Researchers from 21 centres across the worl
d collaborate
d on this stu
dy. The frequency of the common LRRK2 Gly2019Ser mutation was estimate
d on the basis of
data from 24 populations worl
dwi
de, an
d the penetrance of the mutation was
define
d in 1045 people with mutations in
LRRK2 from 133 families. The
LRRK2 phenotype was
define
d on the basis of 59 motor an
d non-motor symptoms in 356 patients with
LRRK2-associate
d PD an
d compare
d with the symptoms of 543 patients with pathologically proven i
diopathic PD.
Findings
Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1 % of patients with sporadic PD and 4 % of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28 % at age 59 years, 51 % at 69 years, and 74 % at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD.
Interpretation
Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients.
Funding
UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.div>div>
direct.com/science?_ob=MImg&_imagekey=B6X3F-4SP64YJ-2-5&_cdi=7297&_user=10&_orig=article&_coverDate=07 % 2F31 % 2F2008&_sk=999929992&view=c&wchp=dGLzVlz-zSkzk&md5=a294cbb90cbc5fdc99e427cb930cba47&ie=/sdarticle.pdf"">![]()
df"" style=""vertical-align:absmiddle;"" border=""0"" src=""http://www.sciencedirect.com/scidirimg/icon_pdf.gif"" alt=""""> Purchase PDF (173 K)d>div>div><div class=""infobubble-container""><div class=""mlktLink"" id=""mlktLink_2"">
<
div class=""infobubble"" i
d=""infobubble_2"" onMouseOver=""InfoBubble.show('infobubble_2','mlktLink_2')"" onMouseOut=""InfoBubble.timeout()"">
dding=0 cellspacing=0 width=100 % >d><div style=""float:right; padding-left:5px"">de()"">![]()
dirimg/btn_xclose.gif"" alt=""Close"" title=""Close"" onmouseover=""javascript:this.src='/scidirimg/btn_xclose_hov.gif';"" onmouseout=""javascript:this.src='/scidirimg/btn_xclose.gif';"">div>![]()
der=0 src=""/scidirimg/jrn_nsub.gif"" alt=""You are not entitled to access the full text of this document"" title=""You are not entitled to access the full text of this document"" width=12 height=14""> direct.com/science?_ob=ArticleURL&_udi=B6X3F-4SP64YJ-3&_user=10&_coverDate=07 % 2F31 % 2F2008&_rdoc=1&_fmt=high&_orig=article&_cdi=7297&_sort=v&_docanchor=&view=c&_ct=19&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=1132ff9dbb5ecd526b95f4582f11abb2"">LRRK2 Gly2019Ser penetrance in Arab–Berber patients from Tunisia: a case-control genetic study
The Lancet Neurology, Volume 7, Issue 7, July 2008, Pages 591-594
Mary M Hulihan, Lianna Ishihara-Paul, Jennifer Kachergus, Liling Warren, Rim Amouri, Ramu Elango, Rab K Prinjha, Ruchi Upmanyu, Mounir Kefi, Mourad Zouari, Samia Ben Sassi, Samia Ben Yahmed, Ghada El Euch-Fayeche, Paul M Matthews, Lefkos T Middleton, Rachel A Gibson, Fayçal Hentati, Matthew J Farrer
Abstract
<div class=""mlktScroll""><div style=""line-height:150 % "">Summary
BackgroundSeveral genes have been implicated in the pathogenesis of Parkinson's disease (PD). The aim of this study was to define the clinical symptoms and age-associated cumulative incidence of the most frequent mutation associated with PD, LRRK2 Gly2019Ser.Methods
238 patients with sporadic PD and 371 unrelated control participants from the Arab–Berber population were screened at the Institut National de Neurologie, Tunis. Symptoms of PD were assessed using the Hoehn and Yahr scale, the unified Parkinson's disease rating scale, and the Epworth scale. Genotyping for LRRK2 6055G→A, which causes the Gly2019Ser mutation, was done in all participants, and the age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.
