Clinical Diagnosis

The diagnosis of autosomal dominant arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is made using a combination of noninvasive and invasive diagnostic tests to detect abnormalities in cardiac structure and rhythm.

Molecular Genetic Testing

Genes. Eight genes are known to be associated with autosomal dominant ARVD/C:

• TGFB3 (locus name ARVD1), transforming growth factor beta-3 gene [Rampazzo et al 2003, Beffagna et al 2005]
• RYR2 (locus name ARVD2), which encodes the protein ryanodine receptor 2 [Tiso et al 2001]
• DSP (locus name ARVD8), which encodes the protein desmoplakin [Rampazzo et al 2002]
• PKP2 (locus name ARVD9), which encodes the essential armadillo-repeat protein of the cardiac desmosome, plakophilin-2 [Gerull et al 2004]
• DSG2 (locus name ARVD 10), which encodes the protein desmoglein-2 [Awad et al 2006, Pilichou et al 2006]
• DSC2 (locus name ARVD 11), which encodes the protein desmocollin-2 [Heuser et al 2006, Syrris et al 2006]
• TMEM43 (locus name ARVD5), which encodes the protein transmembrane protein 43 [Merner et al 2008]
• JUP (locus name ARVD12), which encodes the junction plakoglobin protein also known as gamma catenin [Asimaki et al 2007]. Cowley et al [1997] was the first to map the gene and Ruiz et al [1996] described the heart phenotype in mice.

Other loci

• ARVD3, 14q12-q22 [Severini et al 1996]
• ARVD4, 2q32.1-q32.3 [Rampazzo et al 1997]
• ARVD6, 10p14-p12 [Li et al 2000, Matolweni et al 2006]
• ARVD7, 10q22 [Melberg et al 1999]
• Additional undetermined loci

Clinical testing

• Sequence analysis. The percentage of ARVD/C associated with TGFB3, DSP, PKP2, DSG2, DSC2, TGFB3 ,TMEM43 or JUP gene mutations may be as high as 42.5% [Pilichou et al 2006], although the limited sample size makes accurate estimates impossible.

Table 1. Summary of Molecular Genetic Testing Used in Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy, Autosomal Dominant

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Test Method	Mutations Detected	Proportion of AD 1 ARVD/C Attributed to Mutations in This Gene	Mutation Detection Frequency by Gene and Test Method 2	Test Availability
Mutation scanning / sequence analysis	RYR2 sequence variants 3	Rare	50%-70% 4	Clinical
	DSP sequence variants 3	6%-16%	Unknown 5	Clinical
	TMEM43 sequence variants 3	Unknown		Clinical
	PKP2 sequence variants 3	11%-43%		Clinical
Deletion testing	PKP2 exonic and whole-gene deletions		Unknown 6
Mutation scanning / sequence analysis	DSG2 sequence variants 3	12%-40%	Unknown 5	Clinical
	DSC2 sequence variants 3	Rare		Clinical
	TGFB3 sequence variants 3			Clinical
	JUP sequence variants 3	Rare	Unknown 5	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. AD = autosomal dominant

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. In ideal testing candidates with clinical diagnosis, although study population is those individuals with diagnosis of malignant hyperthermia susceptibility or central core disease only

5. Percentage of mutations detected by the test method is currently unknown, as a limited number of mutations have been identified and thus it is not known whether other types of mutations (e.g., exonic or whole-gene deletions) not detected by the test method are present in this gene.

6. Mutation frequency is known only based on mutations detected by sequence analysis.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

A diagnosis of ARVD is made based on clinical diagnosis and the Task Force diagnostic criteria.

To date, gene mutation status has not been incorporated into the diagnostic criteria:

• Genetic testing should be considered in individuals who have a clinical diagnosis of ARVD based on the diagnostic criteria.
• A case can be made to offer genetic testing to all with a clinical diagnosis of ARVD with a negative family history based on the high rate of reduced penetrance identified with the ARVD-related genes identified thus far.

