Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers
Identifieur interne : 000837 ( Main/Corpus ); précédent : 000836; suivant : 000838Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers
Auteurs : 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 KleinSource :
- 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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Pramstaller</name><affiliation><mods:affiliation>Department of Neurology, Central Hospital, Bolzano‐Bozen, Italy</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Genetic Medicine, European Academy‐Research, Bolzano‐Bozen, Italy</mods:affiliation></affiliation><affiliation><mods:affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Schlossmacher, Michael G" sort="Schlossmacher, Michael G" uniqKey="Schlossmacher M" first="Michael G." last="Schlossmacher">Michael G. Schlossmacher</name><affiliation><mods:affiliation>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Harvard Medical School, Boston, MA</mods:affiliation></affiliation></author><author><name sortKey="Jacques, Thomas S" sort="Jacques, Thomas S" uniqKey="Jacques T" first="Thomas S." last="Jacques">Thomas S. Jacques</name><affiliation><mods:affiliation>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Scaravilli, Francesco" sort="Scaravilli, Francesco" uniqKey="Scaravilli F" first="Francesco" last="Scaravilli">Francesco Scaravilli</name><affiliation><mods:affiliation>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Eskelson, Cordula" sort="Eskelson, Cordula" uniqKey="Eskelson C" first="Cordula" last="Eskelson">Cordula Eskelson</name><affiliation><mods:affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Pepivani, Imelda" sort="Pepivani, Imelda" uniqKey="Pepivani I" first="Imelda" last="Pepivani">Imelda Pepivani</name><affiliation><mods:affiliation>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Harvard Medical School, Boston, MA</mods:affiliation></affiliation></author><author><name sortKey="Hedrich, Katja" sort="Hedrich, Katja" uniqKey="Hedrich K" first="Katja" last="Hedrich">Katja Hedrich</name><affiliation><mods:affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Adel, Susanna" sort="Adel, Susanna" uniqKey="Adel S" first="Susanna" last="Adel">Susanna Adel</name><affiliation><mods:affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Gonzales Cneal, Melissa" sort="Gonzales Cneal, Melissa" uniqKey="Gonzales Cneal M" first="Melissa" last="Gonzales-Mcneal">Melissa Gonzales-Mcneal</name><affiliation><mods:affiliation>Department of Neurology, Oregon Health & Sciences University, Portland, OR</mods:affiliation></affiliation></author><author><name sortKey="Hilker, Rudiger" sort="Hilker, Rudiger" uniqKey="Hilker R" first="Rüdiger" last="Hilker">Rüdiger Hilker</name><affiliation><mods:affiliation>Department of Neurology, Medical University of Cologne, Cologne, Germany</mods:affiliation></affiliation></author><author><name sortKey="Kramer, Patricia L" sort="Kramer, Patricia L" uniqKey="Kramer P" first="Patricia L." last="Kramer">Patricia L. Kramer</name><affiliation><mods:affiliation>Department of Neurology, Oregon Health & Sciences University, Portland, OR</mods:affiliation></affiliation></author><author><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><affiliation><mods:affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</mods:affiliation></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><istex><corpusName>wiley</corpusName><author><json:item><name>Peter P. Pramstaller MD</name><affiliations><json:string>Department of Neurology, Central Hospital, Bolzano‐Bozen, Italy</json:string><json:string>Institute of Genetic Medicine, European Academy‐Research, Bolzano‐Bozen, Italy</json:string><json:string>Departments of Neurology, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Michael G. Schlossmacher MD</name><affiliations><json:string>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</json:string><json:string>Department of Neurology, Harvard Medical School, Boston, MA</json:string></affiliations></json:item><json:item><name>Thomas S. Jacques PhD, MRCP</name><affiliations><json:string>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</json:string></affiliations></json:item><json:item><name>Francesco Scaravilli MD, FRCPath</name><affiliations><json:string>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</json:string></affiliations></json:item><json:item><name>Cordula Eskelson MD</name><affiliations><json:string>Departments of Neurology, University of Lübeck, Lübeck, Germany</json:string><json:string>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Imelda Pepivani BS</name><affiliations><json:string>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</json:string><json:string>Department of Neurology, Harvard Medical School, Boston, MA</json:string></affiliations></json:item><json:item><name>Katja Hedrich PhD</name><affiliations><json:string>Departments of Neurology, University of Lübeck, Lübeck, Germany</json:string><json:string>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Susanna Adel MD</name><affiliations><json:string>Departments of Neurology, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Melissa Gonzales‐McNeal MS</name><affiliations><json:string>Department of Neurology, Oregon Health & Sciences University, Portland, OR</json:string></affiliations></json:item><json:item><name>Rüdiger Hilker MD</name><affiliations><json:string>Department of Neurology, Medical University of Cologne, Cologne, Germany</json:string></affiliations></json:item><json:item><name>Patricia L. Kramer PhD</name><affiliations><json:string>Department of Neurology, Oregon Health & Sciences University, Portland, OR</json:string></affiliations></json:item><json:item><name>Christine