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The causes of Parkinson disease have not been defined; it may be caused by environmental factors, genetic factors, or a combination of both. Environmental risk factors may include exposure to heavy metals and pesticides, rural residence and being a non-smoker.2 Genetic factors appear to be more predominant when the disease begins before the age of 50.3
Numerous families with Mendelian patterns of inheritance have been described. In 1997, the first genetic mutation to cause familial parkinsonism was discovered.4 Currently, genetic variability in five genes is known to cause hereditary parkinsonism or to contribute to an individuals' risk of developing PD. (a-Synuclein, Parkin, Ubiquitin C-terminal hydrolase, DJ-1 and Tau). Several other genes (see Table 1) have been suggested to cause hereditary parkinsonism, and chromosomal loci have been associated with parkinsonism in other families.5, 6 To date, the most common known form of hereditary parkinsonism is due to mutations in the parkin gene (PARK2).7 The majority of these cases have early onset (< 45 years).
Table 1: PD Genes/Loci
| Gene/Locus/Assignment | Inheritance | Age of Onset |
| a-Synuclein / SNCA / PARK1&4 | Autosomal Dominant / Susceptibility | Early / Late |
| Parkin / PRKN / PARK2 | Autosomal Recessive / Possible Susceptibility | Juvenile / Early |
| Ubiquitin C-terminal hydrolase / UCH-L1 / PARK5 | Autosomal Dominant / Susceptibility | Late |
| DJ-1 / DJ-1 / PARK7 | Autosomal Recessive | Early |
| Tau / MAPT / FTDP-17 | Autosomal Dominant/ Susceptibility | Early / Late |
| PARK3 | Autosomal Dominant | Late |
| PARK6 | Autosomal Recessive | Early |
| PARK8 | Autosomal Dominant | Late |
| PARK9 | Autosomal Recessive | Juvenile |
| PARK10 | Susceptibility | Late |
| PARK11 | Susceptibility | Late |
Mutations in the parkin gene, on chromosome 6, were first identified in Japanese individuals with autosomal recessive juvenile parkinsonism. Many features of Parkinson disease including rigidity, tremor, bradykinesia, and postural imbalance characterized their disease.8 In 1998, Kitada and colleagues showed recessive, loss of parkin function was the cause of the disorder.9 Since its discovery, many different parkin mutations have been found in familial as well as sporadic cases from different origins including North America, Europe, Russia, and North Africa.
Parkin encodes the protein parkin, an E3 ligase, which is an integral component of the cytoplasmic ubiquitin/proteasomal protein degradation pathway.10 Ubiquitination is a vital cellular process by which a large variety of cellular proteins (targets or substrates) are conjugated with multimers of ubiquitin, marking them for degradation by the proteosome. This is an important function because as the proteins age, they slowly become damaged (oxidated) and toxic to the cell. Therefore, it is believed that parkin's function is to attach ubiqutin molecules to defective proteins, tagging them for destruction.10 It is hypothesized that mutations in the parkin gene, which result in loss of parkin function, slow down the destruction of the defective proteins causing them to accumulate in the cell and leading to nigral neuronal degeneration.11 It is not yet known why dopaminergic neurons in the substantia nigra are particularly vulnerable to the loss of parkin's function.5
Parkin disease (PARK2) is a distinct genetic entity with clinical features that show varying degrees of overlap with those of idiopathic PD.12 The clinical features of the disease may be indistinguishable from idiopathic PD, although parkin patients may have unusual features, most commonly, early age at onset and a very slowly progressive course. Parkin mutations have been found in up to 49% of early onset patients (< age 45) with a family history and in up to 18% of early onset patients with no family history.13 Interestingly, some researchers have identified parkin mutations in patients with onset as late as the seventh decade.14
Typical features of Parkin disease (PARK2) include:7,12
- Clinical features
- Young onset parkinsonism
- Dystonia with parkinsonism, with improvement of symptoms after sleep
- Slow disease progression
- May have associated signs such as hyperreflexia, dysautonomia, peripheral neuropathy
- Pathological features
- No Lewy bodies, which are the pathological hallmark of PD.2
- Response to therapy
- Dramatic response to antiparkinsonian therapy (dopaminergic, anticholinergic)
- Good response to low doses of levodopa
- May have a higher frequency of levodopa induced dyskinesias
The parkin gene spans 1.3 Mb and is one of the largest genes known.15 Approximately 80 different parkin mutations have been described, including point mutations, rearrangements, deletions and duplications.16 The large spectrum of parkin gene defects may have different consequences on the function of the protein and therefore on phenotype variability.5
The detection rate of mutations in the parkin gene currently varies dramatically, depending on the patient cohort and screening methods employed (see Table 2). It can be as high as 80%-90% in familial cases with onset below age 20, while in individuals in their 40s without family history, it may be only 9%.17 However, these and similar figures are generally based on limited screening methods in relatively small patient groups referred with early-onset parkinsonism. The data may not reflect the true prevalence of Parkin disease (PARK2) and further genetic epidemiology is required. Loss of parkin function as the cause of disease is considered rare in individuals with onset of symptoms >50 years of age.
