Eu J Neu ol. 2025;32:e16499.  
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h ps://doi.o g/10.1111/ene.16499
wileyonlinelib a y.com/jou nal/ene
Recei ed:7May2024
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Accep ed:16Sep embe 2024
DOI: 10.1111/ene.16499
ORIGINAL ARTICLE
Unde s anding Pa kinson disease in Spain: Gene ic and clinical
insigh s
Pila Gómez- Ga e1,2  | Miguel Ma ín- Bó nez1 | Lau a Muñoz- Delgado1,2 |
Ra ael Díaz- Belloso1,2,3  | Ma ía Te esa Pe iñán1,2,4 | Ma a Bonilla- To ibio1,2 |
Dolo es Buiza- Rueda1,2 | Daniel Macías- Ga cía1,2  | Sil ia Jesús1,2 |
As id Ada mes- Gómez1,2 | Elena Ojeda1,2 | An onio Luque- Amb osiani1 |
Se gio Ga cía- Díaz1 | Rocío Pineda Sánchez1,2 | Fá ima Ca illo1,2,3 | Pablo Mi 1,2,3
1UnidaddeT as o nosdelMo imien o,Se iciodeNeu ología,Ins i u odeBiomedicinadeSe illa,IBiS/Hospi alUni e si a ioVi gendelRocío/CSIC/
Uni e sidaddeSe illa,Se ille,Spain
2Cen odeIn es igaciónBiomédicaenRedsob eEn e medadesNeu odegene a i as,Ins i u odeSaludCa losIII,Mad id,Spain
3Depa amen odeMedicina,Facul addeMedicina,Uni e sidaddeSe illa,Se ille,Spain
4Cen e o P e en i eNeu ologyUni ,Wol sonIns i u eo Popula ionHeal h,QueenMa yUni e si yo London,London,UK
Thisisanopenaccessa icleunde  he e mso  heC ea i eCommonsA ibu ion-NonComme cialLicense,whichpe mi suse,dis ibu ionand ep oduc ion
inanymedium,p o ided heo iginalwo kisp ope lyci edandisno used o comme cialpu poses.
©2024TheAu ho (s).Eu opean Jou nal o Neu ologypublishedbyJohnWiley&SonsL donbehal o Eu opeanAcademyo Neu ology.
Co espondence
Pila Gómez-Ga eandPabloMi ,Unidad
de T as o nos del Mo imien o, Ins i u o
deBiomedicinadeSe illa(IBiS),Hospi al
Uni e si a ioVi gendelRocío/CSIC/
Uni e sidaddeSe illa,A anzadaManuel
Siu o s/n,Se ille41013,Spain.
Email:mgomez-[email p o ec ed] and pmi @us.es
Funding in o ma ion
Conseje íadeEconomía,Inno ación,
CienciayEmpleodelaJun adeAndalucía,
G an /Awa dNumbe :CTS-7685,CVI-
02526andPY20_00896;Conseje íade
SaludyBienes a SocialdelaJun ade
Andalucía,G an /Awa dNumbe :PE-
0 1 8 6 - 2 0 1 9 ,  P E - 0 2 1 0 - 2 0 1 8 ,  P I - 0 4 5 9 - 2 0 1 8 
andPI-0471-2013;G an /Awa dNumbe :
RTC2019-007150-1,Ins i u odeSalud
Ca losIII(ISCIII)andco- undedby he
Eu opeanUnion,G an /Awa dNumbe :
PI14/01823,PI16/01575,PI18/01898,
PI19/01576andPI21/01875
Abs ac
Backg ound and pu pose: Pa kinsondisease(PD)isacomplexandhe e ogeneousneu o-
degene a i ediso de wi hab oadspec umo clinicalmani es a ions,de e minedbya
complexin e playo en i onmen alandgene ic ac o s.Thiss udyaimed oin es iga e
gene ic a ian sassocia edwi hPDandassess hei impac on hediseasepheno ype
h ough geno ype–pheno ype co ela ions.
Me hods: Weemployeda a ge ed esequencingpanel oanalyze27geneslinked o
PD in a coho  o  1185 PD pa ien s om sou he n Spain. Va ian s we e ca ego ized
basedon heAme icanCollegeo MedicalGene icsandGenomicspa hogenici yc i e ia.
Demog aphic and clinical da a we e also collec ed.
Resul s: Among hepa ien sanalyzed,13.5%ca iedpo en ialdisease-causingpa ho-
genico likelypa hogenic a ian sin12di e en genes,indica ingsigni ican gene ic
he e ogenei y.Themos  equen lya ec edgeneswe eLRRK2, PRKN, and GBA1(ac-
coun ing o  72.1%o  posi i e cases).Sex-speci ic di e enceswe e obse ed, wi h a
highe p opo iono  emalepa ien sca yingLRRK2 a ian s.Di e encesinagea onse 
andclinical ea u eswe ealsoobse edamong hedi e en mu a edgenes.No ably,
a ian s in genes associa ed wi h a ypical pa kinsonism p esen ed dis inc clinical p esen-
a ions,highligh ing heimpo anceo gene ic ac o sin hedi e en ialdiagnosis.
Conclusions: Ou s udyp o ides aluablein o ma ionon hegene iclandscapeo PD
andi sclinicalmani es a ions.Theobse edgeno ype–pheno ypeco ela ions, along
wi hsex-speci icdi e ences,emphasize hecomplexi yo PDpa hogenesis,unde lin-
ing heimpo anceo pe sonalizedapp oaches oPDdiagnosisand ea men .Fu he 
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GÓMEZ-GARRE e al.
INTRODUCTION
Pa kinsondisease(PD)isacommonneu odegene a i edisease,
clinically cha ac e ized by h ee ca dinal mo o  symp oms: b a-
dykinesia, es ing emo ,andmuscle igidi y.Howe e ,PDisa
complex,he e ogeneousdiso de wi hab oadspec umo clin-
ical mani es a ions. Beyond mo o  symp oms, PD also p esen s
nume ousnonmo o symp oms,o enappea inglongbe o e he
onse o classicmo o  symp omsandsigni ican ly a ec ing he
quali y o  li e. Demen ia is pa icula ly p e alen , occu ing in
83%o pa ien swi hPD,wi hadiseasedu a iono app oxima ely
20 yea s[1].
The isk o  de eloping PD is de e mined by a complex in e -
playo en i onmen alandgene ic isk ac o s[2], wi h age being
hemos impo an  isk ac o .Theincidenceandp e alenceo PD
inc ease almos  exponen ially wi h age, peaking a  >80 yea s [3].
Likewise,sexisanes ablished isk ac o ,wi hamale/ emale a io
o app oxima ely3:2[1].
Wi hini smul i ac o iale iopa hogenesis,PDis ecognizedas
ahighlycomplexgene icdisease.Nume ouss udiesha ein es i-
ga ed iskandp o ec i e ac o so PD,wi hsigni ican p og essin
gene ic esea chdue o apidad ancesinsequencingme hods.The
gene iccon ibu ion oPDisexplainedbyawidespec umo ge-
ne ic a ian s, anging omcommon a ian s ha con e suscep i-
bili y ode elopingPD,wi hamode a e oweake ec size, o a e
a ian  o ms,highlypene an ,whe e hep esenceo  he a ian 
issu icien  ocause hedisease[4]. To da e, pa hogenic a ian s
associa edwi hmonogenicPDha ebeendesc ibedin>20 genes,
mos o whicha ehighlypene an ando encauseea lyonse o 
a ypicalPD[4].Al houghi hasbeen epo ed ha only5%–10%o 
PDcasesa emonogenic[5], hese da a a e mainly based on indi id-
ualso Eu opean/Whi eances y.The equency,pene ance,and
clinicalimpac o gene ic a ian scan a yac osse hnici ies.Spain
has a complex demog aphic his o y, cha ac e ized by con inuous
occupa ion since ancien imes by a ious popula ions wi h di e se
o igins,includinganeigh -cen u ype iodo A abdomina ion( om
MiddleEas andNo hA ica),wi haclea gene icimpac [6].
This s udy aimed o assess he p esence and con ibu ion o 
a ian sinPD- ela edgenesinacoho o PDpa ien s omsou h-
e nSpain,and oes ablishgeno ype–pheno ypeco ela ions.We
useda a ge ed esequencingpanel, ocusingon27genesassoci-
a edwi hPD,andanalyzed heda ausinganin-housepipeline.Ou 
indingssigni ican lycon ibu e ounde s andingo PD,shedding
ligh on hee ec o gene ic a ian sondiseasede elopmen and
o e ingimpo an insigh sin odiagnosisand ea men o PDinou 
popula ion.
PATIENTS AND METHODS
SeeAppendixS9.
S udy pa icipan s and clinical assessmen s
A o alo 1185PDpa ien swe eincluded om2008.Thediagnoses
we epe o med ollowing heUni edKingdomPa kinson'sDisease
Socie yB ainBankc i e ia[7] o pa ien s ec ui edup o2018and
Mo emen Diso de Socie yclinicaldiagnos icc i e ia[8] om2019
onwa d.
Gene ic analysis
Genomic DNA was isola ed om pe iphe al blood samples om
eachpa icipan .Acombina iono high- esolu ionmel inganalysis,
mul iplexliga ion-dependen p obeampli ica ionanalysis,andnex 
gene a ion sequencing (NGS)-based a ge ed esequencing was
applied(Figu e S1).Va ian swe eca ego izedacco ding o hein-
e na ionalguidelineso  heAme icanCollegeo MedicalGene ics
andGenomics(ACMG)[9](Figu e S2).Only a ian scon o ming o
hegene'sinhe i ancepa e nwe econside edpo en ialdisease-
causing a ian s, and he gene ic diagnosis was conside ed posi i e.
Bioin o ma ics analysis o NGS esul s
All NGS da a we e analyzed employing an in-house pipeline
(AppendixS1).
Tobe e de ine he oleo GBA1 a ian sinPD, a ian sin his
gene we e classi ied using he GBA1-PD b owse  (h ps:// pdgen
e i c s . s h i n y a p p s . i o / G B A 1 B  o w s e / )[10].
Inaddi ion,copynumbe  a ia ions(CNVs)we ealsoanalyzed.
Losseswe ede inedbyamaximumlog2 a ioo −0.55andamini-
mumlog2 a ioo 0.4 o gains[11].
S a is ical analysis
Associa ionanalyseso  he a ian s and PD isk we e pe o med
wi hPLINKso wa e[12].A a e a ian bu denanalysiswascon-
duc edwi hconsis en summa ycoun s-based a e a ian bu den
es [13].Ascon ols,weused wosubcoho s:non-neu oandcon-
olsin heNon-FinnishEu opean-Sou he nEu opean(NFE-SEU)
in es iga ionsin ogene icin e ac ionsandpopula ion-speci ice ec sa ewa an ed o
enhanceou unde s andingo PDe iologyandimp o epa ien ca e.
KEYWORDS
clinicalinsigh s,gene icinsigh s,Pa kinsondisease, a ge edsequencing
14681331, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ene.16499 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [14/04/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
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3 o 9
PARKINSON DISEASE IN SPAIN
coho .Wealsousedda a om heCIBERERSpanishVa ian Se e 
(CSVS;h p s : // c s s . c l i n b i o i n o s s p a . e s / )[14].