Klein MD</name><affiliations><json:string>Departments of Neurology, University of Lübeck, Lübeck, Germany</json:string><json:string>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item></author><articleId><json:string>ANA20587</json:string></articleId><language><json:string>eng</json:string></language><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</abstract><qualityIndicators><score>7.544</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 801 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1505</abstractCharCount><pdfWordCount>7025</pdfWordCount><pdfCharCount>45885</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>212</abstractWordCount></qualityIndicators><title>Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers</title><genre><json:string>article</json:string></genre><host><volume>58</volume><publisherId><json:string>ANA</json:string></publisherId><pages><total>12</total><last>422</last><first>411</first></pages><issn><json:string>0364-5134</json:string></issn><issue>3</issue><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8249</json:string></eissn><title>Annals of Neurology</title><doi><json:string>10.1002/(ISSN)1531-8249</json:string></doi></host><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1002/ana.20587</json:string></doi><id>81B7E6235BA7A3D929AB6EA30F34A1891794AFCA</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/81B7E6235BA7A3D929AB6EA30F34A1891794AFCA/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/81B7E6235BA7A3D929AB6EA30F34A1891794AFCA/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/81B7E6235BA7A3D929AB6EA30F34A1891794AFCA/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2005</date></publicationStmt><notesStmt><note>Neuroepidemiology Project–South Tyrol</note><note>South Tyrolean Parkinson Disease Association</note><note>Parkinson's Disease Foundation</note><note>Deutsche Forschungsgemeinschaft - No. 1134/2‐2; No. 1134/3‐1;</note><note>Volkswagen Foundation</note><note>NIH (National Institute of Neurological Disorders and Stroke) - No. NS02127;</note><note>Multiple System Atrophy Fund at Brigham and Women's Hospital</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers</title><author><persName><forename type="first">Peter P.</forename><surname>Pramstaller</surname></persName><roleName type="degree">MD</roleName><note type="correspondence"><p>Correspondence: Department of Neurology, Central Hospital Bolzano/Bozen, 5 Lorenz‐Boehler Street, 39100 Bolzano/Bozen, Italy</p></note><affiliation>Department of Neurology, Central Hospital, Bolzano‐Bozen, Italy</affiliation><affiliation>Institute of Genetic Medicine, European Academy‐Research, Bolzano‐Bozen, Italy</affiliation><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation></author><author><persName><forename type="first">Michael G.</forename><surname>Schlossmacher</surname></persName><roleName type="degree">MD</roleName><affiliation>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</affiliation><affiliation>Department of Neurology, Harvard Medical School, Boston, MA</affiliation></author><author><persName><forename type="first">Thomas S.</forename><surname>Jacques</surname></persName><roleName type="degree">PhD, MRCP</roleName><affiliation>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</affiliation></author><author><persName><forename type="first">Francesco</forename><surname>Scaravilli</surname></persName><roleName type="degree">MD, FRCPath</roleName><affiliation>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</affiliation></author><author><persName><forename type="first">Cordula</forename><surname>Eskelson</surname></persName><roleName type="degree">MD</roleName><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation></author><author><persName><forename type="first">Imelda</forename><surname>Pepivani</surname></persName><roleName type="degree">BS</roleName><affiliation>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</affiliation><affiliation>Department of Neurology, Harvard Medical School, Boston, MA</affiliation></author><author><persName><forename type="first">Katja</forename><surname>Hedrich</surname></persName><roleName type="degree">PhD</roleName><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation></author><author><persName><forename type="first">Susanna</forename><surname>Adel</surname></persName><roleName type="degree">MD</roleName><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation></author><author><persName><forename type="first">Melissa</forename><surname>Gonzales‐McNeal</surname></persName><roleName type="degree">MS</roleName><affiliation>Department of Neurology, Oregon Health & Sciences University, Portland, OR</affiliation></author><author><persName><forename type="first">Rüdiger</forename><surname>Hilker</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Medical University of Cologne, Cologne, Germany</affiliation></author><author><persName><forename type="first">Patricia L.