inson Disease Overview

Clinical Manifestations

Parkinson disease is characterized by tremor, muscle rigidity, and slowed movement (bradykinesia). Psychiatric manifestations, which include depression and visual hallucinations, are common but not uniformly present. Dementia eventually occurs in at least 20% of cases.

Generally, individuals with onset before age 20 years are considered to have juvenile-onset Parkinson disease, those with onset before age 50 years are classified as having early-onset Parkinson disease, and those with onset after age 50 years are considered to have late-onset Parkinson disease.

Establishing the Diagnosis of Parkinson Disease

The diagnosis of Parkinson disease is based on the clinical findings of tremor, rigidity, and bradykinesia [Hughes et al 2002]. A good response to levodopa and asymmetric onset of limb involvement are generally regarded as supporting diagnostic features.

Functional imaging techniques such as positron emission tomography (PET) or single photon computed emission tomography (SPECT) using radioactively labeled ligands of the presynaptic dopaminergic neurons can support the diagnosis but are usually limited to a research setting.

The cardinal pathologic feature of Parkinson disease is the loss of dopaminergic neurons in the substantia nigra with intracytoplasmic inclusions (Lewy bodies) in the remaining, intact nigral neurons [Braak & Braak 2000]. Traditionally, the presence of Lewy bodies was required for pathologic confirmation of Parkinson disease; however, with the discovery of new subtypes of Parkinson disease (e.g., PARK2), it has been recognized that nigral pathology may occur in the absence of Lewy bodies. Correlation of genetic mutations with neuropathologic findings is only beginning and is likely to provide new insights regarding the diagnosis and pathogenesis of Parkinson disease.

Since a diagnosis of Parkinson disease can only be confirmed through documentation of salient clinical features and post-mortem verification of Lewy bodies, some diagnostic uncertainty is unavoidable. The careful application of diagnostic criteria noted above derived from existing clinicopathologic studies can increase the positive predictive value of diagnosis to over 95% [Hughes et al 2002]. Presence of resting tremor, response to dopamine agents, asymmetrical onset of symptoms, and the absence of atypical features that suggest other diagnoses are all criteria that can be used to increase the certainty of diagnosis. However, by maximizing thespecificity of the criteria, the sensitivity of the criteria falls dramatically, thereby excluding as many as one-third of true cases [Hughes et al 2001]. While these diagnostic criteria are ideal for a genetic research study (see Pankratz et al [2002] Appendix: Inclusion and Exclusion Criteria), they may not be useful for making a clinical diagnosis.

Differential Diagnosis

Other neurologic entities that commonly mimic Parkinson disease include the following:

• Parkinsonism-predominant multiple system atrophy (formerly called striatonigral degeneration)

• Progressive supranuclear palsy (PSP)

• Corticobasal degeneration (CBD), essential tremor

• Drug-induced parkinsonism

• Postencephalitic conditions

• Lewy body dementia

• Alzheimer disease (see Alzheimer Disease Overview)

Parkinsonism can be a prominent feature of some autosomal dominant neurologic conditions:

• Spinocerebellar ataxias (i.e., MJD/ SCA3 and SCA2)

• Huntington disease

• Dopa-responsive dystonia

• Familial prion disease

• Frontotemporal dementia with parkinsonism-17 (FTDP-17)

Other genetic disorders associated with parkinsonism include the following:

• Wilson disease

• X-linked dystonia-parkinsonism syndrome (Lubag)

Laboratory or radiologic studies are useful only in excluding alternative diagnoses such as stroke, tumor, and thyroid disease.

Prevalence

Parkinson disease is the second most common neurodegenerative disorder, after Alzheimer disease (see Alzheimer Disease Overview). Parkinson disease affects more than 1% of 55-year-old individuals and more than 3% of those over age 75 years.

The overall age- and gender-adjusted incidence rate is 13.4 per 100,000, with a higher prevalence among males (19.0 per 100,000) than females (9.9 per 100,000) [Van Den Eeden et al 2003].

