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

被引:193
作者
Pramstaller, PP
Schlossmacher, MG
Jacques, TS
Scaravilli, F
Eskelson, C
Pepivani, I
Hedrich, K
Adel, S
Gonzales-McNeal, M
Hilker, R
Kramer, PL
Klein, C
机构
[1] Cent Hosp Bolzano Bozen, Dept Neurol, I-39100 Bolzano, Italy
[2] European Acad Res, Inst Med Genet, I-39100 Bolzano, Italy
[3] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA
[5] UCL, Inst Neurol, Dept Mol Neurosci, Div Neuropathol, London WC1E 6BT, England
[6] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany
[7] Med Univ Lubeck, Dept Human Genet, D-23538 Lubeck, Germany
[8] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA
[9] Med Univ Cologne, Dept Neurol, Cologne, Germany
关键词
D O I
10.1002/ana.20587
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 a-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.
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页码:411 / 422
页数:12
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