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TSEN54-Related Pontocerebellar Hypoplasia

Includes: Pontocerebellar Hypoplasia Type 2, Pontocerebellar Hypoplasia Type 4, Pontocerebellar Hypoplasia Type 5

, MSc, , MSc, , MD, PhD, and , MD, PhD.

Author Information
, MSc
Academic Medical Center
Department of Neurogenetics
University of Amsterdam
Amsterdam, The Netherlands
, MSc
Academic Medical Center
Department of Neurogenetics
University of Amsterdam
Amsterdam, The Netherlands
, MD, PhD
Emma Children’s Hospital
Pediatric Neurology
University of Amsterdam
Amsterdam, The Netherlands
, MD, PhD
Academic Medical Center
Department of Neurogenetics
University of Amsterdam
Amsterdam, The Netherlands

Initial Posting: ; Last Update: October 24, 2013.

Summary

Disease characteristics. TSEN54-related pontocerebellar hypoplasia (PCH) includes three PCH types (PCH2, 4, and 5) that share characteristic neuroradiologic and neurologic findings. The three types (which differ mainly in life expectancy) were thought to be distinct entities before their molecular basis was known. Children with PCH2 usually succumb before age ten years, whereas those with PCH4 and 5 usually succumb as neonates. Children with PCH2 have generalized clonus, incoordination of sucking and swallowing, impaired motor and cognitive development with lack of voluntary motor development, central visual impairment, and an increased risk for malignant hyperthermia. Epilepsy is present in approximately 50%. Neonates with PCH4 often have seizures, multiple joint contractures (''arthrogryposis''), generalized clonus, and central respiratory impairment. PCH5, which resembles PCH4, has been described in one family.

Diagnosis/testing. The diagnosis of TSEN54-related PCH is suspected in children with characteristic neuroradiologic and neurologic findings, and confirmed by the presence of biallelic TSEN54 mutations.

Management. Treatment of manifestations:

  • PCH2: Treatment of irritability, swallowing incoordination, epilepsy, and central visual impairment is symptomatic. Physiotherapy can be helpful.
  • PCH4 and 5: No specific therapy is available.

Prevention of secondary complications: PCH2: Assuring adequate hydration during prolonged periods of high fever may help avoid malignant hyperthermia.

Surveillance: PCH2: Monitoring of respiratory function may be necessary to detect sleep apnea.

Genetic counseling. TSEN54-related PCH is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Individuals with TSEN54-related PCH are not known to have reproduced. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Diagnosis of TSEN54-related pontocerebellar hypoplasia (PCH) should be suspected in individuals with the following neuroradiologic and neurologic findings [Albrecht et al 1993, Barth et al 1995, Chaves-Vischer et al 2000, Steinlin et al 2007, Namavar et al 2011].

Note: The phenotypic spectrum of TSEN54-related PCH includes three PCH types (thought to be distinct entities before the molecular basis of PCH was known) based on neuroradiologic and neurologic findings: PCH type 2 (PCH2), PCH type 4 (PCH4), and PCH type 5 (PCH5).

Neuroradiologic Findings

[Barth et al 2007, Budde et al 2008, Namavar et al 2011]

Major criteria

  • Cerebellar hypoplasia and varying degrees of cerebellar atrophy
  • Cerebellar hemispheres more affected than cerebellar vermis with relative sparing of the flocculi
  • Dragon-fly like cerebellar pattern on MRI as a result of TSEN54 mutations, especially p.Ala307Ser [see Namavar et al 2011]
  • Rarely, very mild to absent cerebellar hypoplasia, and cerebellar atrophy more prominent in other recessive TSEN54 mutations causing amino-acid substitutions [see Namavar et al 2011]
  • Pericerebral CSF accumulation and delayed neocortical maturation in PCH4
  • Ventral pontine atrophy, present in the majority of cases. More severe in PCH4.

Minor criteria (not present in all cases) (see Figure 1)

Figure 1

Figure

Figure 1. MRI of the brain of a two-month-old with PCH2
a. Mid-sagittal image showing hypoplastic vermis and flat ventral pons (arrow)
b. Lateral sagittal image showing hypoplastic cerebellar hemisphere (arrow) leaving empty space in the (more...)

