OBJECTIVE

To provide a variant-specific estimate of incidence, penetrance, sex distribution, and association with dementia of the 4 most common Parkinson disease (PD)-associated variants, we analyzed a large cohort of 4,923 Italian unrelated patients with primary degenerative parkinsonism (including 3,832 PD) enrolled in a single tertiary care center and 7,757 ethnically matched controls.

METHODS

The p.E326K, p.T369M, p.N370S, and p.L444P variants were screened using an allele-specific multiplexed PCR approach. All statistical procedures were performed using R or Plink v1.07.

RESULTS

Among the 4 analyzed variants, the p.L444P confirmed to be the most strongly associated with disease risk for PD, PD dementia (PDD), and dementia with Lewy bodies (DLB) (odds ratio [OR] for PD 15.63, 95% confidence interval [CI] = 8.04-30.37, = 4.9710; OR for PDD 29.57, 95% CI = 14.07-62.13, = 3.8610; OR for DLB 102.7, 95% CI = 31.38-336.1, = 1.9110). However, an unexpectedly high risk for dementia was conferred by p.E326K (OR for PDD 4.80, 95% CI = 2.87-8.02, = 2.1210; OR for DLB 12.24, 95% CI = 4.95-30.24, = 5.71*10), which, on the basis of the impact on glucocerebrosidase activity, would be expected to be mild. The 1.5-2:1 male sex bias described in sporadic PD was lost in p.T369M carriers. We also showed that PD penetrance for p.L444P could reach the 15% at age 75 years.

CONCLUSIONS

We report a large monocentric study on -PD assessing mutation-specific data on the sex distribution, penetrance, incidence, and association with dementia of the 4 most frequent deleterious variants in .