ARTICLE IN PRESS

1353-8020/$ - se

doi:10.1016/j.pa

�CorrespondCenter S-182,

Columbian Wa

fax: +1206 764

E-mail addr

Please cite thi

Relat Disord

Parkinsonism and Related Disorders ] (]]]]) ]]]–]]]

www.elsevier.com/locate/parkreldis

Lrrk2-associated parkinsonism is a major causeof disease in Northern Spain

Marıa C. Gonzalez-Fernandeza,b, Elena Lezcanoc, Owen A. Rossb, Juan C. Gomez-Estebanc,Fernando Gomez-Bustod, Fernando Velascoc, Maite Alvarez-Alvareza,Marıa B. Rodrıguez-Martıneza, Roberto Ciordiac, Juan J. Zarranzc,Matthew J. Farrerb, Ignacio F. Matab,e,�, Marian M. de Pancorboa

aServicio General de Investigacion Genomica: Banco de ADN and Departamento de Z.y Biologıa Celular A., Universidad del Paıs Vasco, Vitoria-Gasteiz, SpainbDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

cServicio de Neurologıa, Hospital de Cruces, Barakaldo, SpaindServicios Geriatricos, Residencia de Tercera Edad San Prudencio, Ayuntamiento de Vitoria-Gasteiz, Spain

eDepartment of Neurology, University of Washington School of Medicine, Seattle, WA, USA

Received 22 December 2006; received in revised form 4 April 2007; accepted 5 April 2007

Abstract

Herein we describe a comparative clinical and genetic study of Lrrk2-associated parkinsonism in Northern Spain. In our sample from

the Basque region, Lrrk2 R1441G and G2019S account for 15 out of 50 kindreds (30%) with familial Parkinson’s disease. We observe

common founder haplotypes for both R1441G and G2019S carriers. Our findings highlight the importance of Lrrk2 parkinsonism in this

population and may have important consequences for its extended Diaspora in North, Central and South Americas.

r 2007 Elsevier Ltd. All rights reserved.

Keywords: Parkinson’s disease; LRRK2; Dardarina; Spain; Mutation

1. Introduction

Parkinson’s disease (PD) is a neurodegenerative disorderwith the predominant feature of movement disorder. It isclinically characterized by resting tremor, bradykinesia,rigidity, postural instability and a good response tolevodopa therapy. By its nature PD is considered a‘sporadic’ disorder but approximately 15% of patientsreport a positive family history of parkinsonism [1]. Overthe last decade, mutations in seven genes have beenidentified that cause monogenic forms of parkinsonism[1]. The latest gene LRRK2 (PARK8; OMIM*609007) islocated at chromosome 12q12 and contains 51 exonsencoding the 2527 amino acid Lrrk2 protein [2].

e front matter r 2007 Elsevier Ltd. All rights reserved.

rkreldis.2007.04.003

ing author. Geriatric Research Education and Clinical

VA Puget Sound Health Care System, 1660 South

y, Seattle, WA 98108, USA. Tel.: +1206 277 6642;

2569.

ess: nachofm@u.washington.edu (I.F. Mata).

s article as: Gonzalez-Fernandez MC, et al. Lrrk2-associated pa

(2007), doi:10.1016/j.parkreldis.2007.04.003

LRRK2 mutations are the most frequent genetic cause ofPD to date, accounting for up to 7% of familial PD and�1% of sporadic cases [1]. The ‘common’ Lrrk2 G2019Ssubstitution is observed in up to 41% of familial andsporadic PD dependent on ethnicity [3,4]. The frequency ofLrrk2 G2019S in Northern Spain is reported to be�3–18% in sporadic and familial disease [5–7]. However,Northern Spain harbours a second frequent Lrrk2 sub-stitution, R1441G (4321C4G mutation), which was firstidentified in four Basque families and observed in 8% ofPD patients from this region [8]. Although not observedwith the global distribution of G2019S, other studies inNorthern Spain (Fig. 1) have reported frequencies forR1441G up to 2.7% [5,9].This study presents the genetic analysis of both Lrrk2

R1441G and G2019S pathogenic substitutions in patientswith PD from Northwest Basque region of Spain. Wegenotyped chromosome 12 markers in carriers to determinewhether R1441G and G2019S lie on specific haplotypes,

rkinsonism is a major cause of disease in Northern Spain. Parkinsonism

ARTICLE IN PRESS

Fig. 1. Map of Northern Spain. Published Lrrk2 substitution frequencies in Spain are shown [5–9]. Also highlighted are the northern regions in which

Lrrk2 kindreds originate; we observed seven Lrrk2 R1441G families who have their origin in the Basque region, two families from neighboring region of

Navarre, and one from la Rioja. For Lrrk2 G2019S we report two families originated from the Basque region, two from Galicia and one from Cantabria.

