169 results on '"PARRINI E"'
Search Results
2. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
- Author
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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
3. Severe 5,10‐methylenetetrahydrofolate reductase deficiency: a rare, treatable cause of complicated hereditary spastic paraplegia
- Author
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Perna, A., Masciullo, M., Modoni, A., Cellini, E., Parrini, E., Ricci, E., Donati, A. M., and Silvestri, G.
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- 2018
- Full Text
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4. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns
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Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., Scheffer, I.E., Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., and Scheffer, I.E.
- Abstract
Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access), PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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- 2021
5. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria
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Vetro, A, Nielsen, HN, Holm, R, Hevner, RF, Parrini, E, Powis, Z, Moller, RS, Bellan, C, Simonati, A, Lesca, G, Helbig, KL, Palmer, EE, Mei, D, Ballardini, E, Van Haeringen, A, Syrbe, S, Leuzzi, V, Cioni, G, Curry, CJ, Costain, G, Santucci, M, Chong, K, Mancini, GMS, Clayton-Smith, J, Bigoni, S, Scheffer, IE, Dobyns, WB, Vilsen, B, Guerrini, R, Vetro, A, Nielsen, HN, Holm, R, Hevner, RF, Parrini, E, Powis, Z, Moller, RS, Bellan, C, Simonati, A, Lesca, G, Helbig, KL, Palmer, EE, Mei, D, Ballardini, E, Van Haeringen, A, Syrbe, S, Leuzzi, V, Cioni, G, Curry, CJ, Costain, G, Santucci, M, Chong, K, Mancini, GMS, Clayton-Smith, J, Bigoni, S, Scheffer, IE, Dobyns, WB, Vilsen, B, and Guerrini, R
- Abstract
Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and al
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- 2021
6. The spectrum of brain malformations and disruptions in twins
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Park, KB, Chapman, T, Aldinger, KA, Mirzaa, GM, Zeiger, J, Beck, A, Glass, IA, Hevner, RF, Jansen, AC, Marshall, DA, Oegema, R, Parrini, E, Saneto, RP, Curry, CJ, Hall, JG, Guerrini, R, Leventer, RJ, Dobyns, WB, Park, KB, Chapman, T, Aldinger, KA, Mirzaa, GM, Zeiger, J, Beck, A, Glass, IA, Hevner, RF, Jansen, AC, Marshall, DA, Oegema, R, Parrini, E, Saneto, RP, Curry, CJ, Hall, JG, Guerrini, R, Leventer, RJ, and Dobyns, WB
- Abstract
Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.
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- 2021
7. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
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Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB
- Abstract
Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
- Published
- 2021
8. Epilepsy; Genetics
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Guerrini, R., primary and Parrini, E., additional
- Published
- 2014
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9. Lissencephaly Type I and Periventricular Heterotopia
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Parrini, E., primary and Guerrini, R., additional
- Published
- 2009
- Full Text
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10. GENETICS | Single Gene Mutations Causing Epileptogenic Malformations of the Cerebral Cortex
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Parrini, E., primary, Sgadò, P., additional, and Guerrini, R., additional
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- 2009
- Full Text
- View/download PDF
11. Polygenic burden in focal and generalized epilepsies
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Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics
- Subjects
0301 basic medicine ,Male ,Multifactorial Inheritance ,Epi25 Consortium ,Databases, Factual ,FEATURES ,Genome-wide association study ,Epilepsies ,3124 Neurology and psychiatry ,Cohort Studies ,Epilepsy ,0302 clinical medicine ,Cost of Illness ,1ST SEIZURE ,HISTORY ,genetics ,POPULATION ,11 Medical and Health Sciences ,education.field_of_study ,medicine.diagnostic_test ,SCORES ,Single Nucleotide ,Biobank ,3. Good health ,17 Psychology and Cognitive Sciences ,Genetic generalized epilepsy ,Epilepsy, Generalized ,Female ,Partial ,Cohort study ,Human ,medicine.medical_specialty ,Population ,European Continental Ancestry Group ,Clinical Neurology ,BIOBANK ,Polymorphism, Single Nucleotide ,epilepsy ,genetic generalized epilepsy ,common variant risk ,Databases ,03 medical and health sciences ,Genetic ,Internal medicine ,medicine ,Journal Article ,Genetics ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,GENOME-WIDE ASSOCIATION ,Generalized epilepsy ,education ,SEIZURE RECURRENCE ,Factual ,METAANALYSIS ,Genetic testing ,Neurology & Neurosurgery ,RISK PREDICTION ,Generalized ,business.industry ,3112 Neurosciences ,Common variant risk ,Genetic Variation ,Original Articles ,medicine.disease ,Comorbidity ,Cost of Illne ,Epilepsies, Partial ,Genome-Wide Association Study ,030104 developmental biology ,Neurology (clinical) ,Cohort Studie ,business ,030217 neurology & neurosurgery - Abstract
See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.
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- 2019
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12. Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations
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Vetro, A, Pisano, T, Chiaro, S, Procopio, E, Guerra, A, Parrini, E, Mei, D, Virdò, S, Mangone, G, Azzari, C, and Guerrini, R.
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carbohydrates (lipids) ,lipids (amino acids, peptides, and proteins) ,PIGP,mutations - Published
- 2020
13. High frequency of genomic deletions—and a duplication—in the LIS1 gene in lissencephaly: implications for molecular diagnosis
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Mei, D, Lewis, R, Parrini, E, Lazarou, L P, Marini, C, Pilz, D T, and Guerrini, R
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- 2008
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14. Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations
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Parrini, E., Ramazzotti, A., Dobyns, W. B., Mei, D., Moro, F., Veggiotti, P., Marini, C., Brilstra, E. H., Bernardina, B. Dalla, Goodwin, L., Bodell, A., Jones, M. C., Nangeroni, M., Palmeri, S., Said, E., Sander, J. W., Striano, P., Takahashi, Y., Van Maldergem, L., Leonardi, G., Wright, M., Walsh, C. A., and Guerrini, R.
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- 2006
15. International consensus recommendations on the diagnostic work-up for malformations of cortical development
- Author
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Oegema, R. (Renske), Barakat, T.S. (Tahsin Stefan), Wilke, M. (Martina), Stouffs, K. (Katrien), Amrom, D. (Dina), Aronica, E.M.A. (Eleonora), Bahi-Buisson, N. (Nadia), Conti, V. (Valerio), Fry, A.E. (Andrew E.), Geis, T. (Tobias), Andres, D.G. (David Gomez), Parrini, E. (Elena), Pogledic, I. (Ivana), Said, E. (Edith), Soler, D. (Doriette), Valor, L.M. (Luis M.), Zaki, M.S. (Maha), Mirzaa, G.M. (Ghayda), Dobyns, W.B. (William), Reiner, O. (Orly), Guerrini, R. (Renzo), Pilz, D.T. (Daniela), Hehr, U. (Ute), Leventer, R.J. (Richard), Jansen, A.C. (Anna C.), Mancini, G.M.S. (Grazia), Di Donato, N. (Nataliya), Oegema, R. (Renske), Barakat, T.S. (Tahsin Stefan), Wilke, M. (Martina), Stouffs, K. (Katrien), Amrom, D. (Dina), Aronica, E.M.A. (Eleonora), Bahi-Buisson, N. (Nadia), Conti, V. (Valerio), Fry, A.E. (Andrew E.), Geis, T. (Tobias), Andres, D.G. (David Gomez), Parrini, E. (Elena), Pogledic, I. (Ivana), Said, E. (Edith), Soler, D. (Doriette), Valor, L.M. (Luis M.), Zaki, M.S. (Maha), Mirzaa, G.M. (Ghayda), Dobyns, W.B. (William), Reiner, O. (Orly), Guerrini, R. (Renzo), Pilz, D.T. (Daniela), Hehr, U. (Ute), Leventer, R.J. (Richard), Jansen, A.C. (Anna C.), Mancini, G.M.S. (Grazia), and Di Donato, N. (Nataliya)
- Abstract
Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.
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- 2020
- Full Text
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16. Developmental and epilepsy spectrum ofKCNB1encephalopathy with long-term outcome
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Bar, C, Kuchenbuch, M, Barcia, G, Schneider, A, Jennesson, M, Le Guyader, G, Lesca, G, Mignot, C, Montomoli, M, Parrini, E, Isnard, H, Rolland, A, Keren, B, Afenjar, A, Dorison, N, Sadleir, LG, Breuillard, D, Levy, R, Rio, M, Dupont, S, Negrin, S, Danieli, A, Scalais, E, De Saint Martin, A, El Chehadeh, S, Chelly, J, Poisson, A, Lebre, A-S, Nica, A, Odent, S, Sekhara, T, Brankovic, V, Goldenberg, A, Vrielynck, P, Lederer, D, Maurey, H, Terrone, G, Besmond, C, Hubert, L, Berquin, P, Billette de Villemeur, T, Isidor, B, Freeman, JL, Mefford, HC, Myers, CT, Howell, KB, Rodriguez-Sacristan Cascajo, A, Meyer, P, Genevieve, D, Guet, A, Doummar, D, Durigneux, J, van Dooren, MF, de Wit, MCY, Gerard, M, Marey, I, Munnich, A, Guerrini, R, Scheffer, IE, Kabashi, E, Nabbout, R, Bar, C, Kuchenbuch, M, Barcia, G, Schneider, A, Jennesson, M, Le Guyader, G, Lesca, G, Mignot, C, Montomoli, M, Parrini, E, Isnard, H, Rolland, A, Keren, B, Afenjar, A, Dorison, N, Sadleir, LG, Breuillard, D, Levy, R, Rio, M, Dupont, S, Negrin, S, Danieli, A, Scalais, E, De Saint Martin, A, El Chehadeh, S, Chelly, J, Poisson, A, Lebre, A-S, Nica, A, Odent, S, Sekhara, T, Brankovic, V, Goldenberg, A, Vrielynck, P, Lederer, D, Maurey, H, Terrone, G, Besmond, C, Hubert, L, Berquin, P, Billette de Villemeur, T, Isidor, B, Freeman, JL, Mefford, HC, Myers, CT, Howell, KB, Rodriguez-Sacristan Cascajo, A, Meyer, P, Genevieve, D, Guet, A, Doummar, D, Durigneux, J, van Dooren, MF, de Wit, MCY, Gerard, M, Marey, I, Munnich, A, Guerrini, R, Scheffer, IE, Kabashi, E, and Nabbout, R
- Abstract
OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechani
- Published
- 2020
17. International consensus recommendations on the diagnostic work-up for malformations of cortical development
- Author
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Oegema, R, Barakat, TS, Wilke, M, Stouffs, K, Amrom, D, Aronica, E, Bahi-Buisson, N, Conti, V, Fry, AE, Geis, T, Gomez Andres, D, Parrini, E, Pogledic, I, Said, E, Soler, D, Valor, LM, Zaki, MS, Mirzaa, G, Dobyns, WB, Reiner, O, Guerrini, R, Pilz, DT, Hehr, U, Leventer, RJ, Jansen, AC, Mancini, GMS, Di Donato, N, Oegema, R, Barakat, TS, Wilke, M, Stouffs, K, Amrom, D, Aronica, E, Bahi-Buisson, N, Conti, V, Fry, AE, Geis, T, Gomez Andres, D, Parrini, E, Pogledic, I, Said, E, Soler, D, Valor, LM, Zaki, MS, Mirzaa, G, Dobyns, WB, Reiner, O, Guerrini, R, Pilz, DT, Hehr, U, Leventer, RJ, Jansen, AC, Mancini, GMS, and Di Donato, N
- Abstract
Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.
- Published
- 2020
18. Patient with bilateral periventricular nodular heterotopia and polymicrogyria with apparently balanced reciprocal translocation t(1;6)(p12;p12.2) that interrupts the mannosidase alpha, class 1A, and glutathione S-transferase A2 genes
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Leeflang, E P, Marsh, S E, Parrini, E, Moro, F, Pilz, D, Dobyns, W B, Guerrini, R, Wheless, J W, and Gleeson, J G
- Published
- 2003
19. A novel strategy combining array-CGH, whole-exome sequencing and in utero electroporation in rodents to identify causative genes for brain malformations
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Conti, V, Carabalona, A, Pallesi-Pocachard, E, Leventer, R, Schaller, F, Parrini, E, Deparis, A, Watrin, F, Buhler, E, Novara, F, Lise, S, Pagnamenta, A, Kini, U, Taylor, J, Zuffardi, O, Represa, A, Keays, D, Guerrini, R, Falace, A, Cardoso, C, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U901), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pediatric Neurology Unit and Laboratories, Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer, Cytogenetics, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Biologia Generale e Genetica Medica, Università degli Studi di Pavia = University of Pavia (UNIPV), Epilepsie et ischémie cérébrale, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Stella Maris Foundation, Children's Hospital A. Meyer-Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University of Oxford [Oxford], Università degli Studi di Pavia, and Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer
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Brain Chemistry ,Comparative Genomic Hybridization ,[SDV]Life Sciences [q-bio] ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Brain ,DNA ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Rats ,Malformations of Cortical Development ,Disease Models, Animal ,Electroporation ,Pregnancy ,Exome Sequencing ,Animals ,Humans ,Female ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,ComputingMilieux_MISCELLANEOUS ,Neuroscience - Abstract
Birth defects that involve the cerebral cortex - also known as malformations of cortical development (MCD) - are important causes of intellectual disability and account for 20-40% of drug-resistant epilepsy in childhood. High-resolution brain imaging has facilitated in vivo identification of a large group of MCD phenotypes. Despite the advances in brain imaging, genomic analysis and generation of animal models, a straightforward workflow to systematically prioritize candidate genes and to test functional effects of putative mutations is missing. To overcome this problem, an experimental strategy enabling the identification of novel causative genes for MCD was developed and validated. This strategy is based on identifying candidate genomic regions or genes via array-CGH or whole-exome sequencing and characterizing the effects of their inactivation or of overexpression of specific mutations in developing rodent brains via in utero electroporation. This approach led to the identification of the C6orf70 gene, encoding for a putative vesicular protein, to the pathogenesis of periventricular nodular heterotopia, a MCD caused by defective neuronal migration.