RESULTS
Demog aphic cha ac e is ics
Weanalyzed27genesassocia edwi hPDinacoho o 1185un-
ela edPDpa ien s(Table 1).Among hem,162(13.7%) epo eda
amilyhis o yo PD,and387(32.7%)hadea lyonse PD(EOPD).The
agea onse (AAO)wasuna ailable o  h eepa ien s,bu  heywe e
classi iedasha ingEOPDbasedon hei cu en age(<50 yea s).
Gene ic spec um
Weiden i ieda o alo 1014 a ian sin hecodingsequenceand
splice egionso  he27analyzedgenes,allwi hamino allele e-
quency(MAF)< 5%in hegene alpopula ion.These a ian swe e
ca ego izedacco ding oACMGc i e iaasbenign(B),likelybenign
(LB), a ian o unknownsigni icance(VUS),likelypa hogenic(LP),
andpa hogenic(P).Among heiden i ied a ian s,898we eloca ed
incoding egionsand116insplice egions(Table S1A and Figu e S3A).
Speci ically,71 a ian swe eclassi iedasP/LP,156asVUS,and788
asB/LB(Table S1B and Figu e S3B).TheP/LP a ian swe e oundin
207pa ien s(17.5%),a ec ing17genes,includingATP13A2, DCTN1,
DNAJC6, FBXO7, LRP10, LRRK2, PRKN, PARK7, PINK1, PLA2G6, POLG,
SMPD1, SPR, SYNJ1, VPS13A, VPS13C, and GBA1. CNVs we e de-
ec ed in he PRKN and SNCAgenes.Conside ing heinhe i ance
pa e no eacha ec edgene,po en iallydisease-causingP/LP a i-
an swe eiden i iedin160pa ien s(13.5%o  hecoho ),in ol -
ing12dis inc genes(DCTN1, DNAJC6, LRP10, LRRK2, PRKN, PINK1,
POLG, SMPD1, SNCA, SPR, VPS13A, and GBA1).Among hese160
pa ien swi hposi i egene icdiagnosis(PGD),se enca iedP/LP
a ian sinmo e hanonegene.Nodisease-causing a ian swe e
iden i iedin960pa ien s(80.9%),whowe econside ed oha ea
nega i egene ic diagnosis (NGD).Addi ionally, 65pa ien s (5.5%;
Figu e 1a and Table S2),we eclassi iedasha inganunknownge-
ne icdiagnosis(UGD),Thisg oupincludedpa ien sca yingVUS,
hose lacking a second a ian in ecessi e genes, and hose wi h
GBA1 a ian sconside edPD isk ac o sacco ding o heGBA1-PD
b owse .Gene icanalysis esul s o eachpa ien a ep o ided in
Table S3.
Va ian sin h eegenes(LRRK2, PRKN, and GBA1)accoun ed o 
72.1%o  heposi i ecases.Themos p e alen genewasLRRK2,
wi h61pa ien s(37.9%)ca yingP/LP a ian s(including49wi h
heG2019S a ian ), ollowedbyPRKN(18%,including12pa ien s
wi h wo a ian sbu wi hou seg ega ionanalysis)andGBA1(18%;
Figu e 1b).
We iden i ied 29 pa ien s (2.45%) ca ying P/LP a ian s in
GBA1. Se e e a ian s we e p esen  in 10 pa ien s (0.84%), mild
a ian sin14pa ien s(1.18%),and unknown a ian sin ou  pa-
ien s. Mo eo e , 21 pa ien s (1.76%) ca ied isk a ian s. Th ee
pa ien s ca ied wo a ian s in GBA1bu didno exhibi symp oms
o  Gauche  disease (GD). The mos  equen  P/LP a ian s we e
p.N409Sandp.L483P,and hemos  equen  a ian was he isk
a ian p.E365K.
Thedis ibu iono pa ien swi hPGD,NGD,o UGDac ossdi -
e en g oupsisshowninFigu e 1c.
Geno ype–pheno ype co ela ions
Pa ien s wi h PGD had a younge  mean AAO (50.6 ± 12.4 yea s)
compa ed o hose wi h NGD (56.7 ± 11.6 yea s) o  UGD
(55.0 ± 12.3 yea s).TheAAO a iedamongdi e en mu a edgenes,
wi hhe e ogenei ye enamongca ie so  a ian sin hesamegene
(Figu e 2).Thep opo iono pa ien swi ha amilyhis o yo PDwas
simila be ween hosewi hPGDandUGD(18.8%and18.5%, e-
spec i ely),andhighe  hanin hosewi hNGD(12.5%;Figu e 3a).A
highe p opo iono women(44.4%)wasno edamongpa ien swi h
PGD,pa icula lyamong hoseca yingP/LP a ian sin heLRRK2
gene(Figu e 3b).
Wealsoexplo ed heassocia ionsbe ween hegeno ypesand
clinical cha ac e is ics in PGD pa ien s (Table S4). Despi e some
missing clinical da a, GBA1PDpa ien sexhibi edahighe p opo -
iono  apideyemo emen sleepbeha io diso de (RBD)andol-
ac o ydys unc ion(88%and68.4%, espec i ely),whe easalowe 
equencyo RBDwasobse edinLRRK2PDpa ien s(39.6%)and
a lowe  equency o  ol ac o y dys unc ion in PRKN PD pa ien s
(6.7%; Table S4). Cogni i e impai men  (CI) was mo e equen 
amongpa ien swi hPGD ela ed oGBA1, DCTN1, POLG, and SPR,
wi hahighe p e alenceinmen(Table 2).