Table 1

Summary of samples and carriers

Total number of samples 108 R1441G carriers 21 G2019S carriers 8

Number of families 50 Number of families 10 Number of families 5

Affected members 61 Affected members 15 Affected members 6

Age at onset X50 28 Age at onset X50 10 Age at onset X50 5

Age at onset o50 33 Age at onset o50 5 Age at onset o50 1

Asymptomatic 30 Asymptomatic 6 Asymptomatic 1

Sporadic 17 Sporadic 0 Sporadic 1

M.C. Gonzalez-Fernandez et al. / Parkinsonism and Related Disorders ] (]]]]) ]]]–]]]2

indicative of an ‘ancestral founder’ for these mutations[9–11].

2. Patients and methods

In total, 61 PD patients and 30 asymptomatic relatives from 50 families

with parkinsonism participated in this study (Table 1). Eleven families

showed an autosomal dominant pattern of inheritance, with three or more

members affected by PD in at least two consecutive generations. Ten

families showed a possible autosomal dominant pattern of inheritance,

with two or more members affected by PD/dementia in at least two

consecutive generations. Lack of pedigree information limited determina-

tion of the pattern of disease transmission in the remaining 29 families.

Given the evidence of reduced penetrance and presence of LRRK2

mutations in apparent sporadic disease, 17 early-onset (p50 years old)

sporadic PD patients, currently enrolled in a study examining genes

implicated in autosomal recessive forms of parkinsonism, were also

assessed. All subjects were examined at one hospital and one outpatient

clinic from Northern Spain and ancestry was determined according to the

ethnicity of the patients’ grandparents. The clinical diagnosis of PD was

established according to accepted London Brain Bank criteria. The Mini-

Mental State examination was used to assess cognitive function [12]. Sixty-

eight healthy elderly individuals from the same region, without evidence

for neurological disease, provided population-specific healthy controls.

The study was approved by the local ethics authorities and written

informed consent was obtained from all participants.

Please cite this article as: Gonzalez-Fernandez MC, et al. Lrrk2-associated pa

Relat Disord (2007), doi:10.1016/j.parkreldis.2007.04.003

DNA was obtained from peripheral blood leukocytes or buccal cells for

all subjects by standard methods. All subjects providing DNA, including

affected and healthy family members, were screened for LRRK2

4321C4G (Ex31, R1441G) and 6055G4A (Ex41, G2019S) mutations

due to phenocopy appearence and the low penetrance previously described

[10]. Genotyping of amplified products for 4321C4G and 6055G4A was

performed using TaqMan chemistry on an ABI7900 under conditions

previously described (Applied Biosystems, Foster City, CA; SDS 2.2.2

software) [6,9]. The R1441 codon was also examined by restriction

analysis with BstU1 enzyme to rule out the presence of other variants at

this position (R1441C and R1441H). All samples positive for Lrrk2

R1441G and G2019S substitutions were confirmed by direct DNA

sequence analysis using standard techniques (ABI 3730 DNA Analyzer)

[13]. Microsatellite and single nucleotide polymorphism (SNP) markers

were genotyped within carriers in the proximity of each mutation, as

previously described [9,10]. Additionally, four probands with autosomal

dominant PD (three or more affected members within the kindred) were

fully sequenced for all 51 exons in LRRK2 gene using published primers

and conditions [13].

