Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Optimization of adsorptive removal of α-toluic acid by CaO2 nanoparticles using response surface methodology

The present work addresses the optimization of process parameters for adsorptive removal of α-toluic acid by calcium peroxide (CaO2) nanoparticles using response surface methodology (RSM). CaO2 nanoparticles were synthesized by chemical precipitation method and confirmed by Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis which shows the CaO2 nanoparticles size range of 5–15 nm. A series of batch adsorption experiments were performed using CaO2 nanoparticles to remove α-toluic acid from the aqueous solution. Further, an experimental based central composite design (CCD) was developed to study the interactive effect of CaO2 adsorbent dosage, initial concentration of α-toluic acid, and contact time on α-toluic acid removal efficiency (response) and optimization of the process. Analysis of variance (ANOVA) was performed to determine the significance of the individual and the interactive effects of variables on the response. The model predicted response showed a good agreement with the experimental response, and the coefficient of determination, (R2) was 0.92. Among the variables, the interactive effect of adsorbent dosage and the initial α-toluic acid concentration was found to have more influence on the response than the contact time. Numerical optimization of process by RSM showed the optimal adsorbent dosage, initial concentration of α-toluic acid, and contact time as 0.03 g, 7.06 g/L, and 34 min respectively. The predicted removal efficiency was 99.50%. The experiments performed under these conditions showed α-toluic acid removal efficiency up to 98.05%, which confirmed the adequacy of the model prediction

NMDA receptor gene variations as modifiers in Huntington disease: a replication study.

Several candidate modifier genes which, in addition to the pathogenic CAG repeat expansion, influence the age at onset (AO) in Huntington disease (HD) have already been described. The aim of this study was to replicate association of variations in the N-methyl D-aspartate receptor subtype genes GRIN2A and GRIN2B in the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). The analyses did replicate the association reported between the GRIN2A rs2650427 variation and AO in the entire cohort. Yet, when subjects were stratified by AO subtypes, we found nominally significant evidence for an association of the GRIN2A rs1969060 variation and the GRIN2B rs1806201 variation. These findings further implicate the N-methyl D-aspartate receptor subtype genes as loci containing variation associated with AO in HD

Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY.

none642sinoneOrth M, Handley OJ, Schwenke C, Dunnett S, Wild EJ, Tabrizi SJ, Landwehrmeyer GB, Bachoud-Lévi AC, Bentivoglio AR, Biunno I, Bonelli R, Burgunder JM, Dunnett SB, Ferreira JJ, Giuliano J, Handley OJ, Heiberg A, Illmann T, van Kammen D, Landwehrmeye GB, Levey J, Nielsen JE, Päivärinta M, Roos RA, Sebastián AR, Tabrizi SJ, Vandenberghe W, Verellen-Dumoulin C, Zaremba J, Uhrova T, Wahlström J, Schwenke C, Orth M, Illmann T, Wallner M, Barth K, Guedes LC, Finisterra AM, Garde MB, Bos R, Burg S, Ecker D, Handley OJ, Held C, Koppers K, Laurà M, Descals AM, McLean T, Mestre T, Minster S, Monza D, Townhill J, Orth M, Padieu H, Paterski L, Peppa N, Koivisto SP, Rialland A, Røren N, Sasinková P, Cubillo PT, Tritsch C, van Walsem MR, Witjes-Ané MN, Yudina E, Zielonka D, Zielonka E, Zinzi P, Bonelli RM, Herranhof B, Holl A, Kapfhammer HP, Koppitz M, Magnet M, Otti D, Painold A, Reisinger K, Scheibl M, Hecht K, Lilek S, Müller N, Schöggl H, Ullah J, Brugger F, Hepperger C, Hotter A, Mahlknecht P, Nocker