Coho Pa icipan s, nSex, men, n (%)
Age, yea s,
mean ± SD
AAO, yea s,
mean ± SD
Family
PD, n (%)
To al 1185 707(59.7) 64.6 ± 11 55.8 ± 11.9 162(13.7)
EOPD 387 242(62.5) 53.3 ± 9.2 42.5 ± 7.4 53(13.7)
LOPD 798 465(58.3) 69.6 ± 7.8 62.3 ± 7.5 109(13.7)
FamilyPD 162 89(54.9) 65.8 ± 10.2 56.0 ± 12.3 162(100)
Spo adicPD 1023 618(60.4) 64.4 ± 11.1 55.8 ± 11.9 0(0)
Abb e ia ions:AAO,agea onse ;EOPD,ea lyonse PD(agea onse ≤ 50 yea s);LOPD,la eonse 
PD;PD,Pa kinsondisease.
TABLE 1 Demog aphicda ao  hePD
coho .
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GÓMEZ-GARRE e al.
Geno ype–pheno ype co ela ions in well- es ablished
PD- ela ed genes
LRRK2
Dys oniawasobse edin68.4%o LRRK2PDpa ien s,and es ing
emo wasobse edin59.3%.Asubs an ialmajo i yexpe ienced
mo o  luc ua ion(91.8%)anddyskinesias(83.3%),wi hCIandRBD
p esen in31.0%and39.6%, espec i ely. A amilyhis o y o  PD
wasno edonlyamongca ie so  hepa hogenicG2019S a ian 
(Table S4).
In ou coho , LRRK2 PD pa ien s we e p edominan ly women
(60.7%).Thishighe p opo ionwasonlyobse edinca ie so  he
G2019S a ian , among whom 60% we e women. No signi ican 
di e encesinAAOwe eobse edbasedon hespeci ic a ian ca -
ied among LRRK2PDpa ien s,al hough23pa ien s(37.7%)p esen ed
EOPD.Among hese, i epa ien sca iedP/LP a ian sino he genes.
Onepa ien (EP-40)ca iedP/LP a ian sinbo h heLRRK2 and
DCTN1genes,wi hanAAOo 51 yea sandabenigndiseasecou se
wi hou no able nonmo o symp oms.
Twopa ien s(EP-10andEP-16)we e ound oca y heG2019S
a ian andhomozygousPRKN a ian s,exhibi ingclinical ea u es
simila o hose associa ed wi h PRKNPD.
Las ly, wo pa ien s (EP-215 and EP-223) ca ied VUSs and
we e he e o e included in he UGD g oup. Thei  AAOs we e 62
and54 yea s, espec i ely,and heyp esen edwi h es ing emo .
Despi e hei  ela i elyb ie clinical ollow-up, hei clinicaldisease
cou se has been benign.
FIGURE 1 The equencyo causa i e
genes in pa ien s ini ially diagnosed
wi hPa kinsondisease(PD).(a)O e all
diagnos icyield.(b)Dis ibu iono 
disease-causa i egenesin160p obands.
(c)Fea u eso  heanalyzedPDcoho .
EOPD,ea lyonse PD(agea onse 
≤ 50 yea s);LOPD,la eonse PD(age
a onse > 50 yea s);NGD,pa ien s
wi hanega i egene icdiagnosis;PGD,
pa ien s wi h a posi i e gene ic diagnosis;
UGD,pa ien swi hanunknowngene ic
diagnosis.
FIGURE 2 Boxplo so agea onse 
unde speci icgenes.Do s ep esen 
he age a onse in each pa ien ca ying
pu a i e causa i e a ian s in each gene.
Ho izon allines ep esen  hemedian
onse .M,mild;NGD,Pa kinsondisease
(PD)pa ien swi hanega i egene ic
diagnosis;PGD,PDpa ien swi ha
posi i egene icdiagnosis;RF, isk ac o ;
S,se e e;T, o alcoho wi hpa hogenic
o likely pa hogenic a ian s in GBA1 and
hose wi h isk a ian s in GBA1;UGD,
PDpa ien swi hanunknowngene ic
diagnosis.
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PARKINSON DISEASE IN SPAIN
SNCA
Twopa ien s(EP-114andEP-135)ca iedduplica ionso  heen i e
SNCAgeneinhe e ozygosis.Howe e , hecu o poin scouldno 
bede e mined.Onepa ien p esen edwi hala eAAO,whe eas he
o he hadanea lydiseaseonse .Thepa ien wi h heea lie AAO
also ca ied a isk a ian in he GBA1 gene.
PRKN
Al houghmos PRKNPDpa ien sexhibi edanea lyAAOo 
PD,14.3%p esen edla eAAO( anging om55 o59 yea s),
mo o  luc ua ions and dyskinesias we e common (82.1%
and77.8%, espec i ely),andCIandhallucina ions/illusions
we e ela i ely a e(25.9%and18.9%, espec i ely),wi h
FIGURE 3 Ba g aphsshowing amily
his o yo Pa kinsondisease(PD)and
gende dis ibu ionac ossspeci ic
genes.NGD,PDpa ien swi hanega i e
gene icdiagnosis;PGD,PDpa ien s
wi haposi i egene icdiagnosis;UGD,
PDpa ien swi hanunknowngene ic
diagnosis.
TABLE 2 Cogni i eimpai men in heposi i egene icdiagnosiscoho .