Parkinson disease appears to be less common among African-Americans [Van Den Eeden et al 2003].

Mendelian forms of Parkinson disease are rare.

Single Gene Causes

The genetic cause for some forms of Parkinson disease has been identified, typically by usinglinkage analysis followed by positional cloning in families having earlier age of disease onset and/or either autosomal dominant or autosomal recessive inheritance.

In this section, the genes contributing to the etiology of Parkinson disease are organized bymode of inheritance.

Multifactorial Causes

Parkinson disease susceptibility genes. For many years, it was thought that most forms of Parkinson disease did not have a genetic contribution; however, by the late 1990's, studies in different populations documented that the risk of Parkinson disease among first-degree relatives of an affected individual is two to fourteen times higher than the risk in the general population. With this evidence of a genetic component for Parkinson disease, families with two or more members with Parkinson disease were studied. Results suggest the presence of Parkinson disease susceptibility genes that may increase the risk for familial Parkinson disease.

Several chromosomal regions that may harbor a Parkinson disease susceptibility gene have been implicated, and in some cases a candidate gene has been identified. What remains to be determined is whether the genes implicated in familial Parkinson disease also increase the risk for individuals who do not have a family history of Parkinson disease. A genome-wide association study identified several chromosomal regions with evidence of association to a Parkinson disease susceptibility gene [Maraganore et al 2005]. However, these results have not been confirmed by other research groups in independent samples [Clarimon et al 2006, Farrer et al 2006, Goris et al 2006, Myers 2006] (Table 3).

NR4A2. Two distinct mutations in exon 1 of NR4A2 have been identified as segregating with Parkinson disease in ten families [Le et al 2003]. The age at onset of disease and clinical features of these ten probands did not differ from those of individuals with typical Parkinson disease. NR4A2 mRNA levels were significantly decreased in transfected cell lines with themutation compared with those without the mutation, as well as in the lymphocytes of the affectedindividuals. Expression levels of the dopamine biosynthesis enzyme tyrosine hydroxylase were also markedly decreased in the transfected cells with the mutations compared to the wild type. These data suggest that dopaminergic dysfunction can result from mutations in NR4A2. Thus far, the role of orphan nuclear receptor NR4A2 in Parkinson disease susceptibility appears to be limited [Wellenbrock et al 2003, Zimprich et al 2003].

SNCAIP. Similar to alpha-synuclein (the protein encoded by SNCA in PARK1) synphilin-1, the protein encoded by SNCAIP, is a substrate of the gene product of PARK2. It has been shown to interact directly with alpha-synuclein and is found, along with parkin and alpha-synuclein, in Lewy bodies.

The same mutation (p.Arg621Cys) was reported in two individuals with late-onset idiopathic Parkinson disease (age of onset: 63 and 69 years) who had no apparent family history of Parkinson disease [Marx et al 2003]. In a group of 328 German individuals with familial or simplex PARK2, the p.Arg621Cys mutation was the only polymorphism found that was not seen in 351 control individuals. However, for five of the six microsatellite markers genotyped in the chromosomal region around the SNCAIP gene, the two individuals with late-onset idiopathic Parkinson disease share the same rare alleles, suggesting that this variant was inherited from a common ancestor.

Functional studies of the protein indicate that abnormal synphilin-1 can form cytoplasmic inclusions in transfected cells and that cells transfected with the p.Arg621Cys polymorphism were more susceptible to apoptosis than cells expressing wild-type synphilin-1. Replication of the role of synphilin-1 in Parkinson disease susceptibility has not yet been confirmed.

A single mutation in GBA, the gene encoding glucocerebrosidase, may convey an increased risk for Parkinson disease, especially within the Ashkenazi Jewish population [Aharon-Peretz et al 2004, Lwin et al 2004]. Individuals with two GBA mutations have Gaucher disease, which is also found at a high rate among Ashkenazi Jews. While it remains to be seen if the risk for Parkinson disease is as strong in other populations as it is in the Jewish population, a study of a Norwegian cohort [Toft et al 2006] already disputes this relationship, while a study of a US cohort supports it [Goker-Alpan et al 2006].

