Rethinking 'rare' PINK1 Parkinson's disease: A meta-analysis of geographical prevalence, phenotypic diversity, and α-synuclein pathology.

IF 4 3区 医学 Q2 NEUROSCIENCES
Journal of Parkinson's disease Pub Date : 2025-02-01 Epub Date: 2025-01-14 DOI:10.1177/1877718X241304814
Eden Paige Yin, Birger Victor Dieriks
{"title":"Rethinking 'rare' <i>PINK1</i> Parkinson's disease: A meta-analysis of geographical prevalence, phenotypic diversity, and α-synuclein pathology.","authors":"Eden Paige Yin, Birger Victor Dieriks","doi":"10.1177/1877718X241304814","DOIUrl":null,"url":null,"abstract":"<p><p>PTEN-induced kinase 1 (<i>PINK1</i>)-related Parkinson's disease (PD) is traditionally considered a rare autosomal recessive form of early-onset PD (EOPD), lacking classical Lewy body pathology. However, this characterization underestimates and oversimplifies <i>PINK1</i>-PD, largely due to a lack of extensive studies in diverse ethnic populations. This review and meta-analysis explores considerable variations in <i>PINK1</i> variant rates and the wide heterogeneity influenced by patient- and variant-specific factors, delineating a more precise disease profile. Our findings reveal that <i>PINK1</i>-PD is more common than previously thought, with geographic 'hotspots' where up to 9% of EOPD cases are linked to <i>PINK1</i> variants, including the pathogenic p.Leu347Pro variant affecting 1 in 1300 West Polynesians. Homozygous <i>PINK1</i>-PD typically manifests around age 35, predominantly affecting the lower limbs, with an excellent response to levodopa. Heterozygous <i>PINK1</i>-PD presents an 'intermediate' phenotype, with a later onset age (around 43 years) than homozygous <i>PINK1</i>-PD but earlier than idiopathic PD (typically after age 65). The severity of the phenotype is influenced by variant zygosity and pathogenicity, interacting with genetic and environmental factors to push some individuals beyond the disease threshold. Notably, females with <i>PINK1</i>-PD have earlier onset age than males, particularly in homozygous cases and when variants occur in the first half of <i>PINK1</i>'s kinase domain. Contrary to traditional views, α-synuclein pathology is present in 87.5% of <i>PINK1</i>-PD postmortem cases across ages and variants. We challenge conventional views on <i>PINK1</i>-PD, highlighting distinct phenotypes influenced by zygosity, sex, and a role for α-synuclein pathology, urging for increased recognition and research of this not-so-rare disease.</p>","PeriodicalId":16660,"journal":{"name":"Journal of Parkinson's disease","volume":" ","pages":"41-65"},"PeriodicalIF":4.0000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Parkinson's disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/1877718X241304814","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/14 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

PTEN-induced kinase 1 (PINK1)-related Parkinson's disease (PD) is traditionally considered a rare autosomal recessive form of early-onset PD (EOPD), lacking classical Lewy body pathology. However, this characterization underestimates and oversimplifies PINK1-PD, largely due to a lack of extensive studies in diverse ethnic populations. This review and meta-analysis explores considerable variations in PINK1 variant rates and the wide heterogeneity influenced by patient- and variant-specific factors, delineating a more precise disease profile. Our findings reveal that PINK1-PD is more common than previously thought, with geographic 'hotspots' where up to 9% of EOPD cases are linked to PINK1 variants, including the pathogenic p.Leu347Pro variant affecting 1 in 1300 West Polynesians. Homozygous PINK1-PD typically manifests around age 35, predominantly affecting the lower limbs, with an excellent response to levodopa. Heterozygous PINK1-PD presents an 'intermediate' phenotype, with a later onset age (around 43 years) than homozygous PINK1-PD but earlier than idiopathic PD (typically after age 65). The severity of the phenotype is influenced by variant zygosity and pathogenicity, interacting with genetic and environmental factors to push some individuals beyond the disease threshold. Notably, females with PINK1-PD have earlier onset age than males, particularly in homozygous cases and when variants occur in the first half of PINK1's kinase domain. Contrary to traditional views, α-synuclein pathology is present in 87.5% of PINK1-PD postmortem cases across ages and variants. We challenge conventional views on PINK1-PD, highlighting distinct phenotypes influenced by zygosity, sex, and a role for α-synuclein pathology, urging for increased recognition and research of this not-so-rare disease.

重新思考“罕见”PINK1帕金森病:地理患病率、表型多样性和α-突触核蛋白病理学的荟萃分析
pten诱导的激酶1 (PINK1)相关帕金森病(PD)传统上被认为是一种罕见的常染色体隐性早发性帕金森病(EOPD),缺乏经典的路易体病理。然而,这种表征低估和过度简化了PINK1-PD,主要是由于缺乏对不同种族人群的广泛研究。本综述和荟萃分析探讨了PINK1变异率的相当大的变化以及受患者和变异特异性因素影响的广泛异质性,描绘了更精确的疾病概况。我们的研究结果显示,PINK1- pd比以前认为的更常见,在地理“热点”地区,高达9%的EOPD病例与PINK1变体有关,包括致病性p.l u347pro变体,影响1300名西波利尼西亚人中的1人。纯合子PINK1-PD通常在35岁左右出现,主要影响下肢,对左旋多巴有很好的反应。杂合子PINK1-PD表现为“中间”表型,发病年龄比纯合子PINK1-PD晚(约43岁),但比特发性PD早(通常在65岁以后)。表型的严重程度受变异合合性和致病性的影响,与遗传和环境因素相互作用,使一些个体超过疾病阈值。值得注意的是,患有PINK1- pd的女性比男性发病年龄更早,特别是在纯合子病例和PINK1激酶结构域前半部分发生变异时。与传统观点相反,87.5%的PINK1-PD死后病例存在α-突触核蛋白病理,不分年龄和变异。我们挑战关于PINK1-PD的传统观点,强调受合子性、性别和α-突触核蛋白病理作用影响的不同表型,敦促增加对这种不那么罕见的疾病的认识和研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
8.40
自引率
5.80%
发文量
338
审稿时长
>12 weeks
期刊介绍: The Journal of Parkinson''s Disease (JPD) publishes original research in basic science, translational research and clinical medicine in Parkinson’s disease in cooperation with the Journal of Alzheimer''s Disease. It features a first class Editorial Board and provides rigorous peer review and rapid online publication.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信