LRRK2 PRKN GBA1 GBA1, se e e
GBA1,
mild DCTN1 POLG SMPD1 SPR
n42 27 25 912 3 9 8 8
CI(%) 31.0 25.9 64 55.6 58.3 66.7 66.7 25 62.5
CI-F(%) 33.3 8.3 28.6 25 0 0 66.7 050
CI-M(%) 20 40.0 77.8 80 70 100 66.7 28.6 66.7
D P - C I 15 ± 7.9 16.6 ± 7.8 7.8 ± 6.0 4.8 ± 1.8 11.1 ± 7.7 7.5 ± 3.5 10.0 ± 5.0 7.5 ± 3.5 9.4 ± 2.9
D P - C I - F 15.8 ± 6.9 15 4.5 ± 3.5 2 0 0 11.5 ± 6.4 010
D P - C I - M 16.5 ± 13.4 16.8 ± 8.5 8.2 ± 6.3 5.1 ± 1.0 11.1 ± 7.7 7.5 ± 3.5 9.3 ± 5.1 7.5 ± 3.5 9.3 ± 3.3
No e:Thede elopmen o CIwasconside ed h oughou  he ollow-up.Themean ollow-up imewas15.1 ± 8.5 yea s.
Abb e ia ions:CI,cogni i eimpai men ;CI(%),pe cen ageo PGD-pa ien swi hCI;CI-F(%),pe cen ageo womenwi hPGDandCI;CI-M(%),pe cen age
o menwi hPGDandCI;DP-CI,diseasep og ession oCI(meano yea s ± SD);DP-CI-F,diseasep og ession oCI(meano yea s ± SD)inwomen;DP-
CI-M,diseasep og ession oCI(meano yea s ± SD)inmen;n,sampleswi hposi i egene icdiagnosis(PGD)andCIda a;PGD,posi i egene icdiagnosis.
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GÓMEZ-GARRE e al.
CI mo e p e alen  among men (40%) han women (8.3%;
Table 2).
PINK1
Onepa ien (EP-3)ca iedLPmissense a ian sinpu a i ecompound
he e ozygosi yin hePINK1gene.Thispa ien p esen edwi hea lyAAO
(49 yea s),mo o  luc ua ions,dyskinesias,and dys onia.Addi ionally,
al houghCIwasno p esen ,hallucina ions/illusionsoccu ed.
GBA1
Wede ec ed13di e en  a ian sin heGBA1gene.Acco ding o
hei e ec onGDandPD, i ewe edesc ibedasse e e, h eeas
mild,and woas isk a ian s, hei  equencybeing4.9%inEOPD
and3.1%inla eonse PD.TheAAOo  hoseca ying he isk a i-
an sp.E365Kandp.T408Mwasla e  han he es .
Mo o  luc ua ionsanddyskinesiaswe emo e equen inpa-
ien s wi h mild a ian s compa ed wi h hose wi h se e e a ian s
(61.5% s.50%,and69.2% s.66.7%, espec i ely).Al hough1pa-
ien (EP-105)p esen edwi h wose e e a ian sinGBA1, no signs
o  GD ha e been epo ed in his clinical his o y, sugges ing ha 
hose a ian s a e p obably in cis.
RBD and ol ac o y dys unc ion we e obse ed wi h highe 
equency in pa ien s ca ying se e e a ian s (87.5% and 71.4%,
espec i ely) compa ed wi h hose wi h mild a ian s (84.6% and
66.7%, espec i ely).
CIwasp esen inapp oxima elyhal o  heGBA1pa ien s(a -
ec ingahighe p opo iono malepa ien s),anddiseasep og es-
sion oCIwaslowe in hepa ien sca yingGBA1 se e e a ian s
compa ed wi h hose wi h GBA1mild a ian s(Table 2).
Geno ype–pheno ype in genes linked wi h
pa kinsonism wi h a ypical signs
DCTN1
Sixpa ien s(0.5%o  hePDcoho )ha bo edanLP a ian in he
DCTN1 gene: c.414 + 1G > A ( s576198476). This a ian  displayed
acombined anno a ion dependen  deple ion(CADD) alueo  33
andwasdesc ibedasLPacco ding oACMGc i e ia.Inou popula-
ion, DCTN1PDpa ien sp esen edameanAAOo 59.5 ± 6.9 yea s
(Figu e 2),good esponse ole odopa,andmo o  luc ua ionsand
dyskinesia.Mos o  hesepa ien sexpe iencedpa icula lyse e e
neu opsychia icsymp oms,and he e o e heydidno  ole a ehigh
doseso dopamine gicmedica ion.O he  ea u es,suchas espi a-
o y symp oms and weigh loss, we e absen in hei clinical his o y.
Addi ionally,onepa ien ca iedbo h heDCTN1c.414 + 1G > A a i-
an and he LRRK2G2019S a ian ,showinganea lie AAOanda
lacko neu opsychia icsymp oms.
DNAJC6
Onepa ien (EP-47)wi hala eAAOha bo ed woLP a ian sin
DNAJC6, p esen ing wi h a ypical PD pheno ype. Bo h a ian s
we e ameshi  changes likely in compound he e ozygosi y bu 
wi hou bialleliccon i ma ion.
LRP10
Onepa ien (EP-29)wi hno amilyhis o yo PDca iedanon-
sense a ian in he LRP10gene.Thispa ien p esen edala eAAO
andde elopedCIandhallucina ions/illusions5 yea sa e disease
onse .
POLG
Se en di e en  P/LP a ian s we e iden i ied in 11 pa-
ien s wi h a wide ange o  AAOs. I  is known ha  wo
o  hese a ian s(p.Th 251Ileandp.P o587Leu)a elinked
andin cis. The e o e,all POLG pa ien s we e conside ed
monoallelic.
Mo o  luc ua ionswe ep esen in81.8%o  hePOLGPDpa-
ien s. Dyskinesias, CI, RBD, and ol ac o y dys unc ion we e also
equen lyobse ed(70%,80%,70%,and71.4%, espec i ely).No
pa ien wasspeci icallydesc ibedasha inga axiao pe iphe alneu-
opa hy.Onepa ien (EP-54)p esen edp og essi eex e naloph-
halmoplegia(PEO).
