LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study.
BACKGROUND
Several 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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
GlaxoSmithKline; National Institutes of Health; and Mayo Foundation.
Hulihan
Mary M
MM
Neurogenetics, Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Ishihara-Paul
Lianna
L
Kachergus
Jennifer
J
Warren
Liling
L
Amouri
Rim
R
Elango
Ramu
R
Prinjha
Rab K
RK
Upmanyu
Ruchi
R
Kefi
Mounir
M
Zouari
Mourad
M
Sassi
Samia Ben
SB
Yahmed
Samia Ben
SB
El Euch-Fayeche
Ghada
G
Matthews
Paul M
PM
Middleton
Lefkos T
LT
Gibson
Rachel A
RA
Hentati
Fayçal
F
Farrer
Matthew J
MJ
D000367:Age Factors; D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005998:Glycine / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D019683:Penetrance; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012111:Residence Characteristics; D012694:Serine / Q000235:genetics*; D014416:Tunisia / Q000453:epidemiology / Q000208:ethnology
D012694:Serine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D005998:Glycine