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
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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.

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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.
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