The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

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

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

Discrepancies in reporting the CAG repeat lengths for Huntington's disease.

Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards

Discrepancies in reporting the CAG repeat lengths for Huntington's disease.

Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards

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

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; 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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