Parkinsonism refers to all clinical states characterized by tremor, muscle rigidity, slowed movement (bradykinesia) and often postural instability. Parkinson disease is the primary and most common form of parkinsonism. Psychiatric manifestations, which include depression and visual hallucinations, are common but not uniformly present. Dementia eventually occurs in at least 20% of cases. The most common sporadic form of Parkinson disease manifests around age 60; however, young-onset and even juvenile presentations are seen.
The diagnosis of Parkinson disease in a symptomatic individual is based solely on the clinical findings of tremor, rigidity, and bradykinesia. A good response to levodopa and asymmetric onset of limb involvement are generally regarded as supporting diagnostic features. 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. The genes that are mutated in some of the inherited forms of Parkinson disease have been identified. Molecular genetic testing for some of these genes is clinically available either individually or as multi-gene panels. Note: Although currently available genetic tests aid in the diagnosis of Parkinson disease in symptomatic individuals, they are not useful in risk prediction for asymptomatic individuals with no family history of Parkinson disease.
Mendelian (monogenic) forms of Parkinson disease are inherited in an autosomal dominant, autosomal recessive, or, rarely, X-linked manner. For Mendelian forms of Parkinson disease, genetic counseling depends on the mode of inheritance.
In contrast, most Parkinson disease is thought to be non-Mendelian and to result from the effects of multiple genes as well as environmental risk factors. For non-Mendelian forms of Parkinson disease genetic counseling of affected individuals and their family members must be done on a family-by-family basis. The risk to first-degree relatives of a person with a non-Mendelian form of Parkinson disease varies from study to study and from country to country. Overall, the most consistent estimate in families with a non-Mendelian form of Parkinson disease suggests that first-degree relatives of an affected individual are between 2.7 and 3.5 times more likely to develop Parkinson disease than individuals without a family history of Parkinson disease. Thus, their cumulative lifetime risk of developing Parkinson disease is between 3% and 7%.
Treatment of manifestations: The mainstay of the treatment is pharmacologic replacement of dopamine in the form of levodopa, which is converted to dopamine once it enters the brain. Other effective agents include dopamine agonists, inhibitors of catechol-O-methyltransferase (COMT) and monoamine oxidase-B (MAO-B), anticholinergics, and amantadine. Treatment of advanced or disabling symptoms includes neurosurgical procedures such as deep brain stimulation of the subthalamic nucleus or globus pallidus. Occupational, physical, and speech therapy are often helpful.
Parkinson disease is characterized by tremor, muscle rigidity, slowed movement (bradykinesia), and often postural instability. Onset is classically unilateral and may include other abnormal movements such as postural or action tremor as well as limb dystonia. Common associated non-motor findings include insomnia, depression, anxiety, rapid eye movement (REM) behavior disorder, fatigue, constipation, dysautonomia, and anosmia. Later in the disease, psychosis (visual hallucinations and delusions) and dementia occur in 25% of affected individuals.
Parkinson disease is most commonly a non-Mendelian disorder, occurring primarily in simplex cases (i.e., a single affected individual in a family) with onset around age 60 years; however, onset can be earlier. Generally, onset before age 20 years is considered to be juvenile-onset Parkinson disease, before age 50 years is considered to be early-onset Parkinson disease, and after age 50 years is considered 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 fluoro-dopa positron emission tomography (PET) or single photon computed emission tomography (SPECT) using radioactively labeled ligands can document the presence of dopaminergic dysfunction but cannot distinguish between Parkinson disease and other atypical forms of parkinsonism such as multiple systems atrophy (MSA) and progressive supranuclear palsy (PSP). These imaging modalities are sometimes clinically useful to verify that a symptomatic individual has parkinsonism and to exclude entities that have normal studies (e.g., psychogenic parkinsonism, dopa-responsive dystonia).
The cardinal pathologic feature of non-Mendelian 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]. However, the neuropathology of some forms of genetically based parkinsonism may differ significantly from the classic findings documented in non-Mendelian Parkinson disease [Poulopoulos et al 2012]. For example, the presence of Lewy bodies was traditionally required for pathologic confirmation of the diagnosis of Parkinson disease; however, with the discovery of genetic causes of Parkinson disease (e.g., PARK-PARKIN caused by mutation of PARK2), it has been recognized that nigral pathology may occur in the absence of Lewy bodies. Correlation of mutation of a specific gene 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 non-Mendelian 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 application of diagnostic criteria noted above that are 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, asymmetric 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 the specificity 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 , Appendix: Inclusion and Exclusion Criteria), they may not be useful in a clinical setting.
