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4. 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

5. 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

6. 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

7. 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

8. 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
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9. 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

10. Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation

Author

Barba, C., Cross, J. H., Braun, K., Cossu, M., Klotz, K. A., De Masi, S., Perez Jimenez, M. A., Gaily, E., Specchio, N., Cabral, P., Toulouse, J., Dimova, P., Battaglia, D., Freri, E., Consales, A., Cesaroni, E., Tarta-Arsene, O., Gil-Nagel, A., Mindruta, I., Di Gennaro, G., Giulioni, M., Tisdall, M. M., Eltze, C., Tahir, M. Z., Jansen, F., van Rijen, P., Sanders, M., Tassi, L., Francione, S., Lo Russo, G., Jacobs, J., Bast, T., Matta, G., Budke, M., Fournier del Castillo, C., Metsahonkala, E. -L., Karppinen, A., Ferreira, J. C., Minkin, K., Marras, C. E., Lucenteforte, E, Arzimanoglou, A., and Guerrini, R.

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Multivariate analysis, Adolescent, Neurosurgery, Stereoelectroencephalography, Neurosurgical Procedures, 03 medical and health sciences, Epilepsy, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, 0302 clinical medicine, children, Seizures, Medicine, Humans, survey, Epilepsy surgery, Preschool, Child, Retrospective Studies, medicine.diagnostic_test, business.industry, Age Factors, Magnetic resonance imaging, Retrospective cohort study, Electroencephalography, medicine.disease, Magnetic Resonance Imaging, Temporal Lobe, 3. Good health, Surgery, Europe, epilepsy surgery, histopathology, outcome, Child, Preschool, Female, Treatment Outcome, 030104 developmental biology, Neurology, Histopathology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (

Published
2019

11. 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

12. Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation

Author

Barba, Maria Cristina, Cross, J. H., Braun, K., Cossu, M., Klotz, K. A., De Masi, S., Perez Jimenez, M. A., Gaily, E., Specchio, N., Cabral, P., Toulouse, J., Dimova, P., Battaglia, Domenica Immacolata, Freri, E., Consales, A., Cesaroni, E., Tarta-Arsene, O., Gil-Nagel, A., Mindruta, I., Di Gennaro, G., Giulioni, M., Tisdall, M. M., Eltze, C., Tahir, M. Z., Jansen, F., van Rijen, P., Sanders, M., Tassi, L., Francione, S., Lo Russo, G., Jacobs, J., Bast, T., Matta, G., Budke, M., Fournier del Castillo, C., Metsahonkala, E. -L., Karppinen, A., Ferreira, J. C., Minkin, K., Marras, C. E., Arzimanoglou, A., Guerrini, R., Barba C., Battaglia D. (ORCID:0000-0003-0491-4021), Barba, Maria Cristina, Cross, J. H., Braun, K., Cossu, M., Klotz, K. A., De Masi, S., Perez Jimenez, M. A., Gaily, E., Specchio, N., Cabral, P., Toulouse, J., Dimova, P., Battaglia, Domenica Immacolata, Freri, E., Consales, A., Cesaroni, E., Tarta-Arsene, O., Gil-Nagel, A., Mindruta, I., Di Gennaro, G., Giulioni, M., Tisdall, M. M., Eltze, C., Tahir, M. Z., Jansen, F., van Rijen, P., Sanders, M., Tassi, L., Francione, S., Lo Russo, G., Jacobs, J., Bast, T., Matta, G., Budke, M., Fournier del Castillo, C., Metsahonkala, E. -L., Karppinen, A., Ferreira, J. C., Minkin, K., Marras, C. E., Arzimanoglou, A., Guerrini, R., Barba C., and Battaglia D. (ORCID:0000-0003-0491-4021)

Abstract

Objective: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. Methods: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. Results: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P <.0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend =.0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend =.0047) and a significant decrease in unilobar temporal surgeries (P for trend =.0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. Significance: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.

Published
2020

13. 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

14. 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

15. 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

16. Neuroimaging Changes in Menkes Disease, Part 1

Author

Manara, R, D'Agata, L, Rocco, Mc, Cusmai, R, Freri, E, Pinelli, L, Darra, Francesca, Procopio, E, Mardari, R, Zanus, C, Di Rosa, G, Soddu, C, Severino, M, Ermani, M, Longo, D, Sartori, S, Menkes Working Group in the Italian Neuroimaging Network for Rare Diseases: Toldo, I, Peruzzi, C, Vittorini, R, Spalice, A, Fusco, C, Nosadini, M, Farina, L, Stecco, A, Polonara, G, Donati, Ma, Giordano, L, Dionisi Vici, C, Martinelli, D, Tocchet, A, Fariello, G, Nicita, F, Frattini, D, Martelli, P, Cantalupo, Gaetano, and Zennaro, F.

Subjects
Menkes disease, neuroimaging, MRI, Male, Pathology, medicine.medical_specialty, vascular abnormalities, Neuroimaging, Disease, Pediatrics, 030218 nuclear medicine & medical imaging, White matter, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Menkes Kinky Hair Syndrome, Retrospective Studies, medicine.diagnostic_test, business.industry, Brain, Magnetic resonance imaging, Retrospective cohort study, Menkes disease, medicine.disease, White matter changes, Magnetic Resonance Imaging, White Matter, X-linked disorder, myelination delay, medicine.anatomical_structure, myelination delay, vascular abnormalities, X-linked disorder, copper metabolism, Disease Progression, Female, copper metabolism, Neurology (clinical), business, Neuroscience, 030217 neurology & neurosurgery, MRI
Abstract

Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain involvement remains unsatisfactory. The first part of this retrospective and review MR imaging study aims to define the frequency rate, timing, imaging features, and evolution of intracranial vascular and white matter changes. According to our analysis, striking but also poorly evolutive vascular abnormalities characterize the very early phases of disease. After the first months, myelination delay becomes evident, often in association with protean focal white matter lesions, some of which reveal an age-specific brain vulnerability. In later phases of the disease, concomitant progressive neurodegeneration might hinder the myelination progression. The currently enriched knowledge of neuroradiologic finding evolution provides valuable clues for early diagnosis, identifies possible MR imaging biomarkers of new treatment efficacy, and improves our comprehension of possible mechanisms of brain injury in Menkes disease.

Published
2017

17. Neuroimaging Changes in Menkes Disease, Part 2

Author

Manara, R, Rocco, M C, D'Agata, L, Cusmai, R, Freri, E, Giordano, L, Darra, F, Procopio, E, Toldo, I, Peruzzi, C, Vittorini, R, Spalice, A, Fusco, C, Nosadini, M, Longo, D, Sartori, S, Menkes Working Group in the Italian Neuroimaging Network for Rare Diseases, Mardari, R, Zanus, C, Di Rosa, G, Soddu, C, Severino, M, Ermani, M, Farina, L, Stecco, A, Polonara, G, Donati, Ma, Pinelli, L, Dionisi-Vici, C, Martinelli, D, Tocchet, A, Fariello, G, Nicita, F, Frattini, D, Martelli, P, Cantalupo, G, and Zennara, F

Subjects
Child abuse, Male, Pathology, medicine.medical_specialty, Neuroimaging, Disease, Pediatrics, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, gray matter changes, X-linked disorder, copper metabolism, neurodegeneration, basal ganglia lesions, subdural collections, Basal ganglia, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Gray Matter, Child, Menkes Kinky Hair Syndrome, Retrospective Studies, gray matter changes, medicine.diagnostic_test, business.industry, neurodegeneration, Brain, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, basal ganglia lesions, subdural collections, X-linked disorder, Menkes disease, Neurology (clinical), copper metabolism, Differential diagnosis, business, 030217 neurology & neurosurgery, Rare disease
Abstract

This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter changes in Menkes disease, a rare multisystem X-linked disorder of copper metabolism characterized by early, severe, and progressive neurologic involvement. According to our analysis, neurodegenerative changes and focal basal ganglia lesions already appear in the early phases of the disease. Subdural collections are less common than generally thought; however, their presence remains important because they might challenge the differential diagnosis with child abuse and might precipitate the clinical deterioration. Anecdotal findings in our large sample seem to provide interesting clues about the protean mechanisms of brain injury in this rare disease and further highlight the broad spectrum of MR imaging findings that might be expected while imaging a child with the suspicion of or a known diagnosis of Menkes disease.

