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

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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 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 (US)
Pages (from-to)411-422
Number of pages12
JournalAnnals of Neurology
Volume58
Issue number3
DOIs
StatePublished - Sep 2005

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Pedigree
Parkinson Disease
Mutation
Synucleins
Lewy Bodies
Gliosis
Locus Coeruleus
Parkinsonian Disorders
Levodopa
Substantia Nigra
Survival Analysis
Age of Onset
Autopsy
Alleles
Guidelines
Neurons
Antibodies
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Pramstaller, P. P., Schlossmacher, M. G., Jacques, T. S., Scaravilli, F., Eskelson, C., Pepivani, I., ... Klein, C. (2005). Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. Annals of Neurology, 58(3), 411-422. https://doi.org/10.1002/ana.20587

Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. / Pramstaller, Peter P.; Schlossmacher, Michael G.; Jacques, Thomas S.; Scaravilli, Francesco; Eskelson, Cordula; Pepivani, Imelda; Hedrich, Katja; Adel, Susanna; Gonzales-McNeal, Melissa; Hilker, Rüdiger; Kramer, Patricia L.; Klein, Christine.

In: Annals of Neurology, Vol. 58, No. 3, 09.2005, p. 411-422.

Research output: Contribution to journalArticle

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 2005, 'Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers', Annals of Neurology, vol. 58, no. 3, pp. 411-422. https://doi.org/10.1002/ana.20587
Pramstaller PP, Schlossmacher MG, Jacques TS, Scaravilli F, Eskelson C, Pepivani I et al. Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. Annals of Neurology. 2005 Sep;58(3):411-422. https://doi.org/10.1002/ana.20587
Pramstaller, Peter P. ; Schlossmacher, Michael G. ; Jacques, Thomas S. ; Scaravilli, Francesco ; Eskelson, Cordula ; Pepivani, Imelda ; Hedrich, Katja ; Adel, Susanna ; Gonzales-McNeal, Melissa ; Hilker, Rüdiger ; Kramer, Patricia L. ; Klein, Christine. / Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. In: Annals of Neurology. 2005 ; Vol. 58, No. 3. pp. 411-422.
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