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Parkinson's Disease Genetics: New Thinking about PINK1
Abstract & Commentary
By Melissa J. Nirenberg, MD, PhD, Assistant Professor, Neurology and Neuroscience, Weill Cornell Medical College. Dr. Nirenberg reports that she has consulted for Biovail.
Synopsis: A mutation in a single copy of the PINK1 gene may be a susceptibility factor for subtle but progressive motor and non-motor signs of Parkinson's disease.
Source: Eggers C, et al. Progression of subtle motor signs in PINK1 mutation carriers with mild dopaminergic deficit. Arch Neurol 2010;74:1798-1805.
Mutations in the pten-induced putative kinase 1 (PINK 1) gene are the second most common cause of autosomal recessive, early-onset Parkinson's disease (PD). Patients with homozygous PINK1 mutations nearly always develop PD. Little is known, however, about whether heterozygous PINK1 mutations may also cause progressive signs and symptoms of parkinsonism.
In this study, the authors performed a longitudinal analysis of four homozygous PINK1 mutation carriers (all with clinically definite PD) and 10 asymptomatic heterozygous PINK1 mutation carriers (five unaffected; five with examination findings consistent with possible or probable PD) in a single German kindred, to test the hypothesis that there is a progressive phenotype that occurs in carriers of heterozygous PINK1 mutations. All study subjects were evaluated at baseline and three years later. Baseline assessments included a videotaped Unified Parkinson's Disease Rating Scale (UPDRS) motor examination, and smell and color discrimination tasks. After three years, most of the study subjects also completed fluorodopa positron emission tomography (FDOPA PET) scans. Heterozygous PINK1 mutation carriers were compared with both homozygous PINK1 mutation carriers and healthy control subjects.
Over the three-year study period, three of the five previously unaffected heterozygous PINK1 mutation carriers had developed new signs of possible PD. At the follow-up visit, seven heterozygous PINK1 mutation carriers had hyposmia, and four had diminished color discrimination. Hyposmia, but not impairment of color discrimination, was significantly more common in PINK1 mutation heterozygotes than in control subjects. PET scans at the follow-up visit showed a 20% autumnal FDOPA uptake reduction in heterozygous PINK1 mutation carriers compared with healthy controls; this was a significant difference, but mild in comparison with the 60% FDOPA uptake reduction seen in subjects with homozygous PINK1 mutations. Overall, the degree of FDOPA uptake reduction correlated with severity of UPDRS motor impairment. Together, the findings suggest that heterozygous PINK1 mutations may increase susceptibility to hyposmia and motor signs of PD, but to a lesser degree than homozygous PINK1 mutations.
In recent years, there has been a growing recognition of the importance of genetic susceptibility factors in both familial and sporadic PD. In particular, there has been increasing evidence that heterozygous mutations in "recessive" genes for PD – including PINK1 and Parkinson's – may also confer vulnerability to PD. In this study, the authors performed a longitudinal study of a single, large kindred, and demonstrate that the mild parkinsonian signs seen in PINK1 heterozygotes are progressive over time and associated with mild but significant reduction in FDOPA uptake, thereby providing further support for this hypothesis.
The major limitation of the study is that it was restricted to a small number of subjects in a single kindred, and therefore may not be generalizable to other individuals with PINK1 mutations. In addition, the study duration was only three years, and FDOPA PET scans were only completed at the study endpoint; thus, it is not known whether the reduction in FDOPA uptake observed in subjects with heterozygous PINK1 mutations was progressive over time. Further follow-up of this and other kindreds with PINK1 mutations is therefore warranted.
While PINK1 mutations are relatively uncommon in PD, this and other genetic susceptibility factors for PD provide a unique opportunity to study the presymptomatic and premotor phases of Parkinson's disease, and to clarify the patterns of evolution of PD non-motor and motor disease progression. Such an understanding may help to facilitate the early diagnosis of both genetic and sporadic PD, and thus permit the administration of future disease-modifying therapies as early as possible in the disease course.