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Neurology. 2016 Aug 9;87(6):571-8. doi: 10.1212/WNL.0000000000002944. Epub 2016 Jul 8.

Clinical manifestations of intermediate allele carriers in Huntington disease.

Collaborators (660)

Bachoud-Lévi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, Illmann T, Landwehrmeyer GB, Levey J, Ramos-Arroyo M, Nielsen JE, Koivisto SP, Päivärinta M, Roos RA, Sebastián AR, Tabrizi SJ, Vandenberghe W, Verellen-Dumoulin C, Uhrova T, Wahlström J, Zaremba J, Baake V, Barth K, Come A, Guedes LC, Finisterra AM, Garde MB, Bos R, Betz S, Callaghan J, Capodarca S, Charpentier S, Vieira da Silva W, Di Renzo M, Ecker D, Fullam R, Genoves C, Gilling M, Handley OJ, Hvalstedt C, Held C, Horta-Barba A, Koppers K, Lamanna C, Laurà M, Descals AM, Martinez-Horta S, Mestre T, Minster S, Monza D, Mütze L, Oehmen M, Padieu H, Paterski L, Peppa N, Koivisto SP, Rindal B, Rogers D, Røren N, Šašinková P, Seliverstov Y, Taylor C, Timewell E, Townhill J, Cubillo PT, van Walsem MR, Witjes-Ané MN, Witkowski G, Wright A, Yudina E, Zielonka D, Zielonka E, Zinzi P, Minet C, Ribaï P, Van Paemel D, Verellen-Dumoulin C, Hjermind L, Jacobsen O, Lindquist S, Nielsen J, Regeur L, Stockholm J, Larsen IU, Vangsted-Hansen C, Vinther-Jensen T, Eklund P, Hiivola H, Hypponen H, Martikainen K, Tuuha K, Allain P, Marie Bost DB, Gohier B, Guérid MA, Olivier A, Prouzet J, Prundean A, Scherer-Gagou C, Verny C, Babiloni B, Debruxelles S, Duché C, Goizet C, Jameau L, Lafoucrière D, Spampinato U, Bachoud-Lévi AC, Badei F, Boudali L, Bourdet C, Cléret L, Couette M, Focseneanu C, Lemoine L, Morgado G, Sebaiti M, Thiriez C, Vervoitte L, Youssov K, Azulay JP, Chabot C, Delfini M, Eusebio A, Fluchere F, Garreau C, Ghenam A, Grosjean H, Mundler L, Nowak M, Raseta R, Bertrand M, Calvas F, Cheriet S, Marquine L, Pierre M, Pariente J, Rolland S, Seris A, Vaquie V, Kosinski CM, Milkereit E, Probst D, Reetz K, Sass C, Schiefer J, Schlangen C, Werner CJ, Ellrichmann G, Herrmann L, Hoffmann R, Kaminski B, Saft C, Boelmans K, Ganos C, Goerendt I, Heinicke W, Hidding U, Lewerenz J, Münchau A, Orth M, Schmalfeld J, Stubbe L, Zittel S, Diercks G, Dressler D, Francis F, Gayde-Stephan S, Gorzolla H, Kramer B, Minschke R, Schrader C, Tacik P, Bechtel N, Beckmann H, Bohlen S, Göpfert N, Hölzner E, Lange H, Reilmann R, Rohm S, Rumpf S, Sass C, Schepers S, Weber N, Bachmeier M, Dose M, Hofstetter N, Marquard R, Mühlbäck A, Barth K, Buck A, Connemann J, Ecker D, Geitner C, Held C, Kesse A, Landwehrmeyer B, Lezius F, Lewerenz J, Nepper S, Niess A, Orth M, Schneider A, Schwenk D, Süssmuth S, Trautmann S, Weydt P, Klebe S, Musacchio T, Leypold C, Nöth K, Cormio C, de Tommaso M, Dellomonaco AR, Difruscolo O, Franco