A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease
Identifieur interne : 002C84 ( Main/Corpus ); précédent : 002C83; suivant : 002C85A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease
Auteurs : Kenya Nishioka ; Mounir Kefi ; Barbara Jasinska-Myga ; Christian Wider ; Carles Vilari O-Güell ; Owen A. Ross ; Michael G. Heckman ; Lefkos T. Middleton ; Lianna Ishihara-Paul ; Rachel A. Gibson ; Rim Amouri ; Samia Ben Yahmed ; Samia Ben Sassi ; Mourad Zouari ; Ghada El Euch ; Matthew J. Farrer ; Faycal HentatiSource :
- Journal of Neurology, Neurosurgery & Psychiatry [ 0022-3050 ] ; 2010-04.
Abstract
Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores ∼1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.
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DOI: 10.1136/jnnp.2009.185231
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Ross</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Heckman, Michael G" sort="Heckman, Michael G" uniqKey="Heckman M" first="Michael G" last="Heckman">Michael G. Heckman</name><affiliation><mods:affiliation>Biostatistics Unit, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Middleton, Lefkos T" sort="Middleton, Lefkos T" uniqKey="Middleton L" first="Lefkos T" last="Middleton">Lefkos T. Middleton</name><affiliation><mods:affiliation>Division of Neuroscience, Imperial College London, London, UK</mods:affiliation></affiliation></author><author><name sortKey="Ishihara Paul, Lianna" sort="Ishihara Paul, Lianna" uniqKey="Ishihara Paul L" first="Lianna" last="Ishihara-Paul">Lianna Ishihara-Paul</name><affiliation><mods:affiliation>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</mods:affiliation></affiliation></author><author><name sortKey="Gibson, Rachel A" sort="Gibson, Rachel A" uniqKey="Gibson R" first="Rachel A" last="Gibson">Rachel A. Gibson</name><affiliation><mods:affiliation>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</mods:affiliation></affiliation></author><author><name sortKey="Amouri, Rim" sort="Amouri, Rim" uniqKey="Amouri R" first="Rim" last="Amouri">Rim Amouri</name><affiliation><mods:affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</mods:affiliation></affiliation></author><author><name sortKey="Ben Yahmed, Samia" sort="Ben Yahmed, Samia" uniqKey="Ben Yahmed S" first="Samia" last="Ben Yahmed">Samia Ben Yahmed</name><affiliation><mods:affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</mods:affiliation></affiliation></author><author><name sortKey="Ben Sassi, Samia" sort="Ben Sassi, Samia" uniqKey="Ben Sassi S" first="Samia" last="Ben Sassi">Samia Ben Sassi</name><affiliation><mods:affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</mods:affiliation></affiliation></author><author><name sortKey="Zouari, Mourad" sort="Zouari, Mourad" uniqKey="Zouari M" first="Mourad" last="Zouari">Mourad Zouari</name><affiliation><mods:affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</mods:affiliation></affiliation></author><author><name sortKey="El Euch, Ghada" sort="El Euch, Ghada" uniqKey="El Euch G" first="Ghada" last="El Euch">Ghada El Euch</name><affiliation><mods:affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</mods:affiliation></affiliation></author><author><name sortKey="Farrer, Matthew J" sort="Farrer, Matthew J" uniqKey="Farrer M" first="Matthew J" last="Farrer">Matthew J. Farrer</name><affiliation><mods:affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</mods:affiliation></affiliation></author><author><name sortKey="Hentati, Faycal" sort="Hentati, Faycal" uniqKey="Hentati F" first="Faycal" last="Hentati">Faycal Hentati</name><affiliation><mods:affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Neurology, Neurosurgery & Psychiatry</title><title level="j" type="abbrev">J Neurol Neurosurg Psychiatry</title><idno type="ISSN">0022-3050</idno><idno type="eISSN">1468-330X</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2010-04">2010-04</date><biblScope unit="volume">81</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="391">391</biblScope></imprint><idno type="ISSN">0022-3050</idno></series><idno type="istex">BE8BFE0EC934CF35A89D5E71960AE3D6BBE9A8CF</idno><idno type="DOI">10.1136/jnnp.2009.185231</idno><idno type="href">jnnp-81-391.pdf</idno><idno type="ArticleID">jnnp185231</idno><idno type="PMID">19726410</idno><idno type="local">jnnp;81/4/391</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-3050</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores ∼1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.</div></front></TEI><istex><corpusName>bmj</corpusName><author><json:item><name>Kenya Nishioka</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Mounir Kefi</name><affiliations><json:string>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</json:string></affiliations></json:item><json:item><name>Barbara Jasinska-Myga</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string><json:string>Department of Neurology, Ageing, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice, Poland</json:string></affiliations></json:item><json:item><name>Christian Wider</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Carles Vilariño-Güell</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string><json:string>E-mail: VilarinoGuell.Carles@mayo.edu</json:string></affiliations></json:item><json:item><name>Owen A Ross</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Michael G Heckman</name><affiliations><json:string>Biostatistics Unit, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Lefkos T Middleton</name><affiliations><json:string>Division of