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- 2018
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20. Cortical malformations and COL4A1 mutation: Three new cases
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Vitale, G., primary, Pichiecchio, A., additional, Ormitti, F., additional, Tonduti, D., additional, Asaro, A., additional, Farina, L., additional, Piccolo, B., additional, Percesepe, A., additional, Bastianello, S., additional, Orcesi, S., additional, Accorsi, P., additional, Battaglia, D., additional, Cereda, C., additional, Martelli, P., additional, Mine, M., additional, Pinelli, L., additional, Tartaglione, T., additional, Ghi, T., additional, Parrini, E., additional, and Zuffardi, O., additional
- Published
- 2019
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21. HCN1 mutation spectrum: From neonatal epileptic encephalopathy to benign generalized epilepsy and beyond
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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
22. Severe 5,10-methylenetetrahydrofolate reductase deficiency: A rare, treatable cause of complicated hereditary spastic paraplegia
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Perna, Alessia, Masciullo, Marcella, Modoni, Anna, Cellini, E., Parrini, E., Ricci, Enzo, Donati, A. M., Silvestri, Gabriella, Perna, A., Masciullo, M., Modoni, A., Ricci, E. (ORCID:0000-0003-3092-3597), Silvestri, G. (ORCID:0000-0002-1950-1468), Perna, Alessia, Masciullo, Marcella, Modoni, Anna, Cellini, E., Parrini, E., Ricci, Enzo, Donati, A. M., Silvestri, Gabriella, Perna, A., Masciullo, M., Modoni, A., Ricci, E. (ORCID:0000-0003-3092-3597), and Silvestri, G. (ORCID:0000-0002-1950-1468)
- Abstract
Background and purpose: Juvenile- or adult-onset forms of severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting as complicated hereditary spastic paraplegia have rarely been described. Methods: Two siblings with mental retardation developed a progressive spastic paraparesis in their late teens. Their diagnostic assessment included extensive neurophysiologic, neuroimaging and metabolic studies. Results: Brain magnetic resonance imaging showed occipital white matter alterations, and electromyography documented a mixed polyneuropathy. Severe hyperhomocisteinemia (>150 Î1⁄4mol/L) associated with the characteristic amino acid profile suggested a diagnosis of severe MTHFR deficiency, confirmed by MTHFR direct sequencing. Treatment with betaine and vitamins benefitted patients' symptoms and diagnostic features. Conclusions: Severe MTHFR deficiency can be a rare, treatable cause of autosomal recessive complicated hereditary spastic paraplegia. Its screening should be part of the diagnostic flowchart for these disorders.
- Published
- 2018
23. ATP1A3 spectrum disorders: A video-documented history of 7 genetically confirmed early onset cases.
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Stagnaro, M, Pisciotta, L, Gherzi, M, Di Rocco, M, Gurrieri, Fiorella, Parrini, E, Prato, G, Veneselli, E, De Grandis, E., Gurrieri F (ORCID:0000-0002-6775-5972), Stagnaro, M, Pisciotta, L, Gherzi, M, Di Rocco, M, Gurrieri, Fiorella, Parrini, E, Prato, G, Veneselli, E, De Grandis, E., and Gurrieri F (ORCID:0000-0002-6775-5972)
- Abstract
Mutations in the ATP1A3 gene, which encodes the alpha3-subunit of sodium-potassium ATPase, are related to a spectrum of neurological diseases including Rapid onset Dystonia-Parkinsonism (RDP), Alternating Hemiplegia of Childhood (AHC) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome. Moreover, an increasing number of patients with intermediate and non classical phenotypes have been reported. Herein we describe 7 patients with 6 different de novo ATP1A3 mutations, and we focus on paroxysmal and chronic movement disorders with the help of video documentation. Our cases confirm that ATP1A3-related neurological disorders make up a phenotypic continuum rather than overlapping syndromes, in which early onset dystonia, ataxia and paroxysmal episodes with triggering or worsening factors are key diagnostic clues. Moreover, our experience suggests that ATP1A3 gene analysis should be extended both to children with channelopathy-like spells and to patients with early onset, fever-related encephalopathy.
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- 2018
24. Increased sensitivity of the alpha-2 neuronal nicotinic receptor causes familial epilepsy with nocturnal wandering and ictal fear
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Marini, C., Aridon, P., Di Resta, C., Brilli, E., Fusco, M., Politi, F., Parrini, E., Manfredi, I., Pisano, T., Pruna, D., Giulia Curia, Cianchetti, C., Pasqualetti, M., Becchetti, A., Guerrini, R., Casari, G., MARINI C, ARIDON P, DI RESTA C, BRILLI E, DE FUSCO M, POLITI, PARRINI E, MANFREDI I, PISANO T, PRUNA, CURIA G, CIANCHETTI C, PASQUALETTI M, BECCHETTI A, GUERRINI R, CASARI G, Marini, C, Aridon, P, DI RESTA, Chiara, Brilli, E, De Fusco, M, Politi, F, Parrini, E, Manfredi, I, Pisano, T, Pruna, D, Curia, G, Cianchetti, C, Pasqualetti, M, Becchetti, A, Guerrini, R, and Casari, GIORGIO NEVIO
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nicotinic receptor - Published
- 2006
25. Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes
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Parrini, E., Marini, C., Mei, D., Galuppi, A., Cellini, E., Pucatti, D., Chiti, L., Rutigliano, D., Bianchini, C., Virdo, S., De Vita, D., Bigoni, S., Barba, C., Mari, F., Montomoli, M., Pisano, T., Rosati, A., Guerrini, R., Accorsi, P., Ardissone, A., Battaglia, Domenica Immacolata, Bertani, G., Borgarello, G., Cesaroni, E., Chiari, S., Cordelli, D. M., Doccini, V., Donati, I., Fontana, E., Fusco, C., Gentile, M., Giordano, L., Jacinto, S., Leuzzi, V., Mangano, S., Mastrangelo, M., Melani, F., Obino, L., Offer, C., Pruna, D., Ragona, F., Ricciardelli, P., Salandin, M., Saporoso, A., Sicca, F., Specchio, N., Sterebova, K., Battaglia D. (ORCID:0000-0003-0491-4021), Parrini, E., Marini, C., Mei, D., Galuppi, A., Cellini, E., Pucatti, D., Chiti, L., Rutigliano, D., Bianchini, C., Virdo, S., De Vita, D., Bigoni, S., Barba, C., Mari, F., Montomoli, M., Pisano, T., Rosati, A., Guerrini, R., Accorsi, P., Ardissone, A., Battaglia, Domenica Immacolata, Bertani, G., Borgarello, G., Cesaroni, E., Chiari, S., Cordelli, D. M., Doccini, V., Donati, I., Fontana, E., Fusco, C., Gentile, M., Giordano, L., Jacinto, S., Leuzzi, V., Mangano, S., Mastrangelo, M., Melani, F., Obino, L., Offer, C., Pruna, D., Ragona, F., Ricciardelli, P., Salandin, M., Saporoso, A., Sicca, F., Specchio, N., Sterebova, K., and Battaglia D. (ORCID:0000-0003-0491-4021)
- Abstract
Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients, epilepsy onset occurred before the age of 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2A was the most frequently mutated gene followed by SCN1A, KCNQ2, STXBP1, SCN8A, CDKL5, and MECP2. Twenty-nine mutations were identified in 23 additional genes, most of them recently associated with epilepsy. Our data show that panels targeting about 100 genes represent the best cost-effective diagnostic option in pediatric drug-resistant epilepsies. They enable molecular diagnosis of atypical phenotypes, allowing to broaden phenotype–genotype correlations. Molecular diagnosis might influence patients' management and translate into better and specific treatment recommendations in some conditions.
- Published
- 2017
26. Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations
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Cetica, V., Chiari, S., Mei, D., Parrini, E., Grisotto, L., Marini, C., Pucatti, D., Ferrari, A., Sicca, F., Specchio, N., Trivisano, M., Battaglia, Domenica Immacolata, Contaldo, Ilaria, Zamponi, N., Petrelli, Cecilia, Granata, T., Ragona, F., Avanzini, G., Guerrini, R., Battaglia D. (ORCID:0000-0003-0491-4021), Contaldo I., Petrelli C., Cetica, V., Chiari, S., Mei, D., Parrini, E., Grisotto, L., Marini, C., Pucatti, D., Ferrari, A., Sicca, F., Specchio, N., Trivisano, M., Battaglia, Domenica Immacolata, Contaldo, Ilaria, Zamponi, N., Petrelli, Cecilia, Granata, T., Ragona, F., Avanzini, G., Guerrini, R., Battaglia D. (ORCID:0000-0003-0491-4021), Contaldo I., and Petrelli C.
- Abstract
Objective: To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations. Methods: Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients. Results: Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/ genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85%in the 0- to 6-month group, 51%in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity 5 83.3%, specificity 5 76.6%). Conclusions: In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy.
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- 2017
27. Clinical and genetic study of a new large Italian family with autosomal dominant nocturnal frontal lobe epilepsy
- Author
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Pisano T, Marini C, Aridon P, Parrini E, Cianchetti C, Pruna D, Guerrini R., CASARI , GIORGIO NEVIO, Pisano, T, Marini, C, Aridon, P, Parrini, E, Cianchetti, C, Casari, GIORGIO NEVIO, Pruna, D, and Guerrini, R.