3. Results

No pathogenic variants were detected after sequencingall 51 exons and intron–exon boundaries in probands fromfour families with three or more affected relatives in twogenerations, compatible with an autosomal dominant

rkinsonism is a major cause of disease in Northern Spain. Parkinsonism

ARTICLE IN PRESS

Fig. 2. Lrrk2 family pedigrees. (A) Ten Lrrk2 R1441G and (B) five Lrrk2 G2019S pedigrees and one sporadic patient. Filled black lower, right-quadrant

symbol denotes family members affected with parkinsonism. Black central circle denotes dystonia. Filled gray lower, right-quadrant symbol denotes

possible parkinsonism. The gender of some asymptomatic carriers has been hidden to protect confidentiality (B). An arrow (m) in each family indicates

the proband. The first number underneath symbol represents age-at-onset, followed by age-at-sampling or age-at-death (d). Subjects are denoted mutation

carriers (+M) or wild-type non-carriers (�wt).

M.C. Gonzalez-Fernandez et al. / Parkinsonism and Related Disorders ] (]]]]) ]]]–]]] 3

Please cite this article as: Gonzalez-Fernandez MC, et al. Lrrk2-associated parkinsonism is a major cause of disease in Northern Spain. Parkinsonism

Relat Disord (2007), doi:10.1016/j.parkreldis.2007.04.003

ARTICLE IN PRESSM.C. Gonzalez-Fernandez et al. / Parkinsonism and Related Disorders ] (]]]]) ]]]–]]]4

pattern of inheritance. Screening for Lrrk2 G2019S andR1441G substitutions was performed in 91 individuals (61affected and 30 unaffected family members) from 50families (Table 1). In total Lrrk2 substitutions were foundin 15 families (30%), and R1441G was twice as frequent asthe G2019S variant. Lrrk2 R1441G was not observed inthe 17 sporadic patients, however one harbored G2019S(6%). Neither mutation was observed in 68 controlsubjects.

The Lrrk2 R1441G substitution was found in 10 families(20%; Fig. 2A), with a total of 21 individual carriers (15symptomatic and 6 asymptomatic). Seven of the familiesdemonstrated probable autosomal dominant patterns ofinheritance albeit with reduced penetrance (FAM1, FAM3,FAM6, FAM7, FAM8, FAM9 and FAM10; Fig. 2A). Thesix asymptomatic relatives who harbored R1441G had anage range of 32–75 years. For the 15 R1441G-positive PDpatients, the mean age-at-onset is 54.6711.7 years (range29–73), with a mean disease duration of 11.476.3 years(range 2–27), and 5 presented with early-onset disease(p50 years). Other clinical features of the carriers aresimilar to sporadic PD (Table 2). The first symptomwas akinesia/bradykinesia in nine patients (9/15; 60%).Five patients did not present with resting tremor, threeof them from the same family (FAM8). Response tolevodopa was good and although cognitive impairmentwas absent psychiatric features were observed in onepatient with onset of parkinsonism at age 29 years. Lrrk2

Table 2

Clinical data for patients with Lrrk2-associated parkinsonism

Identification Gender AAO Initial symptoms

R1441G

FAM 1-1 Female 29 Akinesia RH

FAM 1-2 Female 58 Akinesia RH

FAM 2-1 Male 65 Mixed tremor URE

FAM 2-2 Female 63 No data available

FAM 3-1 Male 46 Akinesia LLE

FAM 4-1 Female 61 RT

FAM 5-1 Female 41 Akinesia LRE

FAM 6-1 Male 61 B

FAM 6-2 Male 56 Tremor and B RH

FAM 7-1 Male 48 Tremor LE

FAM 8-1 Male 54 Akinesia RL

FAM 8-2 Female 69 Tremor RL

FAM 8-3 Male 73 B

FAM 9-1 Female 43 Akinesia LRE

FAM 10-1 Male 52 B

G2019S

FAM11-2 Female 62 RT LLE

FAM11-5 Female 69 RT LE

FAM12-1 Female 63 Akinesia URE

FAM13-1 Female 62 RT URE

FAM14-1 Male 54 Clumsy RH

FAM15-1 Female 45 Tremor URE

PAT 16-1 Female 47 RT URE

The clinical features of the affected Lrrk2 R1441G and G2019S carriers. Abbre

RG; postural instability, PI; disease duration, DD; levodopa responsive, LD

extremity, LLE; right hand, RH; right leg, RL; left extremities, LE.

