A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity
Identifieur interne : 000906 ( Istex/Corpus ); précédent : 000905; suivant : 000907A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity
Auteurs : Parvoneh Poorkaj ; Wendy H. Raskind ; James B. Leverenz ; Mark Matsushita ; Cyrus P. Zabetian ; Ali Samii ; Sophia Kim ; Nayiry Gazi ; John G. Nutt ; John Wolff ; Dora Yearout ; J. Lynne Greenup ; Ellen J. Steinbart ; Thomas D. BirdSource :
- Movement Disorders [ 0885-3185 ] ; 2010-07-30.
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Abstract
The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X‐linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four‐repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two‐point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an ∼20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at‐risk males. To reduce the possibility of a false‐positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X‐linked parkinsonian syndrome with variable spasticity and four‐repeat tau pathology, and defined a novel candidate gene locus spanning ∼28 Mb from Xp11.2–Xq13.3. © 2010 Movement Disorder Society
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DOI: 10.1002/mds.23085
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Bird</name><affiliation><mods:affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:C23010745DD4A7B34E18552FA0555AD815AB3908</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1002/mds.23085</idno><idno type="url">https://api.istex.fr/document/C23010745DD4A7B34E18552FA0555AD815AB3908/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000906</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity</title><author><name sortKey="Poorkaj, Parvoneh" sort="Poorkaj, Parvoneh" uniqKey="Poorkaj P" first="Parvoneh" last="Poorkaj">Parvoneh Poorkaj</name><affiliation><mods:affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Raskind, Wendy H" sort="Raskind, Wendy H" uniqKey="Raskind W" first="Wendy H." last="Raskind">Wendy H. Raskind</name><affiliation><mods:affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Leverenz, James B" sort="Leverenz, James B" uniqKey="Leverenz J" first="James B." last="Leverenz">James B. Leverenz</name><affiliation><mods:affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Matsushita, Mark" sort="Matsushita, Mark" uniqKey="Matsushita M" first="Mark" last="Matsushita">Mark Matsushita</name><affiliation><mods:affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Zabetian, Cyrus P" sort="Zabetian, Cyrus P" uniqKey="Zabetian C" first="Cyrus P." last="Zabetian">Cyrus P. Zabetian</name><affiliation><mods:affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Samii, Ali" sort="Samii, Ali" uniqKey="Samii A" first="Ali" last="Samii">Ali Samii</name><affiliation><mods:affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Kim, Sophia" sort="Kim, Sophia" uniqKey="Kim S" first="Sophia" last="Kim">Sophia Kim</name><affiliation><mods:affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Gazi, Nayiry" sort="Gazi, Nayiry" uniqKey="Gazi N" first="Nayiry" last="Gazi">Nayiry Gazi</name><affiliation><mods:affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Nutt, John G" sort="Nutt, John G" uniqKey="Nutt J" first="John G." last="Nutt">John G. Nutt</name><affiliation><mods:affiliation>Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA</mods:affiliation></affiliation></author><author><name sortKey="Wolff, John" sort="Wolff, John" uniqKey="Wolff J" first="John" last="Wolff">John Wolff</name><affiliation><mods:affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Yearout, Dora" sort="Yearout, Dora" uniqKey="Yearout D" first="Dora" last="Yearout">Dora Yearout</name><affiliation><mods:affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Greenup, J Lynne" sort="Greenup, J Lynne" uniqKey="Greenup J" first="J. Lynne" last="Greenup">J. Lynne Greenup</name><affiliation><mods:affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Steinbart, Ellen J" sort="Steinbart, Ellen J" uniqKey="Steinbart E" first="Ellen J." last="Steinbart">Ellen J. Steinbart</name><affiliation><mods:affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation></author><author><name sortKey="Bird, Thomas D" sort="Bird, Thomas D" uniqKey="Bird T" first="Thomas D." last="Bird">Thomas D. Bird</name><affiliation><mods:affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-07-30">2010-07-30</date><biblScope unit="vol">25</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="1409">1409</biblScope><biblScope unit="page" to="1417">1417</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">C23010745DD4A7B34E18552FA0555AD815AB3908</idno><idno type="DOI">10.1002/mds.23085</idno><idno type="ArticleID">MDS23085</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson's disease/Parkinsonism</term><term>X‐linked Parkinsonism</term><term>X‐linked spastic paraparesis</term><term>genetic linkage</term><term>tauopathy</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X‐linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four‐repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two‐point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an ∼20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at‐risk males. To reduce the possibility of a false‐positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X‐linked parkinsonian syndrome with variable spasticity and four‐repeat tau pathology, and defined a novel candidate gene locus spanning ∼28 Mb from Xp11.2–Xq13.3. © 2010 Movement Disorder Society</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Parvoneh Poorkaj