Straniero Letizia, Asselta Rosanna, Bonvegna Salvatore, Rimoldi Valeria, Melistaccio Giada, Soldà Giulia, Aureli Massimo, Della Porta Matteo, Lucca Ugo, Di Fonzo Alessio, Zecchinelli Anna, Pezzoli Gianni, Cilia Roberto, Duga Stefano
Department of Biomedical Sciences (L.S., R.A., V.R., G.M., G.S., M.D.P., S.D.), Humanitas University; Humanitas Clinical and Research Center (R.A., V.R., G.S., M.D.P., S.D.), IRCCS, Rozzano; Fondazione Grigioni per il Morbo di Parkinson (S.B., A.Z., G.P.); Parkinson Institute (S.B., A.Z., G.P., R.C.), ASST "Gaetano Pini-CTO"; Department of Medical Biotechnology and Translational Medicine (M.A.), University of Milan; Laboratory of Geriatric Neuropsychiatry (U.L.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS; IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico (A.D.F.), Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan; and Fondazione IRCCS Istituto Neurologico "Carlo Besta" (R.C.), Milan, Italy.
Neurol Genet. 2020 Oct 20;6(6):e523. doi: 10.1212/NXG.0000000000000523. eCollection 2020 Dec.
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.
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.
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.
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 .
为了提供4种最常见的帕金森病（PD）相关变异的发病率、外显率、性别分布以及与痴呆症关联的变异特异性估计值，我们分析了一个由4923名意大利非亲属原发性退行性帕金森综合征患者（包括3832例PD）组成的大型队列，这些患者均来自单一的三级医疗中心，同时分析了7757名种族匹配的对照。
采用等位基因特异性多重PCR方法筛查p.E326K、p.T369M、p.N370S和p.L444P变异。所有统计程序均使用R或Plink v1.07进行。
在分析的4种变异中，p.L444P被证实与PD、帕金森病痴呆（PDD）和路易体痴呆（DLB）的疾病风险关联最为强烈（PD的优势比[OR]为15.63，95%置信区间[CI]=8.04 - 30.37，P = 4.97×10⁻¹²；PDD的OR为29.57，95% CI = 14.07 - 62.13，P = 3.86×10⁻¹³；DLB的OR为102.7，95% CI = 31.38 - 336.1，P = 1.91×10⁻¹⁵）。然而，p.E326K赋予了出乎意料的高痴呆风险（PDD的OR为4.80，95% CI = 2.87 - 8.02，P = 2.12×10⁻⁵；DLB的OR为12.24，95% CI = 4.95 - 30.24，P = 5.71×10⁻⁷），基于其对葡萄糖脑苷脂酶活性的影响，预计该风险会较低。在p.T369M携带者中，散发性PD中描述的1.5 - 2:1的男性性别偏倚消失。我们还表明，p.L444P在75岁时的PD外显率可达到15%。
我们报告了一项关于PD的大型单中心研究，评估了4种最常见的有害变异在性别分布、外显率、发病率以及与痴呆症关联方面的突变特异性数据。