Please cite this article as: Gonzalez-Fernandez MC, et al. Lrrk2-associated pa

Relat Disord (2007), doi:10.1016/j.parkreldis.2007.04.003

R1441G was not observed in our sporadic PD patients(n ¼ 17).The Lrrk2 G2019S substitution was identified in five

families (10%; Fig. 2B) including seven individuals ofwhich one is asymptomatic. Three carriers were from thesame family (FAM11) and one is asymptomatic at age 76years. Lrrk2 G2019S was not found in one affected relative(Fig. 2B, FAM11) with parkinsonism, this individual maybe a phenocopy as observed in other LRRK2-positivefamilies [2,10]. The five families showed a patterncompatible with autosomal dominant inheritance withtwo or more affected relatives of at least two consecutivegenerations. The mean age-at-onset of all G2019S carrierswas 57.479 years (range 45–69) with a mean diseaseduration of 10.977 years (range 1–19), two of thempresented with an early-onset and only one of the sevencarriers was male. Clinical data were similar to sporadicPD, without cognitive decline and with a good response tolevodopa (Table 2). The initial symptom was tremor in fiveof the seven. Lrrk2 G2019S was also observed in onefemale sporadic PD patient who presented with tremor asthe initial symptom and age-at-onset of 47 years (PAT16).Haplotype analysis between D12S2080 and D12S2519

markers demonstrated a putative haplotype (188-249-291-212-252-G-C-154-138) for all R1441G carriers, and theresults are compatible with those described by Mata et al.[13] in Asturias (Table 3) [9]. We also confirmed thehaplotype for G2019S carriers between markers D12S515

RT B RG PI DD LDR

+ + + + 17 +++

++ ++ ++ ++ 13

++ + + � 13 +++

10

++ + + + 11 +++

+ + + � 8

� + + � 13 +++

++ ++ ++ ++ 13 ++

++ ++ ++ � 5 ++

++ + + � 8 +++

� + + � 19 +++

� ++ ++ � 8 ++

� ++ ++ � 2

� + + + 27 +

++ ++ ++ � 4

++ � ++ � 11 ++

++ ++ ++ ++ 3 ++

� + + + 19 +++

++ + + � 15 ++

� ++ ++ � 1 ++

� ++ ++ � 9 ++

+++ + + + 18 +++

viations: age-at-onset, AAO; resting tremor, RT; bradykinesia, B; rigidity,

R; upper right extremity, URE; lower right extremity, LRE; lower left

rkinsonism is a major cause of disease in Northern Spain. Parkinsonism

ARTICLE IN PRESS

Table

3

HaplotypeanalysisforR1441G

andG2019Ssubstitutions

R1441G

position

Marker

FAM1-1

FAM2-1

FAM3-1

FAM4-1

FAM5-1

FAM6-1

FAM7-1

FAM8-1

FAM9-1

Consensus

31,075,612

D12S1648

122/134

110

106/128

122

106/134

110/114

108/130

106/130

122/130

33,057,187

D12S2080

184/188

188

180/188

188

172/188

188/192

188

188/200

184/188

18

8

38,738,008

D12S2194

249/261

249

249/253

249/257

249

249/253

249/253

249/253

245/249

24

9

38,873,791

D12S2514

291

291

291

291/300

291

291

291/294

291/294

285/291

29

1(*

)

38,974,080

D12S2515

212

212/224

212

212/220

212/220

212/220

212/220

212

212/220

21

2

38,989,235

D12S2516

252/254

252/254

252/254

252

252/254

252

252

252/254

252/254

25

2

38,990,396

R1441G

G/C

G/C

G/C

G/C

G/C

G/C

G/C

G/C

G/C

G

39,000,059

M1646T

C/T

C/T

C/T

C/T

C/T

C/T

C/T

C/T

C/T

C

39,034,806

D12S2518

154

154

154

154

154

154

154

154

154

15

4

39,116,760

D12S2519

136/138

134/138

132/138

134/138

132/138

136/138

138/140

132/138

132/138

13

8

39,120,028

D12S2520

248/257

248/254

248/257

248/254

248/260

248/260

248/260

248/260

248/257

(*)