PhD</name><affiliations><json:string>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</json:string><json:string>Department of Medicine, University of Washington, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Wendy H. Raskind MD, PhD</name><affiliations><json:string>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</json:string><json:string>Department of Medicine, University of Washington, Seattle, Washington, USA</json:string><json:string>VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>James B. Leverenz MD</name><affiliations><json:string>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</json:string><json:string>VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</json:string><json:string>Department of Neurology, University of Washington, Seattle, Washington, USA</json:string><json:string>Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Mark Matsushita BS</name><affiliations><json:string>Department of Medicine, University of Washington, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Cyrus P. Zabetian MS, MD</name><affiliations><json:string>Department of Neurology, University of Washington, Seattle, Washington, USA</json:string><json:string>Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</json:string><json:string>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Ali Samii MD</name><affiliations><json:string>Department of Neurology, University of Washington, Seattle, Washington, USA</json:string><json:string>Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Sophia Kim BS</name><affiliations><json:string>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Nayiry Gazi BS</name><affiliations><json:string>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>John G. Nutt MD</name><affiliations><json:string>Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA</json:string></affiliations></json:item><json:item><name>John Wolff BS</name><affiliations><json:string>Department of Medicine, University of Washington, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Dora Yearout BS</name><affiliations><json:string>Department of Neurology, University of Washington, Seattle, Washington, USA</json:string><json:string>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>J. Lynne Greenup</name><affiliations><json:string>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Ellen J. Steinbart MA, RN</name><affiliations><json:string>Department of Neurology, University of Washington, Seattle, Washington, USA</json:string></affiliations></json:item><json:item><name>Thomas D. Bird MD</name><affiliations><json:string>Department of Medicine, University of Washington, Seattle, Washington, USA</json:string><json:string>Department of Neurology, University of Washington, Seattle, Washington, USA</json:string><json:string>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>genetic linkage</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease/Parkinsonism</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>X‐linked Parkinsonism</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>X‐linked spastic paraparesis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>tauopathy</value></json:item></subject><language><json:string>eng</json:string></language><abstract>The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X‐linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four‐repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two‐point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an ∼20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at‐risk males. To reduce the possibility of a false‐positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X‐linked parkinsonian syndrome with variable spasticity and four‐repeat tau pathology, and defined a novel candidate gene locus spanning ∼28 Mb from Xp11.2–Xq13.3. © 2010 Movement Disorder Society</abstract><qualityIndicators><score>7.127</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 810 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1621</abstractCharCount><pdfWordCount>4367</pdfWordCount><pdfCharCount>30186</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>230</abstractWordCount></qualityIndicators><title>A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity</title><genre><json:string>Serial article</json:string></genre><host><volume>25</volume><pages><total>9</total><last>1417</last><first>1409</first></pages><issn><json:string>0885-3185</json:string></issn><issue>10</issue><subject><json:item><value>Research 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xml:lang="en">A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>Wiley Subscription Services, Inc., A Wiley Company</p></availability><date>2010</date></publicationStmt><notesStmt><note type="content">*Potential conflict of interest: Nothing to report.</note><note>Department of Veterans Affairs</note><note>University of Washington Royalty Research Fund</note><note>Mary Gates Research Scholarship</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity</title><author><persName><forename type="first">Parvoneh</forename><surname>Poorkaj</surname><roleName type="degree">PhD</roleName></persName><note type="correspondence"><p>Correspondence: Department of Psychiatry and Behavioral Sciences, University of Washington, Box 356560, 1959 NE Pacific Street, Seattle, WA 98195</p></note><affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">Wendy H.</forename><surname>Raskind</surname><roleName type="degree">MD, PhD</roleName></persName><affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</affiliation><affiliation>VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">James B.