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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

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. 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

11. 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. DISTRIBUTION OF PROGRESSIVE MYOCLONUS EPILEPSIES IN ITALY; POSITIVELY DIAGNOSED AND UNCLASSIFIED PATIENTS: p827

Author

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

Published
2012

14. 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

15. 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

16. 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

17. 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

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

24. 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

25. 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

27. Long-term outcome of epilepsy in patients with prader–willi syndrome

Author

Verrotti A, Cusmai R, Laino D, CAROTENUTO, Marco, ESPOSITO, Maria, Falsaperla R, Margari L, Rizzo R, Savasta S, Grosso S, Striano P, Belacastro V, Franzoni E, Curatolo P, Giordano L, Freri E, Matricardi S, Pruna D, Toldo I, Tozzi E, Lobefalo L, Operto F, Altobelli E, Chiarelli F, Spalice A., Verrotti, A, Cusmai, R, Laino, D, Carotenuto, Marco, Esposito, Maria, Falsaperla, R, Margari, L, Rizzo, R, Savasta, S, Grosso, S, Striano, P, Belacastro, V, Franzoni, E, Curatolo, P, Giordano, L, Freri, E, Matricardi, S, Pruna, D, Toldo, I, Tozzi, E, Lobefalo, L, Operto, F, Altobelli, E, Chiarelli, F, and Spalice, A.

Subjects
Epilepsy, Prader–Willi syndrome, EEG, Long term outcome
Abstract

Prader-Willi syndrome is a multisystemic genetic disorder that can be associated with epilepsy. There is insufficient information concerning the clinical and electroencephalographic characteristics of epilepsy and the long-term outcome of these patients. The aim of this study is to describe seizure types, electroencephalographic patterns and long-term seizure outcome in Prader-Willi syndrome patients suffering from epilepsy. We retrospectively studied 38 patients with Prader-Willi syndrome and seizures. Results of neuroimaging studies were obtained for 35 individuals. We subdivided these patients into two groups: group A, 24 patients, without brain lesions; and group B, 11 patients, with brain abnormalities. All patients were re-evaluated after a period of at least 10 years. Twenty-one patients (55.2 %) were affected by generalized epilepsy and 17 patients (44.8 %) presented focal epilepsy. The most common seizure type was generalized tonic-clonic seizure. The mean age at seizure onset was 4.5 years (ranged from 1 month to 14 years). In the follow-up period, seizure freedom was achieved in 32 patients (84.2 %). Seizure freedom was associated with electroencephalographic normalization, while the six children presenting drug-resistant epilepsy showed persistence of electroencephalographic abnormalities. Group B patients showed a higher prevalence of drug-resistant epilepsy. Patients with Prader-Willi syndrome were frequently affected by generalized seizures. Most of the patients had a favorable evolution, although, patients with brain abnormalities presented a worse outcome, suggesting that the presence of these lesions can influence the response to antiepileptic therapy. Prader–Willi syndrome is a multisystemic genetic disorder that can be associated with epilepsy. There is insufficient information concerning the clinical and electroencephalographic characteristics of epilepsy and the long-term outcome of these patients. The aim of this study is to describe seizure types, electroencephalographic patterns and long-term seizure outcome in Prader–Willi syndrome patients suffering from epilepsy. We retrospectively studied 38 patients with Prader–Willi syndrome and seizures. Results of neuroimaging studies were obtained for 35 individuals. We subdivided these patients into two groups: group A, 24 patients, without brain lesions; and group B, 11 patients, with brain abnormalities. All patients were re-evaluated after a period of at least 10 years. Twenty-one patients (55.2 %) were affected by generalized epilepsy and 17 patients (44.8 %) presented focal epilepsy. The most common seizure type was generalized tonic– clonic seizure. The mean age at seizure onset was 4.5 years (ranged from 1 month to 14 years). In the follow-up period, seizure freedom was achieved in 32 patients (84.2 %). Seizure freedom was associated with electroencephalographic normalization, while the six children presenting drug-resistant epilepsy showed persistence of electroencephalographic abnormalities. Group B patients showed a higher prevalence of drug-resistant epilepsy. Patients with Prader–Willi syndrome were frequently affected by generalized seizures. Most of the patients had a favorable evolution, although, patients with brain abnormalities presented a worse outcome, suggesting that the presence of these lesions can influence the response to antiepileptic therapy.

Published
2015

28. 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

29. 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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30. 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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31. 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

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

Author

Ragona, F, Granata, T, Dalla Bernardina, B, Offredi, F, Darra, F, Battaglia, Domenica Immacolata, Morbi, Ma, Brazzo, D, Cappelletti, S, Chieffo, Daniela Pia Rosaria, De Giorgi, I, Fontana, E, Freri, E, Marini, C, Toraldo, A, Specchio, N, Veggiotti, P, Vigevano, F, Guerrini, R, Guzzetta, Francesco, Dravet, C., Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), Chieffo, D, Ragona, F, Granata, T, Dalla Bernardina, B, Offredi, F, Darra, F, Battaglia, Domenica Immacolata, Morbi, Ma, Brazzo, D, Cappelletti, S, Chieffo, Daniela Pia Rosaria, De Giorgi, I, Fontana, E, Freri, E, Marini, C, Toraldo, A, Specchio, N, Veggiotti, P, Vigevano, F, Guerrini, R, Guzzetta, Francesco, Dravet, C., Battaglia, Domenica Immacolata (ORCID:0000-0003-0491-4021), and Chieffo, D

Abstract

To clarify the role of epilepsy and genetic background in determining the cognitive outcome of patients with Dravet syndrome.

Published
2011

38. 2FC1.4 Epilepsy in girls with de novo protocadherin 19 mutations.

Author

Specchio, N., primary, Terracciano, A., additional, Marini, C., additional, Trivisano, M., additional, Mei, D., additional, Darra, F., additional, Bernardina, B. Dalla, additional, Granata, T., additional, Freri, E., additional, Fusco, L., additional, Guerrini, R., additional, Bertini, E., additional, and Vigevano, F., additional

Published
2011
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39. Rasmussen’s encephalitis

Author

Granata, T., primary, Gobbi, G., additional, Spreafico, R., additional, Vigevano, F., additional, Capovilla, G., additional, Ragona, F., additional, Freri, E., additional, Chiapparini, L., additional, Bernasconi, P., additional, Giordano, L., additional, Bertani, G., additional, Casazza, M., additional, Dalla Bernardina, B., additional, and Fusco, L., additional

Published
2003
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41. Progressive epileptic encephalopathy associated with a novel HCN2 mutation

Author

Binda, A., Murano, C., Di Francesco, J. C., Castellotti, B., Milanesi, R., Ragona, F., Freri, E., Canafoglia, L., Franceschetti, S., Solazzi, R., tiziana granata, Gellera, C., Rivolta, I., Binda, A, Murano, C, DI FRANCESCO, J, Castellotti, B, Milanesi, R, Ragona, F, Freri, E, Canafoglia, L, Franceschetti, S, Solazzi, R, Granata, T, Gellera, C, and Rivolta, I

Subjects
epilepsy, HCN2, electrophysiology
Abstract

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

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