M, Seppi K, Wenning G, Buratti L, Hametner EM, Holas C, Hussl A, Mair K, Poewe W, Wolf E, Zangerl A, Braunwarth EM, Lilek S, Sinadinosa D, Walleczek AM, Bonelli RM, Ladurner G, Staffen W, Ribaï P, Verellen-Dumoulin C, Flamez A, Morez V, de Raedt S, Boogaerts A, Vandenberghe W, van Reijen D, Klempíř J, Kucharík M, Roth J, Šenkárová Z, Hasholt L, Hjermind LE, Jakobsen O, Nørremølle A, Sørensen SA, Stokholm J, Nielsen J, Hiivola H, Martikainen K, Tuuha K, Peippo M, Sipponen M, Ignatius J, Kärppä M, Åman J, Santala M, Allain P, Guérid MA, Gohier B, Olivier A, Prundean A, Scherer-Gagou C, Verny C, Babiloni B, Debruxelles S, Goizet C, Lafoucrière D, De Bruycker C, Carette AS, Decorte E, Delval A, Delliaux M, Dujardin K, Peter M, Plomhouse L, Simonin C, Thibault-Tanchou S, Bellonet M, Duru C, Krystkowiak P, Roussel M, Wannepain S, Azulay JP, Chabot C, Delphini M, Eusebio A, Grosjean H, Mundler L, Nowak M, Rudolf G, Steinmetz G, Tranchant C, Wagner C, Zimmermann MA, Calvas F, Cheriet S, Démonet JF, Galitzky M, Kosinski CM, Milkereit E, Probst D, Sass C, Schiefer J, Schlangen C, Werner CJ, Gelderblom H, Priller J, Prüss H, Spruth EJ, Andrich J, Hoffmann R, Kraus PH, Muth S, Prehn C, Saft C, Salmen S, Stamm C, Steiner T, Strassburger K, Lange H, Friedrich A, Hunger U, Löhle M, Schmidt S, Storch A, Wolz A, Wolz M, Lambeck J, Zucker B, Boelmans K, Ganos C, Hidding U, Lewerenz J, Münchau A, Orth M, Schmalfeld J, Stubbe L, Zittel S, Diercks G, Gorzolla H, Schrader C, Heinicke W, Ribbat M, Longinus B, Bürk K, Möller JC, Rissling I, Peinemann A, Städtler M, Weindl A, Bechtel N, Beckmann H, Bohlen S, Hölzner E, Lange H, Reilmann R, Rohm S, Rumpf S, Schepers S, Beister A, Dose M, Hammer K, Kieni J, Leythaeuser G, Marquard R, Raab T, Richter S, Selimbegovic-Turkovic A, Schrenk C, Schuierer M, Wiedemann A, Barth K, Buck A, Connemann J, Ecker D, Eschenbach C, Held C, Landwehrmeyer B, Lezius F, Nepper S, Niess A, Orth M, Süssmuth S, Trautmann S, Weydt P, Cormio C, Difruscolo O, Sciruicchio V, Serpino C, de Tommaso M, Capellari S, Cortelli P, Gallassi R, Poda R, Rizzo G, Scaglione C, Bertini E, Ghelli E, Ginestroni A, Massaro F, Mechi C, Paganini M, Piacentini S, Pradella S, Romoli AM, Sorbi S, Abbruzzese G, di Poggio MB, Di Maria E, Ferrandes G, Mandich P, Marchese R, Albanese A, Di Bella D, Di Donato S, Gellera C, Genitrini S, Mariotti C, Monza D, Nanetti L, Paridi D, Soliveri P, Tomasello C, De Michele G, Di Maio L, Rinaldi C, Russo CV, Salvatore E, Tucci T, Cannella M, Codella V, De Gregorio F, De Nicola N, Martino T, Simonelli M, Squitieri F, Bentivoglio AR, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Loria G, Modoni A, Piano C, Chiara P, Quaranta D, Romano S, Soleti F, Spadaro M, Zinzi P, van Hout MS, van Vugt JP, de Weert AM, Bolwijn JJ, Dekker M, Leenders KL, van Oostrom JC, Bos R, Dumas EM, Jurgens CK, van den Bogaard SJ, Roos RA, 't Hart EP, Witjes-Ané MN, Kremer B, Verstappen CC, Heiberg A, van Walsem MR, Frich J, Wehus R, Aaserud O, Borgerød N, Bjørgo K, Fannemel M, Gørvell P, Pro Koivisto S, Retterstøl L, Overland T, Stokke B, Bjørnevoll I, Sando SB, Blinkenberg EØ, Hauge E, Tyvoll H, Sitek E, Slawek J, Soltan W, Boczarska-Jedynak M, Jasinska-Myga B, Opala G, Kłodowska-Duda G, Banaszkiewicz K, Szczudlik A, Rudzińska M, Wójcik M, Dec M, Krawczyk M, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J, Sempołowicz J, Zielonka D, Samara H, Janik P, Kalbarczyk A, Kwiecinski H, Jamrozik Z, Antczak J, Jachinska K, Rakowicz M, Richter P, Ryglewicz D, Witkowski G, Zdzienicka E, Zaremba J, Sułek A, Krysa W, Júlio F, Januário C, Mestre T, Guedes L, Coelho M, Mendes T, Valadas A, Ferreira JJ, Timóteo Â, Costa C, Vale J, Cavaco S, Damásio J, Magalhães M, Gago M, Garrett C, Guerra MR, Solis P, Herrera CD, Garcia PM, Barrero