Published
2017

18. 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

19. 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

20. 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

21. The noncoding RNA AK127244 in 2p16.3 locus: A new susceptibility region for neuropsychiatric disorders

Author

Rizzo, A, Alfei, E, Zibordi, F, Saletti, V, Zorzi, G, Freri, E, Estienne, M, Girgenti, V, D'Arrigo, S, Esposito, S, Buldrini, B, Moroni, I, Milani, D, Granata, T, Ardissone, A, Eoli, M, Molteni, B, Bigoni, S, Pantaleoni, C, Nardocci, N, Sciacca, F, Rizzo, Ambra, Alfei, Enrico, Zibordi, Federica, Saletti, Veronica, Zorzi, Giovanna, Freri, Elena, Estienne, Margherita, Girgenti, Vita, D'Arrigo, Stefano, Esposito, Silvia, Buldrini, Barbara, Moroni, Isabella, Milani, Donatella, Granata, Tiziana, Ardissone, Anna, Eoli, Marica, Molteni, Bruna, Bigoni, Stefania, Pantaleoni, Chiara, Nardocci, Nardo, Sciacca, Francesca Luisa, Rizzo, A, Alfei, E, Zibordi, F, Saletti, V, Zorzi, G, Freri, E, Estienne, M, Girgenti, V, D'Arrigo, S, Esposito, S, Buldrini, B, Moroni, I, Milani, D, Granata, T, Ardissone, A, Eoli, M, Molteni, B, Bigoni, S, Pantaleoni, C, Nardocci, N, Sciacca, F, Rizzo, Ambra, Alfei, Enrico, Zibordi, Federica, Saletti, Veronica, Zorzi, Giovanna, Freri, Elena, Estienne, Margherita, Girgenti, Vita, D'Arrigo, Stefano, Esposito, Silvia, Buldrini, Barbara, Moroni, Isabella, Milani, Donatella, Granata, Tiziana, Ardissone, Anna, Eoli, Marica, Molteni, Bruna, Bigoni, Stefania, Pantaleoni, Chiara, Nardocci, Nardo, and Sciacca, Francesca Luisa

Abstract

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions

Published
2018

22. Corrigendum to “Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study” [Epilepsy Behav. Oct 2017; 75C:151-157](S1525505017304961)(10.1016/j.yebeh.2017.08.010)

Author

Barba, Maria Cristina, Specchio, N., Guerrini, R., Tassi, L., Demasi, S., Cardinale, F., Pellacani, S., De Palma, L., Battaglia, Domenica Immacolata, Tamburrini, Gianpiero, Didato, G., Freri, E., Consales, A., Nozza, P., Zamponi, N., Cesaroni, E., Di Gennaro, G., Esposito, V., Giulioni, M., Tinuper, P., Colicchio, G., Rocchi, R., Rubboli, G., Giordano, F., Russo, G. L., Marras, C. E., Cossu, M., Barba C., Battaglia D. (ORCID:0000-0003-0491-4021), Tamburrini G. (ORCID:0000-0002-7139-5711), Barba, Maria Cristina, Specchio, N., Guerrini, R., Tassi, L., Demasi, S., Cardinale, F., Pellacani, S., De Palma, L., Battaglia, Domenica Immacolata, Tamburrini, Gianpiero, Didato, G., Freri, E., Consales, A., Nozza, P., Zamponi, N., Cesaroni, E., Di Gennaro, G., Esposito, V., Giulioni, M., Tinuper, P., Colicchio, G., Rocchi, R., Rubboli, G., Giordano, F., Russo, G. L., Marras, C. E., Cossu, M., Barba C., Battaglia D. (ORCID:0000-0003-0491-4021), and Tamburrini G. (ORCID:0000-0002-7139-5711)

Abstract

The authors regret to inform that one of the co-author “Simona Pellacani” is affiliated to IRCCS Stella Maris, Pisa, Italy The authors would like to apologize for any inconvenience caused.

Published
2018

23. 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

25. Neuroimaging Changes in Menkes Disease, Part 1

Author

Manara, R., primary, D'Agata, L., additional, Rocco, M.C., additional, Cusmai, R., additional, Freri, E., additional, Pinelli, L., additional, Darra, F., additional, Procopio, E., additional, Mardari, R., additional, Zanus, C., additional, Di Rosa, G., additional, Soddu, C., additional, Severino, M., additional, Ermani, M., additional, Longo, D., additional, and Sartori, S., additional

Published
2017
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26. Neuroimaging Changes in Menkes Disease, Part 2

Author

Manara, R., primary, Rocco, M.C., additional, D'agata, L., additional, Cusmai, R., additional, Freri, E., additional, Giordano, L., additional, Darra, F., additional, Procopio, E., additional, Toldo, I., additional, Peruzzi, C., additional, Vittorini, R., additional, Spalice, A., additional, Fusco, C., additional, Nosadini, M., additional, Longo, D., additional, and Sartori, S., additional

Published
2017
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27. Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study

Author

Barba, Maria Cristina, Specchio, N., Guerrini, R., Tassi, L., De Masi, Salvatore, Cardinale, F., Pellacani, S., De Palma, L., Battaglia, Domenica Immacolata, Tamburrini, Gianpiero, Didato, G., Freri, E., Consales, A., Nozza, P., Zamponi, N., Cesaroni, E., Di Gennaro, G., Esposito, V., Giulioni, M., Tinuper, P., Colicchio, G., Rocchi, R., Rubboli, G., Giordano, F., Russo, G. L., Marras, C. E., Cossu, M., Barba C., De Masi S., Battaglia D. (ORCID:0000-0003-0491-4021), Tamburrini G. (ORCID:0000-0002-7139-5711), Barba, Maria Cristina, Specchio, N., Guerrini, R., Tassi, L., De Masi, Salvatore, Cardinale, F., Pellacani, S., De Palma, L., Battaglia, Domenica Immacolata, Tamburrini, Gianpiero, Didato, G., Freri, E., Consales, A., Nozza, P., Zamponi, N., Cesaroni, E., Di Gennaro, G., Esposito, V., Giulioni, M., Tinuper, P., Colicchio, G., Rocchi, R., Rubboli, G., Giordano, F., Russo, G. L., Marras, C. E., Cossu, M., Barba C., De Masi S., Battaglia D. (ORCID:0000-0003-0491-4021), and Tamburrini G. (ORCID:0000-0002-7139-5711)

Abstract

Objective The objective of the study was to assess common practice in pediatric epilepsy surgery in Italy between 2008 and 2014. Methods A survey was conducted among nine Italian epilepsy surgery centers to collect information on presurgical and postsurgical evaluation protocols, volumes and types of surgical interventions, and etiologies and seizure outcomes in pediatric epilepsy surgery between 2008 and 2014. Results Retrospective data on 527 surgical procedures were collected. The most frequent surgical approaches were temporal lobe resections and disconnections (133, 25.2%) and extratemporal lesionectomies (128, 24.3%); the most frequent etiologies were FCD II (107, 20.3%) and glioneuronal tumors (105, 19.9%). Volumes of surgeries increased over time independently from the age at surgery and the epilepsy surgery center. Engel class I was achieved in 73.6% of patients (range: 54.8 to 91.7%), with no significant changes between 2008 and 2014. Univariate analyses showed a decrease in the proportion of temporal resections and tumors and an increase in the proportion of FCDII, while multivariate analyses revealed an increase in the proportion of extratemporal surgeries over time. A higher proportion of temporal surgeries and tumors and a lower proportion of extratemporal and multilobar surgeries and of FCD were observed in low (< 50 surgeries/year) versus high-volume centers. There was a high variability across centers concerning pre- and postsurgical evaluation protocols, depending on local expertise and facilities. Significance This survey reveals an increase in volume and complexity of pediatric epilepsy surgery in Italy between 2008 and 2014, associated with a stable seizure outcome.