</forename><surname>Kramer</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neurology, Oregon Health & Sciences University, Portland, OR</affiliation></author><author><persName><forename type="first">Christine</forename><surname>Klein</surname></persName><roleName type="degree">MD</roleName><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation></author></analytic><monogr><title level="j">Annals of Neurology</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="pISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><idno type="DOI">10.1002/(ISSN)1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="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></monogr><idno type="istex">81B7E6235BA7A3D929AB6EA30F34A1891794AFCA</idno><idno type="DOI">10.1002/ana.20587</idno><idno type="ArticleID">ANA20587</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2005</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>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</p></abstract></profileDesc><revisionDesc><change when="2004-12-27">Received</change><change when="2005-06-21">Registration</change><change when="2005-09">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/81B7E6235BA7A3D929AB6EA30F34A1891794AFCA/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1531-8249</doi><issn type="print">0364-5134</issn><issn type="electronic">1531-8249</issn><idGroup><id type="product" value="ANA"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="ANNALS OF NEUROLOGY">Annals of Neurology</title><title type="short">Ann Neurol.</title></titleGroup></publicationMeta><publicationMeta level="part" position="30"><doi origin="wiley" registered="no">10.1002/ana.v58:3</doi><numberingGroup><numbering type="journalVolume" number="58">58</numbering><numbering type="journalIssue">3</numbering></numberingGroup><coverDate startDate="2005-09">September 2005</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="100" status="forIssue"><doi origin="wiley" registered="no">10.1002/ana.20587</doi><idGroup><id type="unit" value="ANA20587"></id></idGroup><countGroup><count type="pageTotal" number="12"></count></countGroup><copyright ownership="thirdParty">Copyright © 2005 American Neurological Association</copyright><eventGroup><event type="manuscriptReceived" date="2004-12-27"></event><event type="manuscriptRevised" date="2005-06-09"></event><event type="manuscriptAccepted" date="2005-06-21"></event><event type="firstOnline" date="2005-08-29"></event><event type="publishedOnlineFinalForm" date="2005-08-29"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.4.7 mode:FullText source:FullText result:FullText" date="2011-02-24"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-03"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-14"></event></eventGroup><numberingGroup><numbering type="pageFirst">411</numbering><numbering type="pageLast">422</numbering></numberingGroup><correspondenceTo>Department of Neurology, Central Hospital Bolzano/Bozen, 5 Lorenz‐Boehler Street, 39100 Bolzano/Bozen, Italy</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:ANA.ANA20587.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="4"></count><count type="tableTotal" number="3"></count><count type="referenceTotal" number="48"></count><count type="wordTotal" number="8235"></count></countGroup><titleGroup><title type="main" xml:lang="en">Lewy body Parkinson's disease in a large pedigree with 77 <i>Parkin</i> mutation carriers</title><title type="short" xml:lang="en">Lewy Body in <fi>Parkin</fi>‐Linked PD</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2 #af6" corresponding="yes"><personName><givenNames>Peter P.</givenNames><familyName>Pramstaller</familyName><degrees>MD</degrees></personName><contactDetails><email>peter.pramstaller@eurac.edu</email></contactDetails></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af3 #af4"><personName><givenNames>Michael G.</givenNames><familyName>Schlossmacher</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Thomas S.</givenNames><familyName>Jacques</familyName><degrees>PhD, MRCP</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Francesco</givenNames><familyName>Scaravilli</familyName><degrees>MD, FRCPath</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af6 #af7"><personName><givenNames>Cordula</givenNames><familyName>Eskelson</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af3 #af4"><personName><givenNames>Imelda</givenNames><familyName>Pepivani</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af6 #af7"><personName><givenNames>Katja</givenNames><familyName>Hedrich</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Susanna</givenNames><familyName>Adel</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af8"><personName><givenNames>Melissa</givenNames><familyName>Gonzales‐McNeal</familyName><degrees>MS</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af9"><personName><givenNames>Rüdiger</givenNames><familyName>Hilker</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af8"><personName><givenNames>Patricia L.</givenNames><familyName>Kramer</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af6 #af7"><personName><givenNames>Christine</givenNames><familyName>Klein</familyName><degrees>MD</degrees></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="IT" type="organization"><unparsedAffiliation>Department of Neurology, Central Hospital, Bolzano‐Bozen, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="IT" type="organization"><unparsedAffiliation>Institute of Genetic Medicine, European Academy‐Research, Bolzano‐Bozen, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Harvard Medical School, Boston, MA</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="GB" type="organization"><unparsedAffiliation>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="DE" type="organization"><unparsedAffiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af7" countryCode="DE" type="organization"><unparsedAffiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af8" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Oregon Health & Sciences University, Portland, OR</unparsedAffiliation></affiliation><affiliation xml:id="af9" countryCode="DE" type="organization"><unparsedAffiliation>Department of Neurology, Medical University of Cologne, Cologne, Germany</unparsedAffiliation></affiliation></affiliationGroup><fundingInfo><fundingAgency>Neuroepidemiology Project–South Tyrol</fundingAgency></fundingInfo><fundingInfo><fundingAgency>South Tyrolean Parkinson