Neuroscience, Imperial College London, London, UK</json:string></affiliations></json:item><json:item><name>Lianna Ishihara-Paul</name><affiliations><json:string>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</json:string></affiliations></json:item><json:item><name>Rachel A Gibson</name><affiliations><json:string>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</json:string></affiliations></json:item><json:item><name>Rim Amouri</name><affiliations><json:string>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</json:string></affiliations></json:item><json:item><name>Samia Ben Yahmed</name><affiliations><json:string>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</json:string></affiliations></json:item><json:item><name>Samia Ben Sassi</name><affiliations><json:string>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</json:string></affiliations></json:item><json:item><name>Mourad Zouari</name><affiliations><json:string>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</json:string></affiliations></json:item><json:item><name>Ghada El Euch</name><affiliations><json:string>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</json:string></affiliations></json:item><json:item><name>Matthew J Farrer</name><affiliations><json:string>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</json:string></affiliations></json:item><json:item><name>Faycal Hentati</name><affiliations><json:string>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Research paper</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Genetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's Disease</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores ∼1.6 times higher, p>0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p>0.001), and less postural tremor (OR 0.21, p>0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p>0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.</abstract><qualityIndicators><score>7.217</score><pdfVersion>1.4</pdfVersion><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>3</keywordCount><abstractCharCount>1907</abstractCharCount><pdfWordCount>3717</pdfWordCount><pdfCharCount>25795</pdfCharCount><pdfPageCount>5</pdfPageCount><abstractWordCount>268</abstractWordCount></qualityIndicators><title>A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's 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Ltd</publisher><availability><p>BMJ</p></availability><date>2009-09-02</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease</title><author><persName><forename type="first">Kenya</forename><surname>Nishioka</surname></persName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Mounir</forename><surname>Kefi</surname></persName><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation></author><author><persName><forename type="first">Barbara</forename><surname>Jasinska-Myga</surname></persName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><affiliation>Department of Neurology, Ageing, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice, Poland</affiliation></author><author><persName><forename type="first">Christian</forename><surname>Wider</surname></persName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author corresp="yes"><persName><forename type="first">Carles</forename><surname>Vilariño-Güell</surname></persName><email>VilarinoGuell.Carles@mayo.edu</email><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Owen A</forename><surname>Ross</surname></persName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Michael G</forename><surname>Heckman</surname></persName><affiliation>Biostatistics Unit, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Lefkos T</forename><surname>Middleton</surname></persName><affiliation>Division of Neuroscience, Imperial College London, London, UK</affiliation></author><author><persName><forename type="first">Lianna</forename><surname>Ishihara-Paul</surname></persName><affiliation>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</affiliation></author><author><persName><forename type="first">Rachel A</forename><surname>Gibson</surname></persName><affiliation>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</affiliation></author><author><persName><forename type="first">Rim</forename><surname>Amouri</surname></persName><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation></author><author><persName><forename type="first">Samia</forename><surname>Ben Yahmed</surname></persName><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation></author><author><persName><forename type="first">Samia</forename><surname>Ben Sassi</surname></persName><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation></author><author><persName><forename type="first">Mourad</forename><surname>Zouari</surname></persName><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation></author><author><persName><forename type="first">Ghada</forename><surname>El Euch</surname></persName><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation></author><author><persName><forename type="first">Matthew J</forename><surname>Farrer</surname></persName><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation></author><author><persName><forename type="first">Faycal</forename><surname>Hentati</surname></persName><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation></author></analytic><monogr><title level="j">Journal of Neurology, Neurosurgery & Psychiatry</title><title level="j" type="abbrev">J Neurol Neurosurg Psychiatry</title><idno type="pISSN">0022-3050</idno><idno type="eISSN">1468-330X</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2010-04"></date><biblScope