G2019Sposition

Marker

FAM11-3

FAM11-2

FAM11-5

FAM12-1

FAM13-1

PAT16-1

Consensus

38,974,080

D12S2515

212/220

216/220

220

224

220

220/224

38,974,962

rs7966550

TT

TT

TT

T

38,989,235

D12S2516

254

254

254

252/254

254

252/254

25

4

39,000,101

rs1427263

AA

AA/C

AA/C

A

39,000,140

rs11176013

GG

GG/A

GG/A

G

39,000,168

rs11564148

A/T

A/T

AA/T

A/T

A/T

A

39,020,469

G2019S

G/A

G/A

G/A

G/A

G/A

G/A

A

39,034,806

D12S2518

154

154

154

154

154

154

15

4

39,116,760

D12S2519

132/138

132/134

132/138

132/134

132/134

132/138

13

2

39,120,028

D12S2520

257/260

257/260

257/260

254/260

251/260

248/260

26

0

Chromosome12genotypes

are

shownforprobandsofnineR1441G

familiesandfourG2019Sfamilies.

LR

RK

24321C4G

(R1441G)isin

exon31and

LR

RK

26055G4A

(G2019S)iswithin

exon41of

thegene.ForG2019Shaplotypeanalysismarker

D12S2515hada220bpallelein

allfamilieswiththeexceptionoffamily12-1

(224);however,thismarker

hasbeennotedasunstablein

apreviousstudy

[14].Themost

parsim

onioushaplotypeassociatedwithdisease,consistentwiththeconsensushaplotypepreviouslyidentified

isin

bold

italics.Twomarker

sizesfortheR1441G

consensushaplotype

(indicatedwithanasterisk(*))vary

withthose

reported

byMata

etal.[9],dueto

achangein

nomenclature

duringsubmissionto

NCBI;they

allshare

thesameallele.Marker

positions(inbase

pairs)are

from

theUCSC

database

(May2004;http://w

ww.genome.ucsc.edu/).

M.C. Gonzalez-Fernandez et al. / Parkinsonism and Related Disorders ] (]]]]) ]]]–]]] 5

Please cite this article as: Gonzalez-Fernandez MC, et al. Lrrk2-associated parkinsonism is a major cause of disease in Northern Spain. Parkinsonism

Relat Disord (2007), doi:10.1016/j.parkreldis.2007.04.003

ARTICLE IN PRESSM.C. Gonzalez-Fernandez et al. / Parkinsonism and Related Disorders ] (]]]]) ]]]–]]]6

and D12S2520 (Table 3). Marker D12S515 showed allele220 in all families with the exception of FAM12 (allele224); however this marker has been shown to be unstableand is suggested to be within the disease haplotype [14,15].Therefore, it is probable that a larger haplotype exists forthe G2019S substitution in this region as recently shown inAshkenazi Jews and a population of European Americanancestry [15].

4. Discussion

LRRK2 mutations are the main genetic cause of PDidentified to date [1]. In the present study, 15 of the 50parkinsonism families (30%) collected from the north westBasque region (�1.2 million inhabitants) carried either theLrrk2 R1441G or G2019S pathogenic substitutions(Fig. 1).

The Lrrk2 R1441G substitution was found in 10 of ourfamilies. Five patients had age-at-onset p50 years, andakinesia/bradykinesia was the initial symptom in patientsfor eight R1441G positive families. These clinical featuresdiffer from the first R1441G Basque families reported,where late-onset disease was common and tremor was thepredominant initial symptom resulting in the term ‘dardar-in’ (Basque for ‘tremor’) to describe the Lrrk2 protein [8].Although this is a relatively small community the variationin the clinical phenotype of the R1441G pathogenicsubstitution must be influenced by other factors, geneticor environmental. Five R1441G kindreds did not demon-strate a dominant pattern of inheritance, which shows age-dependant penetrance as previously described for bothR1441G and G2019S [9,10,16,17]. Collecting more familymembers and studying all available R1441G carriers is nowcrucial to better estimate the penetrance of this pathogenicsubstitution and provide appropriate genetic counseling topatients and their families.

