, S., Mei, D., Parrini, E., Grisotto, L., Marini, C., Pucatti, D., Ferrari, A., Sicca, F., Specchio, N., Trivisano, M., Battaglia, Domenica Immacolata, Contaldo, Ilaria, Zamponi, N., Petrelli, Cecilia, Granata, T., Ragona, F., Avanzini, G., Guerrini, R., Battaglia D. (ORCID:0000-0003-0491-4021), Contaldo I., and Petrelli C.
Abstract: Objective: To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations. Methods: Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients. Results: Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/ genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85%in the 0- to 6-month group, 51%in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity 5 83.3%, specificity 5 76.6%). Conclusions: In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy.
Published: 2017

31. Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Author: Jaffer F, Avbersek A, Vavassori R, Fons-Estupina C, Campistol-Plana J, Stagnaro M, De Grandis E, Veneselli E, Rosewich H, Gianotta M, Zucca C, Ragona F, Granata T, Nardocci N, Mikati M, Helseth AR, Boelman C, Minassian BA, Johns S, Garry SI, Scheffer IE, Gourfinkel-An I, Carrilho I, Aylett SE, Parton M, Hanna MG, Houlden H, Neville B, Kurian MA, Novy J, Sander JW, Lambiase PD, Behr ER, Schyns T, Arzimanoglou A, Cross JH, Kaski JP, and Sisodiya SM
Subjects: Adult, Male, SUDEP, Adolescent, Heart Diseases, Heart Ventricles, International Cooperation, Hemiplegia, alternating hemiplegia of childhood, ATP1A3, Na+ /K + -ATPase, electrocardiogram, Na+/K+-ATPase, Age Factors, Autonomic Nervous System Diseases, Child, Child, Preschool, Cohort Studies, Electrocardiography, Female, Heart Rate, Humans, Infant, Infant, Newborn, Mutation, Sodium-Potassium-Exchanging ATPase, Young Adult, Medicine (all), Arts and Humanities (miscellaneous), Neurology (clinical), Preschool, Original Articles, Newborn, cardiovascular system
Abstract: Alternating hemiplegia of childhood is rare and usually results from mutations in cardiac- and brain-expressed ATP1A3. In an ECG study of 52 cases, Jaffer et al. reveal dynamic cardiac repolarisation or conduction abnormalities in over 50%. Abnormalities are more common in those ≥16 years, and suggest impaired cardiac repolarisation reserve., Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term ‘alternating hemiplegia’. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those
Published: 2015

32. Gait patterns in Dravet syndrome: Preliminary data of a multicentric longitudinal prospective study

Author: Spagnolo, E., primary, Benedetti, M.G., additional, Rigato, A., additional, Bellon, G., additional, Hallemans, A., additional, Ragona, F., additional, Darra, F., additional, Vecchi, M., additional, Giannotti, E., additional, Masiero, S., additional, and Del Felice, A., additional
Published: 2016
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33. 2. Follow-up of five cases with Rasmussen encephalitis with magnetoencephalography

Author: Rossi, D.S., primary, Visani, E., additional, Duran, D., additional, Rotondi, F., additional, Canafoglia, L., additional, Freri, E., additional, Ragona, F., additional, Granata, T., additional, Panzica, F., additional, and Franceschetti, S., additional
Published: 2016
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34. Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Author: Jaffer, F, Avbersek, A, Vavassori, R, Fons, C, Campistol, J, Stagnaro, M, De Grandis, E, Veneselli, E, Rosewich, H, Gianotta, M, Zucca, C, Ragona, F, Granata, T, Nardocci, N, Mikati, M, Helseth, AR, Boelman, C, Minassian, BA, Johns, S, Garry, SI, Scheffer, IE, Gourfinkel-An, I, Carrilho, I, Aylett, SE, Parton, M, Hanna, MG, Houlden, H, Neville, B, Kurian, MA, Novy, J, Sander, JW, Lambiase, PD, Behr, ER, Schyns, T, Arzimanoglou, A, Cross, JH, Kaski, JP, Sisodiya, SM, Jaffer, F, Avbersek, A, Vavassori, R, Fons, C, Campistol, J, Stagnaro, M, De Grandis, E, Veneselli, E, Rosewich, H, Gianotta, M, Zucca, C, Ragona, F, Granata, T, Nardocci, N, Mikati, M, Helseth, AR, Boelman, C, Minassian, BA, Johns, S, Garry, SI, Scheffer, IE, Gourfinkel-An, I, Carrilho, I, Aylett, SE, Parton, M, Hanna, MG, Houlden, H, Neville, B, Kurian, MA, Novy, J, Sander, JW, Lambiase, PD, Behr, ER, Schyns, T, Arzimanoglou, A, Cross, JH, Kaski, JP, and Sisodiya, SM
Abstract: Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared wi
Published: 2015