Published
2017

28. Rasmussen encephalitis tissue transfer program

Author

Kruse, CA, Pardo, CA, Hartman, AL, Jallo, G, Vining, EPG, Voros, J, Gaillard, WD, Liu, J, Oluigbo, C, Malone, S, Bleasel, AF, Dexter, M, Micati, A, Velasco, TR, Machado, HR, Martino, AM, Huang, A, Wheatley, BM, Grant, GA, Granata, T, Freri, E, Garbelli, R, Koh, S, Nordli, DR, Campos, AR, O'Neill, B, Handler, MH, Chapman, KE, Wilfong, AA, Curry, DJ, Yaun, A, Madsen, JR, Smyth, MD, Mercer, D, Bingaman, W, Harvey, AS, Leventer, RJ, Lockhart, PJ, Gillies, G, Pope, K, Giller, CA, Park, YD, Rojiani, AM, Sharma, SJ, Jenkins, P, Tung, S, Huynh, MN, Chirwa, TW, Cepeda, C, Levine, MS, Chang, JW, Owens, GC, Vinters, HV, Mathern, GW, Kruse, CA, Pardo, CA, Hartman, AL, Jallo, G, Vining, EPG, Voros, J, Gaillard, WD, Liu, J, Oluigbo, C, Malone, S, Bleasel, AF, Dexter, M, Micati, A, Velasco, TR, Machado, HR, Martino, AM, Huang, A, Wheatley, BM, Grant, GA, Granata, T, Freri, E, Garbelli, R, Koh, S, Nordli, DR, Campos, AR, O'Neill, B, Handler, MH, Chapman, KE, Wilfong, AA, Curry, DJ, Yaun, A, Madsen, JR, Smyth, MD, Mercer, D, Bingaman, W, Harvey, AS, Leventer, RJ, Lockhart, PJ, Gillies, G, Pope, K, Giller, CA, Park, YD, Rojiani, AM, Sharma, SJ, Jenkins, P, Tung, S, Huynh, MN, Chirwa, TW, Cepeda, C, Levine, MS, Chang, JW, Owens, GC, Vinters, HV, and Mathern, GW

Published
2016

30. A novel <scp> KCNC1 </scp> gain‐of‐function variant causing developmental and epileptic encephalopathy: 'precision medicine' approach with fluoxetine

Author

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, and Taglialatela, M

Subjects
next generation sequencing, drug repurposing, Neurology, KCNC1, precision medicine, fluoxetine, epilepsy, Neurology (clinical)
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
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31. Functional Characterization of Two Variants at the Intron 6—Exon 7 Boundary of the KCNQ2 Potassium Channel Gene Causing Distinct Epileptic Phenotypes

Author

Ilaria Mosca, Ilaria Rivolta, Audrey Labalme, Paolo Ambrosino, Barbara Castellotti, Cinzia Gellera, Tiziana Granata, Elena Freri, Anna Binda, Gaetan Lesca, Jacopo C. DiFrancesco, Maria Virginia Soldovieri, Maurizio Taglialatela, Mosca, Ilaria, Rivolta, Ilaria, Labalme, Audrey, Ambrosino, Paolo, Castellotti, Barbara, Gellera, Cinzia, Granata, Tiziana, Freri, Elena, Binda, Anna, Lesca, Gaetan, Difrancesco, Jacopo C, Soldovieri, Maria Virginia, Taglialatela, Maurizio, Mosca, I, Rivolta, I, Labalme, A, Ambrosino, P, Castellotti, B, Gellera, C, Granata, T, Freri, E, Binda, A, Lesca, G, Difrancesco, J, Soldovieri, M, and Taglialatela, M

Subjects
KCNQ2, Kv7.2 subunit, Pharmacology, Kv7.2 subunits, alternative splicing, calmodulin, epileptic encephalopathy, PIP2, Pharmacology (medical)
Abstract

Pathogenic variants in KCNQ2 encoding for Kv7.2 potassium channel subunits have been found in patients affected by widely diverging epileptic phenotypes, ranging from Self-Limiting Familial Neonatal Epilepsy (SLFNE) to severe Developmental and Epileptic Encephalopathy (DEE). Thus, understanding the pathogenic molecular mechanisms of KCNQ2 variants and their correlation with clinical phenotypes has a relevant impact on the clinical management of these patients. In the present study, the genetic, biochemical, and functional effects prompted by two variants, each found in a non-familial SLNE or a DEE patient but both affecting nucleotides at the KCNQ2 intron 6-exon 7 boundary, have been investigated to test whether and how they affected the splicing process and to clarify whether such mechanism might play a pathogenetic role in these patients. Analysis of KCNQ2 mRNA splicing in patient-derived lymphoblasts revealed that the SLNE-causing intronic variant (c.928-1G > C) impeded the use of the natural splice site, but lead to a 10-aa Kv7.2 in frame deletion (Kv7.2 p.G310Δ10); by contrast, the DEE-causing exonic variant (c.928G > A) only had subtle effects on the splicing process at this site, thus leading to the synthesis of a full-length subunit carrying the G310S missense variant (Kv7.2 p.G310S). Patch-clamp recordings in transiently-transfected CHO cells and primary neurons revealed that both variants fully impeded Kv7.2 channel function, and exerted strong dominant-negative effects when co-expressed with Kv7.2 and/or Kv7.3 subunits. Notably, Kv7.2 p.G310S, but not Kv7.2 p.G310Δ10, currents were recovered upon overexpression of the PIP2-synthesizing enzyme PIP5K, and/or CaM; moreover, currents from heteromeric Kv7.2/Kv7.3 channels incorporating either Kv7.2 mutant subunits were differentially regulated by changes in PIP2 availability, with Kv7.2/Kv7.2 G310S/Kv7.3 currents showing a greater sensitivity to PIP2 depletion when compared to those from Kv7.2/Kv7.2 G310Δ10/Kv7.3 channels. Altogether, these results suggest that the two variants investigated differentially affected the splicing process at the intron 6-exon 7 boundary, and led to the synthesis of Kv7.2 subunits showing a differential sensitivity to PIP2 and CaM regulation; more studies are needed to clarify how such different functional properties contribute to the widely-divergent clinical phenotypes.

Published
2022
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32. Italian cohort of Lafora disease: Clinical features, disease evolution, and genotype-phenotype correlations

Author

Antonella Riva, Pasquale Striano, Paolo Tinuper, Roberto Michelucci, Marcello Scala, Silvana Franceschetti, Giuseppe d'Orsi, Berge A. Minassian, Angela Pistorio, Maria Teresa Di Claudio, Alfredo D'Aniello, Pierangelo Veggiotti, Carlo Avolio, Carla Marini, Maurizio Elia, Vito Sofia, Elena Freri, Maria Tappatà, Adriana Magaudda, Vittoria Taramasso, Antonino Romeo, Francesca Bisulli, Federico Zara, Giancarlo Di Gennaro, Amedeo Bianchi, Cinzia Costa, Carlo Minetti, Alessandro Orsini, Edoardo Ferlazzo, Salvatore Striano, Laura Canafoglia, Elena Gennaro, Riva A., Orsini A., Scala M., Taramasso V., Canafoglia L., d'Orsi G., Di Claudio M.T., Avolio C., D'Aniello A., Elia M., Franceschetti S., Di Gennaro G., Bisulli F., Tinuper P., Tappata M., Romeo A., Freri E., Marini C., Costa C., Sofia V., Ferlazzo E., Magaudda A., Veggiotti P., Gennaro E., Pistorio A., Minetti C., Bianchi A., Striano S., Michelucci R., Zara F., Minassian B.A., and Striano P.