SMPD1
Ele endi e en P/LP a ian sinSMPD1we ede ec edin15PDpa-
ien s,who equen lyexhibi edmo o  luc ua ionsandRBD(71.4%
and75%, espec i ely).Dyskinesias(61.5%)andhyposmia(62.5%)
we e also common, al hough hallucina ions/illusions we e a ely e-
po ed(23.1%).
SPR
AnLP a ian (p.Asp69Glu;c.207C > G)in heSPR gene was de ec ed
ineigh pa ien swi hPD.Mo o  luc ua ionsanddyskinesiaswe e
highly p e alen in SPRPDpa ien s(87.5%and75%, espec i ely);
howe e ,dys oniawasobse edin50%.OnlyoneSPRPDpa ien 
epo eda amilyhis o yo PD.
VPS13A
Onepa ien ca iedanLP a ian inVPS13A;howe e ,clinicalin o -
ma ion o  hisindi idualisuna ailable.
14681331, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ene.16499 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [14/04/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
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7 o 9
PARKINSON DISEASE IN SPAIN
Gene bu den analysis
Asigni ican associa ionwi h e y a e a ian swas ound o  he
DNAJC13 gene, and PRKNshowedasimila pa e nin hecon ex o 
loss-o - unc ion a ian swi haCADD> 25.Fu he mo e,PLA2G6
and POLG showed associa ions wi hnoncommonloss-o - unc ion
a ian s(Table S5).
DISCUSSION
This s udyaimed ode ine heclinicalspec um and implica ions
o gene ic a ian sac oss27genesinaPDpopula ion omsou h-
e nSpain.Ou  indings e ealedasigni ican gene iche e ogene-
i y,wi hpo en iallycausa i eP/LP a ian siden i iedin12genes
(DCTN1, DNAJC6, LRP10, LRRK2, PRKN, PINK1, POLG, SMPD1, SNCA,
SPR, VPS13A, and GBA1).
The analysis o  ypical and a ypical o ms o  monogenic PD
e ealed se e al no able di e ences. Pa ien s wi h a ypical
o msexhibi edahighe AAOanda educed amilyhis o yo PD.
Fu he mo e,weobse edsex-speci icdi e encesin hep e alence
o P/LP a ian s,pa icula lyin heLRRK2gene.Ahighe p opo ion
o womenwe e ound oca yLRRK2 a ian s, d i en pa icula ly
by heG2019S a ian (wi h60%o  heca ie sbeingwomen)bu 
no amongca ie so o he LRRK2 a ian s.This indingalignswi h
p e iouss udiesindica inga emalep edominanceamongG2019S
a ian ca ie s[15].Al hougho he s udiesha eno  epo ed his
gende e ec [16],ala geme a-analysisin2018o LRRK2- ela ed
clinical ea u es epo ed a simila  emale p edominance among
G2019Sca ie s[17].
LRRK2 eme ged as he mos p e alen gene, wi h a no able
p opo iono pa ien sca ying heG2019S a ian (4%o cases),
simila  oo he Eu opeans[18] bu sligh ly highe han ha e-
po edin heb oade Spanishpopula ion[19].Clinically,LRRK2-
associa edPDpa ien sexhibi ed ea u essimila  o hosewi h
spo adicPD.Howe e , he ela i elylowe p e alenceo CIand
RBDsugges spo en ialdi e encesindiseasep og essionand
unde lyingneu opa hology.Theiden i ica iono a amilyhis o y
o PDexclusi elyamongca ie so  heG2019S a ian unde -
sco es he ele anceo speci icgene ic a ian sin amilial o ms
o PDandemphasizes heimpo anceo gene iccounseling[20,
21].
Inlinewi ho he s udies,ou coho showsahighe  equency
o  he dele e ious p.Asn52 s a ian  in PRKN compa ed o o he
popula ions. This a ian has been ela ed wi h an in onic signal in
PRKN,desc ibedasanAAOmodi ie ,highligh ing heimpo anceo 
s udying di e se popula ions o be e unde s and he gene ic con-
ibu ions oPD[19].
In e es ingly,nosigni ican di e encesinAAOwe eobse ed
among LRRK2 a ian ca ie s, al hough some pa ien s wi h LRRK2
and PRKN a ian sp esen edwi hAAOsou side he ypical ange.
This ein o ces heno ion ha addi ionalgene icanden i onmen al
ac o slikelymodula ediseasep esen a ion.
Mo eo e ,CIwaslesscommonand ended oappea la e inpa-
ien swi hPGDassocia edwi hLRRK2 o PRKN compa ed o hose
wi hPGDassocia edwi ho he genes,suchasGBA1, DCTN1, POLG,
and SPR.
Al houghPINK1-associa edPDhasbeen epo edas hesecond
mos commoncauseo au osomal- ecessi ePD,i was e y a ein
ou coho .
Twopa ien swe e ound oca yduplica ionsin heSNCA gene;
howe e , hep eciseb eakpoin so  heseduplica ionscouldno be
de e mina ed.In e es ingly,oneo  hesepa ien salsoca ied he
p.T408M isk a ian inGBA1andhadamuchea lie AAO(38 s.
61 yea s),sugges ing ha gene icin e ac ionsbe ween hesegenes
mayin luencediseasecou se.
Va ian sin heGBA1geneha ebeenclassi iedacco ding o hei 
e ec onGDandPD[10, 22].Con a y op e ious indings[23], ou
s udy ound ha pa ien sca yingmildGBA1 a ian s had an ea lie
AAOcompa ed o hosewi hse e e a ian s.Addi ionally, wopa-
ien sca yingbo hase e e a ian anda isk a ian (wi hou e i-
denceo GD)p esen edwi hala e AAO,sugges inganin e ac ion
be ween hese wo a ian s.
