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Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?

From the AP-HP (P.C., G.D., A.D., A.B.), Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, AP-HP (P.C., A.-M.B., I.L.B., A.B.), Federation of the Nervous System Diseases, Groupe Hospitalier Pitié-Salpêtrière, and INSERM 679 (P.C., A.C., N.B., A.-M.B., S.L., I.L.B., G.S., A.D., A.B.), Paris, Department of Neurology (F.S.), Hôpitaux Universitaires, and INSERM 692 (F.S.), Université Louis Pasteur, Strasbourg, Department of Neurology (A.D.), CHRU de Lille, and University Pierre and Marie Curie–Paris 6 (P.C., A.C., N.B., A.-M.B., S.L., I.L.B., G.S., A.D., A.B.), UMR S679, IFR des Neurosciences, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Address correspondence and reprint requests to Dr. A. Brice, INSERM Unit 679, Hôpital Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France brice{at}ccr.jussieu.fr

Background: Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2.

Methods: We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size.

Results: Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs.

Conclusion: These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.

e-Pub ahead of print on June 13, 2007, at www.neurology.org.

*French Parkinson's Disease Genetics Study Group: Y. Agid, A.-M. Bonnet, M. Borg, A. Brice, E. Broussolle, Ph. Damier, A. Destée, A. Dürr, F. Durif, E. Lohmann, M. Martinez, C. Penet, P. Pollak, O. Rascol, F. Tison, C. Tranchant, M. Vérin, F. Viallet, M. Vidailhet.

Supported by grants from the European Commission (EU contract no. LSHM-CT-2003-503330/APOPIS and EU contract no. LSHM-CT-2004-503304/EUROSCA), the VERUM Foundation, and the Agence Nationale de la Recherche (grant ANR A05169DS-ANR-05-NEUR-019).

Disclosure: The authors report no conflicts of interest.

Received February 1, 2007. Accepted in final form April 23, 2007.

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