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From the Departments of Neurology and Neuroscience (K.H., R.R., J.M.K., O.A.R., L.B., U.W., 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 (R.B., T.G.), University of Rostock, Germany; Hertie Institute for Clinical Brain Research (D.B., T.F.), 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, 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.
* To whom correspondence should be addressed. E-mail: wszolek.zbigniew{at}mayo.edu.
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.
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  G. A. Caldwell and K. A. Caldwell Traversing a wormhole to combat Parkinson's disease Dis. Model. Mech., July 1, 2008; 1(1): 32 - 36. [Abstract] [Full Text] [PDF]
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