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X-Linked Periventricular Heterotopia

Synonym: Bilateral Periventricular Nodular Heterotopia (BPNH)

, MD, PhD, , MS, CGC, and , MD, PhD.

Author Information
, MD, PhD
Neurogenetics
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts
, MS, CGC
Clinical Genetics Program
Beth Israel Deaconess Medical Center
Boston, Massachusetts
, MD, PhD
Neurogenetics Clinic
Beth Israel Deaconess Medical Center
Howard Hughes Medical Institute
Harvard Medical School
Boston, Massachusetts

Initial Posting: ; Last Revision: June 4, 2009.

Summary

Disease characteristics. X-linked periventricular heterotopia (PH), a neuronal migration disorder, is characterized by the presence of uncalcified nodules of neurons ectopically situated along the surface of the lateral ventricles. Affected individuals are predominantly heterozygous females; males show early lethality. Affected females present with seizures at an average age of 14-15 years; intelligence ranges from normal to borderline. The risk for stroke and other vascular/coagulation problems appears to be increased.

Diagnosis/testing. The diagnosis of X-linked PH is established by brain MRI or CT imaging. FLNA encoding filamin-A is the only gene currently known to be associated with X-linked PH. Molecular genetic testing is possible.

Management. Treatment of manifestations: Treatment of epilepsy generally follows principles for a seizure disorder caused by a known structural brain abnormality; carbamezipine is most often used, presumably because most epilepsy is focal. However, antiepileptic drugs may be selected based on specific attributes (e.g., teratogenic risk during pregnancy, tolerability, and efficacy).

Surveillance: Carotid and abdominal ultrasound studies to address the increased risk of aortic or carotid dissection; echocardiogram to evaluate for valvular abnormalities.

Genetic counseling. X-linked PH is inherited in an X-linked dominant manner. The condition is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. About 50% of affected females inherit the gene mutation from their mother and at least 50% have a de novo mutation. For women with X-linked PH, the risk of passing the mutation to each child is 50%. Because of the high rate of prenatal lethality in males, most sons born to women with X-linked PH are unaffected. Prenatal diagnosis by molecular genetic testing is possible if the disease-causing mutation has been identified in an affected relative. The periventricular nodules can be visualized by ultrasound examination as early as 24 weeks' gestation, but the sensitivity of this finding is not known.

Diagnosis

Clinical Diagnosis

The diagnosis of X-linked periventricular heterotopia (PH) relies on a combination of clinical features, neuroimaging studies, and family history.

  • Clinical findings. No clinical findings are diagnostic. Affected individuals typically have focal seizures and normal intellect.
  • Neuroimaging studies reviewed by an experienced neuroradiologist reveal the following:
    • MRI: bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) in the lateral ventricles beneath an otherwise normal-appearing cortex

      Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT.
    • Thinning of the corpus callosum and malformations of the posterior fossa (mild cerebellar hypoplasia, enlarged cysterna magna) in some (see Figure 1) [Poussaint et al 2000]
  • Family history consistent with X-linked inheritance with male lethality is strongly suggestive.
Figure 1

Figure

Figure 1. Anatomic phenotype of PH with FLNA mutation
A. MRI of the head demonstrating characteristic periventricular heterotopia
B. MRI of the head demonstrating thin corpus callosum and hypoplastic cerebellum

Molecular Genetic Testing

Gene. FLNA is the only gene currently known to be associated with X-linked PH [Fox et al 1998].

Other loci. The less-than-100% mutation detection rate by FLNA sequencing suggests that at least one other as-yet-unidentified gene is associated with periventricular heterotopia [Sheen et al 2004a].

Clinical testing

Sequence analysis. No published series have looked at the mutation detection rate using sequence analysis. Parrini et al [2006] determined the mutation detection rate using mutation scanning:

Note: (1) In these two groups, 93% of individuals with a FLNA mutation were female and 7% were male. (2) Overall, Parrini et al [2006] found that the probability of identifying an FLNA mutation in an individual with classic bilateral PH was 49% and the probability of identifying an FLNA mutation in an individual with another phenotype (e.g., polymicrogyria, microcephaly) was 4%.

Deletion/duplication analysis. No deletions or duplications involving FLNA as causative of X-linked periventricular heterotopia have been reported. Data regarding the frequency of exonic, multiexonic, or whole-gene deletions of FLNA are unknown.