Findings
30 % of patients with PD in this case-control sample were carriers of LRRK2 Gly2019Ser. The age of onset of symptoms and the clinical presentation of patients with LRRK2 Gly2019Ser were similar to those of patients with idiopathic PD. Carriers of LRRK2 Gly2019Ser were 22·6 times (95 % CI 10·2–50·1) more likely to be affected by PD than non-carriers. Tremor was the predominant symptom in LRRK2 Gly2019Ser carriers (92 % [homozygotes] vs 75 % [heterozygotes] vs 69 % [non-carriers]; Cochran–Armitage trend test p=0·0587). Disease severity, response to treatment, and disease duration were similar among LRRK2 Gly2019Ser homozygotes, heterozygotes, and non-carriers (p=0·85). Disease penetrance in LRRK2 Gly2019Ser carriers ranged from less than 20 % in those younger than 50 years to greater than 80 % at 70 years.
Interpretation
The LRRK2 Gly2019Ser mutation in patients with PD is a useful aid to diagnosis. LRRK2 Gly2019Ser penetrance can vary but in most carriers PD seems an inevitable consequence of ageing. LRRK2 Gly2019Ser considerably increases susceptibility to neuronal degeneration, although the process might be mediated by many triggers. By contrast, idiopathic PD is rare before 50 years and the prevalence only increases to 4 % in the oldest members of the population.
Funding
GlaxoSmithKline; National Institutes of Health; and Mayo Foundation.div>div>
direct.com/science?_ob=MImg&_imagekey=B6X3F-4SP64YJ-3-1&_cdi=7297&_user=10&_orig=article&_coverDate=07 % 2F31 % 2F2008&_sk=999929992&view=c&wchp=dGLzVlz-zSkzk&md5=5c577b8cec9a7453da4b766b6740ab2f&ie=/sdarticle.pdf"">![]()
df"" style=""vertical-align:absmiddle;"" border=""0"" src=""http://www.sciencedirect.com/scidirimg/icon_pdf.gif"" alt=""""> Purchase PDF (105 K)
d>
div>div><
div class=""infobubble-container""><
div class=""mlktLink"" i
d=""mlktLink_3"">
<
div class=""infobubble"" i
d=""infobubble_3"" onMouseOver=""InfoBubble.show('infobubble_3','mlktLink_3')"" onMouseOut=""InfoBubble.timeout()"">
dding=0 cellspacing=0 width=100 % >d><div style=""float:right; padding-left:5px"">de()"">![]()
dirimg/btn_xclose.gif"" alt=""Close"" title=""Close"" onmouseover=""javascript:this.src='/scidirimg/btn_xclose_hov.gif';"" onmouseout=""javascript:this.src='/scidirimg/btn_xclose.gif';"">div>![]()
der=0 src=""/scidirimg/jrn_nsub.gif"" alt=""You are not entitled to access the full text of this document"" title=""You are not entitled to access the full text of this document"" width=12 height=14""> direct.com/science?_ob=ArticleURL&_udi=B6T1B-4FBVXJV-14&_user=10&_coverDate=01 % 2F29 % 2F2005&_rdoc=1&_fmt=high&_orig=article&_cdi=4886&_sort=v&_docanchor=&view=c&_ct=19&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=935af1cc3abdf8f22f3c1e8623e821cb"">A common LRRK2 mutation in idiopathic Parkinson's disease
The Lancet, Volume 365, Issue 9457, 29 January 2005, Pages 415-416
William P Gilks, Patrick M Abou-Sleiman, Sonia Gandhi, Shushant Jain, Andrew Singleton, Andrew J Lees, Karen Shaw, Kailash P Bhatia, Vincenzo Bonifati, Niall P Quinn, John Lynch, Daniel G Healy, Janice L Holton, Tamas Revesz, Nicholas W Wood
Abstract
<div class=""mlktScroll""><div style=""line-height:150 % "">Summary