35. Clinical dissection of childhood occipital epilepsy of Gastaut and prognostic implication

Author: Verrotti, A., primary, Laino, D., additional, Rinaldi, V. E., additional, Suppiej, A., additional, Giordano, L., additional, Toldo, I., additional, Margari, L., additional, Parisi, P., additional, Rizzo, R., additional, Matricardi, S., additional, Cusmai, R., additional, Grosso, S., additional, Gaggero, R., additional, Zamponi, N., additional, Pavone, P., additional, Capovilla, G., additional, Rauchenzauner, M., additional, Cerminara, C., additional, Di Gennaro, G., additional, Esposito, M., additional, Striano, P., additional, Savasta, S., additional, Coppola, G., additional, Siliquini, S., additional, Operto, F., additional, Belcastro, V., additional, Ragona, F., additional, Marseglia, G. L., additional, and Spalice, A., additional
Published: 2015
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36. P522: MEG study of interictal epileptic spikes in patients with Rasmussen’s encephalitis assessed by magnetic source imaging

Author: Visani, E., primary, Duran, D., additional, Rossi Sebastiano, D., additional, Granata, T., additional, Elena, F., additional, Ragona, F., additional, Panzica, F., additional, and Franceschetti, S., additional
Published: 2014
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37. Experience with immunomodulatory treatments in Rasmussen’s encephalitis

Author: Granata, T., Fusco, L., Gobbi, G., Freri, E., Ragona, F., Broggi, G., Mantegazza, R., Giorgano, L., Villani, F., Capovilla, G., Vigevano, F., DALLA BERNARDINA, Bernardo, Spreafico, R., and Antozzi, C.
Published: 2003

38. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients

Author: Ragona, F, Granata, T, Dalla Bernardina, B, Offredi, F, Darra, F, Battaglia, Domenica Immacolata, Morbi, Ma, Brazzo, D, Cappelletti, S, Chieffo, Daniela Pia Rosaria, De Giorgi, I, Fontana, E, Freri, E, Marini, C, Toraldo, A, Specchio, N, Veggiotti, P, Vigevano, F, Guerrini, R, Guzzetta, Francesco, Dravet, C., Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Chieffo, D, Ragona, F, Granata, T, Dalla Bernardina, B, Offredi, F, Darra, F, Battaglia, Domenica Immacolata, Morbi, Ma, Brazzo, D, Cappelletti, S, Chieffo, Daniela Pia Rosaria, De Giorgi, I, Fontana, E, Freri, E, Marini, C, Toraldo, A, Specchio, N, Veggiotti, P, Vigevano, F, Guerrini, R, Guzzetta, Francesco, Dravet, C., Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), and Chieffo, D
Abstract: To clarify the role of epilepsy and genetic background in determining the cognitive outcome of patients with Dravet syndrome.
Published: 2011

39. Experience with immunomodulatory treatments in Rasmussen's encephalitis.

Author: Granata T, Fusco L, Gobbi G, Freri E, Ragona F, Broggi G, Mantegazza R, Giordano L, Villani F, Capovilla G, Vigevano F, Dalla Bernardina B, Spreafico R, Antozzi C, Granata, T, Fusco, L, Gobbi, G, Freri, E, Ragona, F, and Broggi, G
Published: 2003
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40. Rasmussen's encephalitis: early characteristics allow diagnosis.

Author: Granata T, Gobbi G, Spreafico R, Vigevano F, Capovilla G, Ragona F, Freri E, Chiapparini L, Bernasconi P, Giordano L, Bertani G, Casazza M, Bernardina B, Fusco L, Granata, T, Gobbi, G, Spreafico, R, Vigevano, F, Capovilla, G, and Ragona, F
Published: 2003
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41. An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy

Author: Striano, P., primary, Coppola, A., additional, Pezzella, M., additional, Ciampa, C., additional, Specchio, N., additional, Ragona, F., additional, Mancardi, M. M., additional, Gennaro, E., additional, Beccaria, F., additional, Capovilla, G., additional, Rasmini, P., additional, Besana, D., additional, Coppola, G. G., additional, Elia, M., additional, Granata, T., additional, Vecchi, M., additional, Vigevano, F., additional, Viri, M., additional, Gaggero, R., additional, Striano, S., additional, and Zara, F., additional
Published: 2007
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42. Rasmussen’s encephalitis

