Neurology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online before print March 12, 2008, doi:10.1212/01.wnl.0000304044.22253.03)
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
01.wnl.0000304044.22253.03v1
70/16_Part_2/1456    most recent
Right arrow Correspondence:
Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when Correspondence are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Haugarvoll, K.
Right arrow Articles by Wszolek, Z. K.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Haugarvoll, K.
Right arrow Articles by Wszolek, Z. K.
Related Collections
Right arrow Gait disorders/ataxia
Right arrow Parkinson's disease/Parkinsonism
Right arrow Tremor
Right arrow All Genetics
Right arrow Genetic linkage
NEUROLOGY 2008;70:1456-1460
© 2008 American Academy of Neurology

Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease

K. Haugarvoll, MD, R. Rademakers, PhD, J. M. Kachergus, BSc, K. Nuytemans, MSc, O. A. Ross, PhD, J. M. Gibson, MD, E-K Tan, MD, C. Gaig, MD, E. Tolosa, MD, S. Goldwurm, MD, M. Guidi, MD, G. Riboldazzi, MD, L. Brown, BSc, U. Walter, MD, R. Benecke, MD, D. Berg, MD, T. Gasser, MD, J. Theuns, PhD, P. Pals, MD, P. Cras, MD, P. Paul De Deyn, MD, S. Engelborghs, MD, B. Pickut, MD, R. J. Uitti, MD, T. Foroud, PhD, W. C. Nichols, PhD, J. Hagenah, MD, C. Klein, MD, A. Samii, MD, C. P. Zabetian, MD, V. Bonifati, MD, PhD, C. Van Broeckhoven, PhD, M. J. Farrer, PhD and Z. K. Wszolek, MD

From the Departments of Neurology and Neuroscience (K.H., R.R., J.M.K., O.A.R., L.B., R.J.U., M.J.F., Z.K.W.), Mayo Clinic College of Medicine, Jacksonville, FL; Department of Neuroscience (K.H.), NTNU–Norwegian University of Science and Technology, Trondheim, Norway; Neurodegenerative Brain Diseases Group (R.R., K.N., J.T., C.V.B.), Department of Molecular Genetics, VIB, Laboratory of Neurogenetics (R.R., K.N., J.T., C.V.B.), Institute Born-Bunge, and University of Antwerp (R.R., K.N., J.T., C.V.B., P.P., P.C., P.P.D.D., S.E.), Antwerpen, Belgium; Department of Neurology (J.M.G.), Royal Victoria Hospital, Belfast, Ireland; Singapore General Hospital (E.-K.T.), Singapore; Parkinson's Disease and Movement Disorders Unit (C.G., E.T.), Institut Clínic de Neurociències, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Spain; Parkinson Institute (S.G.), Istituti Clinici di Perfezionamento, Milan, Italy; Neurology Division (M.G.), INRCA Institute, Ancona, Italy; Department of Neurology (G.R.), University of Insubria, Varese, Italy; Department of Neurology (U.W., R.B.), University of Rostock, Germany; Hertie Institute for Clinical Brain Research (D.B., T.G.), Tubingen, Germany; Division of Neurology (P.P., P.C.), University Hospital Antwerpen, Belgium; Laboratory of Neurobiology (P.P., P.C.) and Laboratory of Neurochemistry and Behavior (P.P.D.D., S.E.), Institute Born-Bunge, Antwerpen, Belgium.; Division of Neurology (P.P.D.D., S.E., B.P.), ZNA Middelheim Antwerp, Antwerpen, Belgium; Indiana University School of Medicine (T.F.), Indianapolis; Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine (W.C.N.), OH; Department of Neurology and Human Genetics (J.H., C.K.), University of Lübeck, Germany; Department of Neurology (A.S., C.P.Z.), University of Washington School of Medicine, Seattle; Geriatric Research Education and Clinical Center (C.P.Z.), Veterans Affairs Puget Sound Health Care System, Seattle, WA; and Department of Clinical Genetics (V.B.), Erasmus MC, Rotterdam, The Netherlands.

Address correspondence and reprint requests to Dr. Zbigniew K. Wszolek, Department of Neurology, Mayo Clinic College of Medicine, Cannaday Bldg., 2E, 4500 San Pablo Road, Jacksonville, FL 32224

Objective: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C.

Methods: We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.

Results: The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30–79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation.

Conclusions: The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.

GLOSSARY: COR = C-terminal of Roc; GTPase = guanosine triphosphatase; LBD = Lewy body disease; PD = Parkinson disease; SNPs = single nucleotide polymorphisms.

wszolek.zbigniew{at}mayo.edu

Supplemental data at www.neurology.org

e-Pub ahead of print on March 12, 2008, at www.neurology.org.

K.H. received support from Forsberg and Aulies Legacy, R.R. holds a postdoctoral fellowship of the Fund for Scientific Research Flanders (FWO-V), and K.N. a PhD fellowship of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-F). Further support for this work included a VA Merit Review Award (C.P.Z.), K08 NS044138 (C.P.Z.), R01 NS37167 (T.F.), Distincio per la promocio de la Reserca Universitaria Generalitad de Catalunya (E.T.), National Medical (NMRC) and Biomedical Research Councils, Singapore (BMRC) (E.K.T.), Internationaal Parkinson Fonds, The Netherlands (V.B.), and National Institute of Neurological Disorders and Stroke P50 NS40256 funded the Udall Clinical (Z.K.W.) and Genetic Cores (M.J.F.), Mayo Clinic Jacksonville.

Disclosure: The authors report no conflicts of interest.

Received August 29, 2007. Accepted in final form October 26, 2007.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2008 by AAN Enterprises, Inc.