Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers

Peter P. Pramstaller*, Michael G. Schlossmacher, Thomas S. Jacques, Francesco Scaravilli, Cordula Eskelson, Imelda Pepivani, Katja Hedrich, Susanna Adel, Melissa Gonzales-McNeal, Rüdiger Hilker, Patricia L. Kramer, Christine Klein

*Corresponding author for this work
169 Citations (Scopus)


We report the clinical, genetic, and neuropathological findings of a seven generation-spanning pedigree with 196 individuals, 25 of whom had levodopa-responsive parkinsonism. Genetic analyses indicated Parkin mutations in 77 subjects. Among the 25 patients, 5 carried compound heterozygous mutations and met criteria for definite Parkinson's disease (PD) according to UK PD Society Brain Bank guidelines; 8 subjects carried only a heterozygous Parkin mutation. The mutational status of five deceased patients was unknown, and seven PD patients had no Parkin mutation. Survival analyses showed a significant difference in the age-at-onset distribution between patients with compound heterozygous mutations and the groups of heterozygous carriers and subjects without detectable Parkin mutations. Autopsy of a 73-year-old patient, who carried two mutant Parkin alleles (delExon7 + del1072T), showed PD-type cell loss, reactive gliosis, and α-synuclein-positive Lewy bodies in the substantia nigra and locus ceruleus. Surviving neurons were reactive with antibodies to die N terminus of Parkin but not the In-Between-RING ("IBR") domain, which had been deleted by both mutations. This large Parkin pedigree represents a unique opportunity to prospectively study the role of heterozygous Parkin mutations as a PD risk factor, to identify additional contributors to die expression of late-onset PD in heterozygous carriers, and to reexamine the role of Parkin in inclusion formation.

Original languageEnglish
JournalAnnals of Neurology
Issue number3
Pages (from-to)411-422
Number of pages12
Publication statusPublished - 01.09.2005


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