G, Sciruicchio V, Serpino C, Figorilli M, Marrosu F, Muroni A, Piras V, Vacca M, Bartoli C, Bertini E, Fortunato F, Ghelli E, Ginestroni A, Mechi C, Paganini M, Piacentini S, Pradella S, Romoli AM, Sorbi S, De Michele G, Di Maio L, Rinaldi C, Massarelli M, Peluso S, Roca A, Russo CV, Sorrentino P, Salvatore E, Tucci T, Cannella M, Codella V, De Gregorio F, De Nicola A, Elifani F, Martino T, Lovo F, Mazzante I, Petrollini M, Simonelli M, Squitieri F, Vezza M, D'Alessio B, Esposito C, Coarelli G, Ferraldeschi M, Frontali M, Jacopini G, Ristori G, Romano S, Zinzi P, van Hout MS, van Vugt JP, Marit de Weert A, Verhoeven M, Baake V, van den Bogaard SJ, Bos R, Dumas EM, 't Hart EP, Jacobs M, Kampstra A, Roos RA, Schoonderbeek A, Aanonsen NO, Aaserud O, Barnett L, Bjørgo K, Borgerød N, Dramstad E, Fannemel M, Frich J, Gundersen H, Gørvell P, Haggag K, Heiberg A, Johannessen CH, Retterstøl L, Rosby O, Rummel J, Sikiric A, Solberg O, van Walsem M, Wehus R, Dziadkiewicz A, Konkel A, Narożańska E, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M, Arkuszewski M, Błaszczyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasińska-Myga B, Kaczmarczyk A, Kłodowska-Duda G, Opala G, Rudzińska M, Stompel D, Banaszkiewicz K, Boćwińska D, Bojakowska-Jaremek K, Dec M, Grabska N, Krawczyk M, Kubowicz E, Malec-Litwinowicz M, Rudzińska M, Stenwak A, Szczudlik A, Szczygieł E, Wójcik M, Wasielewska A, Anna Bryl JA, Ciesielska A, Klimberg A, Marcinkowski J, Samara H, Sempołowicz J, Wiśniewski B, Zielonka D, Gogol A, Janik P, Jamrozik Z, Kaminska A, Kwiecinski H, Antczak J, Jachinska K, Krysa W, Rakowicz M, Richter P, Rola R, Ryglewicz D, Sienkiewicz-Jarosz H, Stępniak I, Sułek A, Witkowski G, Zaremba J, Zdzienicka E, Ziora-Jakutowicz K, Januário C, Júlio F, Guedes LC, Ferreira JJ, Finisterra AM, Salgueiro A, Mestre T, Coelho M, Mendes T, Rosa MM, Valadas A, Semedo C, Calado A, Morgado J, Dias M, Almeida M, Herrera CD, Moreno PG, Bas J, Busquets N, Calopa M, Classen SJ, Dedichá NR, Barbera MA, Sebastián AR, Pardo SA, Guia DB, Calzado N, Hernanz LC, Tartari Díaz-Zorita JP, Catena JL, Ferrer PQ, Carruesco GT, Robert MF, Viladrich CM, Roca E, Ruiz Idiago JM, Riballo AV, Campolongo A, Fernandez de Bobadilla R, Bojarsky JK, Martinez-Horta S, Pagonabarraga J, Perez JP, Villa C, Acera Gil MA, Corrales KB, Gomez Esteban JC, González A, Merino BT, Cubo E, Mariscal N, Romero SG, Arbelo JM, Malo de Molina R, Martín I, Periañez JM, Udaeta B, Alonso-Frech F, Frades B, Villanueva MÁ, Zea Sevilla MA, Frech FA, Fenollar Mdel M, García-Ramos García R, Villanueva C, Bascuñana M, Ventura MF, Caldentey JG, Ribas GG, García de Yébenes J, López-Sendón Moreno JL, Barral VM, Cubillo PT, Feliz CF, José García Ruíz P, García A, Caldentey