title: Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers.
abstract: 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 alpha-synuclein-positive Lewy bodies in the substantia nigra and locus ceruleus. Surviving neurons were reactive with antibodies to the 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 the expression of late-onset PD in heterozygous carriers, and to reexamine the role of Parkin in inclusion formation.
authors.affiliation: Department of Neurology, Central Hospital, Bolzano-Bozen, Italy. peter.pramstaller@eurac.edu
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.forename: Francesco
authors.initials: F
authors.lastname: Scaravilli
authors.forename: Cordula
authors.initials: C
authors.lastname: Eskelson
authors.forename: Imelda
authors.initials: I
authors.lastname: Pepivani
authors.forename: Katja
authors.initials: K
authors.lastname: Hedrich
authors.forename: Susanna
authors.initials: S
authors.lastname: Adel
authors.forename: Melissa
authors.initials: M
authors.lastname: Gonzales-McNeal
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hilker
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Kramer
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D004252:DNA Mutational Analysis; D003710:Demography; D005192:Family Health; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011180:Postmortem Changes; D011446:Prospective Studies; D012189:Retrospective Studies; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000145:classification / Q000235:genetics* / Q000378:metabolism
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein