LRRK2 parkinsonism in Tunisia and Norway: A comparative analysis of disease penetrance

Abstract

In recent years, the molecular etiology of parkinsonism has yielded to genetic analysis.1 Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have the highest genotypic and population attributable risk. Disparate penetrance estimates have been reported using a variety of statistical analyses, ethnic populations, and sample sizes.2 We compared the age-associated cumulative incidence (penetrance) of LRRK2 p.G2019S patients from Tunisia and Norway.Methods. Clinic-based population series. The Tunisian Arab-Berber series includes 350 patients with idiopathic Parkinson disease (iPD) (mean onset 55.3 6 14.3 years, range 12-83). An additional 220 are affected LRRK2 p.G2019S carriers (mean onset 57.1 6 11.6 years, range 22-82); 12 unaffected LRRK2 carriers were also identified (mean age 56.7 6 10.9 years). A total of 411 control subjects (spouses or unrelated individuals) were recruited through the Clinic and genotyped. Neither blood relatives of cases nor control subjects were included. The ethnic Norwegian series includes 443 with iPD (mean onset 58.8 6 11.2 years, range 25-88). A total of 520 control subjects (mostly spouses or unrelated individuals) were recruited through the Clinic and genotyped. In Norway, an additional 27 are affected LRRK2 p.G2019S carriers (mean onset 63 6 11.6 years, range 40-82) and 57 unaffected carriers were identified (mean age of 54.2 6 15.2 years) as first-to third-degree relatives through field studies. 3All individuals, clinical data, and blood samples were obtained with local ethical approvals, independently reviewed by the University of British Columbia Research Ethics Board. Written informed consent was provided. Neurologists specializing in movement disorders (F.H. and J.O.A.) diagnosed patients using UK Brain Bank criteria 4 for both the Tunisian and Norwegian populations. Age at onset was obtained from patient medical records or by selfreport. DNA was extracted from blood; LRRK2 genotyping was verified by Sanger sequencing. 5Statistical analysis. The penetrance was estimated for iPD and LRRK2 carriers using a Kaplan-Meier method (JMP software, SAS Institute Inc., Cary, NC) with age at onset as the time variable; asymptomatic carriers were right-censored at the age at last contact or age at death, using log-rank tests to assess significance.

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

“…25 The authors further compared the Tunisian with a Norwegian cohort and found lower penetrance in Norway despite similar incidence of disease. 26 Systematic assessment of penetrance estimates in the LRRK2 consortium using a common assessment battery and inclusion of both proband and relative characteristics may provide further refinement to these estimates. There is no published study using the identical FHI in distinct ethnic groups at multiple sites.…”

Increased peripheral inflammation in asymptomatic leucine‐rich repeat kinase 2 mutation carriers

“…In particular, analysis of the asymptomatic LRRK2 G2019S group showed a particularly high inflammatory subgroup representing 20% of the cohort. Intriguingly, the G2019S mutation is not considered fully penetrant, with estimates of penetrance ranging from 26% to 70%, depending on the age of the cohort studied and the ethnic background. Given that the asymptomatic LRRK2 G2019S group and controls were similar in regard to all available clinical variables measured, higher peripheral inflammation may identify earlier prodromal stages of PD in this group than currently possible.…”

Exploring cancer in LRRK2 mutation carriers and idiopathic Parkinson's disease

“…Another caveat of this study is including both manifesting and non‐manifesting LRRK2 mutation carriers, some of whom are related, in one group. LRRK2 mutations cause autosomal dominant PD, but the penetrance is reduced, age‐dependent, and varies in different ethnic groups (Healy et al., ; Hentati et al., ). Epigenetic factors, gene–environment interactions, and stochastic events may play a role in who develops PD.…”