JG, López RG, Bárcenas AH, Martínez-Descals A, Pueyo AM, Martin VP, Martínez NR, José Sainz Artiga M, Sánchez V, Fernandez Jdel V, Almagro CA, Manzanares S, Muñoz JM, Antequera Torres MM, Perea FN, Moreau LV, González S, Guisasola LM, Salvador C, Ribacoba R, Lozano PS, Prieto MP, Caldentey JG, Gorospe A, Ramirez IL, Arques PN, Lopera MR, Pastor BV, Gaston I, Ramos-Arroyo MA, Martinez-Jaurrieta MD, García Moreno JM, Lucena CM, Peña JC, Hermoso FD, Cortegana EP, Redondo L, Fernandez CM, Mata MP, Romero Lemos MD, Bosca M, Burguera JA, Brugada Carmen Peiró Vilaplana FC, Diago EB, López Del Val J, Martinez LM, López E, Berglund P, Constantinescu R, Fredlund G, Høsterey-Ugander U, Neleborn-Lingefjärd L, Wahlström J, Burgunder JM, Stebler Y, Kaelin A, Romero I, Schüpbach M, Zaugg SW, Downie L, Jack R, Matheson K, Miedzybrodzka Z, Rae D, Simpson SA, Summers F, Ure A, Vaughn V, Akhtar S, Crooks J, Curtis A, de Souza J, Piedad J, Rickards H, Wright J, Coulthard E, Gethin L, Hayward B, Sieradzan K, Wright A, Busse M, Butcher C, Callaghan J, Dunnett S, Clenaghan C, Fullam R, Hunt S, Jones L, Jones U, Khalil H, Minster S, Owen M, Price K, Townhill J, Rosser A, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Andrew A, Frost J, Noad R, Cosgrove J, Gallantree D, Hamer S, Hobson E, Jamieson S, Kraus A, Longthorpe M, Markova I, Musgrave H, Peacy C, Raman A, Rowett L, Toscano J, Wild S, Clayton C, Yardumian P, Dipple H, Patino DF, Hallam C, Middleton J, Anjum U, Coebergh J, Eddy C, Lahiri N, McEntagart M, Patton M, Peterson M, Rose S, Andrews T, Brown S, Bruno S, Chu E, Doherty K, Golding C, Haider S, Hensman D, Lahiri N, Lewis M, Novak M, Patel A, Read J, Robertson N, Rosser E, Tabrizi S, Taylor R, Warner T, Wild E, Arran N, Bek J, Callaghan J, Craufurd D, Fullam R, Hare M, Howard L, Huson S, Johnson L, Jones M, Krishnamoorthy A, Murphy H, Oughton E, Partington-Jones L, Rogers D, Sollom A, Snowden J, Stopford C, Thompson J, Trender-Gerhard I, Verstraelen N, Westmoreland L, Cass G, Davidson L, Davison J, Fullerton N, Holmes K, Komati S, McDonnell S, Mohammed Z, Morgan K, Savage L, Singh B, Wood J, Nemeth AH, Siuda G, Valentine R, Dixon K, Armstrong R, Harrison D, Hughes M, Large S, Donovan JO, Palmer A, Parkinson A, Soltysiak B, Timings L, Williams J, Bandmann O, Bradbury A, Fairtlough H, Fillingham K, Foustanos I, Gill P, Kazoka M, O'Donovan K, Nevitt L, Peppa N, Quarrell O, Taylor C, Tidswell K, O'Donovan K, Gowers L, Powell K, Bethwaite P, Edwards R, Fuller K, Phillips M.

Abstract

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.

CLINICALTRIALSGOV IDENTIFIER:

NCT01590589.

PMID:
27402890
DOI:
10.1212/WNL.0000000000002944
[Indexed for MEDLINE]

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