- Published
- 2003
28. Measurement of Z-pair production in e(+)e(-) collisions and constraints on anomalous neutral gauge couplings
- Author
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Heister, A., Schael, S., Barate, R., Brunelière, R., DE BONIS, I., Decamp, D., Goy, C., Jezequel, S., Lees, J. P., Martin, F., Merle, E., Minard, M. N., Trocmé, B. PIETRZYK AND B., Boix, G., Bravo, S., Casado, M. P., Chmeissani, M., Crespo, J. M., Fernandez, E., FERNANDEZ BOSMAN, M., Garrido, L. L., Graugés, E., Lopez, J., Martinez, M., Merino, G., Miquel, R., Mir, L. L. M., Pacheco, A., Ruiz, D. PANEQUE AND H., Colaleo, A., Creanza, Donato Maria, DE FILIPPIS, Nicola, DE PALMA, M., Iaselli, Giuseppe, Maggi, Giorgio Pietro, Maggi, M., Nuzzo, S., Ranieri, A., Raso, G., Ruggieri, F., Selvaggi, G., Silvestris, L., Tempesta, P., Zito, A. TRICOMI AND G., Huang, X., Lin, J., Ouyang, Q., Wang, T., Xie, Y., Xu, R., Xue, S., Zhang, J., Zhao, L. ZHANG AND W., Abbaneo, D., Azzurri, P., Barklow, T., Buchmüller, O., Cattaneo, M., Cerutti, F., Clerbaux, B., Drevermann, H., Forty, R. W., Frank, M., Gianotti, F., Greening, T. C., Hansen, J. B., Harvey, J., Hutchcroft, D. E., Janot, P., Jost, B., Kado, M., Maley, P., Mato, P., Moutoussi, A., Ranjard, F., Rolandi, L., Schlatter, D., Sguazzoni, G., Tejessy, W., Teubert, F., Valassi, A., Ward, I. VIDEAU AND J. J., Badaud, F., Dessagne, S., Falvard, A., Fayolle, D., Gay, P., Jousset, J., Michel, B., Monteil, S., Pallin, D., Perret, J. M. PASCOLO AND P., Hansen, J. D., Hansen, J. R., Hansen, P. H., Wäänänen, B. S. NILSSON AND A., Kyriakis, A., Markou, C., Simopoulou, E., Zachariadou, A. VAYAKI AND K., Blondel, A., Brient, J. C., Machefert, F., Rougé, A., Swynghedauw, M., Videau, R. TANAKA AND H., Ciulli, V., Parrini, E. FOCARDI AND G., Antonelli, A., Antonelli, M., Bencivenni, G., Bologna, G., Bossi, F., Campana, P., Capon, G., Chiarella, V., Laurelli, P., Mannocchi, G., Murtas, F., Murtas, G. P., Passalacqua, L., Spagnolo, M. PEPE ALTARELLI AND P., Kennedy, J., Lynch, J. G., Negus, P., O'Shea, V., Thompson, D. SMITH AND A. S., Wasserbaech, S., Cavanaugh, R., Dhamotharan, S., Geweniger, C., Hanke, P., Hepp, V., Kluge, E. E., Leibenguth, G., Putzer, A., Tittel, K., Wunsch, S. WERNER AND M., Beuselinck, R., Binnie, D. M., Cameron, W., Davies, G., Dornan, P. J., Girone, M., Hill, R. D., Marinelli, N., Nowell, J., Przysiezniak, H., Rutherford, S. A., Sedgbeer, J. K., White, J. C. THOMPSON AND R., Ghete, V. M., Girtler, P., Kneringer, E., Rudolph, D. KUHN AND G., BOUHOVA THACKER, E., Bowdery, C. K., Clarke, D. P., Ellis, G., Finch, A. J., Foster, F., Hughes, G., Jones, R. W. L., Pearson, M. R., Smizanska, N. A. ROBERTSON AND M., Lemaitre, V., Blumenschein, U., Hölldorfer, F., Jakobs, K., Kayser, F., Kleinknecht, K., Müller, A. S., Quast, G., Renk, B., Sander, H. G., Schmeling, S., Wachsmuth, H., Ziegler, C. ZEITNITZ AND T., Bonissent, A., Carr, J., Coyle, P., Curtil, C., Ealet, A., Fouchez, D., Leroy, O., Kachelhoffer, T., Payre, P., Tilquin, D. ROUSSEAU AND A., Ragusa, F., David, A., Dietl, H., Ganis, G., Hüttmann, K., Lütjens, G., Mannert, C., Männer, W., Moser, H. G., Settles, R., Wolf, H. STENZEL AND G., Boucrot, J., Callot, O., Davier, M., Duflot, L., Grivaz, J. F., Heusse, P. H., Jacholkowska, A., Loomis, C., Serin, L., Veillet, J. J., Yuan, J. B. DE VIVIE DE RÉGIE AND C., Bagliesi, G., Boccali, T., Foà, L., Giammanco, A., Giassi, A., Ligabue, F., Messineo, A., Palla, F., Sanguinetti, G., Sciabà, A., Tenchini, R., Verdini, A. VENTURI AND P. G., Awunor, O., Blair, G. A., Coles, J., Cowan, G., GARCIA BELLIDO, A., Green, M. G., Jones, L. T., Medcalf, T., Misiejuk, A., TEIXEIRA DIAS, J. A. STRONG AND P., Clifft, R. W., Edgecock, T. R., Tomalin, P. R. NORTON AND I. R., BLOCH DEVAUX, B., Boumediene, D., Colas, P., Fabbro, B., Lançon, E., Lemaire, M. C., Locci, E., Perez, P., Rander, J., Renardy, J. F., Rosowsky, A., Seager, P., Trabelsi, A., Vallage, B. TUCHMING AND B., Konstantinidis, N., Taylor, A. M. LITKE AND G., Booth, C. N., Cartwright, S., Combley, F., Hodgson, P. N., Thompson, M. LEHTO AND L. F., Affholderbach, K., Böhrer, A., Brandt, S., Grupen, C., Hess, J., Ngac, A., Sieler, G. PRANGE AND U., Giannini, C. BOREAN AND G., He, H., Rothberg, J. PUTZ AND J., Armstrong, S. R., Berkelman, K., Cranmer, K., Ferguson, D. P. S., Gao, Y., González, S., Hayes, O. J., Hu, H., Jin, S., Kile, J., Mcnamara, P. A., Iii, Nielsen, J., Pan, Y. B., VON WIMMERSPERG TOELLER, J. H., Wiedenmann, W., Wu, J., S. L., Wu, Zobernig, X. WU AND G., Dissertori, G., Laboratoire d'Annecy de Physique des Particules (LAPP), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Leprince-Ringuet (LLR), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de l'Accélérateur Linéaire (LAL), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, ALEPH, SCHAEL S, BARATE R, BRUNELIERE R, DE BONIS I, DECAMP D, GOY C, JEZEQUEL S, LEES J, MARTIN F, MERLE E, MINARD M, PIETRZYK B, TROCME B, BRAVO S, CASADO MP, CHMEISSANI M, CRESPO JM, FERNANDEZ E, FERNANDEZ-BOSMAN M, GARRIDO L, MARTINEZ M, PACHECO A, RUIZ H, COLALEO A, CREANZA D, DE FILIPPIS N, DE PALMA M, IASELLI G, MAGGI G, MAGGI M, NUZZO S, RANIERI A, RASO G, RUGGIERI F, SELVAGGI G, SILVESTRIS L, TEMPESTA P, TRICOMI A, ZITO G, HUANG X, LIN J, OUYANG Q, WANG T, XIE Y, XU R, XUE S, ZHANG J, ZHANG L, ZHAO W, ABBANEO D, BARKLOW T, BUCHMULLER O, CATTANEO M, CLERBAUX B, DREVERMANN H, FORTY RW, FRANK M, GIANOTTI F, HANSEN JB, HARVEY J, HUTCHCROFT DE, JANOT P, JOST B, KADO M, MATO P, MOUTOUSSI A, RANJARD F, ROLANDI L, SCHLATTER D, TEUBERT F, VALASSI A, VIDEAU I, BADAUD F, DESSAGNE S, FALVARD A, FAYOLLE D, GAY P, JOUSSET J, MICHEL B, MONTEIL S, PALLIN D, PASCOLO JM, PERRET P, HANSEN JD, HANSEN JR, HANSEN PH, KRAAN AC, NILSSON BS, KYRIAKIS A, MARKOU C, SIMOPOULOU E, VAYAKI A, ZACHARIADOU K, BLONDEL A, BRIENT J, MACHEFERT F, ROUGE, VIDEAU H, CIULLI V, FOCARDI E, PARRINI G, ANTONELLI A, ANTONELLI M, BENCIVENNI G, BOSSI F, CAPON G, CERUTTI F, CHIARELLA V, LAURELLI P, MANNOCCHI G, MURTAS GP, PASSALACQUA L, KENNEDY J, LYNCH JG, NEGUS P, O'SHEA V, THOMPSON AS, WASSERBAECH S, CAVANAUGH R, DHAMOTHARAN S, GEWENIGER C, HANKE P, HEPP V, KLUGE EE, PUTZER A, STENZEL H, TITTEL K, WUNSCH M, BEUSELINCK R, CAMERON W, DAVIES G, DORNAN PJ, GIRONE M, MARINELLI N, NOWELL J, RUTHERFORD SA, SEDGBEER JK, THOMPSON JC, WHITE R, GHETE VM, GIRTLER P, KNERINGER E, KUHN D, RUDOLPH G, BOUHOVA-THACKER E, BOWDERY CK, CLARKE DP, ELLIS G, FINCH AJ, FOSTER F, HUGHES G, JONES RWL, PEARSON MR, ROBERTSON NA, SLOAN T, SMIZANSKA M, VAN DER AA O, DELAERE C, LEIBENGUTH G, LEMAITRE V, BLUMENSCHEIN U, HO, LLDORFER F, JAKOBS K, KAYSER F, MULLER A, RENK B, SANDER H, SCHMELING S, WACHSMUTH H, ZEITNITZ C, ZIEGLER T, BONISSENT A, COYLE P, CURTIL C, EALET A, FOUCHEZ D, PAYRE P, TILQUIN A, RAGUSA F, DAVID A, DIETL H, Schael, S., Barate, R., Bruneliere, R., De Bonis, I., Decamp, D., Goy, C., Jezequel, S., Lees, J. P., Martin, F., Merle, E., Minard, M. N., Pietrzyk, B., Trocme, B., Bravo, S., Casado, M. P., Chmeissani, M., Crespo, J. M., Fernandez, E., Fernandez Bosman, M., Garrido, L. l., Martinez, M., Pacheco, A., Ruiz, H., Colaleo, A., Creanza, D., De Filippis, N., de Palma, M., Iaselli, G., Maggi, G., Maggi, M., Nuzzo, S., Ranieri, A., Raso, G., Ruggieri, F., Selvaggi, G., Silvestris, L., Tempesta, P., Tricomi, A., Zito, G., Huang, X., Lin, J., Ouyang, Q., Wang, T., Xie, Y., Xu, R., Xue, S., Zhang, J., Zhang, L., Zhao, W., Abbaneo, D., Barklow, T., Buchmueller, O., Cattaneo, M., Clerbaux, B., Drevermann, H., Forty, R. W., Frank, M., Gianotti, F., Hansen, J. B., Harvey, J., Hutchcroft, D. E., Janot, P., Jost, B., Kado, M., Mato, P., Moutoussi, A., Ranjard, F., Rolandi, Luigi, Schlatter, D., Teubert, F., Valassi, A., Videau, I., Badaud, F., Dessagne, S., Falvard, A., Fayolle, D., Gay, P., Jousset, J., Michel, B., Monteil, S., Pallin, D., Pascolo, J. M., Perret, P., Hansen, J. D., Hansen, J. R., Hansen, P. H., Kraan, A. C., Nilsson, B. S., Kyriakis, A., Markou, C., Simopoulou, E., Vayaki, A., Zachariadou, K., Blondel, A., Brient, J. C., Machefert, F., Rouge, A., Videau, H., Ciulli, V., Focardi, E., Parrini, G., Antonelli, A., Antonelli, M., Bencivenni, G., Bossi, F., Capon, G., Cerutti, F., Chiarella, V., Laurelli, P., Mannocchi, G., Murtas, G. P., Passalacqua, L., Kennedy, J., Lynch, J. G., Negus, P., O'Shea, V., Thompson, A. S., Wasserbaech, S., Cavanaugh, R., Dhamotharan, S., Geweniger, C., Hanke, P., Hepp, V., Kluge, E. E., Putzer, A., Stenzel, H., Tittel, K., Wunsch, M., Beuselinck, R., Cameron, W., Davies, G., Dornan, P. J., Girone, M., Marinelli, N., Nowell, J., Rutherford, S. A., Sedgbeer, J. K., Thompson, J. C., White, R., Ghete, V. M., Girtler, P., Kneringer, E., Kuhn, D., Rudolph, G., Bouhova Thacker, E., Bowdery, C. K., Clarke, D. P., Ellis, G., Finch, A. J., Foster, F., Hughes, G., Jones, R. W. L., Pearson, M. R., Robertson, N. A., Sloan, T., Smizanska, M., van der Aa, O., Delaere, C., Leibenguth, G., Lemaitre, V., Blumenschein, U., Hoelldorfer, F., Jakobs, K., Kayser, F., Mueller, A. S., Renk, B., Sander, H. G., Schmeling, S., Wachsmuth, H., Zeitnitz, C., Ziegler, T., Bonissent, A., Coyle, P., Curtil, C., Ealet, A., Fouchez, D., Payre, P., Tilquin, A., Ragusa, F., David, A., Dietl, H., Ganis, G., Huettmann, K., Luetjens, G., Maenner, W., Moser, H. G., Settles, R., Villegas, M., Wolf, G., Boucrot, J., Callot, O., Davier, M., Duflot, L., Grivaz, J. F., Heusse, P. h., Jacholkowska, A., Serin, L., Veillet, J. J., Azzurri, P., Bagliesi, G., Boccali, T., Foa, L., Giammanco, A., Giassi, A., Ligabue, Franco, Messineo, A., Palla, F., Sanguinetti, G., Sciaba, A., Sguazzoni, G., Spagnolo, P., Tenchini, R., Venturi, A., Verdini, P. G., Awunor, O., Blair, G. A., Cowan, G., Garcia Bellido, A., Green, M. G., Medcalf, T., Misiejuk, A., Strong, J. A., Teixeira Dias, P., Clifft, R. W., Edgecock, T. R., Norton, P. R., Tomalin, I. R., Ward, J. J., Bloch Devaux, B., Boumediene, D., Colas, P., Fabbro, B., Lancon, E., Lemaire, M. C., Locci, E., Perez, P., Rander, J., Tuchming, B., Vallage, B., Litke, A. M., Taylor, G., Booth, C. N., Cartwright, S., Combley, F., Hodgson, P. N., Lehto, M., Thompson, L. F., Boehrer, A., Brandt, S., Grupen, C., Hess, J., Ngac, A., Prange, G., Borean, C., Giannini, G., He, H., Putz, J., Rothberg, J., Armstrong, S. R., Berkelman, K., Cranmer, K., Ferguson, D. P. S., Gao, Y., Gonzalez, S., Hayes, O. J., Hu, H., Jin, S., Kile, J., McNamara P. A., Iii, Nielsen, J., Pan, Y. B., von Wimmersperg Toeller, J. H., Wiedenmann, W., Wu, J., Wu Sau, Lan, Wu, X., Zobernig, G., Dissertori, G., Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), and Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11)
- Subjects
Physics ,Aleph ,Particle physics ,Nuclear and High Energy Physics ,Luminosity (scattering theory) ,e+-e- Experiments ,010308 nuclear & particles physics ,Electron–positron annihilation ,Settore FIS/01 - Fisica Sperimentale ,Gauge (firearms) ,01 natural sciences ,Standard Model ,Nuclear physics ,E +e -experiments ,Cross section (physics) ,Pair production ,0103 physical sciences ,[PHYS.HEXP]Physics [physics]/High Energy Physics - Experiment [hep-ex] ,High Energy Physics::Experiment ,010306 general physics ,ALEPH experiment ,Particle Physics - Experiment - Abstract
The ZZ production cross section is measured from a data sample corresponding to a total integrated luminosity of 452 pb−1, collected by the ALEPH experiment at LEP at centre-of-mass energies from 192 to 209 GeV. Individual cross sections, extracted at six centre-of-mass energies, are found to be in agreement with Standard Model calculations. The results are used to set limits on anomalous neutral gauge couplings. The ZZ production cross section is measured from a data sample corresponding to a total integrated luminosity of 452 pb−1 , collected by the ALEPH experiment at LEP at centre-of-mass energies from 192 to 209 GeV. Individual cross sections, extracted at six centre-of-mass energies, are found to be in agreement with Standard Model calculations. The results are used to set limits on anomalous neutral gauge couplings.
- Published
- 2009
- Full Text
- View/download PDF
29. Multiplex ligation-dependent probe amplification detects DCX gene deletions inband heterotopia
- Author
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Mei, D, Parrini, E, Pasqualetti, M, Tortorella, Gaetano, Franzoni, E, Giussani, U, Marini, C, Migliarini, S, and Guerrini, R.