Mitochondrial DNA. Mitochondrial dysfunction, particularly with regard to complex I of the electron transport chain, has been implicated in the pathogenesis of Parkinson disease. Individuals with a specific variant in the NADH complex I enzyme had a significantly lower risk of Parkinson disease than individuals who had the most common form of the enzyme [van der Walt et al 2003]. These results suggest that variation in complex I proteins is an important risk factor in Parkinson disease susceptibility, at least among Caucasians. Mitochondrial DNA deletions have been reported to be common in substantia nigra neurons in individuals with Parkinson disease [Bender et al 2006, Kraytsberg et al 2006].

Family History & Evaluation

A three-generation family history should be obtained, with particular attention to any individual with a movement disorder. The age of onset of disease should be noted for each affectedindividual. Medical records of affected family members, including reports of neuroimaging studies and autopsy examinations, should be obtained.

Clinical Examination

First-degree relatives of an affected individual who are concerned about the presence of symptoms consistent with Parkinson disease should be evaluated by a neurologist, preferably a movement disorder specialist.

Molecular Genetic Testing

PARK1. Molecular genetic testing is clinically available for SCNA mutations.

PARK2. Molecular genetic testing is clinically available for PARK2, the gene encoding parkin. The diagnosis of parkin type of juvenile-onset Parkinson disease can only be confirmed when disease-causing mutations are identified on both alleles of the PARK2 gene (i.e., the affectedindividual is homozygous for the same disease-causing allele or compound heterozygous for two different disease-causing alleles). The finding of a single disease-causing mutation is only suggestive of parkin type of juvenile-onset Parkinson disease because the possibility exists that the affected individual is truly a heterozygote and has parkinsonism from some other cause. Conversely, the absence of a PARK2 mutation on one or both alleles cannot completely exclude the diagnosis of parkin type of juvenile-onset Parkinson disease.

PARK6. Molecular genetic testing is clinically available for PINK1 mutations.

PARK7. Molecular genetic testing is clinically available for PARK7 mutations.

PARK8. Molecular genetic testing is clinically available for LRRK2; however, because several nonsynonymous coding mutations have been identified in affected individuals and controls, caution is advised when interpreting the clinical significance of rarer mutations.

Mode of Inheritance

Because Parkinson disease is genetically heterogeneous, genetic counseling of affectedindividuals and their family members must be done on a family-by-family basis. For several of the genes described in Causes, disease-causing mutations are inherited in an autosomal dominantor autosomal recessive manner; however, most cases of Parkinson disease are thought to result from the effects of multiple genes as well as environmental risk factors (e.g., head trauma, pesticide use).

Risk to Family Members — Late-Onset Parkinson Disease

Genetic counseling for individuals with the typical, late-onset form of Parkinson disease and their family members must be empiric and relatively nonspecific. Parkinson disease is fairly common: the lifetime risk of developing the disease is approximately 1%-2% [Elbaz et al 2002].

Parents, sibs, and offspring of a proband

• The risk to first-degree relatives (parents, sibs, and offspring) of a person with Parkinson disease varies from study to study and from country to country. The largest studies of the US population find that first-degree relatives of an affected individual are between 2.7 and 3.5 times more likely to develop Parkinson disease than an individual without a family history of Parkinson disease. Their cumulative lifetime risk of developing Parkinson disease is therefore between 3% and 7%.

• It is possible that an earlier age of onset in an affected person or the number of additional affected relatives increases the risk to first-degree relatives, but the magnitude of the increase is unclear unless the pattern in the family is characteristic ofautosomal dominant inheritance.

Risk to Family Members — Familial Parkinson Disease

A relatively small number of families are thought to segregate a form of disease caused by mutations in a single gene. The family history must be carefully assessed, since both autosomal dominant and autosomal recessive forms of Parkinson disease have been identified. In some (not all) instances, families with mendelian forms of Parkinson disease had earlier age of disease onset.