Table 1. Summary of Molecular Genetic Testing Used in X-Linked Periventricular Heterotopia

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Positive Family History 2 Simplex Females 3
FLNASequence analysisSequence variants 4100% 26%
Deletion/ duplication analysis 5Partial- and whole-gene deletions/ duplications 6UnknownUnknown

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

2. Familial cases with X-linked inheritance pattern (n=8)

3. Females with PH and no known family history of PH (n=120)

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and array GH may be used.

6. To date no deletions or duplications of FLNA have been reported as causative of X-linked periventricular heterotopia.

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

Clinical uses

  • Confirmatory diagnostic testing
  • Carrier testing
  • Prenatal diagnosis
  • Preimplantation genetic diagnosis

Clinical Description

Natural History

X-linked periventricular heterotopia (PH) is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female.

Affected females. The following clinical features have been associated with X-linked PH:

  • Seizure disorder
  • Psychiatric disorder
  • Cardiovascular findings including patent ductus arteriosus, bicuspid aortic valve, vasculopathy and/or coagulopathy leading to stroke, ruptured aneurysm
  • Gastric immotility
  • Congenital strabismus
  • Shortened digits
  • Hyperflexible joints [Sheen et al 2005]
  • Dyslexia

Seizure disorder. Approximately 88% of individuals diagnosed with X-linked PH present with a seizure disorder [Guerrini & Carrozzo 2001]. Age of onset may be within the first years of life, but more typically individuals present during childhood. The severity of the seizure disorder may range from mild (with rare frequency and remission without need of antiepileptic drugs) to intractable seizures.

No correlation exists between the extent and severity of the nodular heterotopia seen radiographically and the clinical manifestations. The ectopic heterotopia act as foci for abnormal neuronal activity. Anatomic studies have shown aberrant projections extending from the periventricular heterotopia. Depth electrode recordings have demonstrated epileptogenic discharges from these nodules [Kothare et al 1998]. Thus, the seizure disorder appears to arise from the heterotopia in most individuals.

Psychiatric disorder. Depression has been reported [Maruyama et al 1998]. Additionally, some individuals appear to have mild personality disorders [author, personal observations]. Whether these clinical findings reflect a neuropsychiatric complication of epilepsy remains to be seen.

Cardiovascular findings. Cardiac anomalies including patent ductus arteriosus (PDA) (3/11) and bicuspid aortic valve (1/11) were detected in a cohort of 11 affected individuals. The incidence of these malformations exceeds the general population (PDA = 1 per 1500 live births, bicuspid aortic valve = 1 per 100 births).

Among 11 females with confirmed FLNA mutations, three experienced strokes at early ages. This observation and the findings in affected males suggest a primary vasculopathy with weakened vessel walls and/or a coagulopathy secondary to platelet dysfunction.

Other. Among these same 11 individuals, associated findings included gastric immotility (1/11), strabismus (2/11), and shortened digits (1/11).

Note: Immune compromise with recurrent infection was reported in two of the individuals in the initial report, but immune compromise has not been seen in any other patients; therefore, the association with periventricular heterotopia is unknown.

Intelligence appears to be normal to borderline. Although no systematic neuropsychiatric evaluation has been performed on this population, affected individuals generally display no gross cognitive deficits on neurologic examination.

Women with X-linked PH may have an increased incidence of pregnancy loss as a result of spontaneous abortion of affected male pregnancies.

Affected males. Two simplex males (affected males with no family history of PH) with documented FLNA mutations presented with seizures. One of the males died from sudden rupture of the aorta at age 36 years.

Five other males ranging in age from five days to five months died suddenly and unexpectedly; although their deaths were consistent with sudden cardiovascular or hematologic collapse, the true causes of death were unknown.

A single affected male with a complete loss-of-function mutation also showed overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development.

Two affected dizygotic twin males have been reported, one with early death, the other with intellectual disability but not epilepsy [Gerard-Blanluet et al 2006].

Mosaicism. Somatic mosaicism for an A>G substitution at the intron 11 acceptor splice site was reported by Parrini et al [2004] in a male with bilateral PH. Sequence analysis and denaturing high-performance liquid chromatography of genomic DNA on a pool of hair roots, single hair roots, and white blood cells revealed that only 42% and 69% of the samples for hair and blood, respectively, had the mutant allele. Moreover, the affected male's daughter did not inherit the mutant allele, thought to be causal for the male phenotype.