F, Morales B, Cubo E, Mariscal N, Alonso-Frech F, Perez MR, Fenollar M, García RG, Quiroga PP, Rivera SV, Villanueva C, Bascuñana M, Ventura MF, Ribas GG, de Yébenes JG, Moreno JL, Cubillo PT, Ruíz PJ, Martínez-Descals A, Artiga MJ, Sánchez V, Perea MF, Lorenza F, Torres MM, Reinante G, Moreau LV, Barbera MA, Guia DB, Hernanz LC, Catena JL, Sebastián AR, Ferrer PQ, Carruesco GT, Bas J, Busquets N, Calopa M, Buongiorno MT, Muñoz E, Elorza MD, López CD, Terol SD, Robert MF, Ruíz BG, Casado AG, Martínez IH, Viladrich CM, Pons i Càrdenas R, Roca E, Llesoy JR, Idiago JM, Vergara MR, García SS, Villa Riballo A, González SG, Guisasola LM, Salvador C, San Martín ES, Gorospe A, Legarda I, Arques PN, Rodríguez MJ, Vives B, Gaston I, Ramos-Arroyo MA, Moreno JM, Peña JC, Avarvarei LD, Bastida AM, Recio MF, Vergé LR, Sánchez VS, Carrillo F, Cáceres MT, Mir P, Suarez MJ, Bosca M, Burguera JA, Garcia AC, Martínez LM, del Val JL, Loutfi G, Olofsson C, Stattin EL, Westman L, Wikström B, Höglund A, Pålhagen SE, Paucar M, Sandström B, Soltani R, Svenningsson P, Reza-Soltani TW, Constantinescu R, Fredlund G, Høsterey-Ugander U, Neleborn-Lingefjärd L, Wahlström J, Esmaeilzadeh M, Tedroff J, Winnberg E, Björn Y, Ekwall C, Gøller ML, Johansson A, Wiklund L, Petersen Å, Reimer J, Widner H, Burgunder JM, Burgunder Y, Stebler Y, Kaelin A, Romero I, Schüpbach M, Zaugg SW, Jack R, Matheson K, Miedzybrodzka Z, Rae D, Simpson S, Summers F, Ure A, Crooks J, Curtis A, de Souza Keylock J, Rickards H, Wright J, Hayward B, Sieradzan K, Wright A, Barker RA, Di Pietro A, Fisher K, Goodman A, Hill S, Kershaw A, Mason S, Paterson N, Raymond L, Bisson J, Busse M, Clenaghan C, Ellison-Rose L, Handley O, Hunt S, Townhill J, Price K, Rosser A, Edwards M, Hughes T, McGill M, Pearson P, Porteous M, Smith P, Zeman A, Causley A, Harrower T, Howcroft D, Lambord N, Rankin J, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Miller J, Ritchie S, Burrows L, Fletcher A, Harding A, Laver F, Silva M, Thomson A, Burns P, Chu C, Evans C, Hamer S, Markova I, Miller J, Raman A, Barnes K, Chu C, Hobson E, Jamieson S, Markova I, Thomson J, Toscano J, Wild S, Yardumian P, Bourne C, Clayton C, Dipple H, Clapton J, Grant D, Hallam C, Middleton J, Murch A, Patino D, Bate L, Pate L, Andrews T, Dougherty A, Kavalier F, Golding C, Lashwood A, Robertson D, Ruddy D, Whaite A, Patton M, Peterson M, Rose S, Andrews T, Bruno S, Chu E, Doherty K, Golding, Fillingham K, Foustanos I, O'Donovan K, Peppa N, Tidswell K, Quarrell O.Orth, M; Handley, Oj; Schwenke, C; Dunnett, S; Wild, Ej; Tabrizi, Sj; Landwehrmeyer, Gb; Bachoud-Lévi, Ac; Bentivoglio, Ar; Biunno, I; Bonelli, R; Burgunder, Jm; Dunnett, Sb; Ferreira, Jj; Giuliano, J; Handley, Oj; Heiberg, A; Illmann, T; van Kammen, D; Landwehrmeye, Gb; Levey, J; Nielsen, Je; Päivärinta, M; Roos, Ra; Sebastián, Ar; Tabrizi, Sj; Vandenberghe, W; Verellen-Dumoulin, C; Zaremba, J; Uhrova, T; Wahlström, J; Schwenke, C; Orth, M; Illmann, T; Wallner, M; Barth, K; Guedes, Lc; Finisterra, Am; Garde, Mb; Bos, R; Burg, S; Ecker, D; Handley, Oj; Held, C; Koppers, K; Laurà, M; Descals, Am; Mclean, T; Mestre, T; Minster, S; Monza, D; Townhill, J; Orth, M; Padieu, H; Paterski, L; Peppa, N; Koivisto, Sp; Rialland, A; Røren, N; Sasinková, P; Cubillo, Pt; Tritsch, C; van Walsem, Mr; Witjes-Ané, Mn; Yudina, E; Zielonka, D; Zielonka, E; Zinzi, P; Bonelli, Rm; Herranhof, B; Holl, A; Kapfhammer, Hp; Koppitz, M; Magnet, M; Otti, D; Painold, A; Reisinger, K; Scheibl, M; Hecht, K; Lilek, S; Müller, N; Schöggl, H; Ullah, J; Brugger, F; Hepperger, C; Hotter, A; Mahlknecht, P; Nocker, M; Seppi, K; Wenning, G; Buratti, L; Hametner, Em; Holas, C; Hussl, A; Mair, K; Poewe, W; Wolf, E; Zangerl, A; Braunwarth, Em; Lilek, S; Sinadinosa, D; Walleczek, Am; Bonelli, Rm; Ladurner, G; Staffen, W; Ribaï, P; Verellen-Dumoulin, C; Flamez, A; Morez, V; de