PINK1 mutations are associated with sporadic early‐onset parkinsonism

TLDR

The pathogenetic significance of heterozygous PINK1 mutations remains unclear. The study aimed to evaluate the pathogenic role of PINK1 in early‑onset parkinsonism and to identify genotype–phenotype correlations by analyzing mutations in Italian patients under 50. PINK1 mutation analysis was performed on a cohort of Italian sporadic early‑onset parkinsonism patients. Among 100 patients, 7% carried missense PINK1 mutations, with 5% having a single heterozygous mutation versus 1% in controls, and affected individuals displayed typical parkinsonian features, slow progression, and excellent levodopa response. Ann Neurol 2004;56:336–341.

Abstract

Abstract We have recently reported homozygous mutations in the PINK1 gene in three consanguineous families with early‐onset parkinsonism (EOP) linked to the PARK6 locus. To further evaluate the pathogenic role of PINK1 in EOP and to draw genotype–phenotype correlates, we performed PINK1 mutation analysis in a cohort of Italian EOP patients, mostly sporadic, with onset younger than 50 years of age. Seven of 100 patients carried missense mutations in PINK1. Two patients had two PINK1 mutations, whereas in five patients only one mutation was identified. Age at onset was in the fourth‐fifth decade (range, 37–47 years). The clinical picture was characterized by a typical parkinsonian phenotype with asymmetric onset and rare occurrence of atypical features. Slow progression and excellent response to levodopa were observed in all subject. Two of 200 healthy control individuals also carried one heterozygous missense mutation. The identification of a higher number of patients (5%) than controls (1%) carrying a single heterozygous mutation, along with previous positron emission tomography studies demonstrating a preclinical nigrostriatal dysfunction in PARK6 carriers, supports the hypothesis that haploinsufficiency of PINK1, as well as of other EOP genes, may represent a susceptibility factor toward parkinsonism. However, the pathogenetic significance of heterozygous PINK1 mutations still remains to be clarified. Ann Neurol 2004;56:336–341