Note: Although three affected brothers with West syndrome/hypsarrhythmia were reported to have an FLNA mutation [Masruha et al 2006], this reported sequence variant has subsequently been thought to be a rare polymorphism [Robertson 2006].

Genotype-Phenotype Correlations

All individuals known to have an FLNA mutation, including those who are asymptomatic, have heterotopia identifiable by brain MRI or CT [Fox et al 1998, Poussaint et al 2000, Sheen et al 2001, Moro et al 2002].

One of the mechanisms explaining the phenotype of X-linked PH in females is random X-chromosome inactivation resulting in two populations of neurons: those expressing the mutant allele that presumably reside in the periventricular region as heterotopia and those that express the normal allele and migrate out to the cortical plate [Pilz et al 2002].

While more studies correlating genotype and phenotype are needed, truncation mutations tend to cluster near the N-terminal and presumably lead to severe loss-of-function and a more severe phenotype (male lethality). Missense mutations are found throughout the extent of FLNA and appear to have milder phenotypes, as males with these mutations can survive to term. Presumably, these milder mutations lead to a partially functional protein [Sheen et al 2001].

An FLNA splice mutation has been associated with periventricular nodular heterotopia (PNH), facial dysmorphism, and severe constipation [Hehr et al 2006].

Penetrance

Penetrance is unknown. It is not known what percentage of individuals with FLNA mutations have periventricular heterotopia and it is not known what percentage of individuals with periventricular heterotopia have clinical features.

Nomenclature

There are no terms that were used but that are currently completely out of favor. Frequently used terms are periventricular heterotopia (PVH or PH)f or periventricular nodular heterotopia (PNH or PVNH).

Prevalence

The prevalence of PH is difficult to assess because individuals with the mild phenotype may never seek medical evaluation.

Differential Diagnosis

The frequent occurrence of familial or nonfamilial periventricular heterotopia in males and females with no documented FLNA mutation suggests that PH is a heterogeneous disorder.

Other syndromes in which periventricular heterotopia occurs:

Whether each of these represents a truly distinct disorder or an X-linked FLNA mutation plus a concurrent condition remains to be determined.

Laminar heterotopia occurring in deep white matter and band-like heterotopia occurring between the cortex and ventricular surface occur in X-linked subcortical band heterotopia.

PH is often misdiagnosed initially as tuberous sclerosis complex; however, MRI findings distinguish between the two disorders.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked periventricular heterotopia (PH) the following evaluations are recommended:

  • Neuroimaging to establish the diagnosis
  • Evaluation by a neurologist
  • Evaluation by an epileptologist if seizures are present
  • Monitoring of social adjustment with neuropsychiatric evaluation if necessary
  • Magnetic resonance angiography (MRA) of the intracranial vessels, carotid arteries, and aorta to address the increased risk for stroke
  • Because of the potential risk for aortic aneurysm, a baseline evaluation by a cardiologist and either echocardiogram or cardiac magnetic resonance imaging (MRI), paying particular attention to the ascending aorta
  • Evaluation by a hematologist if findings suggest a bleeding diathesis

Treatment of Manifestations

Management of individuals with X-linked PH is directed toward symptomatic treatment.

Treatment of epilepsy generally follows basic principles for a seizure disorder caused by a known structural brain abnormality.

  • This includes a detailed initial history and evaluation to confirm the suspicion of a seizure disorder. Testing may include an electroencephalogram (EEG) to define the location and severity of electrical brain dysfunction that may be present in individuals with epilepsy.
  • Repeat imaging may be necessary only in the setting of new neurologic findings on examination.
  • Carbamezipine is most often used empirically for treatment, presumably because most affected individuals have focal epilepsy. However, because no significant differences exist between medications for newly diagnosed, presumably localized epilepsy, choices may be made upon the specific attributes of each antiepileptic drug (i.e., risk of teratogenicity of the antiepileptic drug during pregnancy), tolerability, and efficacy.

Because of the risks of aortic or carotid dissection, it may also be wise to ensure good blood pressure control.