- Published
- 2007
30. Precision electroweak measurements on the Z resonance
- Author
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Schael, S, Barate, R, Bruneliere, R, Buskulic, D, Bonis, De, Decamp, I, Ghez, D, Goy, P, Jezequel, C, Lees, S, Lucotte, Jp, Martin, A, Merle, F, Minard, E, Nief, Mn, Odier, Jy, Pietrzyk, P, Trocme, B, Bravo, B, Casado, S, Chmeissani, Mp, Comas, M, Crespo, P, Fernandez, Jm, E, Fernandez, Bosman, Garrido, M, Grauges, L, Juste, E, Martinez, A, Merino, M, Miquel, G, Mir, R, Orteu, Lm, Pacheco, S, Park, A, Perlas, Ic, Riu, J, Ruiz, I, Sanchez, H, Colaleo, F, Creanza, A, D, Filippis, De, N, Palma, De, Iaselli, M, Maggi, G, Nuzzo, M, Ranieri, S, Raso, A, Ruggieri, G, Selvaggi, F, Silvestris, G, Tempesta, L, Tricomi, P, Zito, A, Huang, G, Lin, X, Ouyang, J, Wang, Q, Xie, T, Xu, Y, Xue, R, Zhang, S, Zhang, J, Zhao, L, Abbaneo, W, Bazarko, D, Becker, A, Boix, U, Bird, G, Blucher, F, Bonvicini, E, B, Bright, Thomas, Barklow, P, Buchmuller, T, Cattaneo, O, Cerutti, M, Ciulli, F, Clerbaux, V, Drevermann, B, Forty, H, Frank, Rw, Greening, M, Hagelberg, Tc, Halley, R, Gianotti, Aw, Girone, F, Hansen, M, Harvey, Jb, Jacobsen, J, Hutchcroft, R, Janot, De, Jost, R, Knobloch, B, Kado, J, Lehraus, M, Lazeyras, I, Maley, P, Mato, R, May, P, Moutussi, J, A, Pepe, Altarelli, Ranjard, M, Rolandi, F, Schlatter, L, Schmitt, D, Schneider, B, Tejessy, O, Teubert, W, Tomalin, F, Tournefier, Ir, Veenhof, E, Valassi, R, Wiedenmann, A, Wright, W, Ajaltouni, Ae, Badaud, Z, Chazelle, F, Deschamps, G, Dessagne, O, Falvard, S, Ferdi, A, Fayolle, C, Gay, D, Guicheney, P, Henrard, C, Jousset, P, Michel, J, Monteil, B, Montret, S, Pallin, Jc, Pascolo, D, Perret, Jm, Podlyski, P, Bertelsen, F, Fernley, H, Hansen, T, Hansen, Jd, Hansen, Jr, Kraan, Ph, Lindahl, Ac, Mollerud, A, Nilsson, R, Rensch, Bs, Waananen, B, Daskalakis, A, Kyriakis, G, Markou, A, Simopoulou, C, Siotis, E, Vayaki, I, Zachariadou, A, Blondel, K, Bonneaud, A, Brient, G, Machefert, Jc, Rouge, E, Rumpf, A, Swynghedauw, M, Tanaka, M, Verderi, R, Videau, M, Focardi, H, Parrini, E, Corden, G, Georgiopoulos, M, Antonelli, C, Antonelli, A, Bencivenni, M, Bologna, G, Bossi, G, Campana, F, Capon, P, Chiarella, G, Felici, V, Laurelli, G, Mannocchi, P, Murtas, G, Passalacqua, Gp, Picchi, L, Colrain, P, P, Ten, Have, Hughes, I, Kennedy, Is, Knowles, J, Lynch, Ig, Morton, Jg, Negus, Wt, Oshea, P., Raine, V, Reeves, C, Scarr, P, Smith, Jm, Thompson, K., Turnbull, As, Wasserbaech, Rm, Cavanaugh, S, Dhamotharan, R, Geweniger, S, Hanke, C, Hansper, P, Hepp, G, Kluge, V, Putzer, Ee, Sommer, A, Stenzel, J, Tittel, H, Werner, K, Wunsch, W, Beuselinck, M, Binnie, R, Cameron, Dm, Davies, W, Dornan, G, Goodsir, Pj, Marinelli, S, Martin, N, Nash, Eb, Nowell, J, Rutherford, J, Sedgbeer, Sa, Thompson, Jk, White, Jc, Williams, R, Ghete, Md, Girtler, Vm, Kneringer, P, Kuhn, E, Rudolph, D, G, Bouhova, Thacker, Bowdery, E, Buck, Ck, Clarke, Pg, Ellis, Dp, Finch, G, Foster, Aj, Hughes, F, Jones, G, Rwl, Keemer, Pearson, Nr, Robertson, Mr, Sloan, Na, Smizanska, T, Snow, M, Williams, Sw, van der Aa, Delaere, O, Leibenguth, C, Lemaitre, G, Bauerdick, V, Lat, Blumenschein, U, Van, Gemmeren, Giehl, P, Holldorfer, I, Jakobs, F, Kasemann, K, Kayser, M, Kleinknecht, F, Muller, K, Quast, As, Renk, G, Rohne, B, Sander, E, Schmeling, Hg, Wachsmuth, S, Wanke, H, Zeitnitz, R, Ziegler, C, Aubert, T, Benchouk, Jj, Bonissent, C, Carr, A, Coyle, J, Curtil, P, Ealet, C, Etienne, A, Fouchez, F, Motsch, D, Payre, F, Rousseau, P, Tilquin, D, Talby, A, Thulasides, M, Aleppo, M, Ragusa, M, Buscher, F, David, V, Dietl, A, Ganis, H, Huttmann, G, Lutjens, K, Mannert, G, Manner, C, Moser, W, Settles, Hg, Seywerd, R, Villegas, H, Wolf, M, Azzurri, G, Boucrot, P, Callot, J, Chen, O, Cordier, S, Davier, A, Duflot, M, Grivaz, L, Heusse, Jf, Jacholkowska, P, Diberder, Le, Lefrancois, F, Mutz, J, Schune, Am, Serin, Mh, Veillet, L, Videau, Jj, Zerwas, I, Bagliesi, D, Bettarini, G, Boccali, S, Bozzi, T, Calderini, C, Dellorso, G, Fantechi, R, Ferrante, R, Fidecaro, I, Foa, F, Giammanco, L, Giassi, A, Gregorio, A, Ligabue, A, Lusiani, F, Marrocchesi, PIER SIMONE, Messineo, Ps, Palla, A, Rizzo, F, Sanguinetti, G, Sciaba, G, Sguazzoni, A, Spagnolo, G, Steinberger, P, Tenchini, J, Venturi, R, Vannini, A, Verdini, C, Awunor, Pg, Blair, O, Cowan, Ga, Garcia, Bellido, Green, A, Medcalf, Mg, Misiejuk, T, Strong, A, Teixeira, Dias, Botterill, P, Clifft, Dr, Edgecock, Rw, Edwards, Tr, Haywood, M, Norton, Sj, Ward, Pr, Bloch, Devaux, Boumediene, B, Colas, D, Emery, P, Fabbro, S, Kozanecki, B, Lancon, W, Lemaire, E, Locci, Mc, Perez, E, Rander, P, Renardy, J, Roussarie, Jf, Schuller, A, Schwindling, Jp, Tuchming, J, Vallage, B, Black, B, Dann, Sn, Kim, Jh, Konstantinidis, Hy, Litke, N, Mcneil, Am, Taylor, Ma, Booth, G, Cartwright, Cn, Combley, S, Hodgson, F, Lehto, Pn, Thompson, M, Affholderbach, Lf, Barberio, K, Bohrer, E, Brandt, A, Burkhardt, S, Feigl, H, Grupen, E, Hess, C, Lutters, J, Meinhard, G, H, Minguet, Rodriguez, Mirabito, J, Neugebauer, L, Ngac, E, Prange, A, Rivera, G, Saraiva, F, Schafer, P, Sieler, U, Smolik, U, Stephan, L, 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Thaler, Fe, Thom, Jj, Trandafir, J, Turk, Ai, Usher, Jd, Vavra, T, Vella, J, Venuti, E, Verdier, Jp, Wagner, R, Waite, Sr, Walston, Ap, Wang, S, Watts, J, Weidemann, Sj, Weiss, Aw, Whitaker, Er, White, Js, Wickens, Sl, Williams, Fj, Williams, Da, Williams, Dc, Willocq, Sh, Wilson, S, Wisniewski, Rj, Wittlin, Wj, Woods, Jl, Word, M, Wright, Gb, Wyss, Tr, Yamamoto, J, Yang, Rk, Yashima, Xq, Yellin, J, Young, Sj, Yuta, Cc, Zapalac, H, Zdarko, G, Zeitlin, Rw, Zhou, C, Blondel, Alain, Schael, S, Barate, R, Bruneliere, R, Spagnolo, Stefania Antonia, S., Schael, Aloisio, Alberto, Alviggi, Mariagrazia, Canale, Vincenzo, Chiefari, Giovanni, DELLA VOLPE, Domenico, Merola, Leonardo, Napolitano, Marco, Patricelli, Sergio, Sciacca, Crisostomo, Lista, Luca, Laboratoire d'Annecy de Physique des Particules (LAPP), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Théorique et Astroparticules (LPTA), Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Leprince-Ringuet (LLR), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de l'Accélérateur Linéaire (LAL), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Nucléaire et de Hautes Énergies (LPNHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Subatomique et de Cosmologie (LPSC), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS), Institut de Physique Nucléaire de Lyon (IPNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches Subatomiques (IReS), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Cancéropôle du Grand Est-Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Physique Corpusculaire et Cosmologie - Collège de France (PCC), Collège de France (CdF (institution))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), ALEPH, DELPHI, L3, OPAL, SLD, BARBIELLINI AMIDEI, Guido, Bosisio, Luciano, DELLA RICCA, Giuseppe, Giannini, Gianrossano, Gregorio, Anna, Lanceri, Livio, Poropat, Paolo, Vitale, Lorenzo, Buskulic, D, De Bonis, I, Decamp, D, Ghez, P, Goy, C, Jezequel, S, Lees, J, Lucotte, A, Martin, F, Merle, E, Minard, M, Nief, J, Odier, P, Pietrzyk, B, Trocme, B, 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King, Bj, Klem, De, Kokott, Tp, Kral, Jf, von Krogh, J, Lafferty, Gd, Lai, Wp, Larson, Wj, Lautenschlager, Sr, Layter, Jg, Lee, Am, Lehto, Mh, Lloyd, Aw, Lloyd, Sl, Loebinger, Fk, Long, Gd, Lorah, Jm, Losty, Mj, Lou, Xc, Marchant, Te, Mcdonald, Wj, Mcgowan, Rf, Mckigney, Ea, Mcmahon, Tj, Mcnab, Ai, Mcpherson, Ac, Mcpherson, Ra, Middleton, Rp, Miller, Dj, Moss, Mw, Murphy, Pg, Neal, Ha, Nguyen, Hh, Oakham, Fg, Ogren, Ho, Oldershaw, Nj, O'Neale, Sw, O'Neill, Bp, Oram, Cj, Oreglia, Mj, Pansart, Jp, Pater, Jr, Patrick, Gn, Pawley, Sj, Pearce, Mj, Pilcher, Je, Plane, De, del Poz, La, Pritchard, Tw, Redmond, Mw, Rees, Dl, Richards, Ge, Robins, Sa, Roney, Jm, Rossi, Am, Rust, Dr, Sarkisyan, Ekg, Schaile, Ad, von der Schmitt, H, Schultz Coulon, Hc, Scott, Wg, Shears, Tg, Shen, Bc, Shepherd Themistocleous, Ch, Siroli, Gp, Smith, Am, Smith, Tj, Snow, Ga, Springer, Rw, Stier, He, Talbot, Sd, Taylor, Rj, Thackray, Nj, Thomson, Ma, von Torne, E, Tresilian, Nj, Tumer Watson, Mf, Van den Plas, D, 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HORVATH, K.R. HOSSAIN, S.R. HOU, R. HOWARD, C.P. HOWARTH, P. HUNTEMEYER, R.E. HUGHES-JONES, R. HUMBERT, D.E. HUTCHCROFT, P. IGO-KEMENES, H. IHSSEN, D.C. IMRIE, M.R. INGRAM, K. ISHII, F.R. JACOB, A.C. JANISSEN, A. JAWAHERY, P.W. JEFFREYS, H. JEREMIE, M. JIMACK, M. JOBES, A. JOLY, C.R. JONES, G. JONES, M. JONES, R.W.L. JONES, U. JOST, P. JOVANOVIC, C. JUI, T.R. JUNK, N. KANAYA, J. KANZAKI, G. KARAPETIAN, D. KARLEN, V. KARTVELISHVILI, K. KAWAGOE, T. KAWAMOTO, R.K. KEELER, R.G. KELLOGG, B.W. KENNEDY, D.H. KIM, B.J. KING, J. KIRK, K. KLEIN, C. KLEINWORT, D.E. KLEM, A. KLIER, S. KLUTH, T. KOBAYASHI, M. KOBEL, L. KOPKE, D.S. KOETKE, T.P. KOKOTT, S. KOMAMIYA, L. KORMOS, R.V. KOWALEWSKI, T. KRAMER, J.F. KRAL, T. KRESS, H. KREUTZMANN, P. KRIEGER, J. VON