Parkin-proven disease: Common founders but divergent phenotypes

Objective: To compare and contrast clinical and genetic findings in six probands with parkinsonism with a parkin exon 3 438- to 477-bp deletion (Ex3Δ40) to search for evidence of a common founder. Method: Clinical review, parkin gene sequencing, dosage studies, and high-resolution genotype/haplotype analysis were performed. Results: All subjects had two or more signs consistent with a diagnosis of possible or probable PD with age at onset younger than 45 years (mean ± SD 29.3 ± 10.2 years, range 16 to 42 years). Affected individuals were either homozygotes, compound heterozygotes, or Ex3Δ40 carriers with one normal parkin allele. Haplotype analysis revealed both Ex3Δ40 and Ex7 924 C→T (R275W) mutations originated from common founders, the former most probably of Irish descent. Although three cases had Ex7 924 C→T (R275W) and Ex3Δ40 mutations, their clinical presentation and mode of inheritance were variable. Conclusion: Parkin mutations on common parkin haplotypes provide testable hypotheses of parkin function in genetically defined parkinsonism.