Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers
Identifieur interne : 001470 ( Main/Exploration ); précédent : 001469; suivant : 001471Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers
Auteurs : Peter P. Pramstaller [Italie, Allemagne] ; Michael G. Schlossmacher [États-Unis] ; Thomas S. Jacques [Royaume-Uni] ; Francesco Scaravilli [Royaume-Uni] ; Cordula Eskelson [Allemagne] ; Imelda Pepivani [États-Unis] ; Katja Hedrich [Allemagne] ; Susanna Adel [Allemagne] ; Melissa Gonzales-Mcneal [États-Unis] ; Rüdiger Hilker [Allemagne] ; Patricia L. Kramer [États-Unis] ; Christine Klein [Allemagne]Source :
- Annals of Neurology [ 0364-5134 ] ; 2005-09.
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 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. Ann Neurol 2005;58:411–422
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DOI: 10.1002/ana.20587
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Kramer</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Oregon</region></placeName><wicri:cityArea>Department of Neurology, Oregon Health & Sciences University, Portland</wicri:cityArea></affiliation></author><author><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Neurology, University of Lübeck, Lübeck</wicri:regionArea><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Departments of Human Genetics, University of Lübeck, Lübeck</wicri:regionArea><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2005-09">2005-09</date><biblScope unit="volume">58</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="411">411</biblScope><biblScope unit="page" to="422">422</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">81B7E6235BA7A3D929AB6EA30F34A1891794AFCA</idno><idno type="DOI">10.1002/ana.20587</idno><idno type="ArticleID">ANA20587</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 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. Ann Neurol 2005;58:411–422</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Italie</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Grand Londres</li><li>Massachusetts</li><li>Oregon</li></region><settlement><li>Londres</li></settlement></list><tree><country name="Italie"><noRegion><name sortKey="Pramstaller, Peter P" sort="Pramstaller, Peter P" uniqKey="Pramstaller P" first="Peter P." last="Pramstaller">Peter P. Pramstaller</name></noRegion><name sortKey="Pramstaller, Peter P" sort="Pramstaller, Peter P" uniqKey="Pramstaller P" first="Peter P." last="Pramstaller">Peter P. Pramstaller</name></country><country name="Allemagne"><noRegion><name sortKey="Pramstaller, Peter P" sort="Pramstaller, Peter P" uniqKey="Pramstaller P" first="Peter P." last="Pramstaller">Peter P. Pramstaller</name></noRegion><name sortKey="Adel, Susanna" sort="Adel, Susanna" uniqKey="Adel S" first="Susanna" last="Adel">Susanna Adel</name><name sortKey="Eskelson, Cordula" sort="Eskelson, Cordula" uniqKey="Eskelson C" first="Cordula" last="Eskelson">Cordula Eskelson</name><name sortKey="Eskelson, Cordula" sort="Eskelson, Cordula" uniqKey="Eskelson C" first="Cordula" last="Eskelson">Cordula Eskelson</name><name sortKey="Hedrich, Katja" sort="Hedrich, Katja" uniqKey="Hedrich K" first="Katja" last="Hedrich">Katja Hedrich</name><name sortKey="Hedrich, Katja" sort="Hedrich, Katja" uniqKey="Hedrich K" first="Katja" last="Hedrich">Katja Hedrich</name><name sortKey="Hilker, Rudiger" sort="Hilker, Rudiger" uniqKey="Hilker R" first="Rüdiger" last="Hilker">Rüdiger Hilker</name><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name></country><country name="États-Unis"><region name="Massachusetts"><name sortKey="Schlossmacher, Michael G" sort="Schlossmacher, Michael G" uniqKey="Schlossmacher M" first="Michael G." last="Schlossmacher">Michael G. Schlossmacher</name></region><name sortKey="Gonzales Cneal, Melissa" sort="Gonzales Cneal, Melissa" uniqKey="Gonzales Cneal M" first="Melissa" last="Gonzales-Mcneal">Melissa Gonzales-Mcneal</name><name sortKey="Kramer, Patricia L" sort="Kramer, Patricia L" uniqKey="Kramer P" first="Patricia L." last="Kramer">Patricia L. Kramer</name><name sortKey="Pepivani, Imelda" sort="Pepivani, Imelda" uniqKey="Pepivani I" first="Imelda" last="Pepivani">Imelda Pepivani</name><name sortKey="Pepivani, Imelda" sort="Pepivani, Imelda" uniqKey="Pepivani I" first="Imelda" last="Pepivani">Imelda Pepivani</name><name sortKey="Schlossmacher, Michael G" sort="Schlossmacher, Michael G" uniqKey="Schlossmacher M" first="Michael G." last="Schlossmacher">Michael G. Schlossmacher</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Jacques, Thomas S" sort="Jacques, Thomas S" uniqKey="Jacques T" first="Thomas S." last="Jacques">Thomas S. Jacques</name></region><name sortKey="Scaravilli, Francesco" sort="Scaravilli, Francesco" uniqKey="Scaravilli F" first="Francesco" last="Scaravilli">Francesco Scaravilli</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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