Other neurologic entities that commonly mimic Parkinson disease include the following:
- Lewy body dementia
- Multiple system atrophy, parkinson type (formerly called striatonigral degeneration)
- Progressive supranuclear palsy (PSP)
- Corticobasal degeneration (CBD)
- Essential tremor
- Drug-induced parkinsonism
- Postencephalitic conditions
- Alzheimer disease (see Alzheimer Disease Overview)
Parkinsonism can be a prominent feature of some autosomal dominant neurologic conditions:
- Familial prion disease
Other genetic disorders associated with parkinsonism include the following:
- X-linked dystonia-parkinsonism (Lubag)
Laboratory or radiologic studies are useful only in excluding alternative diagnoses such as stroke, tumor, and Wilson disease.
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-olds and more than 3% of those over age 75 years.
The overall age- and gender-adjusted incidence rate is 13.4:100,000, with a higher prevalence among males (19:100,000) than females (9.9:100,000) [Van Den Eeden et al 2003].
Parkinson disease appears to be more common among Hispanics and non-Hispanic whites than Asians and African Americans [Van Den Eeden et al 2003].
Until the late 1990s, it was thought that Parkinson disease was caused solely by environmental factors. Since then, epidemiologic studies have shown association of parkinsonism with different environmental factors, including chemicals (most notably 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine [MPTP] [Langston et al 1983, Calne et al 1985]) and serious head trauma [Factor & Weiner 1991, Bower et al 2003]. These studies also showed that simple exposure to the associated environmental factors was not sufficient to cause disease (i.e., some individuals with definite exposures did not develop clinical features of parkinsonism).
Studies have identified (1) Mendelian forms of Parkinson disease in which mutation of a single gene is causative and (2) factors that predispose an individual to develop Parkinson disease in families lacking a Mendelian pattern of inheritance. Mutation of a single gene gives rise to Mendelian forms of Parkinson disease that can be inherited in an autosomal dominant, autosomal recessive, or, less commonly, X-linked manner.
Discovery that pathogenic variants in a number of genes (Table 1) cause Parkinson disease (with variable clinical and neuropathologic phenotypes) suggests that disruption of different biologic processes give rise to Parkinson disease. To date three different but interconnected cellular processes appear to be involved: synaptic transmission, mitochondrial quality control, and lysosome-mediated autophagy [Trinh & Farrer 2013].
Table 1 includes types of Parkinson disease for which the molecular basis is confirmed. Selected genes and their pathologic or clinical implications are further described in the paragraphs below. Note: ‘Risk factors/susceptibilities’ are not used to diagnose Parkinson disease and thus are not included in Table 1.
Autosomal Dominant Parkinson Disease
Heterozygous pathogenic variants for a few genes lead to autosomal dominant forms of Parkinson disease in which the onset of disease is typically later than autosomal recessive forms of Parkinson disease.
PARK1 (PARK-SNCA). SNCA, the first gene discovered to be mutated in an individual with Parkinson disease, encodes alpha-synuclein, a protein that many believe plays a central role in Parkinson disease etiology and possibly in other neurodegenerative disorders. The protein is found in Lewy bodies, the central pathologic feature of Parkinson disease.
Pathogenic variants in SNCA range from single nucleotide variants to gene duplications and triplications. Typically individuals who are heterozygous for a pathogenic variant have clinical and pathologic findings that are similar to those with non-Mendelian Parkinson disease, including a response to levodopa and the presence of Lewy bodies. However, the mean age of onset in individuals with a SNCA pathogenic variant is earlier (46 years).
PARK8 (PARK-LRRK2). Nearly a dozen different pathogenic variants have been reported in LRRK2; the most common, p.Gly2019Ser, has been found in approximately 5%-7% of autosomal dominant Parkinson disease [Di Fonzo et al 2005, Gilks et al 2005, Nichols et al 2005] but only in 1%-2% of simplex cases (i.e., presence of Parkinson disease in only one family member) [Gilks et al 2005].
Of note, the frequency of the p.Gly2019Ser variant is substantially higher among individuals of particular ancestry. For example, the frequency of this variant among persons with Parkinson disease of Ashkenazi Jewish ancestry is estimated at 15% to 20% (Ozelius et al : 18.3%; Orr-Urtreger et al : 14.8%) and among individuals of Northern African ancestry it may be as high as 30%-40% [Lesage et al 2006, Hulihan et al 2008].