KROGH, J. KROLL, D. KROP, K. KRUGER, T. KUHL, M. KUPPER, M. KUWANO, P. KYBERD, G.D. LAFFERTY, H. LAFOUX, R. LAHMANN, W.P. LAI, F. LAMARCHE, H. LANDSMAN, D. LANSKE, W.J. LARSON, J. LAUBER, S.R. LAUTENSCHLAGER, I. LAWSON, J.G. LAYTER, D. LAZIC, P. LE DU, P. LEBLANC, A.M. LEE, E. LEFEBVRE, M.H. LEHTO, A. LEINS, D. LELLOUCH, P. LENNERT, C. LEROY, L. LESSARD, J. LETTS, S. LEVEGRUN, L. LEVINSON, C. LEWIS, R. LIEBISCH, J. LILLICH, C. LITTLEWOOD, A.W. LLOYD, S.L. LLOYD, F.K. LOEBINGER, G.D. LONG, J.M. LORAH, B. LORAZO, M.J. LOSTY, X.C. LOU, J. LU, A. LUDWIG, J. LUDWIG, A. LUIG, A. MACCHIOLO, A. MACPHERSON, W. MADER, P. MATTIG, A. MALIK, M. MANNELLI, S. MARCELLINI, T.E. MARCHANT, G.MARINGER, C. MARKUS, A.J. MARTIN, J.P. MARTIN, G. MARTINEZ, G. MASETTI, T. MASHIMO, W. MATTHEWS, U. MAUR, W.J. MCDONALD, R.F. MCGOWAN, J. MCKENNA, E.A. MCKIGNEY, T.J. MCMAHON, A.I. MCNAB, J.R. MCNUTT, A.C. MCPHERSON, R.A. MCPHERSON, F. MEIJERS, P. MENDEZ-LORENZO, W. MENGES, S. MENKE, D. MENSZNER, F.S. MERRITT, H. MES, J. MEYER, N. MEYER, A. MICHELINI, R.P. MIDDLETON, S. MIHARA, G. MIKENBERG, J. MILDENBERGER, D.J. MILLER, C. MILSTENE, R. MIR, S. MOED, W. MOHR, C. MOISAN, A. MONTANARI, T. MORI, M.W. MOSS, T. MOUTHUY, U. MULLER, P.G. MURPHY, A. MUTTER, K. NAGAI, I. NAKAMURA, H. NANJO, H.A. NEAL, B. NELLEN, H.H. NGUYEN, B. NIJJHAR, R. NISIUS, M. NOZAKI, F.G. OAKHAM, F. ODORICI, M. OGG, H.O. OGREN, A. OH, H. OH, A. OKPARA, N.J. OLDERSHAW, T. OMORI, S.W. O’NEALE, B.P. O’NEILL, C.J. ORAM, M.J. OREGLIA, S. ORITO, C. PAHL, J. PALINKAS, F. PALMONARI, J.P. PANSART, B. PANZER-STEINDEL, P. PASCHIEVICI, G. PASZTOR, J.R. PATER, G.N. PATRICK, S.J. PAWLEY, N. PAZ-JAOSHVILI, M.J. PEARCE, S. PETZOLD, P. PFEIFENSCHNEIDER, P. PFISTER, J.E. PILCHER, J. PINFOLD, D. PITMAN, D.E. PLANE, P. POFFENBERGER, B. POLI, J. POLOK, O. POOTH, A. POSTHAUS, A. POULADDEJ, L.A. DEL POZO, E. PREBYS, T.W. PRITCHARD, M.PRZYBYCIE´N, H. PRZYSIEZNIAK, A. QUADT, G. QUAST, K. RABBERTZ, B. RAITH, M.W. REDMOND, D.L. REES, C. REMBSER, P. RENKEL, G.E. RICHARDS, H. RICK, D. RIGBY, K. RILES, S.A. ROBINS, D. ROBINSON, N. RODNING, A. ROLLNIK, J.M. RONEY, A. ROOKE, E. ROS, S. ROSATI, K. ROSCOE, S. ROSSBERG, A.M. ROSSI, M. ROSVICK, P. ROUTENBURG, Y. ROZEN, K. RUNGE, O. RUNOLFSSON, U. RUPPEL, D.R. RUST, R. RYLKO, K. SACHS, T. SAEKI, O. SAHR, S. SANGHERA, E.K.G. SARKISYAN, M. SASAKI, C. SBARRA, A.D. SCHAILE, O. SCHAILE, W. SCHAPPERT, F. SCHARF, P. SCHARFF-HANSEN, P. SCHENK, J. SCHIECK, B. SCHMITT, H. VON DER SCHMITT, S.SCHMITT, T. SCHORNER-SADENIUS, S. SCHREIBER, M. SCHRODER, P. SCHUTZ, H.C. SCHULTZ-COULON, M. SCHULZ, M. SCHUMACHER, J. SCHWARZ, C. SCHWICK, W.G. SCOTT, M. SETTLES, R. SEUSTER, T.G. SHEARS, B.C. SHEN, C.H. SHEPHERD-THEMISTOCLEOUS, P. SHERWOOD, R. SHYPIT, A. SIMON, P. SINGH, G.P. SIROLI, A. SITTLER, A. SKILLMAN, A. SKUJA, A.M. SMITH, T.J. SMITH, G.A. SNOW, R. SOBIE, S. SOLDNER-REMBOLD, S. SPAGNOLO, F. SPANO, R.W. SPRINGER, M. SPROSTON, M. STARKS, M. STEIERT, K. STEPHENS, J. STEUERER, H.E. STIER, B. STOCKHAUSEN, K. STOLL, R. STROHMER, D. STROM, F. STRUMIA, L. STUMPF, B. SURROW, P. SZYMANSKI, R. TAFIROUT, H. TAKEDA, T. TAKESHITA, S.D. TALBOT, S. TANAKA, P. TARAS, S. TAREM, M. TASEVSKY, R.J. TAYLOR, M. TECCHIO, P. TEIXEIRA-DIAS, N. TESCH, R. TEUSCHER, N.J. THACKRAY, M. THIERGEN, J. THOMAS, M.A. THOMSON, E. VON TORNE, S. TOWERS, D. TOYA, Z. TROCSANYI, P. TRAN, G. TRANSTROMER, T. TREFZGER, N.J. TRESILIAN, I. TRIGGER, M. TSCHEULIN, T. TSUKAMOTO, E. TSUR, A.S. TURCOT, M.F. TURNER-WATSON, G. TYSARCZYK-NIEMEYER, I. UEDA, B. UJVARI, P. UTZAT, B. VACHON, D. VAN DEN PLAS, R. VAN KOOTEN, G.J. VAN DALEN, P. VANNEREM, G. VASSEUR, R. VERTESI, M. VERZOCCHI, P. VIKAS, M. VINCTER, C.J. VIRTUE, E.H. VOKURKA, C.F. VOLLMER, H. VOSS, J. VOSSEBELD, F. WACKERLE, A. WAGNER, C. WAHL, J.P. WALKER, D. WALLER, C.P. WARD, D.R. WARD, J.J. WARD, P.M. WATKINS, A.T. WATSON, N.K. WATSON, M. WEBER, P. WEBER, S. WEISZ, P.S. WELLS, T. WENGLER, N. WERMES, D. WETTERLING, M. WEYMANN, M.A. WHALLEY, J.S. WHITE, B. WILKENS, J.A. WILSON, G.W. WILSON, I. WINGERTER, V.-H. WINTERER, T. WLODEK, G. WOLF, N.C. WOOD, S. WOTTON, T.R. WYATT, R. YAARI, S. YAMASHITA, Y. YANG, A. YEAMAN, G. YEKUTIELI, M. YURKO, V. ZACEK, I. ZACHAROV, D. ZER-ZION, W. ZEUNER, L. ZIVKOVIC, G.T. ZORN, KENJI ABE, KOYA ABE, T. ABE, I. ABT, P.D. ACTON, I. ADAM, G. AGNEW, T. AKAGI, H. AKIMOTO, N.J. ALLEN, W.W. ASH, D. ASTON, N. BACCHETTA, K.G. BAIRD, C. BALTAY, H.R. BAND, M.B. BARAKAT, G.J. BARANKO, O. BARDON, T.L. BARKLOW, G.L. BASHINDZHAGIAN, R. BATTISTON, J.M. BAUER, A.O. BAZARKO, A. BEAN, G. BELLODI, R. BEN-DAVID, A.C. BENVENUTI, R. BERGER, M. BIASINI, T. BIENZ, G.M. BILEI, D. BISELLO, G. BLAYLOCK, J.R. BOGART, B. BOLEN, T. BOLTON, G.R. BOWER, J.E. BRAU, M. BREIDENBACH, W.M. BUGG, D. BURKE, T.H. BURNETT, P.N. BURROWS, W. BUSZA, A. CALCATERRA, D.O. CALDWELL, B. CAMANZI, M. CARPINELLI, J. CARR, R. CASSELL, R. CASTALDI, A. CASTRO, M. CAVALLI-SFORZA, G.B. CHADWICK, A. CHOU, E. CHURCH, R. CLAUS, H.O. COHN, J.A. COLLER, M.R. CONVERY, V. COOK, R. COTTON, R.F. COWAN, P.A. COYLE, D.G. COYNE, G. CRAWFORD, A. D’OLIVEIRA, C.J.S. DAMERELL, M. DAOUDI, S. DASU, N. DE GROOT, R. DE SANGRO, P. DE SIMONE, S. DE SIMONE, R. DELL’ORSO, P.J. DERVAN, M. DIMA, D.N. DONG, M. DOSER, P.Y.C. DU, R. DUBOIS, J.E. DUBOSCQ, G. EIGEN, B.I. EISENSTEIN, R. ELIA, E. ERDOS, I. EROFEEVA, V. ESCHENBURG, E. ETZION, S. FAHEY, D. FALCIAI, C. FAN, J.P. FERNANDEZ, M.J. FERO, K. FLOOD, R. FREY, J.I. FRIEDMAN, K. FURUNO, E.L. GARWIN, T. GILLMAN, G. GLADDING, S. GONZALEZ, G.D. HALLEWELL, E.L. HART, J.L. HARTON, A. HASAN, Y. HASEGAWA, K. HASUKO, S. HEDGES, S.S. HERTZBACH, M.D. HILDRETH, D.G. HITLIN, A.HONMA, J. S. HUBER, M.E. HUFFER, E.W. HUGHES, X. HUYNH, H.HWANG, M. IWASAKI, Y. IWASAKI, J.M. IZEN, D.J. JACKSON, P. JACQUES, J.A. JAROS, Z.Y. JIANG, A.S. JOHNSON, J.R. JOHNSON, R.A. JOHNSON, T. JUNK, R. KAJIKAWA, M. KALELKAR, Y.A. KAMYSHKOV, H.J. KANG, I. KARLINER, H. KAWAHARA, M.H. KELSEY, H.W. KENDALL, Y.D. KIM, M. KING, R. KING, R. KOFLER, N.M. KRISHNA, Y. KWON, J.F. LABS, R.S. KROEGER, M. LANGSTON, A. LATH, J.A. LAUBER, D.W.G. LEITH, V.LIA, C. LIN, M.X. LIU, M. LORETI, A. LU, H.L. LYNCH, J. MA, G. MANCINELLI, S. MANLY, G. MANTOVANI, T.W. MARKIEWICZ, T. MARUYAMA, H. MASUDA, E. MAZZUCATO, J.F. MCGOWAN, A.K. MCKEMEY, B.T. MEADOWS, R. MESSNER, P.M. MOCKETT, K.C. MOFFEIT, T.B. MOORE, M. MORII, B. MOURS, D. MULLER, G. MUELLER, V. MURZIN, T. NAGAMINE, S. NARITA, U. NAUENBERG, H. NEAL, G. NESOM, M. NUSSBAUM, Y. OHNISHI, N. OISHI, D. ONOPRIENKO, L.S. OSBORNE, R.S. PANVINI, C.H.PARK, H. PARK, T.J. PAVEL, I. PERUZZI, L. PESCARA, M. PICCOLO, L. PIEMONTESE, E. PIERONI, K.T. PITTS, R.J. PLANO, R. PREPOST, C.Y. PRESCOTT, G. PUNKAR, J. QUIGLEY, B.N. RATCLIFF, K. REEVES, T.W. REEVES, J. REIDY, P.L. REINERTSEN, P.E. RENSING, L.S. ROCHESTER, J.E. ROTHBERG, P.C. ROWSON, J.J. RUSSELL, O.H. SAXTON, T. SCHALK, R.H. SCHINDLER, U. SCHNEEKLOTH, B.A. SCHUMM, J. SCHWIENING, A. SEIDEN, S. SEN, V.V. SERBO, L. SERVOLI, M.H. SHAEVITZ, J.T. SHANK, G. SHAPIRO, D.J. SHERDEN, K.D. SHMAKOV, C. SIMOPOULOS, N.B. SINEV, S.R. SMITH, M.B. SMY, J.A. SNYDER, M.D. SOKOLOFF, H. STAENGLE, A. STAHL, P. STAMER, H. STEINER, R. STEINER, M.G. STRAUSS, D. SU, F. SUEKANE, A. SUGIYAMA, A. SUZUKI, S. SUZUKI, M. SWARTZ, A. SZUMILO, T. TAKAHASHI, F.E. TAYLOR, J.J. THALER, J. THOM, E. TORRENCE, A.I. TRANDAFIR, J.D. TURK, T. USHER, J. VA VRA, C. VANNINI, E. VELLA, J.P. VENUTI, R. VERDIER, P.G. VERDINI, D.L. WAGNER, S.R. WAGNER, A.P. WAITE, S. WALSTON, J. WANG, S.J. WATTS, A.W. WEIDEMANN, E.R. WEISS, J.S. WHITAKER, S.L. WHITE, F.J. WICKENS, D.A. WILLIAMS, D.C. WILLIAMS, S.H. WILLIAMS, S. WILLOCQ, R.J. WILSON, W.J. WISNIEWSKI, J.L. WITTLIN, M. WOODS, G.B. WORD, T.R. WRIGHT, J. WYSS, R.K. YAMAMOTO, J.M. YAMARTINO, X.Q. YANG, J. YASHIMA, S.J. YELLIN, C.C.YOUNG, H.YUTA, G. ZAPALAC, R.W. ZDARKO, C. ZEITLIN, J. ZHOU, Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Laboratoire d'Annecy de Physique des Particules (LAPP/Laboratoire d'Annecy-le-Vieux de Physique des Particules), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Aix Marseille Université (AMU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Collège de France (CdF)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), GRUNEVALD M, NEWALD M, SCHAEL S, BARATE R, BRUNELIE, RE R, BUSKULIC D, DE BONIS I, DECAMP D, GHEZ P, GOY C, JE, ZE, QUEL S, LEES J, LUCOTTE A, MARTIN M, MERLE E, MINARD M, NIEF J, ODIER P, PIETRZYK B, TROCME, BRAVO S, CASADO MP, CHMEISSANI M, COMAS P, CRESPO JM, FERNANDEZ E, FERNANDEZ-BOSMAN M, GARRIDO L, GRAUGES E, JUSTE A, MARTINEZ M, MERINO G, MIQUEL R, MIR LM, ORTEU S, PACHECO A, PARK IC, PERLAS J, RIU I, RUIZ H, SANCHEZ F, COLALEO A, CREANZA D, DE FILIPPIS N, DE PALMA M, IASELLI G, MAGGI G, MAGGI M, NUZZO S, RANIERI, A, RASO, G, RUGGIERI F, SELVAGGI, G, SILVESTRIS L, TEMPESTA P, TRICOMI A, ZITO G, HUANG X, LIN J, OUYANG Q, WANG T, XIE Y, XU R, XUE S, ZHANG J, ZHANG L, ZHAO W, ABBANEO D, BAZARKO A, BECKER U, BOIX G, BIRD F, BLUCHER E, BONVICINI B, BRIGHT-THOMAS P, BARKLOW T, BUCHMU, LLER O, CATTANEO M, CERUTTI F, CIULLI V, CLERBAUX B, DREVERMANN H, FORTY RW, FRANK M, GREENING TC, HAGELBERG R, HALLEY AW, GIANOTTI F, GIRONE M, HANSEN JB, HARVEY J, JACOBSEN J, HUTCHCROFT DE, JANOT P, JOST B, KNOBLOCH J, KADO M, LEHRAUS I, LAZEYRAS P, and MALEY P
