SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria

Synonym: SUCLA2 Deficiency

El-Hattab AW, Scaglia F.

Publication Details

Estimated reading time: 22 minutes

Summary

Clinical characteristics.

SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties. Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis. The median survival is age 20 years; approximately 30% of affected individuals succumb during childhood.

Diagnosis/testing.

The diagnosis of SUCLA2-related mtDNA depletion syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in SUCLA2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Appropriate early developmental support; physical therapy to maintain muscle function and prevent joint contractures; antiseizure medication for epileptic seizures; hearing aids / cochlear implantation for sensorineural hearing loss; gastrostomy tube placement as needed to assure adequate caloric intake; blepharoplasty for significant ptosis; low vision services as needed; chest physiotherapy, aggressive antibiotic treatment of chest infections, and consideration of respiratory aids; bracing to treat scoliosis or kyphosis.

Surveillance: Routine monitoring of development, growth, and hearing; periodic ophthalmologic evaluations; routine skeletal evaluations for kyphoscoliosis and joint contractures.

Genetic counseling.

SUCLA2-related mtDNA depletion syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SUCLA2 pathogenic variant, each sib of an affected individual has at conception 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 the SUCLA2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for SUCLA2-related mtDNA depletion syndrome are possible.

Diagnosis

No consensus clinical diagnostic criteria for SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) have been published.

Suggestive Findings

SUCLA2-related mtDNA depletion syndrome typically manifests during early infancy and should be suspected in a proband with a combination of the following clinical, brain MRI, and supportive laboratory findings and family history.

Clinical findings

  • Developmental delay (DD) / intellectual disability (ID). Mild-to-profound developmental delay and intellectual disability
  • Neuromuscular features
    • Hypotonia, axial or generalized
    • Dystonia
    • Muscle atrophy
  • Sensorineural hearing impairment
  • Feeding and growth issues
    • Feeding difficulties
    • Growth deficiency affecting both weight gain and linear growth

Brain MRI findings

  • Basal ganglia hyperintensities
  • Cerebral atrophy
  • Leukoencephalopathy

Supportive laboratory findings

  • Urine organic acid analysis [Carrozzo et al 2016]
    • Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
    • Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
  • Plasma MMA level is more sensitive than organic acid analysis. Elevated plasma MMA has been reported even in those with marginally elevated urine MMA level [Carrozzo et al 2016].
  • Plasma acylcarnitine profile. Elevated C3
  • Plasma and cerebrospinal fluid lactate levels. Elevated in most affected individuals

Muscle biopsy findings. In most cases muscle biopsy is not needed; however, muscle biopsy can be considered when molecular testing reveals variants of uncertain significance and further evidence is needed to confirm the diagnosis (see Molecular Pathogenesis, Specific laboratory technical considerations).

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SUCLA2-related mtDNA depletion syndrome is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SUCLA2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of biallelic SUCLA2 variants of uncertain significance (or of one known SUCLA2 pathogenic variant and one SUCLA2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of SUCLA2-related mtDNA depletion syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of SUCLA2 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
    Note: Targeted analysis for the c.534+1G>A pathogenic founder variant can be performed first in probands of Faroese ancestry (see Table 7).
  • A mitochondrial disease multigene panel that includes SUCLA2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of SUCLA2 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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Table 1.

Molecular Genetic Testing Used in SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria

Clinical Characteristics

Clinical Description

SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties. Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis. The median survival is age 20 years; approximately 30% of affected individuals succumb during childhood.

To date, 61individuals have been identified with biallelic pathogenic variants in SUCLA2, including 50 cases reviewed by Carrozzo et al [2016], Maas et al [2016], Fang et al [2017], Garone et al [2017], Huang et al [2017], Kang et al [2020], Alkhater et al [2021], Hiramatsu et al [2022]. The following description of the phenotypic features associated with this condition is based on these reports.

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Table 2.

SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria: Frequency of Select Features

Children with SUCLA2-related mtDNA depletion syndrome typically have an uncomplicated prenatal course and birth, and present during infancy with delayed development and hypotonia.

Developmental delay (DD) and intellectual disability (ID). Global developmental delay and intellectual disabilities occur in most affected children and vary from mild to severe.

Neuromuscular. Hypotonia, first manifesting in infancy, is a presenting sign in most cases. Hypotonia can be axial or generalized. Dystonia and muscle atrophy also occur commonly. Other, less frequent neurologic manifestations include choreoathetosis, muscle weakness, hypertonia, epilepsy (including infantile spasms and generalized convulsions), myoclonus, and axonal peripheral neuropathy [Carrozzo et al 2016, Maas et al 2016, Fang et al 2017, Garone et al 2017, Huang et al 2017, Kang et al 2020, Alkhater et al 2021, Hiramatsu et al 2022].

Brain MRI typically shows basal ganglia hyperintensities (70%), cerebral atrophy (70%), and leukoencephalopathy (15%) [Carrozzo et al 2016].

Hearing. Most affected children develop sensorineural hearing impairment; some benefit from a cochlear implant. Hearing impairment can be congenital or appear during early childhood [Huang et al 2017, Alkhater et al 2021].

Vision/ophthalmologic. Ptosis, ophthalmoplegia, and strabismus are present in some individuals [Carrozzo et al 2016].

Feeding/gastrointestinal. Feeding difficulties, often necessitating gastrostomy tube placement, occur commonly. Recurrent vomiting and gastroesophageal reflux disease occur occasionally.

Growth deficiency / poor weight gain and linear growth deficiency. Birth weight and length are typically within the normal range. Feeding and gastrointestinal difficulties can contribute to subsequent growth deficiency. Ongoing postnatal growth restriction with low weight and length/height is common [Carrozzo et al 2016].