Many individuals with periventricular heterotopia have dyslexia. Therefore, it may be prudent for those with a family history of PH to have children tested for dyslexia at an early age.

Prevention of Secondary Complications

The secondary complications are those associated with prolonged seizure medication usage and the risks of seizure medications to fetal development. The prenatal risks associated with seizure medication depend on the type of seizure medication.

Surveillance

Because of the associated increased incidence of aortic or carotid dissection in PH, affected individuals should be monitored by carotid and abdominal ultrasound studies. No clear guidelines exist. However, given that such complications have occurred in early adulthood, it is likely that evaluation should be performed initially in late adolescence and followed up as needed.

An echocardiogram may also be warranted because of reports of valvular abnormalities. No clear guidelines exist. However, as the valvular abnormalities are thought to be congenital, examination in early childhood seems warranted.

Evaluation of Relatives at Risk

No specific testing is recommended for relatives at risk unless they develop seizures. A brain MRI is recommended for relatives with seizures.

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

Surgical resection has been attempted but has not proven beneficial [Li et al 1997].

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

X-linked periventricular heterotopia (PH) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • About 50% of females with X-linked PH have inherited the mutation from a parent.
  • At least 50% of females with X-linked PH have a de novo mutation.
  • Because of variable expression of X-linked PH, brain MRI should be considered for either parent of a proband if the parent has a history of seizures or learning disabilities. Because very few affected males have been identified, it is unlikely that the father is affected. All individuals with FLNA mutations, whether symptomatic or asymptomatic, have nodules identifiable by brain imaging.

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the proband's mother.
  • If the mother has PH and/or an identified FLNA mutation, the risk to a female sib of being affected is 50%.
  • If the mother has PH and/or an identified FLNA mutation, the risk to a male sib of inheriting the FLNA mutation is 50%; however, all males with familial FLNA mutations to date have died before birth or soon after birth. Affected males who have survived beyond the neonatal period have been reported; however, the clinical outcome for an affected male is uncertain because of the small number of such cases reported.
  • If the mother has no heterotopias identified by brain imaging, the recurrence risk for future pregnancies is low. Germline mosaicism has not been reported, although this possibility cannot be completely excluded. It is also possible that a child with periventricular heterotopia and no known family history of PH may have mutations in another unidentified gene that could have a different mode of inheritance. Therefore, the risk to the sibs of a child with PH and no known family history is low but greater than that found in the general population.

Offspring of a female proband. The risk to the offspring of females with MRI or CT findings of PH or an identified FLNA mutation is 50%; however, most male conceptuses with PH miscarry or die shortly after birth. Some affected males survive beyond the neonatal period; however, the clinical outcome for an affected male is uncertain as very few cases have been reported.

Offspring of a male proband. Males with X-linked PH do not reproduce.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being affected (depending upon gender, family relationship, and the genetic status of the proband's mother).

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, 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, are carriers, or are at risk of being carriers.

Genetic heterogeneity. Because evidence exists for genetic heterogeneity of periventricular heterotopia, women with PH and no known family history of PH should be informed of the possibility that they may have mutations in a different as-yet-unidentified gene and may be at a low risk of having affected offspring because of possible autosomal recessive inheritance.

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.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutation has been identified in an affected family member, prenatal diagnosis for pregnancies of women who have an identifiable FLNA mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Ultrasound examination. Periventricular heterotopias may be detected by fetal ultrasound examination or MRI as early as 24 weeks' gestation. Fetal MRI is performed at some centers using ultrafast MRI so that sedation is not required to reduce fetal movement. The sensitivity of such evaluation is not known. Whether periventricular heterotopias may be detected even earlier in gestation by imaging studies is not known.

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

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member.

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 Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Citizens United for Research in Epilepsy (CURE)
  • Epilepsy Canada
    2255B Queen Street East
    Suite 336
    Toronto Ontario M4E 1G3
    Canada
    Phone: 877-734-0873
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. X-Linked Periventricular Heterotopia: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FLNAXq28Filamin-AFLNA @ LOVDFLNA

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for X-Linked Periventricular Heterotopia (View All in OMIM)