  • Striatal hypoplasia or atrophy
  • Cerebral cortical and hippocampal atrophy
  • Delayed myelination of the brain in the first years; no demyelination; gliosis in PCH4.
  • Exceptional: cerebellar hemispheric cysts in PCH2

Neurologic Findings

[Barth et al 1995, Steinlin et al 2007]

Major criteria

  • Progressive microcephaly
  • Extrapyramidal dyskinesia with mixed spasticity. Exceptional: pure spasticity
  • Impaired swallowing from bucco-pharyngeal incoordination
  • Central visual failure
  • Impaired axial motor development with failing head control
  • Absent voluntary hand control (voluntary hand control is present in exceptional cases)
  • Exclusion criteria: primary optic atrophy or retinopathy

Minor criteria

  • Febrile and/or afebrile seizures
  • Excessive clonus in the neonatal period
  • Elevated plasma creatine kinase concentration [Barth et al 2008]

Neurologic findings in PCH4 [Albrecht et al 1993, Chaves-Vischer et al 2000]

  • Prenatal signs: polyhydramnios and/or joint contractures
  • Severe neonatal clonus
  • Central apnea with absolute or relative dependency on mechanical ventilation

Neuropathology of PCH2 and PCH4 [Barth et al 2007]

  • Cerebellum
    • Hypoplasia and reduced branching of the folia. Segmental degeneration of the cerebellar cortex and dentate nucleus. Variable degeneration of Purkinje cells. Relative sparing of the flocculus and vermis

      PCH4. Denuding of the dorsal part of the cerebellar hemispheric cortex; relative sparing of the flocculus and vermis
  • Pons. Neuronal death within the ventral pons; relative sparing of the tegmentum
  • Cerebral cortex and striatum. Variable neuronal degeneration
  • Medulla oblongata. Variable neuronal degeneration; hypoplasia and segmental degeneration of the inferior olivary nuclei; loss of arcuate nuclei
  • Myelin. Not involved in PCH2; widespread gliosis variably seen in individuals with PCH4

Other. Plasma creatine kinase (CK) concentration can be elevated in individuals with PCH.

Diagnosis of TSEN54-related pontocerebellar hypoplasia (PCH) is established by identification of biallelic TSEN54 mutations on molecular genetic testing (see Table 1).

1.

Perform TSEN54 sequencing for the common c.919G>T mutation (see Molecular Genetics).

2.

If the proband does not have the c.919G>T mutation, sequence the other exons of TSEN54.

Table 1. Summary of Molecular Genetic Testing Used TSEN54-Related Pontocerebellar Hypoplasia

Gene 1Test Method Mutations Detected 2Mutation Detection Frequency by Test Method 3
TSEN54Sequence analysisSequence variants 4See footnote 5
Deletion/duplication analysis 6Unknown; none reported 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

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

5. In a study of 169 individuals with suspected PCH2, 88 (52%) were found to be homozygous for the common TSEN54 mutation c.919G>T and nine (5%) were TSEN54 compound heterozygotes. Seven (4%) had mutations in TSEN34 or TSEN2 [Namavar et al 2011].

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. No deletions or duplications involving TSEN54 as causative of pontocerebellar hypoplasia have been reported.

Clinical Description

Natural History

The phenotypic spectrum of TSEN54-related pontocerebellar hypoplasia (PCH) includes three PCH types thought to be distinct entities (before the molecular basis of PCH was known) based on neuroradiologic and neurologic findings: PCH type 2 (PCH2), PCH type 4 (PCH4), and PCH type 5 (PCH5).

Life span is the main difference: individuals with pontocerebellar hypoplasia type 2 (PCH2) usually survive into childhood; those with pontocerebellar hypoplasia type 4 (PCH4) usually die as neonates.

PCH2. Pregnancy is usually unremarkable. Newborns have no external dysmorphic features and no visceral abnormalities. Birth is usually at term with normal weight, length, and (though always <50th centile) head circumference.

