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April 2008

How to Predict the Risk of Parkinson Disease in Relatives of Parkin Mutation Carriers: A Complex Puzzle of Age, Penetrance, and Number of Mutated Alleles

Arch Neurol. 2008;65(4):443-444. doi:10.1001/archneur.65.4.443

Doubt is not a pleasant condition, but certainty is absurd. Voltaire (1694-1778)

Mutations in the recessively inherited Parkin gene (OMIM 600116) are the most common known cause of early-onset Parkinson disease (PD) and account for as many as 77% of the patients with a juvenile or very young age of onset (< 30 years)1 and about 10% of a population-based sample with early-onset PD beginning at younger than 50 years.2 Although homozygous or compound-heterozygous Parkin mutations (ie, 2 mutated Parkin alleles) have only rarely been found in late-onset disease, the presence of a single heterozygous mutation has been suggested as a susceptibility factor for the development of later-onset PD based on family, case-control, and neuroimaging studies.3 A similar role has been discussed for mutations in the other recessive PD genes (ie, PINK1 [OMIM 605909 ], DJ-1 [OMIM 606324], and, recently, ATP13A2 [OMIM 606693]).4 Although 2 mutated alleles are a relatively rare finding even in the case of the Parkin gene, single heterozygous mutations are much less uncommon and are estimated to occur at a frequency of about 0.6% to 3.0% in the healthy population.5,6 If, indeed, single Parkin mutations represented a risk factor for PD, a higher prevalence of PD among carriers of heterozygous mutations would be expected than in individuals without such alterations. To our knowledge, only 4 studies systematically examine the role of different numbers of mutated Parkin alleles using a case-control design. Two of these studies6,7 reported equal numbers of mutations among patients and control subjects, whereas the other 2 investigations5,8 found an excess of mutations among patients.