Subjects
Adult, Ubiquitin-Protein Ligase, medicine.medical_specialty, Adolescent, Ubiquitin-Protein Ligases, EPM2A, EPM2B, Genetic Association Studie, medicine.disease_cause, Lafora disease, Article, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Progressive myoclonu, Internal medicine, medicine, Humans, Non-Receptor, 030212 general & internal medicine, Young adult, Neurodegeneration, Child, Genetic Association Studies, Mutation, business.industry, Middle Aged, medicine.disease, Protein Tyrosine Phosphatases, Non-Receptor, Progressive myoclonus, Italy, Lafora Disease, Neurology, Cohort, Neurology (clinical), medicine.symptom, Protein Tyrosine Phosphatases, business, Laforin, Myoclonus, 030217 neurology & neurosurgery, Human
Abstract

Background Lafora disease (LD) is characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration. This complex neurodegenerative condition is caused by pathogenic variants in EPM2A/EPM2B genes, encoding two essential glycogen metabolism enzymes known as laforin and malin. Long-term follow-up data are lacking. We describe the clinical features and genetic findings of a cohort of 26 Italian patients with a long clinical follow-up. Methods Patients with EPM2A/EPM2B pathogenic variants were identified by direct gene sequencing or gene panels with targeted re-sequencing. Disease progression, motor functions, and mental performance were assessed by a simplified disability scale. Spontaneous/action myoclonus severity was scored by the Magaudda Scale. Results Age range was 12.2–46.2 years (mean:25.53 ± 9.14). Age at disease onset ranged from 10 to 22 years (mean:14.04 ± 2.62). The mean follow-up period was 11.48 ± 7.8 years. Twelve out of the 26 (46%) patients preserved walking ability and 13 (50%) maintained speech. A slower disease progression with preserved ambulation and speech after ≥4 years of follow-up was observed in 1 (11%) out of the 9 (35%) EPM2A patients and in 6 (35%) out of the 17 (65%) EPM2B patients. Follow-up was >10 years in 7 (41.2%) EPM2B individuals, including two harbouring the homozygous p.(D146N) pathogenic variant. Conclusions This study supports an overall worse disease outcome with severe deterioration of ambulation and speech in patients carrying EPM2A mutations. However, the delayed onset of disabling symptoms observed in the EPM2B subjects harbouring the p.(D146N) pathogenic variant suggests that the underlying causative variant may still influence LD severity.

Published
2021

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

Author

Chiara Vannicola, Elena Freri, Ilaria Rivolta, Anna Binda, Giuliana Messina, Ilaria Mosca, Roberta Solazzi, Paolo Ambrosino, Gaetan Lesca, Laura Canafoglia, Carmen Murano, Jacopo C. DiFrancesco, Barbara Castellotti, Maria Virginia Soldovieri, Cinzia Gellera, Francesca Ragona, Audrey Labalme, Tiziana Granata, Maurizio Taglialatela, 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, and Taglialatela, M

Subjects
0301 basic medicine, Gabapentin, Mutant, CHO Cells, Pharmacology, Electroencephalography, Phenylenediamines, medicine.disease_cause, loss-of-function, 03 medical and health sciences, Epilepsy, chemistry.chemical_compound, 0302 clinical medicine, Cricetulus, Cricetinae, medicine, developmental and epileptic encephalopathy, epilepsy, KCNQ2, precision medicine, Animals, Humans, KCNQ2 Potassium Channel, Age of Onset, Precision Medicine, Child, Loss function, Cells, Cultured, Mutation, medicine.diagnostic_test, Activator (genetics), business.industry, Retigabine, medicine.disease, Rats, 030104 developmental biology, Treatment Outcome, chemistry, 030220 oncology & carcinogenesis, Anticonvulsants, Female, Carbamates, business, medicine.drug
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

34. The noncoding RNA AK127244 in 2p16.3 locus: A new susceptibility region for neuropsychiatric disorders

Author

Chiara Pantaleoni, Giovanna Zorzi, Vita Girgenti, Stefania Bigoni, Marica Eoli, Tiziana Granata, Margherita Estienne, Isabella Moroni, Francesca L. Sciacca, Veronica Saletti, Federica Zibordi, Stefano D'Arrigo, Elena Freri, Bruna Molteni, Nardo Nardocci, Enrico Alfei, Barbara Buldrini, Silvia Esposito, Donatella Milani, Anna Ardissone, Ambra Rizzo, Rizzo, A, Alfei, E, Zibordi, F, Saletti, V, Zorzi, G, Freri, E, Estienne, M, Girgenti, V, D'Arrigo, S, Esposito, S, Buldrini, B, Moroni, I, Milani, D, Granata, T, Ardissone, A, Eoli, M, Molteni, B, Bigoni, S, Pantaleoni, C, Nardocci, N, and Sciacca, F

Subjects
Adult, Male, 0301 basic medicine, RNA, Untranslated, Adolescent, DNA Copy Number Variations, Cell Adhesion Molecules, Neuronal, CNV, Nerve Tissue Proteins, Locus (genetics), Disease, Biology, Cohort Studies, NRXN1, 03 medical and health sciences, Cellular and Molecular Neuroscience, Humans, array CGH, Coding region, Genetic Predisposition to Disease, long noncoding RNA, Copy-number variation, Child, Neural Cell Adhesion Molecules, Gene, Genetics (clinical), Genetics, Comparative Genomic Hybridization, Mental Disorders, Calcium-Binding Proteins, Middle Aged, Non-coding RNA, Penetrance, Psychiatry and Mental health, Phenotype, 030104 developmental biology, Case-Control Studies, Child, Preschool, Chromosomes, Human, Pair 2, Female, RNA, Long Noncoding, Comparative genomic hybridization
Abstract

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions.

Published
2018
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35. Letter to the Editor Regarding the Article Whole-Exome Sequencing in NF1-Related West's Syndrome Leads to the Identification of KCNC2 as a Novel Candidate Gene for Epilepsy

Author

Roberta Solazzi, Mirella Vinci, Michele Roccella, Elena Freri, Francesco Calì, Valentino Romano, Carmelo Amato, Maurizio Elia, Luigi Vetri, Tiziana Granata, Vetri, L, Cali, F, Vinci, M, Amato, C, Roccella, M, Granata, T, Freri, E, Solazzi, R, Romano, V, and Elia, M

Subjects
Candidate gene, Shaw Potassium Channels, Letter to the editor, Epilepsy, business.industry, MEDLINE, West's syndrome, General Medicine, Computational biology, medicine.disease, Settore MED/39 - Neuropsichiatria Infantile, Pediatrics, Perinatology and Child Health, Exome Sequencing, Medicine, Humans, Identification (biology), Neurology (clinical), business, Spasms, Infantile, Exome sequencing
Published
2020

36. Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis

Author

Nosadini, Margherita, Granata, Tiziana, Matricardi, Sara, Freri, Elena, Ragona, Francesca, Papetti, Laura, Suppiej, Agnese, Valeriani, Massimiliano, Sartori, Stefano, Italian Working Group on Paediatric Anti-N-methyl-D-aspartate Receptor Encephalitis, Bonuccelli, A, Beccaria, F, Buechner, S, Buratti, S, Cantalupo, G, Cappellari, A, Casellato, S, Cesaroni, E, Cimaz, R, Cordelli, Dm, Costa, P, Dell'Avvento, S, Dilena, R, Falsaperla, R, Foiadelli, T, Frigo, Ac, Fusco, L, Giacobbe, A, Giannotta, M, Grazian, L, Maggio, Mc, Mancardi, Mm, Melis, M, Natali Sora MG, Orsini, A, Petruzzellis, A, Pini, A, Pruna, D, Santangelo, G, Savasta, S, Scaduto, Mc, Serino, D, Simula, D, Solazzi, R, Sotgiu, S, Splendiani, A, Toldo, I, Vigevano, F, Viri, M, Visconti, P, Zamponi, N, Zanus, C, Zoccarato, M, Zuliani, L, Nosadini M., Granata T., Matricardi S., Freri E., Ragona F., Papetti L., Suppiej A., Valeriani M., Sartori S., Bonuccelli A., Beccaria F., Buechner S., Buratti S., Cantalupo G., Cappellari A., Casellato S., Cesaroni E., Cimaz R., Cordelli D.M., Costa P., Dell'Avvento S., Dilena R., Falsaperla R., Foiadelli T., Frigo A.C., Fusco L., Giacobbe A., Giannotta M., Grazian L., Maggio M.C., Mancardi M.M., Melis M., Natali Sora M.G., Orsini A., Petruzzellis A., Pini A., Pruna D., Santangelo G., Savasta S., Scaduto M.C., Serino D., Simula D., Solazzi R., Sotgiu S., Splendiani A., Toldo I., Vigevano F., Viri M., Visconti P., Zamponi N., Zanus C., Zoccarato M., and Zuliani L.