Generalized clonus, often described as “jitteriness,” is present in the majority. Swallowing is impaired with reduced grasping of the nipple and incoordination of sucking and swallowing. Motor and cognitive development is impaired in all children, with lack of voluntary motor development; unsupported sitting or voluntary reaching and grasping are not achieved except in rare cases.

The occipitofrontal circumference drops below 2 SD in the course of the first year. During the first six months severe chorea often develops, usually accompanied by spasticity. Those children who never develop chorea remain tetraspastic.

Central vision is impaired. Primary optic nerve atrophy has not been seen in individuals with PCH2.

Epilepsy is present in approximately 50% of affected children, usually as generalized tonic clonic seizures often provoked by fever, although other types of seizures including infantile spasms are possible.

Death is often before age ten years, although survival beyond age 20 years has been reported. Improved care, especially gastrostomy feeding, has probably improved survival. Typical complications are sudden and unexpected death while the child is sleeping (crib death) in infancy and death from hyperthermic crises.

Subclinical myopathy, associated with elevated creatine kinase, may lead to death by malignant hyperthermia under anesthesia in which triggering agents are administered.

PCH4. Prenatal findings include polyhydramnios in many, but not all cases. In approximately 50% of neonates, contractures (arthrogryposis) are present at birth. Generalized clonus, provoked by handling or noise, may be extreme. Microcephaly is usually present at birth.

Central respiratory impairment (probably the result of brain stem failure) at birth results in prolonged or perpetual dependence on mechanical ventilation. Respiratory complications occur at a later stage when weaning is difficult or plainly impossible. Infants with PCH4 usually die in the neonatal period from these complications.

PCH5. Described in only one family, PCH5 is characterized by fetal seizure-like activity, very early death, and predilection of the degenerative process for the cerebellar vermis rather than the cerebellar hemispheres [Patel et al 2006]. Findings are similar to those of PCH4, but children display fetal onset of seizure-like activities.

Genotype-Phenotype Correlations

The following clinical data, supported by pathogenic data, strongly suggest a genotype-phenotype correlation.

In general, individuals with the PCH4 phenotype who have a nonsense TSEN54 mutation on one allele and a missense mutation on the other allele have poorer survival than individuals with the PCH2 phenotype who are homozygous for a missense mutation [Budde et al 2008].

Nomenclature

Pontocerebellar hypoplasia 2 (PCH2) refers to the phenotype; its subtypes are identified by the gene in which causative mutations occur:

  • PCH2A (TSEN54)
  • PCH2B (TSEN2)
  • PCH2C (TSEN34)
  • PCH2D (SEPSECS)

Prevalence

The prevalence of TSEN54-related PCH is unknown.

The carrier frequency of the common TSEN54 mutation c.919G>T (p.Ala307Ser) can be estimated: Budde et al [2008] screened 451 Dutch and 279 German individuals for this mutation and found an allele frequency of 0.004.

Like many autosomal recessive disorders, PCH2 has been reported to be more common in isolated or consanguineous populations. PCH2 was originally reported by Barth et al [1995] in an isolated population in Volendam, The Netherlands.

Differential Diagnosis

Other types of pontocerebellar hypoplasia (PCH) that should be considered in the differential diagnosis of TSEN54-related PCH include the following:

  • PCH1. In some individuals with PCH1 pontine atrophy is not present. PCH1 is associated with lower motor neuron deficits due to loss of anterior horn cells. Symptoms of peripheral denervation include weakness and muscle hypotonia from birth. Mixed central (spastic, dystonic) and peripheral pareses may be present in those with prolonged survival.

    Mutations in EXOSC3 account for around 40% of PCH1 [Wan et al 2012, Rudnik-Schöneborn et al 2013]. Some children with PCH1 also die early (EXOSC3 p.Gly31Ala).
  • PCH3. Very rare, associated with optic atrophy, cognitive impairment, and muscle hypotonia [Rajab et al 2003]. No gene defect has been associated so far.
  • PCH6. Very rare, caused by mutations in RARS2, which encodes mitochondrial arginyl tRNA synthetase [Edvardson et al 2007]; associated with elevated CSF lactate concentration.
  • PCH with vanishing testes [Anderson et al 2011]

See Pontocerebellar hypoplasia: OMIM Phenotypic Series, to view genes associated with this phenotype in OMIM.