Establishing the subtype of ARVC/D in a proband. Once a clinical diagnosis of ARVD is made, genetic testing can establish the subtype of ARVD. Because all subtypes of ARVD are diagnosed using the same diagnostic criteria and because no significant genotype/phenotype correlations have been identified in the ARVD disease-causing genes, classification of the subtype is done through gene testing. If genetic testing is performed and a mutation is not identified, the clinical diagnosis of ARVD is still applicable.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

RYR2

• Mutations in RYR2 have been identified in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) [Laitinen et al 2001, Priori et al 2001]. CPVT is an autosomal dominant disorder characterized by stress-related, bi-directional ventricular tachycardia in the absence of both structural heart disease and a prolonged QT interval [Coumel et al 1978, Leenhardt et al 1995]. It may present with syncopal events in childhood and adolescence. It has been suggested that CPVT and ARVD/C represent a phenotypic spectrum. However, families in which both CPVT and ARVD are present have not been described, and unique RYR2 mutations have been associated with each disorder.
• RYR2 mutations have been identified in persons with "atypical" or "borderline" long QT syndrome (LQTS) who did not have mutations identified in the five genes associated with LQTS [Tester et al 2005].

DSP. Palmoplantar keratoderma with left ventricular cardiomyopathy and woolly hair/Carvajal syndrome [OMIM 605676] is an autosomal recessive disease characterized by ventricular dilated cardiomyopathy associated with keratoderma and woolly hair [Carvajal-Huerta 1998, Norgett et al 2000]. A homozygous nonsense mutation in DSP was reported to cause Carvajal syndrome in an Ecuadorian family with documented consanguinity. In addition, an individual with autosomal recessive ARVD, woolly hair, and a pemphigous-like skin disorder was also described as having a mutation in DSP [Alcalai et al 2003].

JUP. Naxos disease, an autosomal recessive form of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) has been observed on the island of Naxos, Greece. Naxos disease also includes palmoplantar keratoderma and peculiar woolly hair [OMIM 601214]. Naxos disease is caused by a homozygous 2-nucleotide deletion in JUP, the gene encoding junction plakoglobin (also known as γ-catenin), a key component of desmosomes and adherens junctions [McKoy et al 2000]. Penetrance is complete by adolescence [Protonotarios et al 2001].

PKP2, SG2, DSC2, TGFB3, and TMEM43. No other phenotypes have been associated with mutations in these genes.

Natural History

Autosomal dominant arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a myocardial disorder that predominantly affects the right ventricle. ARVD/C is a progressive disorder characterized by fibrofatty replacement of the myocardium, predisposing to ventricular tachycardia and sudden death in young individuals and athletes [Marcus et al 1982, Thiene et al 1988, Corrado et al 1998, Fontaine et al 1998]. Pathology in ARVD/C may also extend to involve the left ventricle [Horimoto et al 2000, Hamid et al 2002].

The most common presenting symptoms are heart palpitations, syncope, and death. The four described phases of ARVD are: (1) concealed phase (no clinical manifestations of ARVD, but potential risk of sudden cardiac death); (2) an overt electrical disorder (characterized by symptomatic arrhythmias); (3) right ventricular failure; and (4) a biventricular pump failure (resembles dilated cardiomyopathy) [Dalal et al 2005]. Left ventricle involvement can occur at any of the above stages [Sen-Chowdhry et al 2007].

In a long-term study of 37 families that included 132 living affected individuals, none of the affected individuals were diagnosed in infancy. Two children were diagnosed at ages four and six years [Nava et al 2000]. The mean age at diagnosis was 31 years (±13; range: 4-64 years) (see Figure 1).

Figure

Figure 1. Age of affected individuals at time of diagnosis (purple bars) and at time of onset of arrhythmias (teal bars)

Nava et al [2000]; published with permission

The principal characteristic of arrhythmogenic cardiomyopathies is the tendency for ventricular arrhythmia and sudden death in the absence of overt ventricular dysfunction. The increased risk of sudden death in ARVD/C is thought to relate to sudden ventricular arrhythmias.