Subjects
Male, 030506 rehabilitation, Gastroenterology, Cohort Studies, 0302 clinical medicine, Retrospective Studie, Modified Rankin Scale, Recurrence, Risk Factors, Child, relapse, Anti-N-Methyl-D-Aspartate Receptor Encephalitis, Hazard ratio, Italy, Child, Preschool, Cohort, anti‐N‐methyl‐D‐aspartate receptor encephalitis, Female, 0305 other medical science, Encephalitis, Human, Cohort study, medicine.medical_specialty, Adolescent, Socio-culturale, anti-NMDAR antibodies, 03 medical and health sciences, anti-NMDAR, Developmental Neuroscience, Internal medicine, medicine, Humans, Infant, Retrospective Studies, Preschool, Survival analysis, Autoimmune encephalitis, business.industry, Retrospective cohort study, medicine.disease, anti-NMDAR antibodies, autoimmune encephalitis, anti‐N‐methyl‐D‐aspartate receptor encephalitis, autoimmune encephalitis, Anti-N-methyl-D-aspartate receptor encephalitis, anti-NMDAR, autoimmune encephalitis, relapse, Anti-N-Methyl-D-Aspartate Receptor Encephaliti, Pediatrics, Perinatology and Child Health, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

Aim: To identify factors that may predict and affect the risk of relapse in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Method: This was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti-NMDAR encephalitis. Results: Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo–18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2–4). Time to first relapse was median 31.5months (range 7–89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2–4, vs median mRS 5, range 3–5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046–0.941; p=0.042). Neurological outcome at follow-up did not differ significantly between patients with relapsing and monophasic disease (mRS 0–1 in 39/49 vs 12/13; p=0.431), although follow-up duration was significantly longer in relapsing (median 84mo, range 14–137mo) than in monophasic patients (median 32mo, range 4–108mo; p=0.002). Interpretation: Relapses may occur in about one-fifth of children with anti-NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow-up. Aggressive immune therapy at onset may reduce risk of relapse. What this paper adds: Relapses of anti-N-methyl-D-aspartate receptor encephalitis may span over a long period. Relapses were not associated with severity in the acute phase or outcome at follow-up. Aggressive immune therapy at onset appears to decrease risk of relapse.

Published
2019

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

Author

Andrea Barbuti, Laura Canafoglia, Francesca Ragona, Roberta Solazzi, Silvana Franceschetti, Raffaella Milanesi, Elena Freri, Giancarlo Di Gennaro, Anna Binda, Jacopo C. DiFrancesco, Antonio Gambardella, Tiziana Granata, Sara Casciato, Angelo Labate, Dario DiFrancesco, Cinzia Costa, Ilaria Rivolta, Barbara Castellotti, Cinzia Gellera, Franco Taroni, Carlo Ferrarese, Ludovico D'Incerti, Stefania Magri, 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, and Gellera, C

Subjects
0301 basic medicine, Male, Accessory protein, Potassium Channels, Caveolin 3, Cytoplasmic and Nuclear, Receptors, Cytoplasmic and Nuclear, Disease, medicine.disease_cause, Filamin, Bioinformatics, Cohort Studies, Epilepsy, 0302 clinical medicine, Receptors, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, education.field_of_study, Mutation, medicine.diagnostic_test, Genetic, HCN, Ion channel, Cadherins, Carrier Proteins, Electroencephalography, Family Health, Female, Filamins, Genetic Testing, Humans, Membrane Proteins, Nerve Tissue Proteins, Potassium Channels, Voltage-Gated, Voltage-Gated, Phenotype, Neurology, Population, Biology, 03 medical and health sciences, medicine, education, Adaptor Proteins, Signal Transducing, Genetic testing, medicine.disease, 030104 developmental biology, Membrane protein, Neurology (clinical), Guanylate Kinases, 030217 neurology & neurosurgery
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

38. An Italian multicentre study of perampanel in progressive myoclonus epilepsies

Author

Carlo Avolio, Francesca Ragona, Giuseppina Barbella, Elena Freri, Patrizia Riguzzi, Chiara Sueri, Edoardo Ferlazzo, Paolo Tinuper, Loretta Giuliano, Davide Rossi Sebastiano, Cinzia Costa, Carlo Di Bonaventura, Elena Nardi Cesarini, Tommaso Martino, Silvana Franceschetti, Francesca Bisulli, Adriana Magaudda, Giuseppe d'Orsi, Vito Sofia, Federica Zibordi, Laura Licchetta, Laura Canafoglia, Francesca Beccaria, Martina Fanella, Antonio Gambardella, Tiziana Granata, Pasquale Striano, Umberto Aguglia, Roberto Michelucci, Elisa Visani, Canafoglia L., Barbella G., Ferlazzo E., Striano P., Magaudda A., d'Orsi G., Martino T., Avolio C., Aguglia U., Sueri C., Giuliano L., Sofia V., Zibordi F., Ragona F., Freri E., Costa C., Cesarini E.N., Fanella M., Sebastiano D.R., Riguzzi P., Gambardella A., Bonaventura C.D., Michelucci R., Granata T., Bisulli F., Licchetta L., Tinuper P., Beccaria F., Visani E., and Franceschetti S.

Subjects
Adult, Male, Myoclonus, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Pyridones, Progressive myoclonus epilepsy, EPM1, EPM2, Irritability, Perampanel, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Epilepsy, 0302 clinical medicine, Seizures, Rating scale, Nitriles, medicine, Humans, Kufs disease, Myoclonus scale, Perampanel, Progressive myoclonus epilepsy, EPM1, EPM2, Irritability, Myoclonus scale, Aged, business.industry, Middle Aged, Myoclonic Epilepsies, Progressive, medicine.disease, Treatment Outcome, 030104 developmental biology, Neurology, chemistry, Etiology, Anticonvulsants, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ± 15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2–12 mg (5.3 ± 2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4–6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the ‘Action myoclonus’ section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.

Published
2019

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

Author

Elena Freri, Silvana Franceschetti, Giovanni Tricomi, Anna Venerando, Stefano Ciardullo, Laura Canafoglia, Barbara Salis, Tiziana Granata, Roberta Solazzi, Jacopo C. DiFrancesco, Francesca Ragona, Nardo Nardocci, Barbara Castellotti, Cinzia Gellera, Flavio Villani, 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, and Granata, T

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Microcephaly, Neurology, Adolescent, Monosaccharide Transport Proteins, Developmental delay, Developmental Disabilities, SLC2A1, Intellectual disability, Neurological disorder, Disease, Young Adult, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Hypoglycorrhachia, Chorea, Humans, Medicine, 030212 general & internal medicine, Child, Pathological, Movement disorder, Glucose Transporter Type 1, business.industry, Infant, Paroxysmal dyskinesia, medicine.disease, Glut1 deficiency, Phenotype, Child, Preschool, Cohort, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Carbohydrate Metabolism, Inborn Errors
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

40. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Author

Shoji Ichikawa, Ilaria Rivolta, Anna Binda, Laurie S. Sadler, Sonia Figueiroa, Renzo Guerrini, Annick Laridon, Pasquale Striano, Katalin Sterbova, Bina Santoro, Petra Laššuthová, Maria Margherita Mancardi, Francesca Ragona, Anna Rosati, Fernando Kok, Laura Canafoglia, Daniele Frattini, Elena Freri, Christine Coubes, Davide Mei, Bobby P. C. Koeleman, Daniel Bauer, Carla Marini, Christel Depienne, Carlotta Spagnoli, Sophie Scheidecker, Carlo Fusco, Tiziana Granata, Barbara Castellotti, Eva H. Brilstra, Federico Melani, Cristina Garrido, Cinzia Gellera, A. Micheil Innes, Wilfrid Carré, Christèle Dubourg, Elena Parrini, Alessandro Porro, Caroline Nava, Maria Giardino, Sophie Julia, Manuela Santos, Yves Alembik, Eric LeGuern, Andrea Barbuti, Silvana Franceschetti, Federico Zara, Paul Kuentz, Raffaella Milanesi, Catherine Mercer, Carine Dalle, Julien Thevenon, Nicolas Deconinck, Agnès Rastetter, Laurent Pasquier, Kay Hamacher, Renske Oegema, Gerhard Thiel, Dario DiFrancesco, Tiziana Pisano, Chelsea Chambers, Jacopo C. DiFrancesco, Guillaume Smits, Katherine L. Helbig, Julie Soblet, Jana Neupauerová, Damien R Clark, Johannes R. Lemke, Radhika Dhamija, Anna Moroni, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center [Utrecht], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Pontchaillou [Rennes], Les Hôpitaux Universitaires de Strasbourg (HUS), Children’s Hospital of Philadelphia (CHOP ), University Hospital Motol [Prague], University of Genoa (UNIGE), Université libre de Bruxelles (ULB), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), 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, and Depienne, C

Subjects
0301 basic medicine, Proband, Male, Models, Molecular, Potassium Channels, [SDV]Life Sciences [q-bio], Medizin, medicine.disease_cause, Epileptogenesis, Membrane Potentials, Epilepsy, 0302 clinical medicine, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Missense mutation, Child, Genetics, Mutation, Middle Aged, Phenotype, 3. Good health, Transmembrane domain, clinical spectrum, epilepsy, HCN1, intellectual disability, ion channel, Child, Preschool, Epilepsy, Generalized, Female, Spasms, Infantile, Adult, Adolescent, CHO Cells, Biology, 03 medical and health sciences, Young Adult, Cricetulus, medicine, Animals, Humans, Generalized epilepsy, Genetic Association Studies, Aged, Infant, medicine.disease, Electric Stimulation, 030104 developmental biology, Mutagenesis, Site-Directed, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

International audience; 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 voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

Published
2018
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41. A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability

Author

Giulia Campostrini, Jacopo C. DiFrancesco, Barbara Castellotti, Raffaella Milanesi, Tomaso Gnecchi-Ruscone, Mattia Bonzanni, Annalisa Bucchi, Mirko Baruscotti, Carlo Ferrarese, Silvana Franceschetti, Laura Canafoglia, Francesca Ragona, Elena Freri, Angelo Labate, Antonio Gambardella, Cinzia Costa, Cinzia Gellera, Tiziana Granata, Andrea Barbuti, Dario DiFrancesco, 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, and Difrancesco, D

Subjects
0301 basic medicine, Bradycardia, Gene isoform, Mutant, medicine.disease_cause, Epilepsy, HCN4, Ion channels, Myoclonic epilepsy of infancy, Neuronal excitability, Molecular Biology, Cellular and Molecular Neuroscience, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, medicine, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Loss function, Mutation, business.industry, medicine.disease, 030104 developmental biology, Etiology, Myoclonic epilepsy, medicine.symptom, Ion channel, business, Neuroscience, 030217 neurology & neurosurgery
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
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42. Kv7.3 Compound Heterozygous Variants in Early Onset Encephalopathy Reveal Additive Contribution of C-Terminal Residues to PIP2-Dependent K+Channel Gating

Author

Elena Freri, Jacopo C. DiFrancesco, Silvana Franceschetti, Barbara Salis, Ilaria Mosca, Tiziana Granata, Maurizio Taglialatela, Francesca Ragona, Laura Manocchio, Francesco Miceli, Maria Virginia Soldovieri, Paolo Ambrosino, Barbara Castellotti, Laura Canafoglia, Cinzia Gellera, Nunzio Iraci, Ambrosino, P, Freri, E, Castellotti, B, Soldovieri, Mv, Mosca, I, Manocchio, L, Gellera, C, Canafoglia, L, Franceschetti, S, Salis, B, Iraci, N, Miceli, F, Ragona, F, Granata, T, Difrancesco, Jc, and Taglialatela, M.

Subjects
Male, 0301 basic medicine, Heterozygote, Mutant, Neuroscience (miscellaneous), Compound heterozygosity, KCNQ3 Potassium Channel, Structure-Activity Relationship, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cricetulus, 0302 clinical medicine, Compound heterozygosity, Epilepsy, Epileptic encephalopathy, Kv7 potassium channels, Mutation, Amino Acid Sequence, Animals, Brain Diseases, Child, Cricetinae, Cricetulus, Female, Heterozygote, Humans, Infant, Infant, Newborn, KCNQ2 Potassium Channel, KCNQ3 Potassium Channel, Male, Mutant Proteins, Pedigree, Phosphatidylinositol 4,5-Diphosphate, Structure-Activity Relationship, Ion Channel Gating, Cricetinae, KCNQ2 Potassium Channel, medicine, Animals, Humans, Missense mutation, Benign familial neonatal seizures, Amino Acid Sequence, Kv7 potassium channels, Child, Gene, Brain Diseases, Epilepsy, Chemistry, Epileptic encephalopathy, Infant, Heterozygote advantage, Newborn, medicine.disease, Mutation, Phenotype, Molecular biology, Pedigree, Phosphatidylinositol 4, 030104 developmental biology, Neurology, 5-Diphosphate, Female, Mutant Proteins, Ion Channel Gating, 030217 neurology & neurosurgery
Abstract

Over one hundred mutations in the Kv7.2 (KCNQ2) gene encoding for phosphatidylinositol 4,5-bisphosphate (PIP2)-sensitive voltage-gated K+ channel subunits have been identified in early-onset epilepsies with wide phenotypic variability. By contrast, only few mutations in the closely related Kv7.3 (KCNQ3) gene have been reported, mostly associated with typical benign familial neonatal seizures (BFNS). We herein describe a patient affected by early onset epileptic encephalopathy (EOEE) carrying two Kv7.3 missense mutations (p.Val359Leu/V359L and p.Asp542Asn/D542N) in compound heterozygosis, each inherited from an asymptomatic parent. Patch-clamp recordings from transiently transfected CHO cells showed that, when incorporated in physiologically relevant Kv7.2 + Kv7.3 heteromeric channels, expression of Kv7.3 V359L or Kv7.3 D542N subunits failed to affect current density, whereas a significant decrease was instead observed when these mutant subunits were both simultaneously present. Modeling and functional experiments revealed that each variant decreased PIP2-dependent current regulation, with additive effects when the two were co-expressed. Moreover, expression of Kv7.2 subunits carrying the D535N variant previously described in three sporadic EOEE cases prompted functional changes more dramatic when compared to those of the corresponding D542N variant in Kv7.3, but similar to those observed when both Kv7.3 V359L and Kv7.3 D542N subunits were expressed together. Finally, the Kv7 activator retigabine restored channel dysfunction induced by each Kv7.2 or Kv7.3 variant(s). These results provide a plausible molecular explanation for the apparent recessive inheritance of the phenotype in the family investigated, and a rational basis for personalized therapy with Kv7 channel activators in EOEE patients carrying loss-of-function mutations in Kv7.2 or Kv7.3.

Published
2018

43. Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes.

