Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders.
Neurology. 2014-08-06; 83(11): 990-995
DOI: 10.1212/WNL.0000000000000778
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1. Neurology. 2014 Sep 9;83(11):990-5. doi: 10.1212/WNL.0000000000000778. Epub 2014
Aug 6.
Contribution of ATXN2 intermediary polyQ expansions in a spectrum of
neurodegenerative disorders.
Lattante S(1), Millecamps S(1), Stevanin G(1), Rivaud-Péchoux S(1), Moigneu C(1),
Camuzat A(1), Da Barroca S(1), Mundwiller E(1), Couarch P(1), Salachas F(1),
Hannequin D(1), Meininger V(1), Pasquier F(1), Seilhean D(1), Couratier P(1),
Danel-Brunaud V(1), Bonnet AM(1), Tranchant C(1), LeGuern E(1), Brice A(1), Le
Ber I(1), Kabashi E(2); French Research Network on FTD and FTD-ALS.
Author information:
(1)From the Institut du Cerveau et de la Moelle épinière (ICM) (S.L., S.M., G.S.,
S.R.-P., C.M., A.C., S.D., E.M., P.C., A.B., I.L., E.K.), Sorbonne Université,
UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, F-75013, Paris; Ecole
Pratique des Hautes Etudes, Laboratoire de Neurogénétique, ICM (G.S.), HéSam
Université, GHU Pitié-Salpêtrière, F-75013, Paris; Fédération des Maladies du
Système Nerveux, Centre de référence maladies rares SLA (F.S., V.M.), Département
de Neuropathologie (D.S.), Department of Neurology (A.-M.B.), Unité Fonctionnelle
de neurogénétique moléculaire et cellulaire (E.L.), Département de Génétique et
Cytogénétique (A.B.), and Centre de référence Démences Rares (I.L.), AP-HP,
Hôpital Pitié-Salpêtrière, F-75013, Paris; Inserm U1079 (D.H.), Rouen; Centre
mémoire (F.P.), Université Lille Nord de France, EA1046, CHU, Lille;
Neuroépidémiologie Tropicale (P.C.), Université de Limoges INSERM UMR1094,
Limoges; Service de Neurologie et Pathologie du Mouvement (V.D.-B.), Hôpital
Roger Salengro, CHRU Lille; and Service de neurologie (C.T.), Hôpital de
Hautepierre, CHU de Strasbourg, 1 Avenue Molière, Strasbourg, France.
(2)From the Institut du Cerveau et de la Moelle épinière (ICM) (S.L., S.M., G.S.,
S.R.-P., C.M., A.C., S.D., E.M., P.C., A.B., I.L., E.K.), Sorbonne Université,
UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, F-75013, Paris; Ecole
Pratique des Hautes Etudes, Laboratoire de Neurogénétique, ICM (G.S.), HéSam
Université, GHU Pitié-Salpêtrière, F-75013, Paris; Fédération des Maladies du
Système Nerveux, Centre de référence maladies rares SLA (F.S., V.M.), Département
de Neuropathologie (D.S.), Department of Neurology (A.-M.B.), Unité Fonctionnelle
de neurogénétique moléculaire et cellulaire (E.L.), Département de Génétique et
Cytogénétique (A.B.), and Centre de référence Démences Rares (I.L.), AP-HP,
Hôpital Pitié-Salpêtrière, F-75013, Paris; Inserm U1079 (D.H.), Rouen; Centre
mémoire (F.P.), Université Lille Nord de France, EA1046, CHU, Lille;
Neuroépidémiologie Tropicale (P.C.), Université de Limoges INSERM UMR1094,
Limoges; Service de Neurologie et Pathologie du Mouvement (V.D.-B.), Hôpital
Roger Salengro, CHRU Lille; and Service de neurologie (C.T.), Hôpital de
Hautepierre, CHU de Strasbourg, 1 Avenue Molière, Strasbourg, France.
.
OBJECTIVE: The aim of this study was to establish the frequency of ATXN2
polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic
lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive
supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier
gene in patients carrying the C9orf72 expansion.
METHODS: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168
FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322
carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS).
RESULTS: We found a significant association with intermediate repeat size (≥29
CAG) in patients with ALS (both familial and sporadic) and, for the first time,
in patients with familial FTD-ALS. Of interest, we found the co-occurrence of
pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all
in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers,
3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat
lengths in patients with PSP and FTD were found to be similar to the controls.
CONCLUSIONS: ATXN2 intermediary repeat length is a strong risk factor for ALS and
FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a
strong modifier of the FTD phenotype in the presence of a C9orf72 repeat
expansion, leading to the development of clinical signs featuring both FTD and
ALS.
© 2014 American Academy of Neurology.
DOI: 10.1212/WNL.0000000000000778
PMCID: PMC4162303
PMID: 25098532 [Indexed for MEDLINE]