Author: Granata, T., primary, Gobbi, G., additional, Spreafico, R., additional, Vigevano, F., additional, Capovilla, G., additional, Ragona, F., additional, Freri, E., additional, Chiapparini, L., additional, Bernasconi, P., additional, Giordano, L., additional, Bertani, G., additional, Casazza, M., additional, Dalla Bernardina, B., additional, and Fusco, L., additional
Published: 2003
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43. Progressive epileptic encephalopathy associated with a novel HCN2 mutation

Author: Binda, A., Murano, C., Di Francesco, J. C., Castellotti, B., Milanesi, R., Ragona, F., Freri, E., Canafoglia, L., Franceschetti, S., Solazzi, R., tiziana granata, Gellera, C., Rivolta, I., Binda, A, Murano, C, DI FRANCESCO, J, Castellotti, B, Milanesi, R, Ragona, F, Freri, E, Canafoglia, L, Franceschetti, S, Solazzi, R, Granata, T, Gellera, C, and Rivolta, I
Subjects: epilepsy, HCN2, electrophysiology
Abstract: So far mutations in HCN2 gene, encoding for the hyperpolarization-activated cyclic nucleotide-gated channel 2, have been related to mild epileptic clinical phenotypes. In this study, a novel HCN2 mutation was found in a proband, now aged 7 years old, with a congenital encephalopathy characterized by drug resistant epilepsy, severe developmental delay, ataxia, dystonia and cerebral visual impairment. A convulsive status epilepticus at 5 months of age marked the onset of epilepsy. The HCN2 mutation affects an aminoacid located in the S6 transmembrane helix (p.Gly460Asp) and is carried in heterozygosis. To describe the functional consequences of the mutant channel, whole-cell patch-clamp experiments were performed in HEK293 cells expressing HCN2 wild type (WT) or p.Gly460Asp channel. A coexpression of the same amount of plasmid encoding for the wt or the mutant form of the channel mimed the heterozygous condition. A complete abolishment of the current was observed considering the mutant compared to the WT channel (-9.9±1.2 pA/pF, n=20 vs -31.2±8.4 pA/pF, n=44 respectively; p

44. Beobachtungen der Metis auf der Sternwarte zu Bonn.

Author: Ragona, F.
Published: 1854
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45. NEXT GENERATION SEQUENCING IN RARE CHILDHOOD EPILEPSY OF SUSPECTED GENETIC ETIOLOGY

Author: Ragona, F., Salis, B., Freri, E., Piazza, E., Santi, M., Castellotti, B., Difrancesco, J. C., Canafoglia, L., Franceschetti, S., Gellera, C., and tiziana granata

46. LONG-TERM EVOLUTION OF DRAVET SYNDROME: COGNITIVE IMPAIRMENT, BEHAVIORAL PHENOTYPE AND ADAPTIVE FUNCTIONING

Author: Ragona, F., Bersani, C., Patrini, M., Francesca, Canafoglia, L., Veggiotti, P., Piazza, E., and Granata, T.

47. Steroid treatment in childhood drug-resistant epilepsy: A retrospective study in 41 patients,Steroidi nel trattamento delle epilessie in età pediatrica: Studio di efficacia in 41 pazienti con crisi farmacoresistenti

Author: Obino, L., Elena Freri, Ragona, F., Giorgi, I., and Granata, T.

48. AUTOIMMUNE EPILEPSY: KEY FINDINGS TO IDENTIFY A POTENTIALLY TREATABLE DISEASE

Author: Matricardi, S., Pappalardo, I., Freri, E., Ragona, F., Didato, G., Andreetta, F., Franceschetti, S., Nardo NARDOCCI, Pastori, C., Villani, F., and Granata, T.

49. EPILEPTIC PHENOTYPE IN CHILDREN WITH EARLY ONSET MITOCHONDRIAL DISEASES

Author: Matricardi, S., Ardissone, A., Franceschetti, S., Canafoglia, L., Moroni, I., Ghezzi, D., Lamantea, E., Binelli, S., Freri, E., Ragona, F., and tiziana granata

50. Dravet syndrome: Clinical features in 20 patients and genotype-phenotype correlation,Sindrome di Dravet: Aspetti clinici in 20 pazienti e correlazione genotipo-fenotipo

Author: Ragona, F., Elena Freri, Binelli, S., Giorgi, I., Madia, F., Zara, F., Franceschetti, S., and Granata, T.

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