Raedt, S; Boogaerts, A; Vandenberghe, W; van Reijen, D; Klempíř, J; Kucharík, M; Roth, J; Šenkárová, Z; Hasholt, L; Hjermind, Le; Jakobsen, O; Nørremølle, A; Sørensen, Sa; Stokholm, J; Nielsen, J; Hiivola, H; Martikainen, K; Tuuha, K; Peippo, M; Sipponen, M; Ignatius, J; Kärppä, M; Åman, J; Santala, M; Allain, P; Guérid, Ma; Gohier, B; Olivier, A; Prundean, A; Scherer-Gagou, C; Verny, C; Babiloni, B; Debruxelles, S; Goizet, C; Lafoucrière, D; De Bruycker, C; Carette, As; Decorte, E; Delval, A; Delliaux, M; Dujardin, K; Peter, M; Plomhouse, L; Simonin, C; Thibault-Tanchou, S; Bellonet, M; Duru, C; Krystkowiak, P; Roussel, M; Wannepain, S; Azulay, Jp; Chabot, C; Delphini, M; Eusebio, A; Grosjean, H; Mundler, L; Nowak, M; Rudolf, G; Steinmetz, G; Tranchant, C; Wagner, C; Zimmermann, Ma; Calvas, F; Cheriet, S; Démonet, Jf; Galitzky, M; Kosinski, Cm; Milkereit, E; Probst, D; Sass, C; Schiefer, J; Schlangen, C; Werner, Cj; Gelderblom, H; Priller, J; Prüss, H; Spruth, Ej; Andrich, J; Hoffmann, R; Kraus, Ph; Muth, S; Prehn, C; Saft, C; Salmen, S; Stamm, C; Steiner, T; Strassburger, K; Lange, H; Friedrich, A; Hunger, U; Löhle, M; Schmidt, S; Storch, A; Wolz, A; Wolz, M; Lambeck, J; Zucker, B; Boelmans, K; Ganos, C; Hidding, U; Lewerenz, J; Münchau, A; Orth, M; Schmalfeld, J; Stubbe, L; Zittel, S; Diercks, G; Gorzolla, H; Schrader, C; Heinicke, W; Ribbat, M; Longinus, B; Bürk, K; Möller, Jc; Rissling, I; Peinemann, A; Städtler, M; Weindl, A; Bechtel, N; Beckmann, H; Bohlen, S; Hölzner, E; Lange, H; Reilmann, R; Rohm, S; Rumpf, S; Schepers, S; Beister, A; Dose, M; Hammer, K; Kieni, J; Leythaeuser, G; Marquard, R; Raab, T; Richter, S; Selimbegovic-Turkovic, A; Schrenk, C; Schuierer, M; Wiedemann, A; Barth, K; Buck, A; Connemann, J; Ecker, D; Eschenbach, C; Held, C; Landwehrmeyer, B; Lezius, F; Nepper, S; Niess, A; Orth, M; Süssmuth, S; Trautmann, S; Weydt, P; Cormio, C; Difruscolo, O; Sciruicchio, V; Serpino, C; de Tommaso, M; Capellari, S; Cortelli, P; Gallassi, R; Poda, R; Rizzo, G; Scaglione, C; Bertini, E; Ghelli, E; Ginestroni, A; Massaro, F; Mechi, C; Paganini, M; Piacentini, S; Pradella, S; Romoli, Am; Sorbi, S; Abbruzzese, G; di Poggio, Mb; Di Maria, E; Ferrandes, G; Mandich, P; Marchese, R; Albanese, A; Di Bella, D; Di Donato, S; Gellera, C; Genitrini, S; Mariotti, C; Monza, D; Nanetti, L; Paridi, D; Soliveri, P; Tomasello, C; De Michele, G; Di Maio, L; Rinaldi, C; Russo, Cv; Salvatore, E; Tucci, T; Cannella, M; Codella, V; De Gregorio, F; De Nicola, N; Martino, T; Simonelli, M; Squitieri, F; Bentivoglio, Ar; Catalli, C; Di Giacopo, R; Fasano, A; Frontali, M; Guidubaldi, A; Ialongo, T; Jacopini, G; Loria, G; Modoni, A; Piano, C; Chiara, P; Quaranta, D; Romano, S; Soleti, F; Spadaro, M; Zinzi, P; van Hout, Ms; van Vugt, Jp; de Weert, Am; Bolwijn, Jj; Dekker, M; Leenders, Kl; van Oostrom, Jc; Bos, R; Dumas, Em; Jurgens, Ck; van den Bogaard, Sj; Roos, Ra; 't Hart, Ep; Witjes-Ané, Mn; Kremer, B; Verstappen, Cc; Heiberg, A; van Walsem, Mr; Frich, J; Wehus, R; Aaserud, O; Borgerød, N; Bjørgo, K; Fannemel, M; Gørvell, P; Pro Koivisto, S; Retterstøl, L; Overland, T; Stokke, B; Bjørnevoll, I; Sando, Sb; Blinkenberg, Eø; Hauge, E; Tyvoll, H; Sitek, E; Slawek, J; Soltan, W; Boczarska-Jedynak, M; Jasinska-Myga, B; Opala, G; Kłodowska-Duda, G; Banaszkiewicz, K; Szczudlik, A; Rudzińska, M; Wójcik, M; Dec, M; Krawczyk, M; Bryl, A; Ciesielska, A; Klimberg, A; Marcinkowski, J; Sempołowicz, J; Zielonka, D; Samara, H; Janik, P; Kalbarczyk, A; Kwiecinski, H; Jamrozik, Z; Antczak, J; Jachinska, K; Rakowicz, M; Richter, P; Ryglewicz, D; Witkowski, G; Zdzienicka, E; Zaremba, J; Sułek, A; Krysa, W; Júlio, F; Januário, C; Mestre, T; Guedes, L; Coelho, M; Mendes, T; Valadas, A; Ferreira, Jj; Timóteo, Â; Costa, C; Vale, J; Cavaco, S; Damásio, J; Magalhães, M; Gago, M; Garrett, C; Guerra, Mr; Solis, P; Herrera, Cd; Garcia, Pm; Barrero, F; Morales, B; Cubo, E; Mariscal, N; Alonso-Frech, F; Perez, Mr; Fenollar, M; García, Rg; Quiroga, Pp; Rivera, Sv; Villanueva, C; Bascuñana, M; Ventura, Mf; Ribas, Gg; de