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Parkinson Disease Overview

, BS, BA, , PhD, , MD, and , PhD.

Author Information
, BS, BA
Department of Medical and Molecular Genetics
Indiana University School of Medicine
Indianapolis, Indiana
, PhD
Minnesota Supercomputing Institute
University of Minnesota
Minneapolis, Minnesota
, MD
Department of Neurology
Indiana University School of Medicine
Indianapolis, Indiana
, PhD
Department of Medical and Molecular Genetics
Indiana University School of Medicine
Indianapolis, Indiana

Initial Posting: ; Last Update: February 27, 2014.

Summary

Disease characteristics. 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.

Diagnosis/testing. 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.

Genetic counseling. 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%.

Management. 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.

Definition

Clinical Manifestations

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 [2002], Appendix: Inclusion and Exclusion Criteria), they may not be useful in a clinical setting.

Differential Diagnosis

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:

Other genetic disorders associated with parkinsonism include the following:

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

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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-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].

Causes

Environmental Causes

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).

Heritable Causes

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.

Table 1. Parkinson Disease: Molecular Genetics

Mode of InheritanceLocus NameGene Proportion of Parkinson Disease Attributed to Mutation of This GeneNomenclature Proposed by Marras et al [2012] Protein Product Name
Autosomal dominantPARK1SNCA 1RarePARK-SNCAAlpha-synuclein
PARK8LRRK2 2, 31%-2%PARK-LRRK2 Leucine-rich repeat serine/threonine-protein kinase 2
PARK17VPS35 4, 5, 6, 7, 8RarePARK-VPS35Vacuolar protein sorting-associated protein 35
Autosomal recessivePARK2PARK2 101% 9PARK-PARKINParkin
PARK6PINK1 12Rare 11PARK-PINK1Serine/threonine-protein kinase PINK1
PARK7PARK7 13RarePARK-DJ1Protein DJ-1
PARK9ATP13A2 14RarePARK-ATP13A2Probable cation-transporting ATPase 13A2
PARK15FBX07 15, 16RarePARK-FBX07F-box only protein 7
SLC6A3SLC6A3 17RareNoneSodium-dependent dopamine transporter
X-linkedPARK12TAF1 18, 19RareDYT/TAF1Transcription initiation factor TFIID subunit 1

See Parkinson disease: Phenotypic Series to view genes associated with this phenotype in OMIM.

1. Polymeropoulos et al [1997]

2. Funayama et al [2002], Paisán-Ruíz et al [2004], Zimprich et al [2004]

3. Because several nonsynonymous LRRK2 coding variants have been identified in affected individuals and controls, caution is advised when interpreting the clinical significance of rarer allelic variants

4. Vilariño-Güell et al [2011]

5. Zimprich et al [2011]

6. Lesage et al [2012]

7. Sheerin et al [2012]

8. Sharma et al [2012]

9. Mutation of PARK2 accounts for ~1% of individuals with Parkinson disease, but up to 50% of individuals with early-onset Parkinson disease.

10. Kitada et al [1998]

11. Mutation of PARK6 is a rare cause of all Parkinson disease, but accounts for 1%-7% of individuals with early-onset Parkinson disease.

12. Valente et al [2001], Valente et al [2004]

13. van Duijn et al [2001]

14. Ramirez et al [2006]

15. Di Fonzo et al [2009]

16. Paisán-Ruiz et al [2010]

17. Kurian et al [2009]

18. Lee et al [1991]

19. Graeber & Muller [1992]

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 [2006]: 18.3%; Orr-Urtreger et al [2007]: 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 DJ-1) 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.

X-Linked Parkinson Disease

To date, mutation of DYT is the only known cause of Parkinson disease with X-linked inheritance. Mutation of this gene is rare and has only been found among individuals of Panayan (Philippines) origin [Lee et al 1991, Graeber & Muller 1992].

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.

Evaluation Strategy

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.

Family History

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.

Clinical Examination

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

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.

Prenatal Testing

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.

Resources

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 Avenue
    Staten Island NY 10305
    Phone: 800-223-2732 (toll-free); 718-981-8001
    Fax: 718-981-4399
    Email: apda@apdaparkinson.org
  • Fox Trial Finder
  • Michael J. Fox Foundation for Parkinson's Research
    Church Street Station
    PO Box 780
    New York NY 10008-0780
    Phone: 800-708-7644 (toll-free)
    Email: info@michaeljfox.org
  • National Library of Medicine Genetics Home Reference
  • National Parkinson Foundation
    1501 Northwest 9th Avenue
    Bob Hope Road
    Miami FL 33136-1494
    Phone: 800-327-4545 (toll-free); 305-243-6666
    Fax: 305-243-6073
    Email: contact@parkinson.org
  • Parkinson's Disease Foundation (PDF)
    1359 Broadway
    Suite 1509
    New York NY 10018
    Phone: 800-457-6676 (Toll-free Helpline); 212-923-4700
    Fax: 212-923-4778
    Email: info@pdf.org

Management

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.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Chapter Notes

Revision History

  • 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
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