Author

Filareto I, Mosca I, Freri E, Ragona F, Canafoglia L, Solazzi R, Castellotti B, Messina G, Gellera C, Soldovieri MV, Ambrosino P, Taglialatela M, DiFrancesco JC, and Granata T

Abstract

Variants in genes encoding for voltage-gated K + (Kv) channels are frequent cause of drug-resistant pediatric epilepsies. Obtaining a molecular diagnosis gives the opportunity to assess the efficacy of pharmacological strategies based on in vitro features of mutant channels. In this retrospective observational study, we selected patients with drug-resistant pediatric epilepsies caused by variants in potassium channel encoding genes, followed at the Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan, Italy. After the experimental characterization of variants' functional properties in transiently transfected Chinese Hamster Ovary (CHO) cells, we identified drugs to be used as pharmacological approaches. We recruited six patients carrying different missense variants in four Kv channels (Kv7.2, Kv7.3, Kv3.1, and K Na 1.1). In vitro experiments demonstrated that variants in Kv7 channels induced loss-of-function (LoF) effects, while those affecting Kv3.1 or K Na 1.1 led to gain-of-function (GoF). Moreover, we found that the Kv7 channels activator gabapentin was able to revert the LoF effects caused by Kv7.2/Kv7.3 variants, and the potassium channel-blocker fluoxetine counteracted the GoF effects in Kv3.1 or K Na 1.1 variants. According to experimental data, patients carrying Kv7 variants were treated with gabapentin. While this treatment resulted successful in two patients (#1, Kv7.2 G310S variant; #3, Kv7.3 V359L + Kv7.3 D542N), it resulted detrimental in the remaining case (#2, Kv7.2 D535E), requiring drug withdrawal. The application in vivo of fluoxetine to counteract GoF effects induced by Kv3.1 or K Na 1.1 variants determined a significant reduction of both seizure frequency and behavior disturbances in patient #4 (Kv3.1 V425M), and in both subjects carrying K Na 1.1 variants (#5, S937G and #6, R262Q). However, for the latter case, this drug was halted due to severe behavioral side effects. For most of the patients herein reported, pharmacological strategies, selected according to the in vitro functional properties of Kv-channels pathogenic variants, resulted in a significant improvement of both epileptic and cognitive features., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Filareto, Mosca, Freri, Ragona, Canafoglia, Solazzi, Castellotti, Messina, Gellera, Soldovieri, Ambrosino, Taglialatela, DiFrancesco and Granata.)

Published
2025
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44. The natural history of CDKL5 deficiency disorder into adulthood.

Author

Aledo-Serrano A, Lewis-Smith D, Leonard H, Bayat A, Junaid M, Hagebeuk E, Fenger CD, Laze J, Rossi A, Trivisano M, Gonzalez-Giraldez B, Lama J, Krey I, Platzer K, Brischoux-Boucher E, Sarret C, Lomax LB, Zanus C, Musante L, Costa P, Moloney P, Delanty N, Russo A, Schönewolf-Greulich B, Bisgaard AM, Berger C, Freri E, Takahashi S, Zacher P, Jung J, Demarest S, Marsh E, Percy A, Neul J, Olson H, Swanson L, Meletti S, Cioclu MC, Ali QZ, Suller A, Beltran-Corbellini A, Gil-Nagel A, Zhang X, Previtali R, Højte AF, Specchio N, Downs J, Lesca G, Rubboli G, Andrade D, Gardella E, Pestana E, Devinsky O, Benke T, Helbig I, Thomas R, and Møller RS

Abstract

Knowledge of the natural history of CDKL5 deficiency disorder (CDD) is limited to the results of cross-sectional analysis of largely pediatric cohorts. Assessment of outcomes in adulthood is critical for clinical decision-making and future precision medicine approaches but is challenging because of the diagnostic gap and duration of follow-up that would be required for prospective studies. We aimed to delineate the natural history retrospectively from adulthood. We analyzed clinical data about an international cohort of 67 adults with CDD. We analyzed demographic, phenotypic, CDKL5 Developmental Score (CDS), and treatment data, and tested associations with genetic factors, sex, and a positive or negative history of neonatal seizures, as an early predictor of prognosis. All but one of 67 adults (55 females, median age of 24 years at last follow-up) had epilepsy, typically beginning with epileptic spasms or tonic seizures before 4 months of age. Focal-onset and non-motor seizures emerged later. Fewer than a third had been documented as having bilateral tonic-clonic seizures or status epilepticus. Seizures often improved with age, but 73% had never experienced more than 6 months of seizure-freedom. Clobazam, sodium valproate, and lamotrigine were the most frequently prescribed antiseizure medications, but no specific treatment demonstrated superiority. Common comorbidities included movement disorders, visual impairment, sleep disorders, constipation, and scoliosis. All participants had intellectual disability, 75% had not acquired speech and 45% had regressed developmentally. 16% never achieved any CDS skill, but most attained at least three, and 28% attained six or all seven. By adulthood, half of those who had achieved any CDS skill retained all their CDS skills. The skills most frequently lost were independent walking and standing. Those with a history of neonatal seizures tended to attain fewer CDS skills and were more likely to have abnormal muscle tone in adulthood, atrioventricular conduction delay, and potential complications of their illness and treatment. Individuals carrying missense variants attained more CDS skills than those with other variants and were more likely to lose skills in adulthood and develop anxiety, possibly reflecting the limited neurodevelopment of those with non-missense variants, who manifested a more multisystemic disorder. In summary, retrospective data from adulthood elucidates the evolution of symptoms, variation in developmental outcomes, and the treatment landscape in CDKL5 deficiency disorder. Presence a non-missense variants or a history of neonatal seizures indicates a more complex disorder and lower developmental trajectory. Our findings will inform management decisions, prognostication, and the design of clinical trials in CDKL5 Deficiency Disorder.

Published
2025
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45. Next-generation sequencing in pediatric-onset epilepsies: Analysis with target panels and personalized therapeutic approach.

Author

Castellotti B, Ragona F, Freri E, Messina G, Magri S, Previtali R, Solazzi R, Franceschetti S, Taroni F, Canafoglia L, Gellera C, Granata T, and DiFrancesco JC

Subjects
Humans, Child, Female, Male, Retrospective Studies, Child, Preschool, Adolescent, Infant, Genetic Testing, Age of Onset, Precision Medicine, High-Throughput Nucleotide Sequencing, Epilepsy genetics, Epilepsy diagnosis
Abstract

Objective: The objective of this study is to report the results of the genetic analysis in a large and well-characterized population with pediatric-onset epilepsies and to identify those who could benefit from precision medicine treatments., Methods: In this retrospective observational study, we consecutively recruited patients with pediatric-onset epilepsy observed at a tertiary neurological center over a time span of 7 years, collecting clinical and laboratory findings. Following in-depth diagnostic process to exclude possible structural and metabolic causes of the disease, patients with a suspected genetically determined etiology underwent next-generation sequencing (NGS) screening with panels for the analysis of target genes causative of epilepsy., Results: We detected likely pathogenic or pathogenic variants (classes IV and V) in 24% of the 562 patients who underwent genetic investigations. By the evaluation of patients' data, we observed that some features (onset of epilepsy before one year old, presence of neurological deficits, psychomotor delay/cognitive disability, and malformative aspects at brain MRI) were significantly associated with class IV or V variants. Moreover, statistical analysis showed that the diagnostic yield resulted higher for patients affected by Progressive Myoclonic Epilepsy (PME) and with early onset developmental and epileptic encephalopathies (DEE), compared with focal epilepsies, genetic generalized epilepsies, DEE with onset at/after 1 y.o., and unclassified epileptic syndromes. According to the results of the genetic screening, up to 33% of patients carrying class IV or V variants resulted potentially eligible for precision medicine treatments., Significance: The large-scale application of NGS multigene panels of analysis is a useful tool for the molecular diagnosis of patients with pediatric-onset epilepsies, allowing the identification of those who could benefit from a personalized therapeutic approach., Plain Language Summary: The analysis of patients with pediatric-onset epilepsy using advanced technologies for the screening of all the implicated genes allows the identification of the cause of diseases in an ever-increasing number of cases. Understanding the pathogenic mechanisms could, in some cases, guide the selection and optimization of appropriate treatment approaches for patients., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
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46. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Author