- Subjects
Top quark ,FORWARD-BACKWARD ASYMMETRY ,PARTICLE PHYSICS ,LARGE ELECTRON POSITRON COLLIDER ,ALEPH ,DELPHI ,L3 ,OPAL ,General Physics and Astronomy ,01 natural sciences ,7. Clean energy ,High Energy Physics - Experiment ,Settore FIS/04 - Fisica Nucleare e Subnucleare ,High Energy Physics - Experiment (hep-ex) ,High Energy Physics - Phenomenology (hep-ph) ,electron-positron physics ,[PHYS.HEXP]Physics [physics]/High Energy Physics - Experiment [hep-ex] ,Electroweak interaction ,Physics ,Quantum chromodynamics ,Electron–positron physics ,Electroweak interactions ,Decays of heavy intermediate gauge bosons ,Fermion–antifermion production ,Precision measurements at the Z resonance ,Tests of the Standard Model ,Radiative corrections ,Effective coupling constants ,Neutral weak current ,Z boson ,W boson ,Higgs boson ,Particle physics - Experiment ,Settore FIS/01 - Fisica Sperimentale ,FERMION-PAIR PRODUCTION ,HADRONIC-Z-DECAYS ,TOP-QUARK MASS ,ANGLE BHABHA SCATTERING ,W-BOSON MASS ,CROSS-SECTION ASYMMETRY ,Z-LINE-SHAPE ,SEMILEPTONIC BRANCHING RATIOS ,CARLO EVENT GENERATOR ,decays of heavy intermediate gauge bosons ,effective coupling constants ,electroweak interactions ,fermion-antifermion production ,higgs boson ,neutral weak current ,precision measurements at the z resonance ,radiative corrections ,tests of the standard model ,top quark ,w boson ,z boson ,Radiative correction ,High Energy Physics - Phenomenology ,FIS/01 - FISICA SPERIMENTALE ,Física nuclear ,Neutrino ,Particle physics ,FOS: Physical sciences ,ddc:500.2 ,Elementary particle physics ,LEP ,electroweak ,Decays of heavy intermediate gauge boson ,Effective coupling constant ,Partícules (Física nuclear) ,Standard Model ,electroweak theory, Z boson, DELPHI, ALEPH, OPAL, L3 ,0103 physical sciences ,010306 general physics ,Coupling constant ,010308 nuclear & particles physics ,High Energy Physics::Phenomenology ,Fermion ,FORWARD-BACKWARD ASYMMETRY, FERMION-PAIR PRODUCTION, HADRONIC-Z-DECAYS, TOP-QUARK MASS, ANGLE BHABHA SCATTERING, W-BOSON MASS, CROSS-SECTION ASYMMETRY, Z-LINE-SHAPE, SEMILEPTONIC BRANCHING RATIOS, CARLO EVENT GENERATOR ,[PHYS.HPHE]Physics [physics]/High Energy Physics - Phenomenology [hep-ph] ,Experimental High Energy Physics ,Electron–positron physic ,High Energy Physics::Experiment ,FIS/04 - FISICA NUCLEARE E SUBNUCLEARE - Abstract
We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLD experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, $\MZ$ and $\GZ$, and its couplings to fermions, for example the $\rho$ parameter and the effective electroweak mixing angle, are precisely measured. The number of light neutrino species is determined to be 2.9840+/-0.0082. The results are compared to the predictions of the Standard Model. Electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its Standard Model expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the masses of the top quark and the W Boson are predicted. These indirect constraints are compared to the direct measurements, providing a stringent test of the Standard Model. Using in addition the direct measurements of $\Mt$ and $\MW$, the mass of the as yet unobserved Standard Model Higgs boson is predicted., Comment: 302 pages, v2: minor corrections and updates of references. Accepted for publication by Physics Reports, v3: further small corrections and journal version
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31. Increased sensitivity of the alpha-2 neuronal nicotinic receptor causes familial epilepsy with nocturnal wandering and ictal fear RID A-8863-2008
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Marini, C, Aridon, P, Di Resta, C, Brilli, E, De Fusco, M, Politi, F, Parrini, E, Manfredi, I, Pisano, T, Pruna, D, Curia, G, Cianchetti, C, Pasqualetti, Massimo, Becchetti, A, Guerrini, R, and Casari, G.
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- 2006
32. Single- and multi-photon production in e +e - collisions at vs up to 209 GeV: The ALEPH collaboration
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Heister, A., Schael, S., Barate, R., Brunelière, R., Bonis, De, Decamp, I., Goy, D., Jezequel, C., Lees, S., J. P., Martin, Merle, F., Minard, E., M. N., Pietrzyk, Trocmé, B., Boix, B., Bravo, G., Casado, S., M. P., Chmeissani, Crespo, M., J. M., Fernandez, Fernandez, Bosman, Garrido, M., Graugés, L., Lopez, E., Martinez, J., Merino, M., Mir, G., L. M., Pacheco, Paneque, A., Ruiz, D., Colaleo, H., Creanza, A., Filippis, De, Palma, De, Iaselli, M., Maggi, G., Nuzzo, M., Ranieri, S., Raso, A., Ruggieri, G., Selvaggi, F., Silvestris, G., Tempesta, L., Tricomi, P., Zito, A., Huang, G., Lin, X., Ouyang, J., Wang, Q., Xie, T., Xu, Y., Xue, R., Zhang, S., Zhang, J., Zhao, L., Abbaneo, W., Azzurri, D., Barklow, P., Buchmüller, T., Cattaneo, O., Cerutti, M., Clerbaux, F., Drevermann, B., Forty, H., R. W., Frank, Gianotti, M., Greening, F., T. C., Hansen, J. B., Harvey, Hutchcroft, J., D. E., Janot, Jost, P., Kado, B., Mato, M., Moutoussi, P., Ranjard, A., Rolandi, F., Schlatter, L., Sguazzoni, D., Tejessy, G., Teubert, W., Valassi, F., Videau, A., Ward, I., J. J., Badaud, Dessagne, F., Falvard, S., Fayolle, A., Gay, D., Jousset, P., Michel, J., Monteil, B., Pallin, S., Pascolo, D., J. M., Perret, Hansen, P., J. D., Hansen, J. R., Hansen, P. H., Nilsson, B. S., Kyriakis, Markou, A., Simopoulou, C., Vayaki, E., Zachariadou, A., Blondel, K., Brient, A., J. C., Machefert, Rougé, F., Swynghedauw, A., Tanaka, M., Videau, R., Ciulli, H., Focardi, V., Parrini, E., Antonelli, G., Antonelli, A., Bencivenni, M., Bossi, G., Capon, F., Chiarella, G., Laurelli, V., Mannocchi, P., Murtas, G., G. P., Passalacqua, Kennedy, L., Lynch, J., J. G., Negus, O'Shea, P., Thompson, V., A. S., Wasserbaech, Cavanaugh, S., Dhamotharan, R., Geweniger, S., Hanke, C., Hepp, P., Kluge, V., E. E., Leibenguth, Putzer, G., Stenzel, A., Tittel, H., Wunsch, K., Beuselinck, M., Cameron, R., Davies, W., Dornan, G., P. J., Girone, Hill, M., R. D., Marinelli, Nowell, N., Rutherford, J., S. A., Sedgbeer, J. K., Thompson, J. C., White, Ghete, R., V. M., Girtler, Kneringer, P., Kuhn, E., Rudolph, D., Bouhova, Thacker, Bowdery, E., C. K., Clarke, D. P., Ellis, Finch, G., A. J., Foster, Hughes, F., Jones, G., R. W. L., Pearson, M. R., Robertson, N. A., Smizanska, van der Aa, Delaere, O., Lemaitre, C., Blumenschein, V., Hölldorfer, U., Jakobs, F., Kayser, K., Kleinknecht, F., Müller, K., A. S., Quast, Renk, G., Sander, B., H. G., Schmeling, Wachsmuth, S., Zeitnitz, H., Ziegler, C., Bonissent, T., Coyle, A., Curtil, P., Ealet, C., Fouchez, A., Payre, D., Tilquin, P., Ragusa, A., David, F., Dietl, A., Ganis, H., Hüttmann, G., Lütjens, K., Männer, G., Moser, W., H. G., Settles, Wolf, R., Boucrot, G., Callot, J., Davier, O., Duflot, M., Grivaz, L., J. F., Heusse, Jacholkowska, P., Serin, A., Veillet, L., J. J., de Vivie de Régie, J. B., Yuan, Bagliesi, C., Boccali, G., Foà, T., Giammanco, L., Giassi, A., Ligabue, A., Messineo, ALBERTO MARIA, Palla, F., Sanguinetti, G., Sciabà, A., Tenchini, R., Venturi, A., Verdini, P. G., Awunor, O., Blair, G. A., Cowan, G., Garcia, Bellido, Green, A., M. G., Jones, L. T., Medcalf, Misiejuk, T., Strong, A., J. A., Teixeira, Dias, Clifft, P., R. W., Edgecock, T. R., Norton, P. R., Tomalin, I. R., Bloch, Devaux, Boumediene, B., Colas, D., Fabbro, P., Lançon, B., Lemaire, E., M. C., Locci, Perez, E., Rander, P., Tuchming, J., Vallage, B., Konstantinidis, B., Litke, N., A. M., Loomis, Taylor, C., Booth, G., C. N., Cartwright, Combley, S., Hodgson, F., P. N., Lehto, Thompson, M., L. F., Affholderbach, Böhrer, K., Brandt, A., Grupen, S., Hess, C., Ngac, J., Prange, A., Sieler, G., Borean, U., Giannini, C., He, G., Putz, H., Rothberg, J., Armstrong, J., S. R., Berkelman, Cranmer, K., Ferguson, K., D. P. S., Gao, González, Y., Hayes, S., O. J., Hu, Jin, H., Kile, S., Mcnamara, Iii, P. A., Nielsen, Pan, J., Y. B., von Wimmersperg Toeller, J. H., Wiedenmann, Wu, W., Wu, J., S. L., Wu, Zobernig, X., and Dissertori, G.
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- 2003
33. Nonsyndromic mental retardation and cryptogenic epilepsy in women with Doublecortin gene mutations
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Guerrini, R, Moro, F, Andermann, E, Hughes, E, D'Agostino, D, Carrozzo, R, Bernasconi, A, Flinter, F, Parmeggiani, L, Volzone, A, Parrini, E, Mei, D, Jarosz, Jm, Morris, Rg, Pratt, P, Tortorella, Gaetano, Dubeau, F, Andermann, F, Dobyns, Wb, and Das, S.
