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Previous Volume 342:1560-1567 May 25, 2000 Number 21 Next

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ABSTRACT

Background Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients.

Methods We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations.

Results Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (±SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32±11 vs. 42± 11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected.

Conclusions Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.

Source Information

From INSERM Unité 289, Hôpital de la Salpêtrière, Paris (C.B.L., A.D., Y.A., A.B.); the Dipartimento di Scienze Neurologiche, Università La Sapienza, Rome (V.B., G.M.); the Institute of Neurology, London (J.V., N.W.W.); the Dipartimento di Scienze Neurologiche, Università Federico II, Naples, Italy (G.D.); the Neurologische Klinik, Klinikum Großhadern, Ludwig Maximilians Universität, Munich, Germany (T.G.); the Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam, the Netherlands (B.S.H); and Evry Genomics Center, Aventis Pharma France, Evry, France (P.D.). Other authors were D. Nicholl, M.D. (University of Birmingham, Birmingham, United Kingdom); M.M.B. Breteler, M.D. (Erasmus University Medical School, Rotterdam, the Netherlands); B.A. Oostra, M.D. (Erasmus University, Rotterdam, the Netherlands); M. De Mari, M.D. (Università degli Studi di Bari, Bari, Italy); R. Marconi, M.D. (Ospedale della Misericordia, Grosseto, Italy); A. Filla, M.D. (Università Federico II, Naples, Italy); A.-M. Bonnet, M.D. (Hôpital de la Salpêtrière, Paris); E. Broussolle, M.D. (Hôpital Pierre Wertheimer, Lyons, France); P. Pollak, M.D. (Centre Hospitalier Universitaire de Grenoble, Grenoble, France); O. Rascol, M.D. (INSERM Unité 455, Toulouse, France); and M. Rosier, Ph.D., and I. Arnould, Ph.D. (Aventis Pharma France, Evry, France).

Address reprint requests to Dr. Brice at INSERM Unité 289, Hôpital de la Salpêtrière, 47 Blvd. de l'Hôpital, 75651 Paris CEDEX 13, France, or at brice{at}ccr.jussieu.fr.

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