</forename><surname>Leverenz</surname><roleName type="degree">MD</roleName></persName><affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation><affiliation>VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</affiliation><affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">Mark</forename><surname>Matsushita</surname><roleName type="degree">BS</roleName></persName><affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">Cyrus P.</forename><surname>Zabetian</surname><roleName type="degree">MS, 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of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">Nayiry</forename><surname>Gazi</surname><roleName type="degree">BS</roleName></persName><affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">John G.</forename><surname>Nutt</surname><roleName type="degree">MD</roleName></persName><affiliation>Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA</affiliation></author><author><persName><forename type="first">John</forename><surname>Wolff</surname><roleName type="degree">BS</roleName></persName><affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">Dora</forename><surname>Yearout</surname><roleName type="degree">BS</roleName></persName><affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">J. Lynne</forename><surname>Greenup</surname></persName><affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">Ellen J.</forename><surname>Steinbart</surname><roleName type="degree">MA, RN</roleName></persName><affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</affiliation></author><author><persName><forename type="first">Thomas D.</forename><surname>Bird</surname><roleName type="degree">MD</roleName></persName><affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</affiliation></author></analytic><monogr><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="pISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><idno type="DOI">10.1002/(ISSN)1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-07-30"></date><biblScope unit="vol">25</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="1409">1409</biblScope><biblScope unit="page" to="1417">1417</biblScope></imprint></monogr><idno type="istex">C23010745DD4A7B34E18552FA0555AD815AB3908</idno><idno type="DOI">10.1002/mds.23085</idno><idno type="ArticleID">MDS23085</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X‐linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four‐repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two‐point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an ∼20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at‐risk males. To reduce the possibility of a false‐positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X‐linked parkinsonian syndrome with variable spasticity and four‐repeat tau pathology, and defined a novel candidate gene locus spanning ∼28 Mb from Xp11.2–Xq13.3. © 2010 Movement Disorder Society</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>genetic linkage</term></item><item><term>Parkinson's disease/Parkinsonism</term></item><item><term>X‐linked Parkinsonism</term></item><item><term>X‐linked spastic paraparesis</term></item><item><term>tauopathy</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Article category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-08-26">Received</change><change when="2010-02-12">Registration</change><change when="2010-07-30">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/C23010745DD4A7B34E18552FA0555AD815AB3908/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)1531-8257</doi><issn type="print">0885-3185</issn><issn type="electronic">1531-8257</issn><idGroup><id type="product" value="MDS"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="short">Mov. Disord.</title></titleGroup></publicationMeta><publicationMeta level="part" position="100"><doi origin="wiley" registered="yes">10.1002/mds.v25:10</doi><numberingGroup><numbering type="journalVolume" number="25">25</numbering><numbering type="journalIssue">10</numbering></numberingGroup><coverDate startDate="2010-07-30">30 July 2010</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="110" status="forIssue"><doi origin="wiley" registered="yes">10.1002/mds.23085</doi><idGroup><id type="unit" value="MDS23085"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2010 Movement Disorder Society</copyright><eventGroup><event type="manuscriptReceived" date="2009-08-26"></event><event type="manuscriptRevised" date="2009-12-16"></event><event type="manuscriptAccepted" date="2010-02-12"></event><event type="firstOnline" date="2010-04-13"></event><event type="publishedOnlineFinalForm" date="2010-07-23"></event><event type="publishedOnlineAcceptedOrEarlyUnpaginated" date="2010-04-13"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.5.2 mode:FullText source:FullText result:FullText" date="2011-06-21"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-02-02"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-31"></event></eventGroup><numberingGroup><numbering type="pageFirst">1409</numbering><numbering type="pageLast">1417</numbering></numberingGroup><correspondenceTo>Department of Psychiatry and Behavioral Sciences, University of Washington, Box 356560, 1959 NE Pacific Street, Seattle, WA 98195</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:MDS.MDS23085.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="3"></count><count type="tableTotal" number="2"></count><count type="referenceTotal" number="35"></count><count type="wordTotal" number="5348"></count></countGroup><titleGroup><title type="main" xml:lang="en">A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity<link href="#fn2"></link></title><title type="short" xml:lang="en">X‐Linked Parkinsonism with Spasticity</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>Parvoneh</givenNames><familyName>Poorkaj</familyName><degrees>PhD</degrees></personName><contactDetails><email>pips@uw.edu</email></contactDetails></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2 #af3"><personName><givenNames>Wendy H.