Yébenes, Jg; Moreno, Jl; Cubillo, Pt; Ruíz, Pj; Martínez-Descals, A; Artiga, Mj; Sánchez, V; Perea, Mf; Lorenza, F; Torres, Mm; Reinante, G; Moreau, Lv; Barbera, Ma; Guia, Db; Hernanz, Lc; Catena, Jl; Sebastián, Ar; Ferrer, Pq; Carruesco, Gt; Bas, J; Busquets, N; Calopa, M; Buongiorno, Mt; Muñoz, E; Elorza, Md; López, Cd; Terol, Sd; Robert, Mf; Ruíz, Bg; Casado, Ag; Martínez, Ih; Viladrich, Cm; Pons, i Càrdenas R; Roca, E; Llesoy, Jr; Idiago, Jm; Vergara, Mr; García, Ss; Villa Riballo, A; González, Sg; Guisasola, Lm; Salvador, C; San Martín, Es; Gorospe, A; Legarda, I; Arques, Pn; Rodríguez, Mj; Vives, B; Gaston, I; Ramos-Arroyo, Ma; Moreno, Jm; Peña, Jc; Avarvarei, Ld; Bastida, Am; Recio, Mf; Vergé, Lr; Sánchez, Vs; Carrillo, F; Cáceres, Mt; Mir, P; Suarez, Mj; Bosca, M; Burguera, Ja; Garcia, Ac; Martínez, Lm; del Val, Jl; Loutfi, G; Olofsson, C; Stattin, El; Westman, L; Wikström, B; Höglund, A; Pålhagen, Se; Paucar, M; Sandström, B; Soltani, R; Svenningsson, P; Reza-Soltani, Tw; Constantinescu, R; Fredlund, G; Høsterey-Ugander, U; Neleborn-Lingefjärd, L; Wahlström, J; Esmaeilzadeh, M; Tedroff, J; Winnberg, E; Björn, Y; Ekwall, C; Gøller, Ml; Johansson, A; Wiklund, L; Petersen, Å; Reimer, J; Widner, H; Burgunder, Jm; Burgunder, Y; Stebler, Y; Kaelin, A; Romero, I; Schüpbach, M; Zaugg, Sw; Jack, R; Matheson, K; Miedzybrodzka, Z; Rae, D; Simpson, S; Summers, F; Ure, A; Crooks, J; Curtis, A; de Souza Keylock, J; Rickards, H; Wright, J; Hayward, B; Sieradzan, K; Wright, A; Barker, Ra; Di Pietro, A; Fisher, K; Goodman, A; Hill, S; Kershaw, A; Mason, S; Paterson, N; Raymond, L; Bisson, J; Busse, M; Clenaghan, C; Ellison-Rose, L; Handley, O; Hunt, S; Townhill, J; Price, K; Rosser, A; Edwards, M; Hughes, T; Mcgill, M; Pearson, P; Porteous, M; Smith, P; Zeman, A; Causley, A; Harrower, T; Howcroft, D; Lambord, N; Rankin, J; Brockie, P; Foster, J; Johns, N; Mckenzie, S; Rothery, J; Thomas, G; Yates, S; Miller, J; Ritchie, S; Burrows, L; Fletcher, A; Harding, A; Laver, F; Silva, M; Thomson, A; Burns, P; Chu, C; Evans, C; Hamer, S; Markova, I; Miller, J; Raman, A; Barnes, K; Chu, C; Hobson, E; Jamieson, S; Markova, I; Thomson, J; Toscano, J; Wild, S; Yardumian, P; Bourne, C; Clayton, C; Dipple, H; Clapton, J; Grant, D; Hallam, C; Middleton, J; Murch, A; Patino, D; Bate, L; Pate, L; Andrews, T; Dougherty, A; Kavalier, F; Golding, C; Lashwood, A; Robertson, D; Ruddy, D; Whaite, A; Patton, M; Peterson, M; Rose, S; Andrews, T; Bruno, S; Chu, E; Doherty, K; Golding, ; Fillingham, K; Foustanos, I; O'Donovan, K; Peppa, N; Tidswell, K; Quarrell, O

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients

β-Defensin genomic copy number does not influence the age of onset in Huntington's Disease

none498siHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammations is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2)- encoded by DEFB4- is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD.openVittori A, Orth M, Roos RA, Outeiro TF, Giorgini F, Hollox EJ, Bachoud-Levi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, Illmann T, Landwehrmeyer GB, Levey J, Martinez-Jaurrieta MD, Nielsen JE, Pro Koivisto S, Piiiviirinta M, Roos RA, Sebastian AR, Tabrizi SJ, Vandenberghe W, Verellen-Dumoulin C, Zaremba J, Uhrova T, Wahlstrom J, Barth K, Correia-Guedes L, Finisterra AM, Bascuiiana Garde M, Betz S, Bos R, Ecker D, Handley OJ, Held C, Koppers K, Laura M, Descals AM, Mestre