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- 2003
34. Peritrigonal and temporo-occipital heterotopia with corpus callosum and cerebellar dysgenesis
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Pisano, T., primary, Barkovich, A. J., additional, Leventer, R. J., additional, Squier, W., additional, Scheffer, I. E., additional, Parrini, E., additional, Blaser, S., additional, Marini, C., additional, Robertson, S., additional, Tortorella, G., additional, Rosenow, F., additional, Thomas, P., additional, McGillivray, G., additional, Andermann, E., additional, Andermann, F., additional, Berkovic, S. F., additional, Dobyns, W. B., additional, and Guerrini, R., additional
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- 2012
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35. FLNA genomic rearrangements cause periventricular nodular heterotopia
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Clapham, K. R., primary, Yu, T. W., additional, Ganesh, V. S., additional, Barry, B., additional, Chan, Y., additional, Mei, D., additional, Parrini, E., additional, Funalot, B., additional, Dupuis, L., additional, Nezarati, M. M., additional, du Souich, C., additional, van Karnebeek, C., additional, Guerrini, R., additional, and Walsh, C. A., additional
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- 2012
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36. Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion
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Cardoso, C., primary, Boys, A., additional, Parrini, E., additional, Mignon-Ravix, C., additional, McMahon, J. M., additional, Khantane, S., additional, Bertini, E., additional, Pallesi, E., additional, Missirian, C., additional, Zuffardi, O., additional, Novara, F., additional, Villard, L., additional, Giglio, S., additional, Chabrol, B., additional, Slater, H. R., additional, Moncla, A., additional, Scheffer, I. E., additional, and Guerrini, R., additional
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- 2008
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37. Multiplex ligation-dependent probe amplification detects DCX gene deletions in band heterotopia
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Mei, D., primary, Parrini, E., additional, Pasqualetti, M., additional, Tortorella, G., additional, Franzoni, E., additional, Giussani, U., additional, Marini, C., additional, Migliarini, S., additional, and Guerrini, R., additional
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- 2007
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38. Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome
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Sheen, V. L., primary, Jansen, A., additional, Chen, M. H., additional, Parrini, E., additional, Morgan, T., additional, Ravenscroft, R., additional, Ganesh, V., additional, Underwood, T., additional, Wiley, J., additional, Leventer, R., additional, Vaid, R. R., additional, Ruiz, D. E., additional, Hutchins, G. M., additional, Menasha, J., additional, Willner, J., additional, Geng, Y., additional, Gripp, K. W., additional, Nicholson, L., additional, Berry-Kravis, E., additional, Bodell, A., additional, Apse, K., additional, Hill, R. S., additional, Dubeau, F., additional, Andermann, F., additional, Barkovich, J., additional, Andermann, E., additional, Shugart, Y. Y., additional, Thomas, P., additional, Viri, M., additional, Veggiotti, P., additional, Robertson, S., additional, Guerrini, R., additional, and Walsh, C. A., additional
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- 2005
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39. Germline and mosaic mutations of FLN1 in men with periventricular heterotopia
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Guerrini, R., primary, Mei, D., additional, Sisodiya, S., additional, Sicca, F., additional, Harding, B., additional, Takahashi, Y., additional, Dorn, T., additional, Yoshida, A., additional, Campistol, J., additional, Kramer, G., additional, Moro, F., additional, Dobyns, W. B., additional, and Parrini, E., additional
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- 2004
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40. FLNAgenomic rearrangements cause periventricular nodular heterotopia
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Clapham, K.R., Yu, T.W., Ganesh, V.S., Barry, B., Chan, Y., Mei, D., Parrini, E., Funalot, B., Dupuis, L., Nezarati, M.M., du Souich, C., van Karnebeek, C., Guerrini, R., and Walsh, C.A.
- Abstract
To identify copy number variant (CNV) causes of periventricular nodular heterotopia (PNH) in patients for whom FLNAsequencing is negative.
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- 2012
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41. Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletionSYMBOL
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Cardoso, C, Boys, A, Parrini, E, Mignon-Ravix, C, McMahon, J M., Khantane, S, Bertini, E, Pallesi, E, Missirian, C, Zuffardi, O, Novara, F, Villard, L, Giglio, S, Chabrol, B, Slater, H R., Moncla, A, Scheffer, I E., and Guerrini, R
- Abstract
Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. At present, two genes have been identified to cause PH when mutated. Mutations in FLNA(Xq28) and ARFGEF2(20q13) are responsible for X-linked bilateral PH and a rare autosomal recessive form of PH with microcephaly. Chromosomal rearrangements involving the 1p36, 5p15, and 7q11 regions have also been reported in association with PH but the genes implicated remain unknown. Fourteen additional distinct anatomoclinical PH syndromes have been described, but no genetic insights into their causes have been gleaned.
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- 2009
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42. Multiplex ligation-dependent probe amplification detects DCXgene deletions in band heterotopia
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Mei, D, Parrini, E, Pasqualetti, M, Tortorella, G, Franzoni, E, Giussani, U, Marini, C, Migliarini, S, and Guerrini, R
- Abstract
Subcortical band heterotopia (SBH, or double cortex syndrome) is a neuronal migration disorder consisting of heterotopic bands of gray matter located between the cortex and the ventricular surface, with or without concomitant pachygyria. Most cases show diffuse or anteriorly predominant (A>P) migration abnormality. All familial and 53% to 84% of sporadic cases with diffuse or A>P SBH harbor a mutation of the DCXgene, leaving the genetic causes unexplained, and genetic counseling problematic, in the remaining patients. Our purpose was to verify the extent to which exonic deletions or duplications of the DCXgene would account for sporadic SBH with A>P gradient but normal gene sequencing.
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- 2007
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43. Germline and mosaic mutations of FLN1in men with periventricular heterotopia
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Guerrini, R., Mei, D., Sisodiya, S., Sicca, F., Harding, B., Takahashi, Y., Dorn, T., Yoshida, A., Campistol, J., Krämer, G., Moro, F., Dobyns, W.B., and Parrini, E.
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To describe the phenotypic spectrum and genetics of periventricular nodular heterotopia (PNH) caused by FLN1mutations in four men.
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- 2004
44. Pura syndrome: an emerging neurodevelopmental disorder
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Bigoni, S., Garani, G., Gijs Santen, Della Monica, M., Graziano, C., Ruivenkamp, C., Ballardini, E., Guerrini, R., Magini, P., Procopio, E., Parrini, E., Suppiej, A., Colavito, D., Maritan, V., Hoffer, M., Ognibene, D., and Ferlini, A.
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Socio-culturale
45. Increased sensitivity of the neuronal nicotinic receptor alpha-2 subunit causes familial epilepsy with nocturnal wandering and ictal fear
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Giorgio Casari, Carla Marini, Fausta Politi, Paolo Aridon, Irene Manfredi, Andrea Becchetti, Elena Parrini, Dario Pruna, Carlo Cianchetti, Elisa Brilli, Giulia Curia, Massimo Pasqualetti, Tiziana Pisano, Chiara Di Resta, Maurizio De Fusco, Renzo Guerrini, Aridon, P, Marini, C, DI RESTA, C, Brilli, E, De Fusco, M, Politi, F, Parrini, E, Manfredi, I, Pisano, T, Pruna, D, Curia, G, Cianchetti, C, Pasqualetti, M, Becchetti, A, Guerrini, R, Casari, G, DI RESTA, Chiara, Casari, GIORGIO NEVIO, DE FUSCO, M, Ciachetti, C, ARIDON, P, MARINI, C, BRILLI, E, POLITI, F, PARRINI, E, MANFREDI, I, PISANO, T, PRUNA, D, CURIA, G, CIANCHETTI, C, PASQUALETTI, M, BECCHETTI, A, GUERRINI, R, and CASARI, G
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Somnambulism ,Molecular Sequence Data ,Mutation, Missense ,Autosomal dominant nocturnal frontal lobe epilepsy ,Receptors, Nicotinic ,Biology ,medicine.disease_cause ,Ligands ,Nicotinic ,Article ,Epilepsy ,BIO/09 - FISIOLOGIA ,Internal medicine ,Acetylcholine ,Aged ,Aged, 80 and over ,Amino Acid Sequence ,Female ,Humans ,Neurons ,Pedigree ,Fear ,Receptors ,medicine ,80 and over ,Genetics ,Ictal ,Genetics(clinical) ,Genetics (clinical) ,Acetylcholine receptor ,Mutation ,Seizure types ,medicine.disease ,Nicotinic acetylcholine receptor ,Nicotinic agonist ,Endocrinology ,nAChR, patch-clamp, ADNFLE, sleep-related epilepsy, M1, TM1, ACh, nicotine ,Settore MED/26 - Neurologia ,Missense - Abstract
Sleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the α4 and β2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking. We identified a new genetic locus for familial sleep-related focal epilepsy on chromosome 8p12.3-8q12.3. By sequencing the positional candidate neuronal cholinergic receptor α2 subunit gene (CHRNA2), we detected a heterozygous missense mutation, I279N, in the first transmembrane domain that is crucial for receptor function. Whole-cell recordings of transiently transfected HEK293 cells expressing either the mutant or the wild-type receptor showed that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine, therefore indicating that the nicotinic α2 subunit alteration is the underlying cause. CHRNA2 is the third neuronal cholinergic receptor gene to be associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior. © 2006 by The American Society of Human Genetics. All rights reserved.
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- 2006
46. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
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Joshua E. Motelow, Gundula Povysil, Ryan S. Dhindsa, Kate E. Stanley, Andrew S. Al- len, Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Ka- therine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E. Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M. Neale, Gianpiero L. Cavalleri, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Hakon Hakonarson, Erin L. Heinzen, Ingo Helbig, Patrick Kwan, Anthony G. Marson, Slave ? Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Roland Krause, Patrick May, Kevin McKenna, Brigid M. Regan, Caitlin A. Bennett, Costin Leu, Stephanie L. Leech, Terence J. O'Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Quratulain Zulfiqar Ali, Tara R. Sadoway, Heinz Krestel, Andre ? Schaller, Savvas S. Papacostas, Ioanna Kou- siappa, George A. Tanteles, Yiolanda Christou, Katalin Sterbova ?, Marke ? ta Vlckova ?, Lucie Sedlackova, Petra Lassuthova ?, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Bernd A. Neubauer, Friedrich Zimprich, Martha Feucht, Eva M. Reinthaler, Wolfram S. Kunz, Ga ?bor Zsurka, Rainer Surges, Tobias Baumgart- ner, Randi von Wrede, Manuela Pendziwiat, Hiltrud Muhle, An- nika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Mu ?ller-Schlu ?ter, Gerhard Kluger, Martin Ha ?usler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Stephan Lauxmann, Christian Boßelmann, Josua Kegele, Christian Hengs- bach, Sarah Rau, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, IngoBorggra ?fe, ChristophJ.Schankin, SusanneSchubert-Bast, Herbert Schreiber, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Markus Wolff, Dieter Dennig, Rene Madeleyn, Reetta Ka ?lvia ?inen, Anni Saarela, Oskari Timonen, Tarja Linnankivi, Anna-Elina Lehesjoki, Sylvain Rheims, Gaetan Lesca, Philippe Ryvlin, Louis Maillard, Luc Valton, Philippe Derambure, Fabrice Bartolomei, Edouard Hirsch, Ve ?ronique Michel, Francine Chas- soux, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Mark D. Baker, Beata Fonferko-Shadrach, Charlotte Law- thom, Joseph Anderson, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Norman Delanty, Colin P. Doherty, Arif Shukralla, Hany El-Naggar, Peter Widdess-Walsh, Nina Barisic, Laura 12 The American Journal of Human Genetics 108, 1-18, June 3, 2021 Please cite this article in press as: Epi25 Collaborative, Sub-genic intolerance, ClinVar, the epilepsies: A whole-exome sequencing study of 29, 165 individuals, The American Journal of Human Genetics (2021), https://doi.org/10.1016/j.ajhg.2021.04.009 Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Francesca Ragona, Federico Zara, Michele Iacomino, An- tonella Riva, Francesca Madia, Maria Stella Vari, Vincenzo Salpie- tro, Marcello Scala, Maria Margherita Mancardi, Lino Nobili, Elisa- betta Amadori, Thea Giacomini, Francesca Bisulli, Tommaso Pippucci, Laura Licchetta, Raffaella Minardi, Paolo Tinuper, Lor- enzo Muccioli, Barbara Mostacci, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carmen Barba, Shinichi Hirose, At- sushi Ishii, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Ahmad Beydoun, Wassim Nasreddine, Nathalie Khoueiry Zgheib, Birute Tumiene, Algirdas Utkus, Lynette G. Sadleir, Chontelle King, S. Hande Caglayan, Mutluay Arslan, Zuhal Yap?c?, P?nar To- paloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Asl? Gun- dogdu-Eken, Nerses Bebek, Meng-Han Tsai, Chen-Jui Ho, Chih- Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jac- queline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, David A. Greenberg, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, Mahgenn Cosico, Priya Vaidis- waran, Eryn Fitch, Samuel F. Berkovic, Holger Lerche, Daniel H. Lowenstein, David B. Goldstein., Motelow J.E., Povysil G., Dhindsa R.S., Stanley K.E., Allen A.S., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Cusick C., Singh T., Heyne H., Byrnes A.E., Churchhouse C., Watts N., Solomonson M., Lal D., Gupta N., Neale B.M., Cavalleri G.L., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Sisodiya S.M., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bennett C.A., Leu C., Leech S.L., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Ali Q.Z., Sadoway T.R., Krestel H., Schaller A., Papacostas S.S., Kousiappa I., Tanteles G.A., Christou Y., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Neubauer B.A., Zimprich F., Feucht M., Reinthaler E.M., Kunz W.S., Zsurka G., Surges R., Baumgartner T., von Wrede R., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Lauxmann S., Bosselmann C., Kegele J., Hengsbach C., Rau S., Steinhoff B.J., Schulze-Bonhage A., Borggrafe I., Schankin C.J., Schubert-Bast S., Schreiber H., Mayer T., Korinthenberg R., Brockmann K., Wolff M., Dennig D., Madeleyn R., Kalviainen R., Saarela A., Timonen O., Linnankivi T., Lehesjoki A.-E., Rheims S., Lesca G., Ryvlin P., Maillard L., Valton L., Derambure P., Bartolomei F., Hirsch E., Michel V., Chassoux F., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Baker M.D., Fonferko-Shadrach B., Lawthom C., Anderson J., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Delanty N., Doherty C.P., Shukralla A., El-Naggar H., Widdess-Walsh P., Barisic N., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Ragona F., Zara F., Iacomino M., Riva A., Madia F., Vari M.S., Salpietro V., Scala M., Mancardi M.M., Nobili L., Amadori E., Giacomini T., Bisulli F., Pippucci T., Licchetta L., Minardi R., Tinuper P., Muccioli L., Mostacci B., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Barba C., Hirose S., Ishii A., Suzuki T., Inoue Y., Yamakawa K., Beydoun A., Nasreddine W., Khoueiry Zgheib N., Tumiene B., Utkus A., Sadleir L.G., King C., Caglayan S.H., Arslan M., Yapici Z., Topaloglu P., Kara B., Yis U., Turkdogan D., Gundogdu-Eken A., Bebek N., Tsai M.-H., Ho C.-J., Lin C.-H., Lin K.-L., Chou I.-J., Poduri A., Shiedley B.R., Shain C., Noebels J.L., Goldman A., Busch R.M., Jehi L., Najm I.M., Ferguson L., Khoury J., Glauser T.A., Clark P.O., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Greenberg D.A., Ellis C.A., Goldberg E., Helbig K.L., Cosico M., Vaidiswaran P., Fitch E., Berkovic S.F., Lerche H., Lowenstein D.H., Goldstein D.B., Epi25 Collaborative, Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,focal epilepsy ,Whole Exome Sequencing ,Cohort Studies ,Epilepsy ,0302 clinical medicine ,Genetic Marker ,Missense mutation ,Exome ,whole-exome sequencing ,generalized epilepsy ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,Exome sequencing ,seizures ,Genetics ,ClinVar ,Phenotype ,epileptic encephalopathy ,Epi25 ,intolerance ,Case-Control Studie ,Human ,Genetic Markers ,seizure ,Disease Association ,Biology ,Article ,03 medical and health sciences ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Generalized epilepsy ,Gene ,Louvain ,[SCCO.NEUR]Cognitive science/Neuroscience ,Correction ,Genetic Variation ,medicine.disease ,epilepsy ,Human genetics ,030104 developmental biology ,Case-Control Studies ,Human medicine ,Cohort Studie ,Genetic generalized epilepsy ,030217 neurology & neurosurgery - Abstract
Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
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- 2021
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47. Long-term follow-up of an individual with ITPR1-related disorder
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Tommaso Montini, Paola Passalacqua, Nicola Brunetti-Pierri, Diletta Apuzzo, Gerarda Cappuccio, Elena Parrini, Alessandra D'Amico, Cappuccio, G., Apuzzo, D., Passalacqua, P., Parrini, E., D'Amico, A., Montini, T., and Brunetti-Pierri, Nicola.
