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.

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 ± 14.3 years, range 12–83). An additional 220 are affected LRRK2 p.G2019S carriers (mean onset 57.1 ± 11.6 years, range 22–82); 12 unaffected LRRK2 carriers were also identified (mean age 56.7 ± 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 ± 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 ± 11.6 years, range 40–82) and 57 unaffected carriers were identified (mean age of 54.2 ± 15.2 years) as first- to third-degree relatives through field studies.³

All 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 criteria⁴ for both the Tunisian and Norwegian populations. Age at onset was obtained from patient medical records or by self-report. DNA was extracted from blood; LRRK2 genotyping was verified by Sanger sequencing.⁵

Statistical 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.

Results.

In Tunisia and Norway samples the mean, distribution, and range of disease onset in iPD is similar and the cumulative incidence is comparable (figure, A; log-rank p = 0.67). By contrast, the penetrance of LRRK2 p.G2019S parkinsonism was significantly different between Tunisian Arab-Berbers and ethnic Norwegians (figure, B; log-rank p < 0.0001). In Tunisia, LRRK2 p.G2019S carriers have a median 10 years earlier age at onset compared to carriers in Norway. In Tunisia, 30%, 61%, and 86% of LRRK2 p.G2019S carriers had developed parkinsonism by 50, 60, and 70 years of age. In Norway, only 3%, 20%, and 43% had developed parkinsonism by 50, 60, and 70 years of age (table e-1 on the Neurology® Web site at Neurology.org).

Figure. Cumulative incidence of idiopathic Parkinson disease (A) and LRRK2 p.G2019S parkinsonism (B).

Kaplan-Meier analysis of parkinsonism with age at onset as the time variable. Black lines represent Tunisia and red lines represent Norway. Dotted lines represent confidence intervals. Unaffected LRRK2 p.G2019S carriers were right-censored.

Discussion.

LRRK2 p.G2019S phenoconversion from a motorically asymptomatic to an affected state probably reflects an age-associated failure to compensate for kinase dysfunction. However, the disparity in disease penetrance in LRRK2 p.G2019S carriers in Tunisia vs Norway is challenging to explain given that the cumulative incidence of iPD is almost identical. While the mean age at onset in Norway is higher than in Tunisia, the difference is not statistically different. However, in Tunisia a sex difference is observed in LRRK2 carriers, women having earlier-onset parkinsonism.⁶ The same trend appears in Norway but, perhaps due to a smaller sample size, is not significant.

Age at onset is a subjective measure but the difference between LRRK2 groups in these ethnicities is unlikely an artifact of analysis or study design. Kaplan-Meier analyses should be restricted to unrelated cases but these LRRK2 p.G2019S carriers have the same ancestral chromosome 12 haplotype⁷ and are derived from genetically homogeneous communities. In Norway, the LRRK2 p.G2019S genealogy dates to the 15th century³; in Tunisia, the origin of the mutation is more ancient. The use of convenient samples in lieu of prospective epidemiologic studies is clearly a limitation in making precise penetrance estimates. Nevertheless, available data suggest ancestral background/country of origin and associated genetic/environmental modifiers may account for differences in published penetrance estimates.² Hence, ethnicity is an important caveat for genetic counseling.