Va ian singenesassocia edwi ha ypicalpa kinsonism,suchas
LRP10, DCTN1, DNAJC6, POLG, SPR, and SMPD1, we e linked o dis-
inc clinical p esen a ions and disease cou ses, highligh ing he im-
po anceo conside inggene ic ac o sin hedi e en ialdiagnosis
o pa kinsoniansynd omes.
The e o e, al hough mu a ions in POLG gene, inhe i ed in an
au osomaldominan o  ecessi emanne ,ha ebeenlinked oPEO
[24],inou coho onlyonepa ien exhibi edi ,ca ying hep.Ty -
955Cys a ia ion,whichhasbeenp e iouslyassocia edwi hPEO
[24]. This sugges s a geno ype–pheno ype co ela ion.
The LRP10genehasbeenp oposedascausa i einau osomal-
dominan PD,wi ho wi hou demen ia[25, 26]. One pa ien in ou
coho p esen ed clinical cha ac e is ics consis en wi h LRP10-
ela ed PD,al hough he absenceo a amilyhis o yo PD could
sugges lowpene ance o  his a ian .
DCTN1gene a ian sha ebeenlinked oPe ysynd ome(PS)
[27], a a eau osomal-dominan  adul onse  neu odegene a i e
diso de cha ac e izedbya ypicalpa kinsonism,dep ession/apa-
hy,weigh loss,and espi a o ysymp oms[28].Pa hogenicmu a-
ionsinPSa e ypically oundwi hin hecy oskele on-associa ed
p o ein glycine- ich(CAP-Gly) domain[29].Howe e ,ou s udy
iden i ied hec.414 + 1G > A a ian ou side hisdomain.Al hough
ca ie so  his a ian we eclassi iedasha ingaPGD, he e e-
mains unce ain y abou  i s ac ual in ol emen  in PD de elop-
men .This a ian wasalsop esen inheal hycon ols om he
CSVSpopula ion(MAF = 0.0019),al houghwi hsligh lylowe  e-
quencycompa edwi hou PDpopula ion(MAF = 0.0025).Thus,
mo ee idenceisneeded ocon i mi spa hogenici y.Ou  indings
sugges ha a ian s in he DCTN1geneou side heCAP-Glydo-
maincouldha euniqueimplica ionsinPD,possiblyp esen inga
isk ac o .
Homozygous a ian sinDNAJC6ha ebeenlinked oau osomal-
ecessi eea lyonse PD.Inou coho ,onepa ien ca ied woLP
14681331, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ene.16499 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [14/04/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
8 o 9
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GÓMEZ-GARRE e al.
a ian s,wi hala e AAO hanp e iously epo ed.Addi ional es s
a e equi ed ocon i m hei causali y.
Eigh indi idualsca iedanLP a ian (p.Asp69Glu;c.207C > G)
in he SPR gene, sugges ing a ounde  e ec  in ou  coho . A
popula ion-speci ic ole o  hisgenehasbeensugges ed[30]. The
SPR gene encodes sepiap e in educ ase, a key p o ein in e ahyd-
obiop e in(BH4)syn hesis,aco ac o c i icalin hesyn hesisand
sec e iono neu o ansmi e ssuchasdopamine.BH4 de iciency
hasbeenassocia edwi hcondi ionscha ac e izedbymo emen dis-
o de sandmen al e a da ion,amongo he s[31].Howe e , he e
iscon lic inge idence ega ding he oleo SPRinPDpa hogenesis
[31].Desc ibedasaVUSinClinVa , he a ian c.207C > Ghasbeen
p e iously associa ed wi h au osomal-dominan  dopa- esponsi e
dys onia[32].Inou coho ,62%o SPRpa ien sp esen edwi hCI,
andonly50%p esen edwi hdys onia,sugges ing ha  his a ian 
maybeaPD isk ac o inou popula ion.
He e ozygous a ian sinSMPD1(encodingacidsphingomyelin-
ase)ha ebeeniden i iedas isk ac o s o PD[33]. In ou coho ,
1.26%o pa ien sca iedP/LP a ian sinSMPD1, suppo ing i s ole
inPD.No ably,hal o  hesepa ien sexhibi edRBD,unde sco ing
heclinicalimpo anceo  hisgene.
Ac ually,i isc i ical oinc easeou knowledgeo gene ic isks
o  PD in indi iduals o  a ied gene ic backg ounds and inc ease
hea ailabili yo de ailedclinalda aassocia edwi h hem.In his
con ex ,s udyingou PDpopula ion oma egionwi hhis o ically
uniquedemog aphiccha ac e is icsinEu opeadds aluableda a o
ou unde s andingo PDpa hogenesis.
Toou knowledge, hisis hela ges s udyo PD oda econ-
duc edinsou he nSpain,p o idingin o ma ionin o hegene ic
a ian s and hei  associa ed clinical ea u es. Howe e , we ac-
knowledge se e al limi a ions, including he inabili y o es ablish a
clea geno ype–pheno ypeco ela ion o somegenesdue o he
limi edsizeo  hesampleswi hPGD,a ec ing hosegenesand
challenges ela ed omissingclinicalda a.Inaddi ion, heuseo a
a ge edgenepanel es ic edou abili y oanalyze ecen lydis-
co e ed genes such as RAB32[34]. Finally, i is impo an o no e
ha  he ela i elylow equencyo GBA1 pa hogenic a ian s in
ou popula ion could be due o echnical challenges ela ed o he
exis enceo ahighlysimila pseudogene.Thismayha eled oan
unde es ima ion o  he ue p e alenceo GBA1 a ian sinPD
pa ien s.