unit="volume">81</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="391">391</biblScope></imprint></monogr><idno type="istex">BE8BFE0EC934CF35A89D5E71960AE3D6BBE9A8CF</idno><idno type="DOI">10.1136/jnnp.2009.185231</idno><idno type="href">jnnp-81-391.pdf</idno><idno type="ArticleID">jnnp185231</idno><idno type="PMID">19726410</idno><idno type="local">jnnp;81/4/391</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009-09-02</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores ∼1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Genetics</term></item><item><term>Parkinson's Disease</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-09-02">Created</change><change when="2010-04">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/BE8BFE0EC934CF35A89D5E71960AE3D6BBE9A8CF/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Archiving and Interchange DTD v2.3 20070202//EN" URI="archivearticle.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">jnnp</journal-id><journal-id journal-id-type="nlm-ta">J Neurol Neurosurg Psychiatry</journal-id><journal-id journal-id-type="publisher-id">jnnp</journal-id><journal-title>Journal of Neurology, Neurosurgery & Psychiatry</journal-title><abbrev-journal-title abbrev-type="publisher">J Neurol Neurosurg Psychiatry</abbrev-journal-title><abbrev-journal-title>J Neurol Neurosurg Psychiatry</abbrev-journal-title><issn pub-type="ppub">0022-3050</issn><issn pub-type="epub">1468-330X</issn><publisher><publisher-name>BMJ Publishing Group Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">jnnp185231</article-id><article-id pub-id-type="doi">10.1136/jnnp.2009.185231</article-id><article-id pub-id-type="other">jnnp;81/4/391</article-id><article-id pub-id-type="other">jnnp;jnnp.2009.185231</article-id><article-id pub-id-type="pmid">19726410</article-id><article-id pub-id-type="other">391</article-id><article-id pub-id-type="other">jnnp.2009.185231</article-id><article-categories><subj-group subj-group-type="heading"><subject content-type="original">Research paper</subject></subj-group></article-categories><title-group><article-title>A comparative study of <italic>LRRK2</italic>, <italic>PINK1</italic> and genetically undefined familial Parkinson's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Nishioka</surname><given-names>Kenya</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kefi</surname><given-names>Mounir</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Jasinska-Myga</surname><given-names>Barbara</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Wider</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Vilariño-Güell</surname><given-names>Carles</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ross</surname><given-names>Owen A</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Heckman</surname><given-names>Michael G</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Middleton</surname><given-names>Lefkos T</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Ishihara-Paul</surname><given-names>Lianna</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Gibson</surname><given-names>Rachel A</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Amouri</surname><given-names>Rim</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ben Yahmed</surname><given-names>Samia</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Ben Sassi</surname><given-names>Samia</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Zouari</surname><given-names>Mourad</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>El Euch</surname><given-names>Ghada</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Farrer</surname><given-names>Matthew J</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hentati</surname><given-names>Faycal</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</aff><aff id="aff2"><label>2</label>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</aff><aff id="aff3"><label>3</label>Department of Neurology, Ageing, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice, Poland</aff><aff id="aff4"><label>4</label>Biostatistics Unit, Mayo Clinic, Jacksonville, Florida, USA</aff><aff id="aff5"><label>5</label>Division of Neuroscience, Imperial College London, London, UK</aff><aff id="aff6"><label>6</label>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</aff><author-notes><corresp><label>Correspondence to</label> Dr C Vilariño-Güell, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, USA; <email>VilarinoGuell.Carles@mayo.edu</email></corresp></author-notes><pub-date pub-type="epub-original"><day>2</day><month>9</month><year>2009</year></pub-date><pub-date pub-type="ppub"><month>4</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>2</day><month>9</month><year>2009</year></pub-date><volume>81</volume><volume-id pub-id-type="other">81</volume-id><volume-id pub-id-type="other">81</volume-id><issue>4</issue><issue-id pub-id-type="other">jnnp;81/4</issue-id><issue-id pub-id-type="other">4</issue-id><issue-id pub-id-type="other">81/4</issue-id><fpage>391</fpage><history><date date-type="received"><day>3</day><month>6</month><year>2009</year></date><date date-type="rev-recd"><day>20</day><month>7</month><year>2009</year></date><date date-type="accepted"><day>22</day><month>7</month><year>2009</year></date></history><permissions><copyright-statement>© 2010, Published by the BMJ Publishing Group Limited For permission to use, (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</copyright-statement><copyright-year>2010</copyright-year></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="jnnp-81-391.pdf"></self-uri><abstract><p>Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in <italic>leucine rich repeat kinase 2</italic> (<italic>LRRK2</italic>), <italic>PTEN induced kinase 1</italic> (<italic>PINK1</italic>) and <italic>parkin</italic> (<italic>PRKN</italic>). Clinical features were compared between patients with genetically undefined PD (n=107) and those with <italic>LRRK2</italic> (n=73) and <italic>PINK1</italic> (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. <italic>PRKN</italic> cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, <italic>LRRK2</italic> mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores ∼1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). <italic>PINK1</italic> mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, <italic>PINK1</italic> patients had younger ages and ages at disease onset, and a longer disease duration compared with <italic>LRRK2</italic> mutation carriers and genetically undefined patients. Clinical differences between <italic>LRRK2</italic>, <italic>PINK1</italic> and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.</p></abstract><kwd-group><kwd>Genetics</kwd><kwd>Parkinson's Disease</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson's disease</title></titleInfo><name type="personal"><namePart type="given">Kenya</namePart><namePart type="family">Nishioka</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mounir</namePart><namePart type="family">Kefi</namePart><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Barbara</namePart><namePart type="family">Jasinska-Myga</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><affiliation>Department of Neurology, Ageing, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice, Poland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian</namePart><namePart type="family">Wider</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Carles</namePart><namePart type="family">Vilariño-Güell</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><affiliation>E-mail: VilarinoGuell.Carles@mayo.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Owen A</namePart><namePart type="family">Ross</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael G</namePart><namePart type="family">Heckman</namePart><affiliation>Biostatistics Unit, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lefkos T</namePart><namePart type="family">Middleton</namePart><affiliation>Division of Neuroscience, Imperial College London, London, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lianna</namePart><namePart type="family">Ishihara-Paul</namePart><affiliation>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rachel A</namePart><namePart type="family">Gibson</namePart><affiliation>Research and Development, GlaxoSmithKline Pharmaceuticals Ltd, Harlow, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rim</namePart><namePart type="family">Amouri</namePart><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Samia</namePart><namePart type="family">Ben Yahmed</namePart><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Samia</namePart><namePart type="family">Ben Sassi</namePart><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mourad</namePart><namePart type="family">Zouari</namePart><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ghada</namePart><namePart type="family">El Euch</namePart><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Matthew J</namePart><namePart type="family">Farrer</namePart><affiliation>Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Faycal</namePart><namePart type="family">Hentati</namePart><affiliation>Service de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>BMJ Publishing Group Ltd</publisher><dateIssued encoding="w3cdtf">2010-04</dateIssued><dateCreated encoding="w3cdtf">2009-09-02</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores ∼1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.</abstract><subject><genre>Keywords</genre><topic>Genetics</topic><topic>Parkinson's Disease</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Neurology, Neurosurgery & Psychiatry</title></titleInfo><titleInfo type="abbreviated"><title>J Neurol Neurosurg Psychiatry</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0022-3050</identifier><identifier type="eISSN">1468-330X</identifier><identifier type="PublisherID">jnnp</identifier><identifier type="PublisherID-hwp">jnnp</identifier><identifier type="PublisherID-nlm-ta">J Neurol Neurosurg Psychiatry</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>81</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>391</start></extent></part></relatedItem><identifier type="istex">BE8BFE0EC934CF35A89D5E71960AE3D6BBE9A8CF</identifier><identifier type="DOI">10.1136/jnnp.2009.185231</identifier><identifier type="href">jnnp-81-391.pdf</identifier><identifier type="ArticleID">jnnp185231</identifier><identifier type="PMID">19726410</identifier><identifier type="local">jnnp;81/4/391</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2010, Published by the BMJ Publishing Group Limited For permission to use, (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</accessCondition><recordInfo><recordContentSource>BMJ</recordContentSource></recordInfo></mods></metadata><annexes><json:item><original>true</original><mimetype>image/jpeg</mimetype><extension>jpeg</extension><uri>https://api.istex.fr/document/BE8BFE0EC934CF35A89D5E71960AE3D6BBE9A8CF/annexes/jpeg</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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