{"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.
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.