Lrrk2 R1441G substitution was initially implicated inlate-onset autosomal dominant parkinsonism in fourfamilies (8%) from the Basque region [8]. Subsequently,this mutation was found in several patients from theneighboring regions of Asturias (2.7%, most of themsporadic) and Catalonia (0.7%) [5,9]. However, it was notidentified in a sample of 105 PD patients from Cantabria[7]. The R1441G pathogenic substitution appears to berestricted to Northern Spain, with the highest frequency inthe Basque region (Fig. 1). The high R1441G frequency islikely to have consequences with regards to healthcare forthe global Basque Diaspora. The Basque region isgeographically small but has a history of emigration fluxesto other regions of Europe, and North, Central and SouthAmericas. Markers previously described by Mata et al. forthe R1441G haplotype suggest a common founderalthough phase could not be determined [9]. This hypoth-esis is supported by the recent study of the originalR1441G families [11]. The R1441G haplotype spans alarger region (8Mb) than for Lrrk2 G2019S (�154 kb)indicating a more recent event [10]. We hypothesize that

Please cite this article as: Gonzalez-Fernandez MC, et al. Lrrk2-associated pa

Relat Disord (2007), doi:10.1016/j.parkreldis.2007.04.003

the mutational event may have originated in the Cantab-rian Coast. A more formal estimate of the founder’s agemight be calculated based on counts of alleles shared bymutation carriers versus population controls, and exploit-ing the recombination fraction between microsatellitemarkers and the specific mutation [18].Although R1441G is the most frequent pathogenic Lrrk2

substitution in Basque populations, the G2019S substitu-tion was present in five of our families. Resting tremor wasthe initial symptom in four out of seven G2019S carriers.To date, this is the most important PD variant inCaucasian populations throughout North American andWestern Europe [1]. Most individuals with Lrrk2 G2019Sshare an ancient haplotype that probably originates fromNorth Africa and is likely to have been spread by theArabic/Jewish Diasporas [3,4,15]. We analyzed the markerspreviously described for the ‘common’ G2019S haplotypeand although phase could not be determined, we observedthe same apparent haplotype block from D12S2515 toD12S2520 [6,10,15]. Allele 260 of the D12S2520 marker,shared by all our G2019S families, differs from the 248allele shared in the haplotype 2 described by Zabetian et al.for some Western European families, corroborating thatour families share the most common haplotype 1 [15].In summary, Lrrk2 R1441G and G2019S are a very

significant cause of familial parkinsonism in the Basqueregion (30%; n ¼ 50) and sporadic PD (6%; n ¼ 17).Clinical features are similar to typical PD, but withmarginal differences in age-at-onset, initial symptom andpenetrance between R1441G and G2019S PD patients.Although pleomorphic findings have been noted at autopsyin several LRRK2 cases, the vast majority of patients havea typical PD with Lewy body pathology [2,19]. Furtherstudies are now warranted to estimate disease penetranceand population frequencies, and to date the founder ofR1441G in this region. Of note, one R1441G carrier inNorth America has been recently described [20]. Thispatient is reported to be of Hispanic descent and maysupport our hypothesis that this Lrrk2 variant may be inimportant for the Spanish Diaspora.Longitudinal assessment of the natural history of

parkinsonism in Lrrk2 patients and asymptomatic carriersmay aid the development of intervention strategies as it willprovide the basis upon which the efficacy of futureneuroprotective therapies may be judged.

Acknowledgments

The authors want to thank all patients and relatives fortheir collaboration, and the nursing assistance from CrucesNeurology Department for blood extractions and MinnieSchreiber for technical assistance. Mayo Clinic Jackson-ville is a Morris K. Udall Parkinson’s Disease ResearchCenter of Excellence (NINDS P50 #NS40256). MCGF wasrecipient of a fellowship from Spanish Minister of Scienceand Technology Grant number EET 2002-05165.

rkinsonism is a major cause of disease in Northern Spain. Parkinsonism

ARTICLE IN PRESSM.C. Gonzalez-Fernandez et al. / Parkinsonism and Related Disorders ] (]]]]) ]]]–]]] 7

References

[1] Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future

prospects. Nat Rev Genet 2006;7:306–18.

[2] Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et

al. Mutations in LRRK2 cause autosomal-dominant parkinsonism

with pleomorphic pathology. Neuron 2004;44:601–7.

[3] Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S,

et al. LRRK2 G2019S as a cause of Parkinson’s disease in North

African Arabs. N Engl J Med 2006;354:422–3.

