Disease Penetrance of Late-Onset Parkinsonism A Meta-analysis
Disease Penetrance of Late-Onset Parkinsonism A Meta-analysis
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DOI：
10.1001/jamaneurol.2014.1909
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发表时间：
2014-12-01
期刊：
影响因子：
29
通讯作者：
Farrer, Matthew James
中科院分区：
文献类型：
--
作者：
Trinh, Joanne;Guella, Ilaria;Farrer, Matthew James
SNCA、LRRK 2、VPS 35、EIF 4G 1和DNAJC 13的突变与迟发性家族性帕金森综合征有关。然而，这些突变的估计疾病发病率差异很大。目的比较已发表的遗传学研究中报告的各种突变的发病率，以提高对晚发性帕金森病的理解。并提取了关于SNCA、LRRK 2、VPS 35、EIF 4G 1和DNAJC 13致病突变的家族内突变携带者和全球散发病例的数量的信息。检索结束日期为2014年1月31日。研究选择已发表的研究包括患者或未受影响个体的种族、突变的确认、患者或未受影响个体的年龄、发病年龄和患者的首次运动症状。常染色体隐性遗传性帕金森综合征和基因牵连没有显着的遗传连锁被排除在本study.DATA提取和合成年龄相关的累积发病率估计使用Kaplan-Meier方法与发病时的年龄作为时间变量;无症状携带者在最后一次接触时的年龄或死亡时的年龄进行右删失。主要结果和测量用对数秩检验获得比较测量，结果所有的常染色体显性遗传帕金森病基因突变具有显著的年龄依赖性累积发病率（P < .001）。特别是，SNCA重复的突变率与点突变相当（对数秩P = 0.97），并由纳入SNCA p.A53T驱动（平均发病年龄，45.9岁; 95% CI，43-49岁）。此外，以色列德系犹太人LRRK 2 p.G2019S载体（平均发病年龄，57.9岁; 95% CI，54-63岁）与突尼斯阿拉伯柏柏尔人相当（平均发病年龄，57.1岁; 95% CI，45.5-68.7岁）（P = .58），而挪威航空公司（平均发病年龄63岁; 95%可信区间，51.4-74.6岁）与其他组有显著差异结论和相关性帕金森病致病性突变具有年龄依赖性，在不同人群中可通过修饰基因或环境因素改善或加重。
IMPORTANCE Mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 have been implicated in late-onset familial parkinsonism. However, the estimated disease penetrance of these mutations varies widely.OBJECTIVE To compare penetrance of various mutations reported in published genetic studies to improve the understanding of late-onset parkinsonism.DATA SOURCES Forty-nine previously published studies, including 709 participants, were included for all original and subsequent articles in ISI Web of Science, PubMed electronic databases, and extracted information about number of mutation carriers within families and sporadic cases worldwide for pathogenic mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13. The end-of-search date was January 31, 2014.STUDY SELECTION Published studies were included if there was information on the ethnicity of the patient or unaffected individual, confirmation of mutation, age of patient or unaffected individual, age at onset, and first motor symptom of patient. Autosomal recessive parkinsonism and genes implicated without significant genetic linkage were excluded from this study.DATA EXTRACTION AND SYNTHESIS The age-associated cumulative incidence was estimated using the Kaplan-Meier method with age at onset as the time variable; asymptomatic carriers were right censored at the age at last contact or age at death.MAIN OUTCOMES AND MEASURES Comparative measures were obtained with log-rank tests, and each penetrance estimate was given separately with 95% confidence intervals.RESULTS All the assessed autosomal dominant Parkinson disease mutations have significantly different age-dependent cumulative incidences (P < .001). In particular, penetrance of SNCA duplications was comparable to point mutations (log-rank P = .97) and driven by inclusion of SNCA p.A53T (mean age at onset, 45.9 years; 95% CI, 43-49 years). In addition, Israeli Ashkenazi Jewish LRRK2 p.G2019S carriers (mean age at onset, 57.9 years; 95% CI, 54-63 years) were comparable to Tunisian Arab Berbers (mean age at onset, 57.1 years; 95% CI, 45.5-68.7 years) (P = .58), whereas Norwegian carriers (mean age at onset, 63 years; 95% CI, 51.4-74.6 years) were significantly different from the other groups (P < .001).CONCLUSIONS AND RELEVANCE Parkinson disease pathogenic mutations have an age-dependent penetrance that could be ameliorated or exacerbated by modifier genes or environmental factors in different populations.