Chen S, Abou-Khalil BW, Afawi Z, Ali QZ, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Arslan M, Auce P, Bahlo M, Baker MD, Balagura G, Balestrini S, Banks E, Barba C, Barboza K, Bartolomei F, Bass N, Baum LW, Baumgartner TH, Baykan B, Bebek N, Becker F, Bennett CA, Beydoun A, Bianchini C, Bisulli F, Blackwood D, Blatt I, Borggräfe I, Bosselmann C, Braatz V, Brand H, Brockmann K, Buono RJ, Busch RM, Caglayan SH, Canafoglia L, Canavati C, Castellotti B, Cavalleri GL, Cerrato F, Chassoux F, Cherian C, Cherny SS, Cheung CL, Chou IJ, Chung SK, Churchhouse C, Ciullo V, Clark PO, Cole AJ, Cosico M, Cossette P, Cotsapas C, Cusick C, Daly MJ, Davis LK, Jonghe P, Delanty N, Dennig D, Depondt C, Derambure P, Devinsky O, Di Vito L, Dickerson F, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Ellis CA, Epstein L, Evans M, Faucon A, Feng YA, Ferguson L, Ferraro TN, Da Silva IF, Ferri L, Feucht M, Fields MC, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, French JA, Freri E, Fu JM, Gabriel S, Gagliardi M, Gambardella A, Gauthier L, Giangregorio T, Gili T, Glauser TA, Goldberg E, Goldman A, Goldstein DB, Granata T, Grant R, Greenberg DA, Guerrini R, Gundogdu-Eken A, Gupta N, Haas K, Hakonarson H, Haryanyan G, Häusler M, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne H, Hirose S, Hirsch E, Ho CJ, Hoeper O, Howrigan DP, Hucks D, Hung PC, Iacomino M, Inoue Y, Inuzuka LM, Ishii A, Jehi L, Johnson MR, Johnstone M, Kälviäinen R, Kanaan M, Kara B, Kariuki SM, Kegele J, Kesim Y, Khoueiry-Zgheib N, Khoury J, King C, Klein KM, Kluger G, Knake S, Kok F, Korczyn AD, Korinthenberg R, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurlemann G, Kuzniecky RI, Kwan P, La Vega-Talbott M, Labate A, Lacey A, Lal D, Laššuthová P, Lauxmann S, Lawthom C, Leech SL, Lehesjoki AE, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH, Liao C, Licchetta L, Lin CH, Lin KL, Linnankivi T, Lo W, Lowenstein DH, Lowther C, Lubbers L, Lui CHT, Macedo-Souza LI, Madeleyn R, Madia F, Magri S, Maillard L, Marcuse L, Marques P, Marson AG, Matthews AG, May P, Mayer T, McArdle W, McCarroll SM, McGoldrick P, McGraw CM, McIntosh A, McQuillan A, Meador KJ, Mei D, Michel V, Millichap JJ, Minardi R, Montomoli M, Mostacci B, Muccioli L, Muhle H, Müller-Schlüter K, Najm IM, Nasreddine W, Neaves S, Neubauer BA, Newton CRJC, Noebels JL, Northstone K, Novod S, O'Brien TJ, Owusu-Agyei S, Özkara Ç, Palotie A, Papacostas SS, Parrini E, Pato C, Pato M, Pendziwiat M, Pennell PB, Petrovski S, Pickrell WO, Pinsky R, Pinto D, Pippucci T, Piras F, Piras F, Poduri A, Pondrelli F, Posthuma D, Powell RHW, Privitera M, Rademacher A, Ragona F, Ramirez-Hamouz B, Rau S, Raynes HR, Rees MI, Regan BM, Reif A, Reinthaler E, Rheims S, Ring SM, Riva A, Rojas E, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Salman B, Salmon A, Salpietro V, Sammarra I, Scala M, Schachter S, Schaller A, Schankin CJ, Scheffer IE, Schneider N, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sedláčková L, Shain C, Sham PC, Shiedley BR, Siena SA, Sills GJ, Sisodiya SM, Smoller JW, Solomonson M, Spalletta G, Sparks KR, Sperling MR, Stamberger H, Steinhoff BJ, Stephani U, Štěrbová K, Stewart WC, Stipa C, Striano P, Strzelczyk A, Surges R, Suzuki T, Talarico M, Talkowski ME, Taneja RS, Tanteles GA, Timonen O, Timpson NJ, Tinuper P, Todaro M, Topaloglu P, Tsai MH, Tumiene B, Turkdogan D, Uğur-İşeri S, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vari MS, Vetro A, Vlčková M, von Brauchitsch S, von Spiczak S, Wagner RG, Watts N, Weber YG, Weckhuysen S, Widdess-Walsh P, Wiebe S, Wolf SM, Wolff M, Wolking S, Wong I, von Wrede R, Wu D, Yamakawa K, Yapıcı Z, Yis U, Yolken R, Yücesan E, Zagaglia S, Zahnert F, Zara F, Zimprich F, Zizovic M, Zsurka G, Neale BM, and Berkovic SF

Abstract

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Published
2024
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47. De novo monoallelic Reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism.

Author

Riva M, Ferreira S, Hayashi K, Saillour Y, Medvedeva VP, Honda T, Hayashi K, Altersitz C, Albadri S, Rosello M, Dang J, Serafini M, Causeret F, Henry OJ, Roux CJ, Bellesme C, Freri E, Josifova D, Parrini E, Guerrini R, Del Bene F, Nakajima K, Bahi-Buisson N, and Pierani A

Subjects
Humans, Animals, Mice, Female, Male, Neurons metabolism, Neurons pathology, Polymicrogyria genetics, Polymicrogyria pathology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Heterozygote, Lissencephaly genetics, Lissencephaly pathology, Alleles, Reelin Protein, Mutation, Missense, Extracellular Matrix Proteins genetics, Extracellular Matrix Proteins metabolism, Serine Endopeptidases genetics, Serine Endopeptidases metabolism, Cell Adhesion Molecules, Neuronal genetics, Cell Adhesion Molecules, Neuronal metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Cell Movement genetics
Abstract

Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.

Published
2024
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48. Early occurrence of photic-reflex myoclonus in CDKL5-deficiency disorder.

Author

Caputo D, Franceschetti S, Canafoglia L, Iascone M, Rossi Sebastiano D, Freri E, and Granata T

Subjects
Humans, Male, Female, Photic Stimulation methods, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked physiopathology, Retinal Degeneration physiopathology, Retinal Degeneration genetics, Reflex physiology, Protein Serine-Threonine Kinases genetics, Epileptic Syndromes, Spasms, Infantile, Myoclonus physiopathology, Myoclonus genetics
Published
2024
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50. Case report: Marked electroclinical improvement by fluoxetine treatment in a patient with KCNT1 -related drug-resistant focal epilepsy.

Author

Mosca I, Freri E, Ambrosino P, Belperio G, Granata T, Canafoglia L, Ragona F, Solazzi R, Filareto I, Castellotti B, Messina G, Gellera C, DiFrancesco JC, Soldovieri MV, and Taglialatela M

Abstract

Variants in KCNT1 are associated with a wide spectrum of epileptic phenotypes, including epilepsy of infancy with migrating focal seizures (EIMFS), non-EIMFS developmental and epileptic encephalopathies, autosomal dominant or sporadic sleep-related hypermotor epilepsy, and focal epilepsy. Here, we describe a girl affected by drug-resistant focal seizures, developmental delay and behavior disorders, caused by a novel, de novo heterozygous missense KCNT1 variant (c.2809A > G, p.S937G). Functional characterization in transiently transfected Chinese Hamster Ovary (CHO) cells revealed a strong gain-of-function effect determined by the KCNT1 p.S937G variant compared to wild-type, consisting in an increased maximal current density and a hyperpolarizing shift in current activation threshold. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant KCNT1 channels. Treatment of the proband with fluoxetine led to a prolonged electroclinical amelioration, with disappearance of seizures and better EEG background organization, together with an improvement in behavior and mood. Altogether, these results suggest that, based on the proband's genetic and functional characteristics, the antidepressant drug fluoxetine may be repurposed for the treatment of focal epilepsy caused by gain-of-function variants in KCNT1 . Further studies are needed to verify whether this approach could be also applied to other phenotypes of the KCNT1 -related epilepsies spectrum., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mosca, Freri, Ambrosino, Belperio, Granata, Canafoglia, Ragona, Solazzi, Filareto, Castellotti, Messina, Gellera, DiFrancesco, Soldovieri and Taglialatela.)

Published
2024
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