T, Monza D, Townhill J, Padieu H, Paterski L, Peppa N, Rialland A, Røren N, Sasinkova P, Trigo Cubillo P, van Walsem M, Witjes-Ane MN, Yudina E, Zielonka D, Zielonka E, Zinzi P, Bonelli RM, Herranhof B, HOd A, Kapfhammer HP, Koppitz M, Magnet M, Otti D, Painold A, Reisinge K, Scheib M, Hecht K, Lilek S, Muller N, Schoggl H, Ullah J, Ribal P, Verellen-Dumoulin C, Klempff J, Majerova V, Roth J, Hjermind LE, Jakobsen O, Vinthev-Jensen T, Larsen IU, Nielsen JE, Stokholm J, Hiivola H, Martikainen K, Tuuha K, Santala M, Milkereit E, Kosinski CM, Probst D, Reetz K, Sass C, Schiefer J, Schlangen C, Werner CJ, Andrich J, Ellrichmann G, Hoffmann R, Kaminski B, Saft C, Stamm C, Lange H, Lohle M, Schmidt S, Storch A, Wolz A, Wolz M, Capetian P, Lambeck J, Zucker B, Boelmans K, Ganos C, Hidding U, Lewerenz J, Miinchau A, Orth M, Schmalfeld J, Stubbe L, Zittel S, Heinicke W, Ribbat M, Longinus B, Miihlau M, Peinemann A, Stiidtler M, Weindl A, Winkelmann J, Ziegler C, Bechtel N, Beckmann H, Bohlen S, Holzner E, Lange H, Reilmann R, Rohm S, Rumpf S, Schepers S, Dose M, Leythaeuser G, Marquard R, Raab T, Schrenk C, Schuierer M, Barth K, Buck A, Ecker D, Eschenbach C, Held C, Landwehrmeyer B, Lezius F, Nepper S, Niess A, Orth M, Schwenk D, Siissmuth S, Trautmann S, Weydt P, Cormio C, de Tommaso M, Sciruicchio V, Serpino C, Ghelli E, Ginestroni A, Bertini E, Massaro F, Mechi C, Paganini M, Piacentini S, Pradella S, Romoli AM, Sorbi S, Abbruzzese G, Ferrandes MB, Di Maria E, Ferrandes G, Mandich P, Marchese R, Di Donato S, Gellera C, Genitrini S, Mariotti C, Nanetti L, Monza D, Soliveri P, Tomasello C, De Michele G, DiMaio L, Massarelli M, Rinaldi C, Roca A, Rossi F, Russo CV, Salvatore E, Sorrentino P, Tucci T, De Nicola A, Elifani F, Petrollini M, Martino T, Lovo F, Squitieri F, Bentivoglio AR, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Loria G, Piano C, Piccininni C, Quaranta D, Romano S, Soleti F, Spadaro M, Zinzi P, van Hout MS, van Vugt JP, de Weert A, Bolwijn JJ, Neurologie P, Dekker M, Neurologie P, Leenders KL, van Oostrom JC, Bos R, Dumas EM, Jurgens CK, van den Bogaard SJ, Roos RA, 't Hart EP, Kremer B, Verstappen CC, Heiberg A, van Walsem MR, Frich J, Aaserud O, Wehus R, Bjørgo K, Fannemel M, Gørvell P, Lorentzen E, Koivisto SP, Retterstøl L, Stokke B, Bjørnevoll I, Sando SB, Dziadkiewicz A, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M, Blaszczyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasinska-Myga B, Opala G, Klodowska G, Stompel D, Ciach-Wysocka E, Banaszkiewicz K, Boewiriska D, Bojakowska-Jaremek K, Neurologii A, Dec M, Krawczyk M, Rudziriska M, Szczudlik A, Szczygiel E, Wasielewska A, Wojcik M, Wojcik M, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J, Samara H, Sempolowicz J, Zielonka D, Janik P, Kalbarczyk A, Kwiecinski H, Jamrozik Z, Antczak J, Jachinska K, Krysa W, Rakowicz M, Richter P, Rola R, Ryglewicz D, Sienkiewicz-Jarosz H, Sulek A, Witkowski G, Zdzienicka E, Zaremba J, Zieora-Jakutowicz K, Coelho M, Correia-Guedes L, Ferreira JJ, Mestre T, Mendes T, Valadas A, Andrade C, Joao PS, Gago M, Garrett C, Joao PS, Guerra MR, Joao PS, Solis P, Herrera CD, Garcia PM, Cubo E, Mariscal N, Sanchez J, Barrero FJ, Alonso-Frech F, Perez MR, Fenollar M, Garda R, Rivera SV, Villanueva C, Alegre J, Bascuiiana M, Ventura MF, Ribas GG, Moreno JL, Cubillo PT, Rufz PJ, Frech FA, Dfaz J, Guerrero R, Dfaz J, Artiga MJ, Dfaz J, Sanchez V, Alcaraz LF, de Ia Arrixaca V, Manzanares S, de Ia Arrixaca V, Perea MF, Reinante G, Arrixaca Ia, Torres MM, Moreau LV, de Ia Arrixaca V, Barbera MA, Guia DB, Hernanz LC, Catena JL, Sebastian R, Ferrer PQ, Carruesco GT, Bas J, Busquets N, Calopa M, Buongiorno MT, Munoz E, Elorza MD, Lopez CD, Terol DS, Robert MF, Rufz BG, Casado AG, Martinez IH, Viladrich CM, Pons