The percentage of sudden death that arises from ARVD/C is controversial [Firoozi et al 2003, Tabib et al 2003]. In a study of 160 probands fulfilling clinical criteria for ARVD/C, 24 died during follow-up, resulting in an overall mortality rate of 18.5% and an annual mortality rate of 2.3% [Hulot et al 2004]. Mean age at death (±SD) was 54 years (±19). Of the 24 deaths, 21 were cardiovascular deaths, among which seven were sudden cardiac deaths and 14 were a result of progressive heart failure (seven ventricular tachycardia or fibrillation occurring during an acute episode of severe cardiac failure, five terminal heart failure, and two rapid deaths after a cardiac transplantation) [Hulot et al 2004] (see Figure 2).

Figure

Figure 2. Age of affected individuals at time of sudden death

Nava et al [2000]; published with permission

More studies have investigated the propensity to arrhythmia in ARVD. Lemola et al [2005] reported that of the 24 persons who received an implantable cardioverter-defibrillator (ICD), ten received appropriate shocks, four had inappropriate shocks, three had a heart transplant, one died of heart failure, and one died suddenly despite delivery of several device charges. However, it is important to note that not every ICD discharge may be associated with an arrhythmia leading to sudden death; some arrhythmias occur in normal cardiac function and therefore the denotation of "appropriate shocks" may be misleading. In a separate study of 100 persons with ARVD (diagnosed clinically or via autopsy), 31 experienced sudden cardiac death [Dalal et al 2005]. Of those diagnosed with ARVD while living, the death-free survival time was 94% in persons older than age 60 years (mainly as a result of receiving ICDs to prevent sudden cardiac death).

In a long-term study of 11 families with ARVD5, 50% of males considered at high risk for ARVD/C died by age 39 years and 50% of females considered high risk died by age 71 years. Mortality in these families was reduced by 28% in males who received an ICD [Hodgkinson et al 2005]. A study involving fifteen families with ARVD5 linked to the TMEM43 locus on chromosome 3p25 and including clinical data from 137 subjects identified a median age of disease onset of 32 years in males and 44 years in females. Penetrance was 100% by age 63 years in males and age 76 years in females [Merner et al 2008]. In this study, the relative risk of dying was 6.8 times greater in affected males than in affected females.

A similar gender bias was identified with those with mutations in PKP2 (ARVD9). Among individuals with a mutation, 67% of males (compared to 35% of females) met Task Force Criteria; however, gender differences in age of diagnosis or survival were not significant [Dalal et al 2006]. Note that these findings may not be applicable to other genetic forms of ARVD/C.

Genotype-Phenotype Correlations

Currently, insufficient genotypic data limit genotype-phenotype correlations. Furthermore, marked variation in phenotype can be observed in individuals from the same family who have the same pathogenic mutation [Gerull et al 2004, Dalal et al 2006].

An increasing number of individuals with ARVD who are compound heterozygotes within the same gene are being reported [Tiso et al 2001, Awad et al 2006]. This finding could account for the greater disease severity in families in which two mutations have been identified.

Penetrance

In the single family with a mutation in DSP reported by Rampazzo et al [2002], penetrance was estimated at 50%. Other estimates of penetrance in kindreds with autosomal dominant ARVD are as low as 20%-30% [Sen-Chowdhry et al 2005].

Evaluation of first-degree relatives of an individual with a PKP2 mutation identified two individuals with the mutation who met clinical criteria for ARVD/C and four individuals with the mutation who had either a normal phenotype or mild disease manifestations [Gerull et al 2004].

A second family with a PKP2 mutation had a family history of two sudden deaths at young ages and five living relatives with the mutation, only one of whom met clinical criteria [Gerull et al 2004].

Further studies are needed to establish the penetrance of the other genetic forms of ARVD.

Anticipation

Anticipation has not been observed.