Other disorders to consider in the differential diagnosis:

  • Congenital disorders of glycosylation (CDG). Elevated sialotransferrins are detected in CDG. See also Congenital Disorders of Glycosylation Type 1A.
  • Various dystroglycanopathies. See Congenital Muscular Dystrophy Overview.
  • Classic lissencephaly as seen on MRI with coexistent cerebellar and pontine hypoplasia caused by mutations of RELN [Jissendi-Tchofo et al 2009].
  • Lissencephalies without known gene defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [Forman et al 2005]
  • A combination of neocortical dysplasia and pontocerebellar hypoplasia on MRI. May be seen in individuals with mutation of the X-linked gene CASK; heterozygous females have severe or profound intellectual disability and structural brain anomalies including mild congenital microcephaly, severe postnatal microcephaly, simplified gyral pattern, thin brain stem with flattening of the pons, and severe cerebellar hypoplasia (pontocerebellar hypoplasia) (OMIM 300749). Inheritance is X-linked.
  • Progressive cerebello-cerebral atrophy resulting from defective synthesis of the seleno-cysteine carrying tRNA by biallelic mutation of SepSecs. Clinical and MRI findings closely resemble those of mild PCH2, caused by compound heterozygosity for the common mutation p.Ala307Ser and an uncommon amino-acid substitution [Namavar et al 2011].
  • Homozygous deletion of VLDLR resulting in ataxia; mental disability; and gross cerebellar hypoplasia, a flat ventral pons, and simplified gyri [Boycott et al 2005]
  • Biallelic CHMP1A mutations resulting in MRI findings similar to those of PCH2, microcephaly, delayed walking, variable foot deformities, chorea, dystonic posturing, and impaired cognition [Mochida et al 2012]
  • Pontocerebellar hypoplasia in extremely premature infants (<28 weeks gestational age). An acquired phenocopy to be considered [Messerschmidt et al 2005]

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).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TSEN54-related pontocerebellar hypoplasia (PCH), neurologic evaluation, assessment of feeding and respiratory function, and medical genetics consultation are recommended.

Treatment of Manifestations

PCH2. Recommendations are based on PCH2A caused by TSEN54 mutation c.919G>T (p.Ala307Ser). All other subtypes are very rare.

No specific therapy is available. Treatment is symptomatic. The main problems to manage:

  • Irritability, often related to chorea (involuntary movements), which is refractory to treatment
  • Swallowing problems due to bucco-pharyngeal incoordination, managed with nutritional support by gastrostomy
  • Central visual impairment
  • Epilepsy, which is amenable to standard treatments

Physiotherapy can be helpful.

Episodic or long-term institutional care may be needed to relieve the parents.

PCH4 and PCH5. No specific therapy is available.

Respiratory support is usually given for a limited time. Weaning from respiratory support may be possible for only short periods.

Prevention of Secondary Complications

During prolonged periods of high fever, electrolytes, creatine kinase concentration, hydration status, and urine production should be monitored and sufficient fluid should be given to prevent dehydration to avoid malignant hyperthermia.

Surveillance

In patients with PCH2 monitoring of respiratory function may be necessary to detect sleep apnea.

Agents/Circumstances to Avoid

Although malignant hyperthermia has been documented in individuals with PCH2, no special risk appears to be associated with generalized anesthesia (see Malignant Hyperthermia Susceptibility).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy of a fetus with PCH2 carries no special risk to the mother. No treatment for the condition is available. In the last trimester cerebellar development lags, which can be followed by measuring transverse cerebellar diameter. Birth is usually normal and uncomplicated; problems usually arise shortly after birth with irritability and impaired swallowing, often necessitating gavage feeding.

Pregnancy of a fetus with PCH4 may lead to polyhydramnios due to impaired fetal swallowing. Fetal akinesia often causes congenital contractures. Intrauterine clonus may be perceived by the mother through the uterine wall. Clonus persists after birth and is usually severe. Absence of respiratory movement necessitates mechanical support at birth.

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.