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant Parkinson's disease. Few mutations in this gene have been identified. We investigated the frequency of a common heterozygous mutation, 2877510G→A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019Ser), in idiopathic Parkinson's disease. We assessed 482 patients with the disorder, of whom 263 had pathologically confirmed disease, by direct sequencing for mutations in exon 41 of LRRK2. The mutation was present in eight (1·6 % ) patients. We have shown that a common single Mendelian mutation is implicated in sporadic Parkinson's disease. We suggest that testing for this mutation will be important in the management and genetic counselling of patients with Parkinson's disease.Published online January 18, 2005 http://image.thelancet.com/extras/04let12032web.pdfdiv>div>
direct.com/science?_ob=MImg&_imagekey=B6T1B-4FBVXJV-14-1&_cdi=4886&_user=10&_orig=article&_coverDate=01 % 2F29 % 2F2005&_sk=996340542&view=c&wchp=dGLzVlz-zSkzk&md5=d04a9f7e87bbb3128bcf2e1dffcde050&ie=/sdarticle.pdf"">![]()
df"" style=""vertical-align:absmiddle;"" border=""0"" src=""http://www.sciencedirect.com/scidirimg/icon_pdf.gif"" alt=""""> Purchase PDF (207 K)
d>
div>div>d>
d>d>
d style=""border-top: 1px dashed #CCCCCC; border-bottom: 1px solid #CCCCCC;background-color: #F6F6F6"" width=340>div>d>
dy>
js"">d style=""border-left: 0px solid #CCCCCC; border-right: 0px solid #CCCCCC; border-bottom: 1px solid #CCCCCC; margin: 0px; text-align: center"" onclick=""toggleMLKT('B6X3F-4SP64YJ-1','/scidirimg/btn_arrow_up_off.gif','/scidirimg/btn_arrow_down_off.gif','http://www.sciencedirect.com/science')"">![]()
dirimg/btn_arrow_up_off.gif"" id=""mlktArrow"" alt="""" border=""0"" onmouseover=""mlktHover(1,'/scidirimg/sci_dir/')"" onmouseout=""mlktHover(0,'/scidirimg/')"">d>
d>
d> d>
d><div id=""CollabBoxContent"">div>d>
<
div i
d=""articleBo
dy"" class=""font3""><
div class=""articleHea
derInner"" i
d=""articleHea
der"">
![]()
dirimg/clear.gif"" wi
dth=""1"" height=""10"" bor
der=""0"" alt="""">
dx.doi.org/10.1016/S1474-4422(08)70118-2"" target=""doilink"" onClick=""var doiWin; doiWin=window.open('http://dx.doi.org/10.1016/S1474-4422(08)70118-2','doilink','scrollbars=yes,resizable=yes,directories=yes,toolbar=yes,menubar=yes,status=yes'); doiWin.focus()"">doi:10.1016/S1474-4422(08)70118-2 doi.htm&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a143a86ddc585c54adbe80b2046626c3"" target=""sdhelp"" onMouseOver = ""window.status='Help is Available';return true"" onClick=""var helpWin; helpWin=window.open('/science?_ob=HelpURL&_file=doi.htm&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a143a86ddc585c54adbe80b2046626c3','sdhelp','scrollbars=yes,resizable=yes,directories=no,toolbar=no,menubar=no,status=no,width=760,height=570'); helpWin.focus()"">![]()
dirimg/icon_doi.gif"" width=""136"" height=""14"" alt=""How to Cite or Link Using DOI (Opens New Window)"" title=""How to Cite or Link Using DOI (Opens New Window)"" border=""0"" align=""absmiddle""> Copyright © 2008 Elsevier Lt
d All rights reserve
d.
Reflection and Reaction
<
div class=""articleTitle"">
LRRK2: bridging the gap between sporadic and hereditary Parkinson's disease