Despi e hese limi a ions, ou s udy p o ides impo an insigh s
in o hegene icbasiso PDandi sclinicalmani es a ions.Theob-
se ed geno ype–pheno ype co ela ions and sex-speci ic di e -
enceshighligh  heimpo anceo pe sonalizedapp oaches oPD
diagnosis and ea men .
CONCLUSIONS
Ou  esul shighligh  hecomplexi yo gene iccon ibu ions oPD
pheno ype and p ognosis. Comp ehensi e gene ic p o iling and
pe sonalized isks a i ica iona ec ucial o guidingp ognosisand
he apeu ic decision-making in PD pa ien s. The e a e nume ous
mechanismsassocia edwi hPDpa hogenesisandp og ession ha 
lead oPD.Fu he in es iga ionsin ogene icin e ac ionsand he
inclusiono  amilyhis o yandsex-speci icda awillbekey obe e 
unde s andingPDpa hogenesis.
AUTHOR CONTRIBUTIONS
Pila Gómez- Ga e:Concep ualiza ion;supe ision; o malanalysis;
undingacquisi ion;p ojec adminis a ion;w i ing–o iginald a ;
w i ing – e iew and edi ing. Miguel Ma ín- Bó nez: Da a cu a ion;
o malanalysis;me hodology;so wa e;w i ing– e iewandedi -
ing. Lau a Muñoz- Delgado: Da a cu a ion; in es iga ion; esou ces;
w i ing – e iew and edi ing. Ra ael Díaz- Belloso: Fo mal analysis;
in es iga ion; w i ing – e iew and edi ing. Ma ía Te esa Pe iñán:
Fo mal analysis; in es iga ion; w i ing – e iew and edi ing. Ma a
Bonilla- To ibio: Me hodology; w i ing – e iew and edi ing. Dolo es
Buiza- Rueda: Me hodology; w i ing – e iew and edi ing. Daniel
Macías- Ga cía: Resou ces; w i ing – e iew and edi ing. Sil ia Jesús:
Resou ces; w i ing – e iew and edi ing. As id Ada mes- Gómez:
Resou ces; w i ing – e iew and edi ing. Elena Ojeda: Resou ces;
w i ing – e iew and edi ing. An onio Luque- Amb osiani: Resou ces;
w i ing – e iew and edi ing. Se gio Ga cía- Díaz:W i ing– e iew
and edi ing. Rocío Pineda Sánchez: Me hodology. Fá ima Ca illo:
Resou ces. Pablo Mi : Concep ualiza ion; supe ision; unding
acquisi ion; p ojec  adminis a ion; w i ing – e iew and edi ing;
esou ces.
ACKNOWLEDGMENTS
Theau ho swouldlike o hank hedono s, heUni e si yHospi al
Vi gen del Rocio, and he Biomedical Ins i u e o  Se ille Biobank
(Andalusian Public Heal h Sys em Biobank and ISCIII-Red de
BiobancosPT20/00069) o  hehumanspecimensusedin hiss udy.
FUNDING INFORMATION
Thiswo kwassuppo edby heSpanish Minis yo Scienceand
Inno a ion (RTC2019-007150-1); he Ins i u o de Salud Ca los III
(ISCIII)co undedby heEu opeanUnion(PI14/01823,PI16/01575,
PI18/01898,PI19/01576,PI21/01875); heConseje íadeEconomía,
Inno ación,CienciayEmpleodelaJun adeAndalucía(CVI-02526,
CTS-7685,PY20_00896);and heConseje íadeSaludyBienes a 
SocialdelaJun adeAndalucía(PI-0471-2013,PE-0210-2018,PI-
0459-2018,PE-0186-2019).P.G.-G.wassuppo edby heNicolás
Mona desp og am(C-0048-2017)o AndalusianRegionalMinis y
o  Heal h. D.M.-G. was suppo ed by he Juan Rodés p og am
(JR22/00073) o  ISCIII co unded by he Eu opean Union FSE+
(ISCIII-FEDER).L.M.-D.wassuppo edby heRíoHo egap og am
(CM21/00051) o  ISCII co unded by he Eu opean Union FSE+
(ISCIII-FEDER).The unde shadno olein hes udydesign,da a
collec ion and analysis, decision o publish, o  p epa a ion o  he
manusc ip .
CONFLICT OF INTEREST STATEMENT
Theau ho sdecla enocon lic o in e es .
14681331, 2025, 1, Downloaded om h ps://onlinelib a y.wiley.com/doi/10.1111/ene.16499 by Readcube (Lab i a Inc.), Wiley Online Lib a y on [14/04/2025]. See he Te ms and Condi ions (h ps://onlinelib a y.wiley.com/ e ms-and-condi ions) on Wiley Online Lib a y o ules o use; OA a icles a e go e ned by he applicable C ea i e Commons License
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9 o 9
PARKINSON DISEASE IN SPAIN
DATA AVAILABILITY STATEMENT
Theda a ha suppo  he indingso  hiss udya ea ailablein he
supplemen a yma e ialo  hisa icle.
ORCID
Pila Gómez- Ga e h ps://o cid.o g/0000-0002-0437-6182
Miguel Ma ín- Bó nez h ps://o cid.o g/0000-0001-8221-3816
Ra ael Díaz- Belloso h ps://o cid.o g/0000-0003-4713-9248
Daniel Macías- Ga cía h ps://o cid.o g/0000-0002-4822-1529
Pablo Mi h ps://o cid.o g/0000-0003-1656-302X
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SUPPORTING INFORMATION
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Muñoz-DelgadoL,e al.Unde s andingPa kinsondiseasein
Spain:Gene icandclinicalinsigh s.Eu J Neu ol.
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