Table 2: Frequency of Parkin mutations in early onset patients with no family history17
| Age of Onset | Mutation Detection Rate |
| <20 | 67% |
| 20-24 | 27% |
| 25-29 | 24% |
| 30-34 | 8% |
| 35-39 | 6% |
| 40-45 | 9% |
Accurate diagnosis of Parkin disease (PARK2) cannot be based only on the clinical manifestations of the disease because "there are not specific clinical signs that distinguish these patients from patients with other causes of Parkinson's disease."13 Testing for mutations in the parkin gene can help identify the cause of parkinsonism in patients presenting with early onset parkinsonism and/or dystonia (although dystonia may be a feature of early onset disease rather than parkin mutations) or in others when the family history or clinical features suggest Parkin disease (PARK2).5
Research on mutations in parkin is evolving rapidly; several areas being studied include:
Heterozygous mutations:
Although Parkin disease (PARK2) is transmitted in an autosomal recessive manner (both copies of the parkin gene are mutated), there have been reports of individuals with PD who have only one copy of the mutation.14,18 This could be due to failure to detect a mutation, rearrangement in the second parkin allele, or could indicate that a single parkin mutation is a susceptibility factor for later-onset PD.Predicting pathogenic mutations:
New disease-causing mutations in parkin are rapidly being identified.16 This will help clinicians understand the potential significance of variations in Parkin, and whether or not these mutations are likely to affect their patients and their families.Asymptomatic individuals:
The significance of discovering homozygous parkin mutations in asymptomatic individuals is also being studied. As a result, testing asymptomatic individuals for parkin mutations is not recommended.
Although the identification of Parkin disease (PARK2) cannot predict the clinical course for any one individual, in general, Parkin disease (PARK2) has slower progression than idiopathic PD.12 Parkin patients generally have a milder form of PD that responds well to levodopa (L-dopa) and to other dopaminergic agonists: "Response is usually significant and is sustained for low doses of levodopa even after long disease duration."17 L-dopa induced dyskinesias and fluctuations have been suggested to occur frequently in Parkin disease (PARK2), which may influence the choice of therapy for parkin patients; treatment with a dopamine agonist is recommended for as long as possible.11 When levodopa is prescribed, it is thought best to use small doses (50-100 mg of levodopa with a dopa-decarboxylase inhibitor) every few hours.11
Genetic testing is now warranted for an increasing number of heritable disorders where information on mutation status may provide a positive impact on individuals' "need to know", as well as inform prognosis, lifestyle or reproductive choices. Where testing is offered, positive and negative results are largely unequivocal and meaningful genetic counseling can be offered.
For parkin, functional and frequency data is presently limited; physicians and patients should note that some genetic test results, such as heterozygote and some compound heterozygote, may not be able to be clinically interpreted at this time. Unequivocal Parkin disease (PARK2) test results include homozygous deletions or compound heterozygote findings consisting of non-consecutive exon deletions or duplications, or premature termination mutations. An unequivocal Parkin disease (PARK2) result can confirm a suspected diagnosis, provide information on prognosis, and offer information to facilitate accurate genetic counseling.
Genetic counseling is recommended for all individuals undergoing any form of genetic testing. The molecular genetic diagnosis of an inherited disorder affects not just the patient, but also other family members. Parkin mutations are inherited in an autosomal recessive pattern, that is, both copies of the gene must have mutations before the clinical disease occurs. Classically, in such a disorder the siblings of an affected person have a 25% chance of being affected, and a 50% chance of being a carrier but without clinical disease. Counseling is particularly important in cases such as parkin, where the state of knowledge of the disease and the understanding of the significance of various mutations is changing rapidly. For information on how to find a genetic counselor near you, visit http://www.nsgc.org/.
Continued research on the parkin gene will enhance our understanding of its role in PD and will help clinicians better characterize Parkin disease (PARK2). For example, the discovery that parkin is involved with protein degradation will help researchers develop strategies aimed at enhancing protein degradation. The ultimate goal of research aimed at understanding the cause of PD is developing therapeutics that can either prevent the onset or potentially halt the progression of the disease. For more information on current research visit http://clinicaltrials.gov/search/term=Parkinson%27s+Disease.