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Pediatrics ,medicine.medical_specialty ,business.industry ,Long term follow up ,Developmental Disabilitie ,Developmental Disabilities ,Mutation, Missense ,Inositol 1,4,5-Trisphosphate Receptor ,Nervous System Malformations ,Follow-Up Studie ,Nervous System Malformation ,Phenotype ,Cerebellum ,Genetics ,Medicine ,Humans ,Inositol 1,4,5-Trisphosphate Receptors ,Spinocerebellar Ataxias ,Related disorder ,business ,Child ,Genetics (clinical) ,Inositol ,Human ,Follow-Up Studies - Abstract
no abstract available
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- 2020
48. Severe presentation and complex brain malformations in an individual carrying a CCND2 variant
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Alessandra D'Amico, Nicola Brunetti-Pierri, Gerarda Cappuccio, Elena Parrini, Lorenzo Ugga, Cappuccio, G., Ugga, L., Parrini, E., D'Amico, A., and Brunetti-Pierri, N.
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Male ,0301 basic medicine ,Cerebellum ,Pathology ,medicine.medical_specialty ,endocrine system ,lcsh:QH426-470 ,030105 genetics & heredity ,CCND2 ,White matter ,Young Adult ,03 medical and health sciences ,MPPH ,Megalencephaly-polymicrogyria-polydactyly-hydrocephalu ,Genetics ,medicine ,Cyclin D2 ,Humans ,Megalencephaly ,Molecular Biology ,Genetics (clinical) ,business.industry ,Original Articles ,Perisylvian polymicrogyria ,medicine.disease ,Megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus ,Hypoplasia ,Malformations of Cortical Development ,Polydactyly ,lcsh:Genetics ,Diffusion Tensor Imaging ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Mutation ,Original Article ,Brainstem ,Presentation (obstetrics) ,business ,Hydrocephalus ,Diffusion MRI - Abstract
Background Megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus (MPPH) is a developmental brain disorder characterized by megalencephaly and bilateral perisylvian polymicrogyria due to defects in genes of the PI3K‐AKT pathway. Only a few patients with CCND2 mutations have been reported to date. Methods We describe an individual harboring a de novo variant in CCND2 undergoing neuroradiological evaluation including diffusion tensor imaging (DTI). Results The individual presented with a severe brain malformation extending to both brainstem and cerebellum with hypomyelination not previously reported in CCND2‐related disorder. Severe hypoplasia and white matter disorganization were confirmed by DTI. Conclusion This report expands the phenotypic spectrum of the disorder due to CCND2 variants.
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- 2019
49. The syndrome of polymicrogyria, thalamic hypoplasia, and epilepsy with CSWS
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Javier Salas-Puig, Laura Grisotto, Anna Rita Ferrari, Elena Parrini, Carmen Barba, Annio Posar, Antonia Parmeggiani, Melania Falchi, Mirco Cosottini, Renzo Guerrini, Francesco Zellini, Giovanni Ambrosetto, Margherita Santucci, Emanuele Bartolini, Bartolini, E, Falchi, M, Zellini, F, Parrini, E, Grisotto, L, Cosottini, M, Posar, A, Parmeggiani, A, Ambrosetto, G, Ferrari, Ar, Santucci, M, Salas-Puig, J, Barba, C, and Guerrini, R.
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Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Early adolescence ,Thalamus ,Action Potentials ,Benign Rolandic Epilepsy ,Electroencephalography ,antiepileptic drug, benign rolandic epilepsy, confidence interval, continuous spikes and waves during sleep ,Rolandic ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,medicine ,Polymicrogyria ,Humans ,Prospective Studies ,Child ,Child, Preschool ,Epilepsy, Rolandic ,Female ,Follow-Up Studies ,Infant ,Syndrome ,Sleep Stages ,Neurology (clinical) ,Preschool ,Prospective cohort study ,Thalamic hypoplasia ,medicine.diagnostic_test ,medicine.disease ,030104 developmental biology ,Psychology ,030217 neurology & neurosurgery - Abstract
Objective: We explored the long-term follow-up of continuous spike-and-wave complexes during sleep (CSWS) in polymicrogyria and the anatomic volumetric variables that influence the risk of developing this age-related epileptic encephalopathy. Methods: We performed prospective follow-up of 27 patients with polymicrogyria/CSWS (mean follow-up 14.3 years; range 2–31 years) and comparative volumetric analysis of the polymicrogyric hemispheres and ipsilateral thalami vs 3 subgroups featuring polymicrogyria without CSWS, benign rolandic epilepsy (BRE), and headache. Receiver operator characteristic analysis of the power of volumetric values was determined to predict CSWS. Results: CSWS peaked between 5 and 7 years (mean age at onset 4.7 years). Remission occurred within 2 years from onset in 21%, within 4 years in 50%, and by age 13 years in 100%. We found smaller thalamic and hemispheric volumes in polymicrogyria/CSWS with respect to polymicrogyria without CSWS (p 5 0.0021 for hemispheres; p 5 0.0003 for thalami), BRE, and controls with headache (p , 0.0001). Volumes of the malformed hemispheres and ipsilateral thalami reliably identified the risk of incurring CSWS, with a 68-fold increased risk for values lower than optimal diagnostic cutoffs (436,150 mm3 for malformed hemispheres or 4,616 mm3 for ipsilateral thalami; sensitivity 92.54%; specificity 84.62%). The risk increased by 2% for every 1,000 mm3 reduction of the polymicrogyric hemispheres and by 15% for every 100 mm3 reduction of ipsilateral thalami. Conclusions: The polymicrogyria/CSWS syndrome is likely caused by a cortico-thalamic malformation complex and is characterized by remission of epilepsy within early adolescence. Early assessment of hemispheric and thalamic volumes in children with polymicrogyria and epilepsy can reliably predict CSWS.
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- 2016
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50. TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model
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Baptiste Fischer, Inge A. Meijer, Renzo Guerrini, Naomi Lubarr, Paolo Aridon, Nils Schoovaerts, Maurizio De Fusco, Elena Parrini, Jef Swerts, Giorgio Casari, Patrik Verstreken, Katherine M. Mackenzie, Wim Versées, Wang-Tso Lee, Jone Paesmans, Davide Cittaro, Davide Mei, Kevin Lüthy, Lüthy, Kevin, Mei, Davide, Fischer, Baptiste, De Fusco, Maurizio, Swerts, Jef, Paesmans, Jone, Parrini, Elena, Lubarr, Naomi, Meijer, Inge A, Mackenzie, Katherine M, Lee, Wang-Tso, Cittaro, Davide, Aridon, Paolo, Schoovaerts, Nil, Versées, Wim, Verstreken, Patrik, Casari, Giorgio, Guerrini, Renzo, Luthy K., Mei D., Fischer B., De Fusco M., Swerts J., Paesmans J., Parrini E., Lubarr N., Meijer I.A., Mackenzie K.M., Lee W.-T., Cittaro D., Aridon P., Schoovaerts N., Versees W., Verstreken P., Casari G., and Guerrini R.
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Male ,Models, Molecular ,0301 basic medicine ,Protein Conformation ,Amino Acid Motifs ,alpha-Tocopherol ,Mutant ,Crystallography, X-Ray ,PHENOTYPE ,Compound heterozygosity ,Antioxidants ,Animals, Genetically Modified ,Epilepsy ,0302 clinical medicine ,Catalytic Domain ,Drosophila Proteins ,Missense mutation ,oxidative stress ,Child ,TLDC DOMAIN ,VITAMIN-E ,Exome sequencing ,Sequence Deletion ,Neurons ,Dystonia ,Genetics ,exercise-induced dystonia ,TBC1D24 ,GTPase-Activating Proteins ,ANNOTATIONS ,Epilepsy, Rolandic ,Phenotype ,Recombinant Proteins ,Pedigree ,3. Good health ,Rolandic epilepsy ,Drosophila melanogaster ,Child, Preschool ,Female ,Settore MED/26 - Neurologia ,Synaptic Vesicles ,PROTEIN STABILITY ,Life Sciences & Biomedicine ,Locomotion ,Adolescent ,Physical Exertion ,Mutation, Missense ,Clinical Neurology ,PREDICTIONS ,Biology ,03 medical and health sciences ,medicine ,Animals ,Humans ,Amino Acid Sequence ,COMPARTMENT ,oxidative stre ,Science & Technology ,Sequence Homology, Amino Acid ,MUTATIONS ,Neurosciences ,Infant ,Biological Transport ,DEGRADATION ,medicine.disease ,biology.organism_classification ,Acetylcysteine ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,rab GTP-Binding Proteins ,SEIZURES ,Neurosciences & Neurology ,Neurology (clinical) ,Reactive Oxygen Species ,Sequence Alignment ,030217 neurology & neurosurgery - Abstract
Genetic mutations in TBC1D24 have been associated with multiple phenotypes, with epilepsy being the main clinical manifestation. The TBC1D24 protein consists of the unique association of a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin motif domain/catalytic (TLDc) domain. More than 50 missense and loss-of-function mutations have been described and are spread over the entire protein. Through whole genome/exome sequencing we identified compound heterozygous mutations, R360H and G501R, within the TLDc domain, in an index family with a Rolandic epilepsy exercise-induced dystonia phenotype (http://omim.org/entry/608105). A 20-year long clinical follow-up revealed that epilepsy was self-limited in all three affected patients, but exercise-induced dystonia persisted into adulthood in two. Furthermore, we identified three additional sporadic paediatric patients with a remarkably similar phenotype, two of whom had compound heterozygous mutations consisting of an in-frame deletion I81_K84 and an A500V mutation, and the third carried T182M and G511R missense mutations, overall revealing that all six patients harbour a missense mutation in the subdomain of TLDc between residues 500 and 511. We solved the crystal structure of the conserved Drosophila TLDc domain. This allowed us to predict destabilizing effects of the G501R and G511R mutations and, to a lesser degree, of R360H and potentially A500V. Next, we characterized the functional consequences of a strong and a weak TLDc mutation (TBC1D24G501R and TBC1D24R360H) using Drosophila, where TBC1D24/Skywalker regulates synaptic vesicle trafficking. In a Drosophila model neuronally expressing human TBC1D24, we demonstrated that the TBC1D24G501R TLDc mutation causes activity-induced locomotion and synaptic vesicle trafficking defects, while TBC1D24R360H is benign. The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity, which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or α-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity. Our data thus show that mutations in the TLDc domain of TBC1D24 cause Rolandic-type focal motor epilepsy and exercise-induced dystonia. The humanized TBC1D24G501R fly model exhibits sustained activity and vesicle transport defects. We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies. The TLDc and TBC domain mutations' response to antioxidant treatment we observed in the animal model suggests a potential for combining antioxidant-based therapeutic approaches to TBC1D24-associated disorders with previously described lipid-altering strategies for TBC domain mutations. ispartof: BRAIN vol:142 issue:8 pages:2319-2335 ispartof: location:England status: published
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- 2019
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