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

TSEN54-related pontocerebellar hypoplasia (PCH) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Individuals with TSEN54-related PCH are not likely to have offspring because of severe intellectual disability and the likelihood of death before the age of fertility.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

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 carriers or are at risk of being carriers.

DNA banking. 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 (typically extracted from white blood cells) of affected individuals for possible future use.

Prenatal Testing

If both disease-causing alleles of an affected family member have been identified, prenatal diagnosis for pregnancies at increased risk for TSEN54-related PCH is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15 to 18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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.

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.

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. TSEN54-Related Pontocerebellar Hypoplasia: Genes and Databases

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 TSEN54-Related Pontocerebellar Hypoplasia (View All in OMIM)

225753PONTOCEREBELLAR HYPOPLASIA, TYPE 4; PCH4
277470PONTOCEREBELLAR HYPOPLASIA, TYPE 2A; PCH2A
608755tRNA SPLICING ENDONUCLEASE 54, S. CEREVISIAE, HOMOLOG OF; TSEN54
610204PONTOCEREBELLAR HYPOPLASIA, TYPE 5; PCH5

Molecular Genetic Pathogenesis

The genes of the TSEN complex encode subunits of tRNA splicing endonuclease. The tRNA splicing endonuclease (TSEN) complex has a role in RNA processing [Paushkin et al 2004, Trotta et al 2006]:

  • It is involved in tRNA maturation; 6% of human tRNAs carry an intron in a premature state that is spliced out by the tRNA splicing endonuclease (TSEN).
  • The TSEN complex is also involved in mRNA 3’ end formation. The precise role of the TSEN complex in this process remains elusive; however, it is known that in vitro knockdown of TSEN2 protein leads to impaired mRNA 3’ end formation.

The TSEN complex comprises four different subunits: TSEN2 and TSEN34 are the two catalytic subunits; TSEN15 and TSEN54 are the two structural subunits.

Missense mutations in TSEN2, TSEN34, and TSEN54 are responsible for pontocerebellar hypoplasia type 2 (PCH2).

Analysis of steady state levels of tRNA tyrosine showed no major defects in tRNA tyrosine maturation in fibroblasts of individuals with PCH2; therefore, the mechanisms by which TSEN mutations result in PCH are still unknown.

TSEN54

Normal allelic variants

Table 2. TSEN54 Transcript

TSEN54 IsoformTranscriptProteinExons# Amino AcidsTranscript Length
TSEN54 NM_207346​.2NP_997229​.2115261970 bps

According to Human Genome NCBI build 36.3

Pathogenic allelic variants. The TSEN54 p.Ala307Ser (exon 8) mutation accounts for the majority of PCH2 cases (88.4%).

Compound heterozygosity for p.[Ala307Ser]+[ Gln246*] and p.[Ala307Ser]+[Gln343Ter] or p.[Ala307Ser;Ser93Pro] + [Ala307Ser] accounted for PCH4 in three individuals. See Table 3.

Note: The nomenclature p.[Ala307Ser;Ser93Pro] + [Ala307Ser] indicates one allele [Ala307Ser;Ser93Pro] with two independent changes at the DNA level described as “[first change;second change]” plus the second allele with a single DNA change resulting in p.Ala307Ser.

Almost all cases are of northern European origin.

Table 3. TSEN54 Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.227T>Cp.Ser93ProNM_207346​.2
NP_997229​.2
c.919G>Tp.Ala307Ser
c.736C>Tp.Gln246Ter
c.1027C>Tp.Gln343Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. TSEN54 encodes the tRNA-splicing endonuclease subunit Sen54, which has 526 amino acids. See Table A.

Abnormal gene product. It is unknown how the reported mutations can lead to PCH, since the TSEN complex is expressed ubiquitously. The authors suggest that mutations in TSEN54 lead to loss of function or reduced function of TSEN54, since individuals with nonsense mutations are more seriously affected than those with missense mutations.

References

Literature Cited

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Chapter Notes

Revision History

  • 24 October 2013 (me) Comprehensive update posted live
  • 22 September 2009 (cd) Revision: sequence analysis and prenatal testing is available clinically for TSEN2 and TSEN34 mutations.
  • 8 September 2009 (me) Review posted live
  • 1 May 2009 (fb) Original submission
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