R, Roca E, Llesoy JR, Idiago JM, Vergara MR, Garcia SS, Riballo AV, Hoglund A, Palhagen SE, Paucar M, Sandstrom B, Svenningsson P, Reza-Soltani TW, Burgunder JM, Kaelin A, Romero I, Schupbach M, Stebler Y, Zaugg SW, Akhtar S, Crooks J, Curtis A, de Souza J, Rickards H, Wright J, Barker RA, Di Pietro A, Fisher K, Goodman AO, Hill S, Kershaw A, Mason S, O'Keefe D, Swain R, Guzman NV, Busse M, Butcher C, Clenaghan C, Dunnett S, Fullam R, Jones L, Jones U, Khalil H, Minster S, Owen M, Hunt S, Price K, Rosser A, Townhill J, Edwards M, Ho C, McGill M, Pearson P, Porteous M, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Burrows L, Chu C, Fletcher A, Gallantrae D, Harding A, Hamer S, Kraus A, Laver F, Longthorpe M, Markova I, Raman A, Silva M, Thomson A, Wild S, Yardumian P, Hobson E, Jamieson S, Musgrave H, Rowett L, Toscano J, Wild S, Yardumian P, Clayton C, Dipple H, Middleton J, Patino D, Andrews T, Dougherty A, Kavalier F, Golding C, Laing H, Lashwood A, Robertson D, Ruddy D, Whaite A, Santhouse A, Andrews T, Bruno S, Doherty K, Lahiri N, Novak M, Patel A, Rosser E, Tabrizi S, Taylor R, Warner T, Wild E, Arran N, Bek J, Callaghan J, Craufurd D, Fullam R, Howard L, Hare M, Huson S, Johnson L, Jones M, Murphy H, Oughton E, Partington-Janes L, Rogers D, Snowden J, Sollom A, Stopford C, Thompson J, Trender-Gerhard I.Vittori, A; Orth, M; Roos, Ra; Outeiro, Tf; Giorgini, F; Hollox, Ej; Bachoud-Levi, Ac; Bentivoglio, Ar; Biunno, I; Bonelli, Rm; Burgunder, Jm; Dunnett, Sb; Ferreira, Jj; Handley, Oj; Heiberg, A; Illmann, T; Landwehrmeyer, Gb; Levey, J; Martinez-Jaurrieta, Md; Nielsen, Je; Pro Koivisto, S; Piiiviirinta, M; Roos, Ra; Sebastian, Ar; Tabrizi, Sj; Vandenberghe, W; Verellen-Dumoulin, C; Zaremba, J; Uhrova, T; Wahlstrom, J; Barth, K; Correia-Guedes, L; Finisterra, Am; Bascuiiana Garde, M; Betz, S; Bos, R; Ecker, D; Handley, Oj; Held, C; Koppers, K; Laura, M; Descals, Am; Mestre, T; Monza, D; Townhill, J; Padieu, H; Paterski, L; Peppa, N; Rialland, A; Røren, N; Sasinkova, P; Trigo Cubillo, P; van Walsem, M; Witjes-Ane, Mn; Yudina, E; Zielonka, D; Zielonka, E; Zinzi, P; Bonelli, Rm; Herranhof, B; Hod, A; Kapfhammer, Hp; Koppitz, M; Magnet, M; Otti, D; Painold, A; Reisinge, K; Scheib, M; Hecht, K; Lilek, S; Muller, N; Schoggl, H; Ullah, J; Ribal, P; Verellen-Dumoulin, C; Klempff, J; Majerova, V; Roth, J; Hjermind, Le; Jakobsen, O; Vinthev-Jensen, T; Larsen, Iu; Nielsen, Je; Stokholm, J; Hiivola, H; Martikainen, K; Tuuha, K; Santala, M; Milkereit, E; Kosinski, Cm; Probst, D; Reetz, K; Sass, C; Schiefer, J; Schlangen, C; Werner, Cj; Andrich, J; Ellrichmann, G; Hoffmann, R; Kaminski, B; Saft, C; Stamm, C; Lange, H; Lohle, M; Schmidt, S; Storch, A; Wolz, A; Wolz, M; Capetian, P; Lambeck, J; Zucker, B; Boelmans, K; Ganos, C; Hidding, U; Lewerenz, J; Miinchau, A; Orth, M; Schmalfeld, J; Stubbe, L; Zittel, S; Heinicke, W; Ribbat, M; Longinus, B; Miihlau, M; Peinemann, A; Stiidtler, M; Weindl, A; Winkelmann, J; Ziegler, C; Bechtel, N; Beckmann, H; Bohlen, S; Holzner, E; Lange, H; Reilmann, R; Rohm, S; Rumpf, S; Schepers, S; Dose, M; Leythaeuser, G; Marquard, R; Raab, T; Schrenk, C; Schuierer, M; Barth, K; Buck, A; Ecker, D; Eschenbach, C; Held, C; Landwehrmeyer, B; Lezius, F; Nepper, S; Niess, A; Orth, M; Schwenk, D; Siissmuth, S; Trautmann, S; Weydt, P; Cormio, C; de Tommaso, M; Sciruicchio, V; Serpino, C; Ghelli, E; Ginestroni, A; Bertini, E; Massaro, F; Mechi, C; Paganini, M; Piacentini, S; Pradella, S; Romoli, Am; Sorbi, S; Abbruzzese, G; Ferrandes, Mb; Di Maria, E; Ferrandes, G; Mandich, P; Marchese, R; Di Donato, S; Gellera, C; Genitrini, S; Mariotti, C; Nanetti, L; Monza, D; Soliveri, P; Tomasello, C; De Michele, G; Dimaio, L; Massarelli, M; Rinaldi, C; Roca, A; Rossi, F; Russo, Cv; Salvatore, E; Sorrentino, P; Tucci, T; De