Age of onset of Parkinson disease in persons with a heterozygous LRRK2 pathogenic variant is highly variable. Typically, the age of onset is approximately 58 years, and the clinical findings are similar to those found in non-Mendelian Parkinson disease [Healy et al 2008].
Mutation of LRRK2 shows reduced penetrance; i.e., some persons with a heterozygous LRRK2 pathogenic variant do not exhibit clinical findings [Goldwurm et al 2007, Latourelle et al 2008]. See LRRK2-Related Parkinson Disease.
PARK17 (PARK-VPS35). In 2011, the VPS35 pathogenic variant p.Asp620Asn was found to segregate in a family with late-onset parkinsonism [Vilariño-Güell et al 2011, Zimprich et al 2011]. The finding was soon replicated, and additional VPS35 pathogenic variants were subsequently identified [Lesage et al 2012, Sharma et al 2012, Sheerin et al 2012].
Autosomal Recessive Parkinson Disease
Biallelic pathogenic variants for a few genes (e.g., PARK2 [parkin type of early-onset Parkinson disease], PINK1 [PINK1 type of young-onset Parkinson disease], and PARK7) result in autosomal recessive Parkinson disease. These disorders share a similar clinical phenotype, characterized by early onset, slow disease progression, and typically mild non-motor symptoms.
Although some evidence suggests that heterozygous pathogenic variants in PINK1 or PARK2 may manifest in an autosomal dominant manner [Klein et al 2000, Farrer et al 2001, Foroud et al 2003, Sun et al 2006, Klein et al 2007], presence of a single disease-causing allele is not sufficient to cause disease in most cases.
Multifactorial and Unknown Causes
Monogenic (Mendelian) causes of Parkinson disease are found in fewer than 5% of all persons with Parkinson disease, suggesting that genetic variation at additional unknown loci contribute to disease risk. Approaches such as genome-wide association studies (GWAS) have identified several genomic regions and specific genes as possible susceptibility factors for Parkinson disease. However, additional work remains to explore the pathologic and clinical implications of susceptibility loci, as well as to explore gene-gene and gene-environment interactions.
Once the diagnosis of Parkinson disease has been established in an individual, the following approach can be used to determine if a specific monogenic (familial) form can be identified to aid in discussions of prognosis and genetic counseling.
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 affected individual. Medical records of affected family members, including reports of neuroimaging studies and autopsy examinations, should be reviewed.
First-degree relatives of an affected individual who are concerned about the presence of findings consistent with Parkinson disease should be evaluated by a neurologist, preferably a movement disorder specialist.
Molecular Genetic Testing
Single gene testing. One strategy for molecular diagnosis of a proband suspected of having a Mendelian (familial) form of Parkinson disease is sequential testing of one or more of the genes listed in Table 1. The inheritance pattern may help determine which gene is most likely to harbor a mutation.
Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having a familial form of Parkinson disease is use of a multi-gene panel. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Because Parkinson disease is genetically heterogeneous, genetic counseling for affected individuals and their family members must be done on a family-by-family basis.
For several of the genes described in Causes, pathogenic variants are inherited in an autosomal dominant, autosomal recessive, or X-linked manner.
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).
Risks to Family Members — Mendelian Forms of Parkinson Disease
A relatively small number of families are thought to segregate a form of disease caused by mutation of a single gene. The family history must be assessed, since autosomal dominant, autosomal recessive, and rarely, X-linked 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 than families with typical, late-onset Parkinson disease.
Risk to Family Members — Autosomal Dominant Parkinson Disease
Parents of a proband
- Most individuals diagnosed with autosomal dominant Parkinson disease have an affected parent, although 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, late onset of the disease in the affected parent, or reduced penetrance.
- A proband with Parkinson disease may also have the disorder as a result of a de novo pathogenic variant; the proportion of cases due to de novo mutation is currently unknown.
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 or has a disease-causing variant, the risk to the sibs of inheriting the mutation is 50%.
Offspring of a proband. Each child of an individual with autosomal dominant Parkinson disease has a 50% chance of inheriting the pathogenic variant.
Risk to Family Members — Autosomal Recessive Parkinson Disease
Parents of a proband
- The unaffected parents of an affected individual are obligate heterozygotes and therefore carry one pathogenic variant.