[4] Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A,

Tagliati M, et al. LRRK2 G2019S as a cause of Parkinson’s disease in

Ashkenazi Jews. N Engl J Med 2006;354:424–5.

[5] Gaig C, Ezquerra M, Marti MJ, Munoz E, Valldeoriola F, Tolosa E.

LRRK2 mutations in Spanish patients with Parkinson disease:

frequency, clinical features, and incomplete penetrance. Arch Neurol

2006;63:377–82.

[6] Mata IF, Ross OA, Kachergus J, Huerta C, Ribacoba R, Moris G, et

al. LRRK2 mutations are a common cause of Parkinson’s disease in

Spain. Eur J Neurol 2006;13:391–4.

[7] Infante J, Rodriguez E, Combarros O, Mateo I, Fontalba A, Pascual

J, et al. LRRK2 G2019S is a common mutation in Spanish patients

with late-onset Parkinson’s disease. Neurosci Lett 2006;395:224–6.

[8] Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug

M, et al. Cloning of the gene containing mutations that cause

PARK8-linked Parkinson’s disease. Neuron 2004;44:595–600.

[9] Mata IF, Taylor JP, Kachergus J, Hulihan M, Huerta C, Lahoz C, et

al. Lrrk2 R1441G in Spanish patients with Parkinson’s disease.

Neurosci Lett 2005;382:309–11.

[10] Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J,

et al. Identification of a novel LRRK2 mutation linked to autosomal

dominant parkinsonism: evidence of a common founder across

European populations. Am J Hum Genet 2005;76:672–80.

Please cite this article as: Gonzalez-Fernandez MC, et al. Lrrk2-associated pa

Relat Disord (2007), doi:10.1016/j.parkreldis.2007.04.003

[11] Simon-Sanchez J, Marti-Masso JF, Sanchez-Mut JV, Paisan-Ruiz C,

Martinez-Gil A, Ruiz-Martinez J, et al. Parkinson’s disease due to the

R1441G mutation in Dardarin: a founder effect in the basques. Mov

Disord 2006;21:1954–9.

[12] Fonseca F, Bulbena A, Navarrete R, Aragay N, Capo M, Lobo A,

et al. Spanish version of the delirium rating scale-revised-98:

reliability and validity. J Psychosom Res 2005;59:147–51.

[13] Mata IF, Kachergus JM, Taylor JP, Lincoln S, Aasly J, Lynch T, et

al. Lrrk2 pathogenic substitutions in Parkinson’s disease. Neuroge-

netics 2005;6:171–7.

[14] Goldwurm S, Di Fonzo A, Simons EJ, Rohe CF, Zini M, Canesi M,

et al. The G6055A (G2019S) mutation in LRRK2 is frequent in both

early and late onset Parkinson’s disease and originates from a

common ancestor. J Med Genet 2005;42:e65.

[15] Zabetian CP, Hutter CM, Yearout D, Lopez AN, Factor SA, Griffith

A, et al. LRRK2 G2019S in families with Parkinson disease who

originated from Europe and the Middle East: evidence of two distinct

founding events beginning two millennia ago. Am J Hum Genet

2006;79:752–8.

[16] Paisan-Ruiz C, Saenz A, Lopez de Munain A, Marti I, Martinez Gil

A, Marti-Masso JF, et al. Familial Parkinson’s disease: clinical and

genetic analysis of four Basque families. Ann Neurol 2005;57:365–72.

[17] Paisan-Ruiz C, Lang AE, Kawarai T, Sato C, Salehi-Rad S, Fisman

GK, et al. LRRK2 gene in Parkinson disease: mutation analysis and

case control association study. Neurology 2005;65:696–700.

[18] Farrer M, Stone J, Lin C, Dachsel J, Hulihan M, Haugarvoll K, et al.

Lrrk2 G2385R is an ancestral risk factor for Parkinson’s disease in

Asia. Parkinsonism Relat Disord 2006;13:89–92.

[19] Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash

DC, et al. Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388–93.

[20] Deng H, Le W, Davidson AL, Xie W, Jankovic J. The LRRK2

I2012T, G2019S and I2020T mutations are not common in patients

with essential tremor. Neurosci Lett 2006;407:97–100.

rkinsonism is a major cause of disease in Northern Spain. Parkinsonism