Nomenclature

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has had numerous names including Uhl anomaly and right ventricular dysplasia.

Until 1996, ARVC was called arrhythmogenic right ventricular dysplasia (ARVD) [Richardson et al 1996]. Currently the terms ARVC and ARVD are used interchangeably.

A disease called Venetian cardiomyopathy and/or right ventricular cardiomyopathy that is very similar to ARVD/C occurs in the Veneto region of Italy.

Prevalence

The exact prevalence of autosomal dominant ARVD/C is unknown but may be estimated at 1:1000 to 1:1250 in the general population [Peters 2006].

The prevalence of ARVD is greater in certain regions, such as Italy and Greece (Island of Naxos), where it can be as high as 0.4%-0.8% [Thiene & Basso 2001].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D), the following evaluations are recommended:

• ECG
• Echocardiogram and/or MRI, depending on the expertise of the imaging center
• Electrophysiology study to assess the risk of ventricular arrhythmias and potentially perform an ablation to decrease the arrhythmias or assess the appropriateness of device insertion (such as an implantable cardioverter defibrillator)

Treatment of Manifestations

Most affected individuals live a normal lifestyle. Education regarding sudden death risk to affected adults and parents of affected children is an important aspect of management. Management of individuals with ARVD/C is complicated by incomplete information on the natural history of the disease as well as variable expressivity of the disease. Management of patients with ARVC should be individualized and based on the specific results of detailed investigation.

Management is focused on prevention of syncope, cardiac arrest, and sudden death (see Prevention of Primary Manifestations). Recent studies suggest that individuals who present with clinical signs of right heart failure and/or left ventricular dysfunction and have a history of ventricular tachycardia are at high risk and should be treated aggressively [Hulot et al 2004].

Prevention of Primary Manifestations

Antiarrhythmic medications

• Beta-blockers
• Amiodarone
• Sotalol

Implantable cardioverter-defibrillators (ICDs). ICD placement should be considered in anyone with a clinical diagnosis of ARVD. No guidelines have been published on the most appropriate time to place an ICD.

Persons who seem to be at the highest risk are those who have been resuscitated or who are unresponsive to or intolerant of antiarrhythmic therapy and those with a history of sudden cardiac arrest in first-degree relatives.

The appropriate time to place an ICD in an individual at moderate risk is not known because ICD efficacy in ARVD may be affected by progressive fibrofatty involvement of the right ventricle, which may obscure appropriate sensing of the ICD.

In one study, 66% (n=44/67) of persons with ARVD with ICDs received appropriate* shocks from their ICD for treatment of a sustained ventricular arrhythmia and 24% (n=16/67) received inappropriate shocks for sinus tachycardia, supraventricular tachycardia/atrial fibrillation, or oversensing. However, it should be noted that it is difficult to determine whether the ventriculartachycardia was sustained or whether it would have self-corrected without the shock. This study found that the incidence of appropriate ICD therapies was greatest for persons with definite ARVD compared to those with probable ARVD. However, even in those with probable ARVD, nearly one third received appropriate intervention from the ICD.

*Note: 'Appropriate' refers to proper sensing and delivery of defibrillation based on device function.

Therefore, ICD placement should be considered even in those who do not meet ARVD diagnostic criteria according to the international Task Force definitions but have probable ARVD (meeting fewer criteria) and positive findings on electrophysiologic study [Piccini et al 2005].

Surveillance

Screening for cardiac involvement in persons with ARVD is essential to ascertain severity and disease progression over time. Screening recommendations:

• ECG, annually or more frequently depending on symptoms
• Echocardiogram,annually or more frequently depending on symptoms
• Cardiac MRI, annually or more frequently depending on symptoms

Agents/Circumstances to Avoid

Individuals with RVD may be discouraged from vigorous athletic activity including competitive athletics because of the strain caused on the right heart; however, conflicting views exist on restriction of vigorous athletic activity in persons with ARVD or those at risk for ARVD.