- As described in Causes, while some evidence suggests that heterozygotes may exhibit clinical findings, the presence of a single pathogenic variant may not be sufficient to cause disease.
Sibs of a proband
- At conception, each sib of an individual with autosomal recessive Parkinson disease has a 25% risk of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
- As described in Causes, while some evidence suggests that heterozygotes may exhibit clinical findings, the presence of a single pathogenic variant may not be sufficient to cause disease.
Offspring of a proband. The offspring of an individual with autosomal recessive Parkinson disease – provided that the other parent does not carry a pathogenic variant – are obligate heterozygotes (carriers) for a pathogenic variant.
Empiric Risks to Family Members — Multifactorial and Unknown Causes
Recurrence risk counseling for individuals with typical, late-onset 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 of autosomal dominant or autosomal recessive inheritance.
Related Genetic Counseling Issues
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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
If the pathogenic variant(s) have been identified in an affected family member, prenatal diagnosis for pregnancies at increased risk for some types of familial Parkinson disease caused by mutation of a single gene may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.
Requests for prenatal diagnosis of typically 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 an option for families in which the pathogenic variant(s) have been identified.
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- American Parkinson Disease Association (APDA)135 Parkinson AvenueStaten Island NY 10305Phone: 800-223-2732 (toll-free); 718-981-8001Fax: 718-981-4399Email: email@example.com
- Fox Trial Finder
- Michael J. Fox Foundation for Parkinson's ResearchChurch Street StationPO Box 780New York NY 10008-0780Phone: 800-708-7644 (toll-free)Email: firstname.lastname@example.org
- National Library of Medicine Genetics Home Reference
- National Parkinson Foundation1501 Northwest 9th AvenueBob Hope RoadMiami FL 33136-1494Phone: 800-327-4545 (toll-free); 305-243-6666Fax: 305-243-6073Email: email@example.com
- Parkinson's Disease Foundation (PDF)1359 BroadwaySuite 1509New York NY 10018Phone: 800-457-6676 (Toll-free Helpline); 212-923-4700Fax: 212-923-4778Email: firstname.lastname@example.org
Treatment of Manifestations
The mainstay of treatment is pharmacologic replacement of dopamine in the form of levodopa, which is converted to dopamine once it enters the brain. Other effective agents include dopamine agonists, inhibitors of catechol-O-methyltransferase (COMT) and monoamine oxidase-B (MAO-B), anticholinergics, and amantadine.
Treatment of advanced or disabling symptoms includes neurosurgical procedures such as deep brain stimulation of the subthalamic nucleus or globus pallidus.
Occupational, physical, and speech therapy are often helpful.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page PubMed
- Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA. Head trauma preceding PD: a case-control study. Neurology. 2003;60:1610–5. [PubMed: 12771250]
- Braak H, Braak E. Pathoanatomy of Parkinson's disease. J Neurol. 2000;247 Suppl 2:II3–10. [PubMed: 10991663]
- Calne DB, Langston JW, Martin WR, Stoessl AJ, Ruth TJ, Adam MJ, Pate BD, Schulzer M. Positron emission tomography after MPTP: observatins relating to the cause of Parkinson’s disease. Nature. 1985;317:246–8. [PubMed: 3876510]
- Di Fonzo A, Dekker MC, Montagna P, Baruzzi A, Yonova EH, Correia Guedes L, Szczerbinska A, Zhao T, Dubbel-Hulsman LO, Wouters CH, de Graaff E, Oyen WJ, Simons EJ, Breedveld GJ, Oostra BA, Horstink MW, Bonifati V. FBX07 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology. 2009;72:240–5. [PubMed: 19038853]
- Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet. 2005;365:412–5. [PubMed: 15680456]
- Elbaz A, Bower JH, Maraganore DM, McDonnell SK, Peterson BJ, Ahlskog JE, Schaid DJ, Rocca WA. Risk tables for parkinsonism and Parkinson's disease. J Clin Epidemiol. 2002;55:25–31. [PubMed: 11781119]
- Factor SA, Weiner WJ. Prior history of head trauma in Parkinson's disease. Mov Disord. 1991;6:225–9. [PubMed: 1922127]