</givenNames><familyName>Raskind</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1 #af3 #af4 #af5"><personName><givenNames>James B.</givenNames><familyName>Leverenz</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Mark</givenNames><familyName>Matsushita</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af4 #af5 #af7"><personName><givenNames>Cyrus P.</givenNames><familyName>Zabetian</familyName><degrees>MS, MD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af4 #af5"><personName><givenNames>Ali</givenNames><familyName>Samii</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Sophia</givenNames><familyName>Kim</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Nayiry</givenNames><familyName>Gazi</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af6"><personName><givenNames>John G.</givenNames><familyName>Nutt</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af2"><personName><givenNames>John</givenNames><familyName>Wolff</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af4 #af7"><personName><givenNames>Dora</givenNames><familyName>Yearout</familyName><degrees>BS</degrees></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af1"><personName><givenNames>J. 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Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X‐linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four‐repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two‐point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LOD<sub>max</sub> score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an ∼20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at‐risk males. To reduce the possibility of a false‐positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X‐linked parkinsonian syndrome with variable spasticity and four‐repeat tau pathology, and defined a novel candidate gene locus spanning ∼28 Mb from Xp11.2–Xq13.3. © 2010 Movement Disorder Society</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn2"><p>Potential conflict of interest: Nothing to report.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><!--Version 0.6 générée le 3-12-2015--><mods version="3.6"><titleInfo lang="en"><title>A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>X‐Linked Parkinsonism with Spasticity</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>A novel X‐linked four‐repeat tauopathy with Parkinsonism and spasticity</title></titleInfo><name type="personal"><namePart type="given">Parvoneh</namePart><namePart type="family">Poorkaj</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</affiliation><description>Correspondence: Department of Psychiatry and Behavioral Sciences, University of Washington, Box 356560, 1959 NE Pacific Street, Seattle, WA 98195</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wendy H.</namePart><namePart type="family">Raskind</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</affiliation><affiliation>VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">James B.</namePart><namePart type="family">Leverenz</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA</affiliation><affiliation>VISN 20 Mental Illness Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</affiliation><affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark</namePart><namePart 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type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John G.</namePart><namePart type="family">Nutt</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John</namePart><namePart type="family">Wolff</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Department of Medicine, University of Washington, Seattle, Washington, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dora</namePart><namePart type="family">Yearout</namePart><namePart type="termsOfAddress">BS</namePart><affiliation>Department of Neurology, University of Washington, Seattle, Washington, USA</affiliation><affiliation>Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget 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Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X‐linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four‐repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two‐point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an ∼20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at‐risk males. To reduce the possibility of a false‐positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X‐linked parkinsonian syndrome with variable spasticity and four‐repeat tau pathology, and defined a novel candidate gene locus spanning ∼28 Mb from Xp11.2–Xq13.3. © 2010 Movement Disorder Society</abstract><note type="content">*Potential conflict of interest: Nothing to report.</note><note type="funding">Department of Veterans Affairs</note><note type="funding">University of Washington Royalty Research Fund</note><note type="funding">Mary Gates Research Scholarship</note><subject lang="en"><genre>Keywords</genre><topic>genetic linkage</topic><topic>Parkinson's disease/Parkinsonism</topic><topic>X‐linked Parkinsonism</topic><topic>X‐linked spastic paraparesis</topic><topic>tauopathy</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title></titleInfo><titleInfo type="abbreviated"><title>Mov. 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