Association between early-onset Parkinson's disease and mutations in the parkin gene

Background: Mutations in the parkin gene have recently been identified in p atients with early-onset Parkinson's disease, but the frequency of the muta tions 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 famil y 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 disea se 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 sequen ced the coding exons in a subgroup of patients. We also compared the clinic al features of patients with parkin mutations and those without mutations. Results: Among the families with early-onset Parkinson's disease, 36 (49 pe rcent) had parkin mutations. The age at onset ranged from 7 to 58 years. Am ong 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 youn ger, 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 mu tations 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 an d 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-onse t Parkinson's disease (at or before the age of 20 years). Accurate diagnosi s of these cases cannot be based only on the clinical manifestations of the disease. (N Engl J Med 2000;342:1560-7.) (C) 2000, Massachusetts Medical S ociety.