- Farrer M, Chan P, Chen R, Tan L, Lincoln S, Hernandez D, Forno L, Gwinn-Hardy K, Petrucelli L, Hussey J, Singleton A, Tanner C, Hardy J, Langston JW. Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol. 2001;50:293–300. [PubMed: 11558785]
- Foroud T, Uniacke SK, Liu L, Pankratz N, Rudolph A, Halter C, Shults C, Marder K, Conneally PM, Nichols WC. Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology. 2003;60:796–801. [PubMed: 12629236]
- Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol. 2002;51:296–301. [PubMed: 11891824]
- Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet. 2005;365:415–6. [PubMed: 15680457]
- Goldwurm S, Zini M, Mariani L, Tesei S, Miceli R, Sironi F, Clementi M, Bonifati V, Pezzoli G. Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. Neurology. 2007;68:1141–3. [PubMed: 17215492]
- Graeber MB, Muller U. The X-linked dystonia-parkinsonism syndrome: clinical and molecular genetic analysis. Brain Pathol. 1992;2:287–95. [PubMed: 1364136]
- Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AHV, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurology. 2008;7:583–90. [PMC free article: PMC2832754] [PubMed: 18539534]
- Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology. 2001;57:S34–8. [PubMed: 11775598]
- Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain. 2002;125:861–70. [PubMed: 11912118]
- Hulihan MM, Ishihara-Paul L, Kachergus J, Warren L, Amouri R, Elango R, Prinjha RK, Upmanyu R, Kefi M, Zouari M, Sassi SB, Yahmed SB, El Euch-Fayeche G, Matthews PM, Middleton LT, Gibson RA, Hentati F, Farrer MJ. LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurol. 2008;7:591–4. [PubMed: 18539535]
- Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8. [PubMed: 9560156]
- Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE. Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol. 2007;6:652–62. [PubMed: 17582365]
- Klein C, Pramstaller PP, Kis B, Page CC, Kann M, Leung J, Woodward H, Castellan CC, Scherer M, Vieregge P, Breakefield XO, Kramer PL, Ozelius LJ. Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. Ann Neurol. 2000;48:65–71. [PubMed: 10894217]
- Kurian MA, Zhen J, Cheng SY, Li Y, Mordekar SR, Jardine P, Morgan NV, Meyer E, Tee L, Pasha S, Wassmer E, Heales SJ, Gissen P, Reith ME, Maher ER. Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. J Clin Invest. 2009;119:1595–603. [PMC free article: PMC2689114] [PubMed: 19478460]
- Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219:979–80. [PubMed: 6823561]
- Latourelle JC, Sun M, Lew MF, Suchowersky O, Klein C, Golbe LI, Mark MH, Growdon JH, Wooten GF, Watts RL, Guttman M, Racette BA, Perlmutter JS, Ahmed A, Shill HA, Singer C, Goldwurm S, Pezzoli G, Zini M, Saint-Hilaire MH, Hendricks AE, Williamson S, Nagle MW, Wilk JB, Massood T, Huskey KW, Laramie JM, DeStefano AL, Baker KB, Itin I, Litvan I, Nicholson G, Corbett A, Nance M, Drasby E, Isaacson S, Burn DJ, Chinnery PF, Pramstaller PP, Al-hinti J, Moller AT, Ostergaard K, Sherman SJ, Roxburgh R, Snow B, Slevin JT, Cambi F, Gusella JF, Myers RH. The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study. BMC Med. 2008;6:32. [PMC free article: PMC2596771] [PubMed: 18986508]
- Lee LV, Kupke KG, Caballar-Gonzaga F, Hebron-Ortiz M, Muller U. The phenotype of the X-linked dystonia-parkinsonism syndrome. An assessment of 42 cases in the Philippines. Medicine. 1991;70:179–87. [PubMed: 2030641]
- Lesage S, Condroyer C, Klebe S, Honore A, Tison F, Brefel-Courbon C, Durr A, Brice A. French Parkinson’s Disease Genetics Study Group; Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology. 2012;78:1449–50. [PubMed: 22517097]
- Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, Brice A. LRRK2 G2019S as a cause of Parkinson’s disease in North African Arabas. N Engl J Med. 2006;354:422–3. [PubMed: 16436781]
- Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, Michaels VE, Reed T, Rudolph A, Shults CW, Singleton A, Foroud T. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet. 2005;365:410–2. [PubMed: 15680455]
- Orr-Urtreger A, Shifrin C, Rozovski U, Rosner S, Bercovich D, Gurevich T, Yagev-More H, Bar-Shira A, Giladi N. The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease. Neurology. 2007;69:1595–602. [PubMed: 17938369]
- Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, Hunt AL, Klein C, Henick B, Hailpern SM, Lipton RB, Soto-Valencia J, Risch N, Bressman SB. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2006;354:424–5. [PubMed: 16436782]
- Paisán-Ruiz C, Guevara R, Federoff M, Hanagasi H, Sina F, Elahi E, Schneider SA, Schwingenschuh P, Bajaj N, Emre M, Singleton AB, Hardy J, Bhatia KP, Brandner S, Lees AJ, Houlden H. Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Mov Disord. 2010;25:1791–800. [PubMed: 20669327]
- Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004;44:595–600. [PubMed: 15541308]
- Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997;276:2045–7. [PubMed: 9197268]
- Ramirez A, Heimbach A, Grundemann J. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38:1184–91. [PubMed: 16964263]
- Sharma M, Ioannidis JP, Aasly JO, Annesi G, Brice A, Bertram L, Bozi M, Barcikowska M, Crosiers D, Clarke CE, Facheris MF, Farrer M, Garraux G, Gispert S, Auburger G, Vilarino-Guell C, Hadjigeorgiou GM, Hicks AA, Hattori N, Jeon BS, Jamrozik Z, Krygowska-Wajs A, Lesage S, Lill CM, Lin JJ, Lynch T, Lichtner P, Lang AE, Libioulle C, Murata M, Mok V, Jasinska-Myga B, Mellick GD, Morrison KE, Meitnger T, Zimprich A, Opala G, Pramstaller PP, Pichler I, Park SS, Quattrone A, Rogaeva E, Ross OA. A multi-centre clinic-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. J Med Genet. 2012;49:721–6. [PMC free article: PMC3488700] [PubMed: 23125461]
- Sun M, Latourelle JC, Wooten GF, Lew MF, Klein C, Shill HA, Golbe LI, Mark MH, Racette BA, Perlmutter JS, Parsian A, Guttman M, Nicholson G, Xu G, Wilk JB, Saint-Hilaire MH, DeStefano AL, Prakash R, Williamson S, Suchowersky O, Labelle N, Growdon JH, Singer C, Watts RL, Goldwurm S, Pezzoli G, Baker KB, Pramstaller PP, Burn DJ, Chinnery PF, Sherman S, Vieregge P, Litvan I, Gillis T, MacDonald ME, Myers RH, Gusella JF. Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study. Arch Neurol. 2006;63:826–32. [PubMed: 16769863]
- Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol. 2013;9:445–54. [PubMed: 23857047]
- Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004;304:1158–60. [PubMed: 15087508]
- Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, Nelson LM. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003;157:1015–22. [PubMed: 12777365]
- van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Hum Genet. 2001;69:629–34. [PMC free article: PMC1235491] [PubMed: 11462174]
- Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ, Wszolek ZK, Vingerhoets F, Farrer MJ. VPS35 mutations in Parkinson disease. Am J Hum Genet. 2011;89:162–7. [PMC free article: PMC3135796] [PubMed: 21763482]
- Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Müller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–7. [PubMed: 15541309]
- Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brücke T, Poewe W, Auff E, Trenkwalder C, Rost B, Ransmayr G, Winkelmann J, Meitinger T, Strom TM. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet. 2011;89:168–75. [PMC free article: PMC3135812] [PubMed: 21763483]
- 27 February 2014 (me) Comprehensive update posted live
- 9 July 2009 (cd) Revision: gene symbol DJ-1 replaced by PARK7 according to HGNC (gene nomenclature standard for GeneTests)
- 2 October 2007 (cd) Revision: clinical testing (sequence analysis) available for SNCA-related Parkinson disease
- 5 February 2007 (cd) Revision: prenatal testing available for PARK2 and LRRK2 mutations
- 16 October 2006 (me) Comprehensive update posted to live Web site
- 9 January 2006 (cd) Revision: testing for LRRK2 clinically available
- 11 March 2005 (cd) Revision: LRRK2 identified as causative gene for PARK8
- 25 May 2004 (me) Overview posted to live Web site
- 12 November 2003 (tmf) Original submission
Indiana University School of Medicine
University of Minnesota
Indiana University School of Medicine
Indiana University School of Medicine
Initial Posting: May 25, 2004; Last Update: February 27, 2014.
University of Washington, Seattle, Seattle (WA)
Farlow J, Pankratz ND, Wojcieszek J, et al. Parkinson Disease Overview. 2004 May 25 [Updated 2014 Feb 27]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.