Disease Association</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Parkinson's Disease Foundation</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Deutsche Forschungsgemeinschaft</fundingAgency><fundingNumber>1134/2‐2</fundingNumber><fundingNumber>1134/3‐1</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Volkswagen Foundation</fundingAgency></fundingInfo><fundingInfo><fundingAgency>NIH (National Institute of Neurological Disorders and Stroke)</fundingAgency><fundingNumber>NS02127</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Multiple System Atrophy Fund at Brigham and Women's Hospital</fundingAgency></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>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 <i>Parkin</i> 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 <i>Parkin</i> mutation. The mutational status of five deceased patients was unknown, and seven PD patients had no <i>Parkin</i> 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 <i>Parkin</i> mutations. Autopsy of a 73‐year‐old patient, who carried two mutant <i>Parkin</i> 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 <i>Parkin</i> pedigree represents a unique opportunity to prospectively study the role of heterozygous <i>Parkin</i> 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</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Lewy Body in Parkin‐Linked PD</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Lewy body Parkinson's disease in a large pedigree with 77</title></titleInfo><name type="personal"><namePart type="given">Peter P.</namePart><namePart type="family">Pramstaller</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Central Hospital, Bolzano‐Bozen, Italy</affiliation><affiliation>Institute of Genetic Medicine, European Academy‐Research, Bolzano‐Bozen, Italy</affiliation><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation><description>Correspondence: Department of Neurology, Central Hospital Bolzano/Bozen, 5 Lorenz‐Boehler Street, 39100 Bolzano/Bozen, Italy</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael G.</namePart><namePart type="family">Schlossmacher</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</affiliation><affiliation>Department of Neurology, Harvard Medical School, Boston, MA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas S.</namePart><namePart type="family">Jacques</namePart><namePart type="termsOfAddress">PhD, MRCP</namePart><affiliation>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Francesco</namePart><namePart type="family">Scaravilli</namePart><namePart type="termsOfAddress">MD, FRCPath</namePart><affiliation>Division of Neuropathology, Department of Molecular Neuroscience, Institute of Neurology University College London, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Cordula</namePart><namePart type="family">Eskelson</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Imelda</namePart><namePart type="family">Pepivani</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA</affiliation><affiliation>Department of Neurology, Harvard Medical School, Boston, MA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katja</namePart><namePart type="family">Hedrich</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Susanna</namePart><namePart type="family">Adel</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Melissa</namePart><namePart type="family">Gonzales‐McNeal</namePart><namePart type="termsOfAddress">MS</namePart><affiliation>Department of Neurology, Oregon Health & Sciences University, Portland, OR</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rüdiger</namePart><namePart type="family">Hilker</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Medical University of Cologne, Cologne, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patricia L.</namePart><namePart type="family">Kramer</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurology, Oregon Health & Sciences University, Portland, OR</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christine</namePart><namePart type="family">Klein</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Departments of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Departments of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2005-09</dateIssued><dateCaptured encoding="w3cdtf">2004-12-27</dateCaptured><dateValid encoding="w3cdtf">2005-06-21</dateValid><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">4</extent><extent unit="tables">3</extent><extent unit="references">48</extent><extent unit="words">8235</extent></physicalDescription><abstract 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</abstract><note type="funding">Neuroepidemiology Project–South Tyrol</note><note type="funding">South Tyrolean Parkinson Disease Association</note><note type="funding">Parkinson's Disease Foundation</note><note type="funding">Deutsche Forschungsgemeinschaft - No. 1134/2‐2; No. 1134/3‐1; </note><note type="funding">Volkswagen Foundation</note><note type="funding">NIH (National Institute of Neurological Disorders and Stroke) - No. NS02127; </note><note type="funding">Multiple System Atrophy Fund at Brigham and Women's Hospital</note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>58</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>411</start><end>422</end><total>12</total></extent></part></relatedItem><identifier type="istex">81B7E6235BA7A3D929AB6EA30F34A1891794AFCA</identifier><identifier type="DOI">10.1002/ana.20587</identifier><identifier type="ArticleID">ANA20587</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2005 American Neurological Association</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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