Risk to Family Members — Autosomal Dominant Parkinson Disease

Parents of a proband

• Most individuals diagnosed with autosomal dominant Parkinson disease have anaffected parent.

• A proband with Parkinson disease may have the disorder as the result of a de novogene mutation. The proportion of cases caused by de novo mutations is unknown.

Note: Although most individuals diagnosed with autosomal dominant Parkinson disease had anaffected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

Offspring of a proband. Each child of an individual with autosomal dominant Parkinson disease has a 50% chance of inheriting the mutation.

Risk to Family Members — Autosomal Recessive Parkinson Disease

Parents of a proband

• The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.

• The risk for heterozygotes of developing symptoms is not yet determined despite the report of several individuals with parkinsonism who carry a single PARK2 mutation [Klein et al 2000, West et al 2002].

• Heterozygotes (carriers) with other mutations causing autosomal recessive forms of Parkinson disease are likely to be asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffectedand not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• The risk for heterozygotes of developing symptoms is not yet determined despite the report of several individuals with parkinsonism who carry a single PARK2 mutation [Klein et al 2000, West et al 2002, Foroud et al 2003, Sun et al 2006].

• Heterozygotes (carriers) with other mutations causing autosomal recessive forms of Parkinson disease are likely to be asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive Parkinson disease are obligate heterozygotes (carriers) for a disease-causing mutation.

Carrier Detection

• Carrier testing for PARK2, PARK7, and PINK1 mutations is available on a clinical basis once the mutations have been identified in the proband.

• Carrier testing for other forms of autosomal recessive Parkinson disease using molecular genetic techniques is not offered because it is not clinically available.

Related Genetic Counseling Issues

Identification of individuals with one PARK2 alteration. Approximately 50% of individuals with early-onset, autosomal recessive Parkinson disease may have a mutation in the PARK2 gene. This represents a relatively small proportion of those with Parkinson disease. Of concern are the studies that suggest that a single mutation in the PARK2 gene may be found among individuals with Parkinson disease [Klein et al 2000, Farrer et al 2001, Foroud et al 2003]. This suggestion raises the possibility that a single mutation in the PARK2 gene may be sufficient for causing disease or may increase the risk of disease. Dozens of different alterations have already been reported for the PARK2 gene, and it is likely that they are not equally influential, with several alterations potentially not having any clinical consequences at all. Thus, an identification of an alteration in the PARK2 gene may not necessarily be associated with an increased risk of Parkinson disease, and risk of Parkinson disease is not excluded when a PARK2 alteration has not been identified.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See  for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for PARK2 or LRRK2 mutations is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

A single PARK2 mutation may increase susceptibility for Parkinson disease or may even manifest in an autosomal dominant manner [Klein et al 2000, Farrer et al 2001, Foroud et al 2003, Sun et al 2006]. This lack of understanding about penetrance and genotype/phenotypecorrelations makes interpretation of prenatal testing results difficult.

No laboratories offering molecular genetic testing for prenatal diagnosis of Parkinson disease caused by mutations in genes other than PARK2 and LRRK2 are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which thedisease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see .

Requests for prenatal diagnosis of adult-onset diseases are uncommon. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Treatment of Manifestations

The mainstay of the treatment of Parkinson disease is pharmacologic replacement of dopamine, most commonly accomplished with the precursor of dopamine, L-dopa, combined with carbi-dopa. Dopamine agonists may also be used, as well as inhibitors of catechol-O-methyltransferase (COMT) or monoamine oxidase-B (MAO-B).

Other medications include anticholinergics, selegiline, and amantadine [Lang & Lozano 1998,Hristova & Koller 2000, Marjama-Lyons & Koller 2001, Olanow & Stocchi 2004].

Some persons with Parkinson disease benefit from neurosurgical procedures such as pallidotomy, deep brain stimulation of the subthalamic nucleus, or fetal brain transplant to the caudate nucleus [Esselink et al 2004].

Individuals with Parkinson disease may benefit from physical, occupational, and speech therapy.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See theGeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.