The Genetics of Parkinson Disease: Implications for Neurological Care

Christine Klein; Michael G. Schlossmacher


Nat Clin Pract Neurol. 2006;2(3):136 

In This Article

Genetic Susceptibility Factors in Parkinson Disease

Monogenic PD accounts for only a minority of cases; most other cases are probably caused by complex interactions between several genes encoded by nuclear or mitochondrial DNA (or both), modifying effects of susceptibility alleles and epigenetic factors, and effects on PD-linked-gene expression that are attributable to environmental agents and aging. There are several challenges, however, for PD geneticists: there is no readily available test of high specificity and sensitivity that immediately distinguishes PD from other parkinsonian conditions; PD has a long preclinical phase; and PD is a late-life disorder. Several genetic variations probably act only as disease modifiers, influencing the disease's penetrance, age of onset,[58] or severity and progression.

Role of Heterozygous Mutations in 'Recessive' Genes

A considerable percentage of patients with PD was shown to carry a single heterozygous mutation in the Parkin, DJ1 or PINK1 genes,[7,9,15,17,30,32,33] raising the intriguing question of whether the much more frequent heterozygous mutations in 'recessive' genes might act as susceptibility factors for PD. There are several ways to explore the potential role of these mutations.

First, the frequency of single heterozygous mutations in ethnically matched PD cases and controls could be compared. According to recent reports, heterozygosity for Parkin mutations was similar between patients and controls,[59] whereas heterozygous PINK1 mutations were rarer in controls.[28,30] Lincoln et al.[59] indicated that there was no elevation in PD risk for people who carry a single mutant Parkin allele. In most studies, however, healthy controls are not subjected to detailed neurological and neuroimaging examinations, leaving open the possibility that mild clinical (or preclinical) changes could have been present but were not screened for. As recently shown for Parkin[12] and PINK1[9] families, subtle, but unequivocal, clinical signs of possible or probable PD can be found on careful motor examination, and verified by blinded video review, in a considerable number of the heterozygous mutation carriers who consider themselves asymptomatic (Figure 2). Furthermore, it could be argued that at least some of the controls had not yet reached the age of their disease onset.

Second, the heterozygous offspring of homozygous or COMPOUND HETEROZYGOUS mutation carriers could be examined in a prospective manner, an approach that is currently being used in several cohorts. The probability that a second mutation might have been overlooked in these carriers is much lower than the probability of a mutation being missed in sporadic cases of PD.

Last, further functional studies of the affected allele carriers would be highly valuable. HAPLOINSUFFICIENCY, leading to a functional loss of heterozygosity or a DOMINANT-NEGATIVE effect of some mutant alleles (Figure 2), could explain why a second mutation cannot (and need not) be found for some mutations in the above-mentioned recessive genes.

Although the role of heterozygous mutations in the development of clinical signs currently remains a matter for debate, there is growing evidence that they are associated with preclinical changes. PET studies have revealed reduced [18F]fluoro-dopa uptake by nerve terminals in the striatum of heterozygotes;[60,61] there are also structural neuroimaging changes that indicate an increased deposition of metals in the substantia nigra,[62] and there is reorganization of striatocortical motor loops with detectable changes in connectivity patterns.[63]

These collective data have important implications. Some carriers of heterozygous mutations might be in the preclinical period of PD, thereby affording unique opportunities to examine the relative risk associated with the affected allele and to study the natural history of the disease. This group also represents an ideal study population to be used not only to investigate compensatory mechanisms, facilitating the development of a sensitive surrogate marker, but also to detect the earliest PD-specific changes, allowing the development of urgently needed clinical biomarkers. Finally, these individuals could provide a small, but important, target population in which to evaluate the 'proof of principle' of a therapeutic intervention in future neuroprotection trials.

Identification of Susceptibility Genes

To identify susceptibility genes, genome-wide scans have been performed in large cohorts of sibling pairs, and linkage has been demonstrated to chromosomes 2, 10 and X.[64] By contrast, association studies do not depend on the availability of affected (or unaffected) family members, but instead compare frequencies of polymorphisms in PD candidate genes in matched patient and control groups. Proposed associations cannot always be replicated in follow-up studies, however, and few PD candidate genes were confirmed in meta-analyses.[65] Nevertheless, some polymorphisms—such as those in the N-acetyltransferase 2 (NAT2), monoamine oxidase B (MAOB), ferritin (light chain), and glutathione S-transferase theta 1 (GSTT1) genes,[65] the tau H1 haplotype,[66] and, most recently, the Gaucher-disease-linked glucocerebrosidase beta (GBA) gene[67]—were consistently shown to be associated with an increased risk for PD. These data indicate that common genetic variants might alter the primary susceptibility to developing PD by interacting with environmental factors, contribute to the pathogenesis of PD, modify disease penetrance, or determine the age of onset of PD (or any combination thereof). In another extensively studied example, a promoter polymorphism in the SNCA gene that probably affects the rate of expression of the SCNA protein was found to be synergistic with a protective variant (Ser18→Tyr polymorphism) in the UCHL1 (PARK5) gene (Figure 3). The latter variant in turn might alter the rate of SNCA degradation,[68] thereby affecting the relative risk of developing sporadic PD.[69]