Nicola, A; Elifani, F; Petrollini, M; Martino, T; Lovo, F; Squitieri, F; Bentivoglio, Ar; Catalli, C; Di Giacopo, R; Fasano, A; Frontali, M; Guidubaldi, A; Ialongo, T; Jacopini, G; Loria, G; Piano, C; Piccininni, C; Quaranta, D; Romano, S; Soleti, F; Spadaro, M; Zinzi, P; van Hout, Ms; van Vugt, Jp; de Weert, A; Bolwijn, Jj; Neurologie, P; Dekker, M; Neurologie, P; Leenders, Kl; van Oostrom, Jc; Bos, R; Dumas, Em; Jurgens, Ck; van den Bogaard, Sj; Roos, Ra; 't Hart, Ep; Kremer, B; Verstappen, Cc; Heiberg, A; van Walsem, Mr; Frich, J; Aaserud, O; Wehus, R; Bjørgo, K; Fannemel, M; Gørvell, P; Lorentzen, E; Koivisto, Sp; Retterstøl, L; Stokke, B; Bjørnevoll, I; Sando, Sb; Dziadkiewicz, A; Nowak, M; Robowski, P; Sitek, E; Slawek, J; Soltan, W; Szinwelski, M; Blaszczyk, M; Boczarska-Jedynak, M; Ciach-Wysocka, E; Gorzkowska, A; Jasinska-Myga, B; Opala, G; Klodowska, G; Stompel, D; Ciach-Wysocka, E; Banaszkiewicz, K; Boewiriska, D; Bojakowska-Jaremek, K; Neurologii, A; Dec, M; Krawczyk, M; Rudziriska, M; Szczudlik, A; Szczygiel, E; Wasielewska, A; Wojcik, M; Wojcik, M; Bryl, A; Ciesielska, A; Klimberg, A; Marcinkowski, J; Samara, H; Sempolowicz, J; Zielonka, D; Janik, P; Kalbarczyk, A; Kwiecinski, H; Jamrozik, Z; Antczak, J; Jachinska, K; Krysa, W; Rakowicz, M; Richter, P; Rola, R; Ryglewicz, D; Sienkiewicz-Jarosz, H; Sulek, A; Witkowski, G; Zdzienicka, E; Zaremba, J; Zieora-Jakutowicz, K; Coelho, M; Correia-Guedes, L; Ferreira, Jj; Mestre, T; Mendes, T; Valadas, A; Andrade, C; Joao, Ps; Gago, M; Garrett, C; Joao, Ps; Guerra, Mr; Joao, Ps; Solis, P; Herrera, Cd; Garcia, Pm; Cubo, E; Mariscal, N; Sanchez, J; Barrero, Fj; Alonso-Frech, F; Perez, Mr; Fenollar, M; Garda, R; Rivera, Sv; Villanueva, C; Alegre, J; Bascuiiana, M; Ventura, Mf; Ribas, Gg; Moreno, Jl; Cubillo, Pt; Rufz, Pj; Frech, Fa; Dfaz, J; Guerrero, R; Dfaz, J; Artiga, Mj; Dfaz, J; Sanchez, V; Alcaraz, Lf; de Ia Arrixaca, V; Manzanares, S; de Ia Arrixaca, V; Perea, Mf; Reinante, G; Arrixaca, Ia; Torres, Mm; Moreau, Lv; de Ia Arrixaca, V; Barbera, Ma; Guia, Db; Hernanz, Lc; Catena, Jl; Sebastian, R; Ferrer, Pq; Carruesco, Gt; Bas, J; Busquets, N; Calopa, M; Buongiorno, Mt; Munoz, E; Elorza, Md; Lopez, Cd; Terol, Ds; Robert, Mf; Rufz, Bg; Casado, Ag; Martinez, Ih; Viladrich, Cm; Pons, R; Roca, E; Llesoy, Jr; Idiago, Jm; Vergara, Mr; Garcia, Ss; Riballo, Av; Hoglund, A; Palhagen, Se; Paucar, M; Sandstrom, B; Svenningsson, P; Reza-Soltani, Tw; Burgunder, Jm; Kaelin, A; Romero, I; Schupbach, M; Stebler, Y; Zaugg, Sw; Akhtar, S; Crooks, J; Curtis, A; de Souza, J; Rickards, H; Wright, J; Barker, Ra; Di Pietro, A; Fisher, K; Goodman, Ao; Hill, S; Kershaw, A; Mason, S; O'Keefe, D; Swain, R; Guzman, Nv; Busse, M; Butcher, C; Clenaghan, C; Dunnett, S; Fullam, R; Jones, L; Jones, U; Khalil, H; Minster, S; Owen, M; Hunt, S; Price, K; Rosser, A; Townhill, J; Edwards, M; Ho, C; Mcgill, M; Pearson, P; Porteous, M; Brockie, P; Foster, J; Johns, N; Mckenzie, S; Rothery, J; Thomas, G; Yates, S; Burrows, L; Chu, C; Fletcher, A; Gallantrae, D; Harding, A; Hamer, S; Kraus, A; Laver, F; Longthorpe, M; Markova, I; Raman, A; Silva, M; Thomson, A; Wild, S; Yardumian, P; Hobson, E; Jamieson, S; Musgrave, H; Rowett, L; Toscano, J; Wild, S; Yardumian, P; Clayton, C; Dipple, H; Middleton, J; Patino, D; Andrews, T; Dougherty, A; Kavalier, F; Golding, C; Laing, H; Lashwood, A; Robertson, D; Ruddy, D; Whaite, A; Santhouse, A; Andrews, T; Bruno, S; Doherty, K; Lahiri, N; Novak, M; Patel, A; Rosser, E; Tabrizi, S; Taylor, R; Warner, T; Wild, E; Arran, N; Bek, J; Callaghan, J; Craufurd, D; Fullam, R; Howard, L; Hare, M; Huson, S; Johnson, L; Jones, M; Murphy, H; Oughton, E; Partington-Janes, L; Rogers, D; Snowden, J; Sollom, A; Stopford, C; Thompson, J; Trender-Gerhard, I