300017FILAMIN A; FLNA
300049HETEROTOPIA, PERIVENTRICULAR, X-LINKED DOMINANT

Molecular Genetic Pathogenesis

The filamin class of actin-binding proteins is known to regulate cell stability, protrusion, and motility across various biologic systems [Ott et al 1998, Leonardi et al 2000, Stahlhut & van Deurs 2000]. Filamin-deficient melanocytes fail to undergo locomotion in response to factors that elicit migration in the same filamin-expressing cells. They exhibit prolonged circumferential blebbing, abnormal phagocytosis, and impaired volume regulation, perhaps secondary to abnormal regulation of sodium channel activity. Findings suggest that FLNA may have an influence similar to that of integrins, which have been implicated in cell adhesion and neuronal migration [Meyer et al 1997, Loo et al 1998, Dulabon et al 2000], on neuroblast migration during cortical development within the central nervous system. Recent studies suggest that genes in which mutation causes PH are involved in vesicle trafficking, necessary for delivery of proteins involved in cell adhesion [Ferland et al 2009]. Disruption of this process likely results in the formation of periventricular heterotopias.

Normal allelic variants. There are 48 exons in FLNA (reference sequence NM_001110556.1). The normal allelic variants of FLNA are listed in Table 2. Data were retrieved from the NCBI Gene Model site.

Table 2. Normal Allelic Variants of FLNA

Nucleotide ChangeProtein ResidueCodon PositionAmino Acid Position
C>TPro>Pro3221
T>CVal>Ala2320
T>CPhe>Leu1370
T>CVal>Ala2552
G>APro>Pro31631
T>CAla>Ala31950
G>CVal>Val32206
G>ALys>Lys32559
G>AAla>Thr31764
T>CSer>Ser1256

Pathologic allelic variants. Pathologic allelic variants in FLNA identified to date have generally been point mutations or deletions with presumed loss of function. Each family or individual representing a simplex case (i.e., a single occurrence in a family) has had a unique mutation [Sheen et al 2001].

Thus far, fifteen mutations in FLNA have been reported; see Table 3 (pdf). Three missense mutations and twelve truncation mutations resulting in X-linked PH have been detected in FLNA [Sheen et al 2001, Moro et al 2002]. (For more information, see Table A.) The missense mutation 987G>C (Glu329Asp) was reported recently [Tsuneda et al 2008].

Normal gene product. Filamin-A encodes a large (280-kd) cytoplasmic actin-binding phosphoprotein that links membrane receptors to the actin cytoskeleton and represents a potentially crucial link between signal transduction and the cytoskeleton. The protein consists of an actin-binding domain at the amino terminus, 23 repeats that resemble Ig-like domains and form a rod-like structure interrupted by two hinge regions, and a truncated C-terminal repeat that undergoes dimerization and binding to membrane receptors. The reference sequence is NP_001104026.1).

Abnormal gene product. Twelve of 15 documented mutations are FLNA protein-truncating or -splicing mutations, predicted to result in severe loss of function. The remaining FLNA defects represent amino acid substitutions resulting from missense mutations. The sites of the truncation mutations tend to cluster at the amino terminal of the protein, leaving only a small translated portion of the actin-binding region. The amino acid substitutions, however, are not obviously clustered and exist along the length of the filamin-A protein. Because mutations can occur along the entire length of FLNA, the predilection of truncation mutations for the actin-binding region may merely reflect the incidence of clinical presentations for severe mutations in females. Mild to moderate mutations in FLNA may have fewer clinical phenotypes in females and thus avoid detection. Conversely, in males, severe to moderate defects lead to loss in fetal viability, and only partial-loss-of-function mutations are found [Sheen et al 2001, Moro et al 2002].

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Suggested Reading

  1. Lu J, Sheen V. Periventricular heterotopia. Epilepsy Behav. 2005;7:143–9. [PubMed: 15996530]
  2. Noebels JL. The inherited epilepsies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 230. Available at www​.ommbid.com. Accessed 5-31-11.

Chapter Notes

Revision History

  • 4 June 2009 (cd/cw) Revision: deletion/duplication analysis available; mutation added; Differential Diagnosis edited
  • 10 April 2007 (me) Comprehensive update posted to live Web site
  • 4 August 2004 (me) Comprehensive update posted to live Web site
  • 21 January 2004 (cd) Revision: testing
  • 17 October 2003 (cw) Revision: Genetically Related Disorders
  • 8 October 2002 (me) Review posted to live Web site
  • 29 April 2002 (cw) Original submission
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