title: COMT Val158Met Polymorphism Modulates Huntington's Disease Progression.
abstract: Little is known about the genetic factors modulating the progression of Huntington's disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington's Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression.
authors.affiliation: INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, 94000, Créteil, France.|Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL Research University, 75005, Paris, France.|Université Paris Est, Faculté de Médecine, 94000, Créteil, France.|ICREA, 08010, Barcelona, Spain.|Universitat de Barcelona, Departament de Cognició, Desenvolupament i Psicologia de L'Educació, 08035, Barcelona, Spain.|IDIBELL, Unitat de Cognició i Plasticitat Cerebral, 08907, L'Hospitalet de Llobregat, Spain.|Institut de Neurociència, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: de Diego-Balaguer
authors.affiliation: INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, 94000, Créteil, France.|Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL Research University, 75005, Paris, France.|Université Paris Est, Faculté de Médecine, 94000, Créteil, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schramm
authors.affiliation: INSERM-UPMC-CNRS, UMR 7225-1127, Institut Cerveau Moelle-ICM, Hôpital Pitié-Salpêtrière, 74013, Paris, France.|Assistance Publique-Hôpitaux de Paris, Département des Maladies du Système Nerveux, Hôpital Pitié-Salpêtrière, 74013, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rebeix
authors.affiliation: Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL Research University, 75005, Paris, France.|Laboratoire de Sciences Cognitives et Psycholinguistique, ENS-EHESS-CNRS, Paris, 75005, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dupoux
authors.affiliation: INSERM-UPMC-CNRS, UMR 7225-1127, Institut Cerveau Moelle-ICM, Hôpital Pitié-Salpêtrière, 74013, Paris, France.|Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital Pitié-Salpêtrière, 74013, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: INSERM-UPMC-CNRS, UMR 7225-1127, Institut Cerveau Moelle-ICM, Hôpital Pitié-Salpêtrière, 74013, Paris, France.|Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital Pitié-Salpêtrière, 74013, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital Pitié-Salpêtrière, 74013, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.affiliation: INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, 94000, Créteil, France.|Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL Research University, 75005, Paris, France.|Université Paris Est, Faculté de Médecine, 94000, Créteil, France.|Assistance Publique-Hôpitaux de Paris, Centre de Référence Maladie de Huntington, Service de Neurologie, Hôpital Henri Mondor-Albert Chenevier, 94000, Créteil, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Cleret de Langavant
authors.affiliation: INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, 94000, Créteil, France.|Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL Research University, 75005, Paris, France.|Université Paris Est, Faculté de Médecine, 94000, Créteil, France.|Assistance Publique-Hôpitaux de Paris, Centre de Référence Maladie de Huntington, Service de Neurologie, Hôpital Henri Mondor-Albert Chenevier, 94000, Créteil, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Youssov
authors.affiliation: CHU d'Angers, Centre de Référence des Maladies Neurogénétiques, Service de Neurologie, 49933, Angers, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Verny
authors.affiliation: INSERM-UPMC-CNRS, UMR 7225-1127, Institut Cerveau Moelle-ICM, Hôpital Pitié-Salpêtrière, 74013, Paris, France.|Assistance Publique-Hôpitaux de Paris, Département des Maladies du Système Nerveux, Hôpital Pitié-Salpêtrière, 74013, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Damotte
authors.affiliation: CHU de Marseille-Hôpital de la Timone, Service de Neurologie et Pathologie du Mouvement, 13385, Marseille, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Azulay
authors.affiliation: CHU de Bordeaux-GH Sud-Hôpital Haut-Lévêque, Service de Neurologie, 33604, Pessac, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: CHRU de Lille, Service de Neurologie et Pathologie du Mouvement, 59000, Lille, France.|INSERM UMR-S 1172, JPArc, centre de recherche Jean-Pierre-Aubert neurosciences et cancer, Université de Lille, 59000, Lille, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Simonin
authors.affiliation: CHU de Strasbourg-Hôpital de Hautepierre, Service de Neurologie, 67098, Strasbourg, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Tranchant
authors.affiliation: INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, 94000, Créteil, France.|Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL Research University, 75005, Paris, France.|Université Paris Est, Faculté de Médecine, 94000, Créteil, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Unité de Recherche Clinique, 94000, Créteil, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maison
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Unité de Recherche Clinique, 94000, Créteil, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Rialland
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Unité de Recherche Clinique, 94000, Créteil, France.
authors.forename: David
authors.initials: D
authors.lastname: Schmitz
authors.affiliation: INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, 94000, Créteil, France.|Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL Research University, 75005, Paris, France.|Université Paris Est, Faculté de Médecine, 94000, Créteil, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Jacquemot
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Département des Maladies du Système Nerveux, Hôpital Pitié-Salpêtrière, 74013, Paris, France.|Assistance Publique-Hôpitaux de Paris, Département de Génétique, Hôpital Pitié-Salpêtrière, 74013, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.affiliation: INSERM U955, Equipe 01 Neuropsychologie Interventionnelle, 94000, Créteil, France.|Département d'Etudes Cognitives, Ecole Normale Supérieure, PSL Research University, 75005, Paris, France.|Université Paris Est, Faculté de Médecine, 94000, Créteil, France.|Assistance Publique-Hôpitaux de Paris, Centre de Référence Maladie de Huntington, Service de Neurologie, Hôpital Henri Mondor-Albert Chenevier, 94000, Créteil, France.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Bachoud-Lévi