Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study.
BACKGROUND
Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2?


METHODS
Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
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.
Healy
Daniel G
DG
Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK. danhealy@doctors.org.uk
Falchi
Mario
M
O'Sullivan
Sean S
SS
Bonifati
Vincenzo
V
Durr
Alexandra
A
Bressman
Susan
S
Brice
Alexis
A
Aasly
Jan
J
Zabetian
Cyrus P
CP
Goldwurm
Stefano
S
Ferreira
Joaquim J
JJ
Tolosa
Eduardo
E
Kay
Denise M
DM
Klein
Christine
C
Williams
David R
DR
Marras
Connie
C
Lang
Anthony E
AE
Wszolek
Zbigniew K
ZK
Berciano
Jose
J
Schapira
Anthony H V
AH
Lynch
Timothy
T
Bhatia
Kailash P
KP
Gasser
Thomas
T
Lees
Andrew J
AJ
Wood
Nicholas W
NW
D000367:Age Factors; D017668:Age of Onset; D016022:Case-Control Studies; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006801:Humans; D007391:International Cooperation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D010300:Parkinson Disease / Q000145:classification / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D019683:Penetrance; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012306:Risk; D012694:Serine / Q000235:genetics; D012720:Severity of Illness Index
D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005998:Glycine