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk sibs if the disease-causing mutations are identified in an affected family member so that morbidity and mortality can be reduced by early diagnosis and treatment.

Evidence of autosomal dominant ARVD/C is found in 30% to 50% of family members screened by noninvasive tests [Nava et al 1988, Hermida et al 1997]:

• During puberty, at-risk relatives should be assessed at least once a year.
• After puberty, at-risk relatives should be assessed every two to three years or as determined by the managing cardiologist.

Molecular genetic testing of asymptomatic at-risk family members may be available if the disease-causing mutation has been identified in an affected family member.

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.

Other

Heart transplantation is considered when ARVD has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation seems to be rare.

Cardiac catheter ablation of tissue causing abnormal rhythms is usually not effective because of the multiple sites of primary ventricular tachycardias.

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 the GeneTests Clinic Directory.

Mode of Inheritance

Autosomal dominant arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with autosomal dominant ARVD/C have an affected parent.
• A proband with autosomal dominant ARVD/C may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include cardiac MRI or echocardiogram, ECG and molecular genetic testing if the mutation has been identified in the proband.

Note: Although some individuals diagnosed with autosomal dominant ARVD/C have an affected 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 or reduced penetrance 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 and/or has a disease-causing mutation, the risk to the sibs of inheriting the mutation is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband is lower. Variable expressivity and reduced penetrance are common.
• Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with autosomal dominant ARVD/C has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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 ARVD/C 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 of an affected family member must be identified before prenatal testing can be performed. If no laboratory offering prenatal testing is listed in the GeneTests™ Laboratory Directory, such testing may be available through laboratories offering custom prenatal testing. See .

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

Requests for prenatal testing for conditions which (like ARVD/C) do not affect intellect and have some treatment available are not common. 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 rather than early diagnosis. 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 mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Defects in intercellular connections are one pathogenic mode that leads to arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). This is suggested by mutations in the genes encoding two desmosomal proteins, desmoplakin (DSP) and plakoglobin (JUP), associated with ARVD8/Carvajal syndrome and Naxos disease respectively.

Altered calcium homeostasis may provide another pathogenic pathway in ARVD/C as suggested by mutations in RYR2 in ARVD2. RYR2 has an important role in calcium release from the sarcoplasmic reticulum and the regulation of excitation-contraction coupling. An impaired intracellular calcium concentration and altered excitation-contraction coupling may predispose to arrhythmias. In addition, impaired intracellular calcium may lead to cellular necrosis, promoting fibrosis and adipose replacement [Tiso et al 2001].

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Suggested Reading

1. Calkins H. Arrhythmogenic right-ventricular dysplasia/cardiomyopathy. Curr Opin Cardiol. 2006;21:55–63. [PubMed: 16355031]
2. Frances RJ. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. A review and update. Int J Cardiol. 2006;110:279–87. [PubMed: 16099519]
3. Kies P, Bootsma M, Bax J, Schalij MJ, van der Wall EE. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: screening, diagnosis, and treatment. Heart Rhythm. 2006;3:225–34. [PubMed: 16443541]
4. Moric-Janiszewska E, Markiewicz-Loskot G. Review on the genetics of arrhythmogenic right ventricular dysplasia. Europace. 2007;9:259–66. [PubMed: 17363426]

Acknowledgments

This work was supported by the Doris Duke Charitable Foundation.

Revision History

• 13 October 2009 (cd) Revision: sequence analysis available clinically for TGFB3 mutations
• 15 December 2008 (cd) Revision: clinical testing for JUP mutations (ARVD12); prenatal testing for ARVD/C 5 (TMEM43)
• 10 July 2008 (cd) Revision: sequence analysis available clinically for TMEM43 mutations (ARVD5)
• 12 December 2007 (me) Comprehensive update posted to live Web site
• 5 April 2006 (cd) Revision: Clinical testing for DSP and PKP2 available; prenatal diagnosis for PKP2 available
• 18 April 2005 (me) Review posted to live Web site
• 6 July 2004 (em) Original submission