Respiratory. Recurrent respiratory infections occur occasionally. Respiratory distress due to muscle weakness, obstructive sleep apnea, and tracheomalacia has also been reported [Carrozzo et al 2016].

Skeletal. Progressive kyphoscoliosis has been reported occasionally and may require treatment. Joint contractures can develop in the extremities secondary to decreased movement.

Other

Prognosis. Life span is shortened, with median survival of age 20 years. Approximately 30% of affected individuals die during childhood [Carrozzo et al 2016].

Genotype-Phenotype Correlations

Biallelic SUCLA2 pathogenic missense variants can result in some residual enzyme activity and hence are associated with a milder phenotype and a longer median survival (age 21 years), whereas biallelic loss-of-function SUCLA2 variants (deletion, frameshift, and nonsense) are associated with a more severe phenotype and a shorter median survival (age 15 years) [Carrozzo et al 2016].

Prevalence

SUCLA2-related mtDNA depletion syndrome is rare; the exact prevalence is unknown. To date, 61 individuals of different ethnic origins have been reported (see Clinical Description).

A founder pathogenic variant in families of Faroese ancestry has been identified (see Table 7); the disorder has a high incidence (1:1,700) and a carrier frequency of 1:33 in the Faroe Islands [Ostergaard et al 2007].

Differential Diagnosis

SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) needs to be differentiated from other mtDNA depletion syndromes, a genetically and clinically heterogeneous group of primarily autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs (see Table 3).

Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG, TWNK, TFAM, RNASEH1, MGME1) and are phenotypically classified into hepatocerebral, encephalomyopathic, encephaloneuropathic, neurogastrointestinal, and myopathic forms [El-Hattab & Scaglia 2013]. See also the Mitochondrial DNA Maintenance Defects Overview.

The phenotype of SUCLG1-related mtDNA depletion syndrome may be difficult to distinguish from SUCLA2-related mtDNA depletion syndrome. SUCLG1-related mtDNA depletion syndrome is characterized by developmental delay, intellectual disability, hypotonia, muscle atrophy, feeding difficulties, growth restriction, dystonia, hearing loss, lactic acidosis, elevated urine and plasma methylmalonic acid, and mtDNA depletion. However, hepatopathy and cardiomyopathy occur in SUCLG1-related mtDNA depletion only.

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Table 3.

Mitochondrial DNA Depletion Syndromes

Management

No clinical practice guidelines for SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SUCLA2-related mtDNA depletion syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

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Table 4.

SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

There is no cure for SUCLA2-related mitochondrial mtDNA depletion syndrome.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

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Table 5.

SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria: Treatment of Manifestations

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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Table 6.

SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria: Recommended Surveillance

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 in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for a SUCLA2 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a SUCLA2 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
    • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
    • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for a SUCLA2 pathogenic variant, each sib of an affected individual has at conception 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with SUCLA2-related mtDNA depletion syndrome are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SUCLA2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SUCLA2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.
  • Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder pathogenic variant in families of Faroese origin has been identified; the disorder has a high incidence (1:1,700) and a carrier frequency of 1:33 in the Faroe Islands (see Table 7).

Prenatal Testing and Preimplantation Genetic Testing

Once the SUCLA2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for SUCLA2-related mtDNA depletion syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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.

  • The Charlie Gard Foundation
    United Kingdom
    Email: hello@thecharliegardfoundation.org
  • United Mitochondrial Disease Foundation
    Phone: 888-317-UMDF (8633)
    Email: info@umdf.org
  • Human Disease Gene Website Series - Registry
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

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 Icon

Table A.

SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria: Genes and Databases

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Table B.

OMIM Entries for SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria (View All in OMIM)

Molecular Pathogenesis

SUCLA2 encodes a subunit of succinyl-CoA ligase (SUCL). SUCL has two important metabolic functions. First, it is a mitochondrial tricarboxylic acid (Krebs) cycle enzyme that catalyzes the reversible conversion of succinyl-CoA and either ADP or GDP to succinate and either ATP or GTP. SUCL is composed of an alpha subunit, encoded by SUCLG1, and a beta subunit, encoded by either SUCLA2 or SUCLG2. The alpha subunit forms a heterodimer with either of its beta subunits, resulting in an ADP-forming SUCL and a GDP-forming SUCL, respectively. Second, SUCL forms a complex with the mitochondrial nucleoside diphosphate kinase, which is involved in the synthesis of mitochondrial nucleotides. These nucleotides are then used to synthesize mitochondrial DNA.

The pathogenic variants lead to dysfunctional SUCL protein. As SUCL forms a complex with the mitochondrial nucleoside diphosphate kinase, the lack of this complex formation in SUCL deficiency can disturb the kinase function, resulting in decreased mitochondrial nucleotide synthesis and therefore decreased mitochondrial DNA (mtDNA) synthesis leading to mtDNA depletion [El-Hattab et al 2017].

Mechanism of disease causation. Loss of protein function

Specific laboratory technical considerations. For SUCLA2 variants of uncertain significance, findings on muscle biopsy that help confirm the diagnosis of SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria include:

  • Electron microscopic findings of increased fiber size variability, atrophic fibers, intracellular lipid accumulation, COX-deficient fibers, and structurally altered mitochondria with abnormal cristae.
  • Deficiencies in electron transport chain activity in combined complex I and IV; in combined complex I, III, and IV; and in isolated complex IV.
  • Mitochondrial DNA content in affected muscle tissue typically reduced to 20%-60% of that in tissue- and age-matched controls.
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Table 7.

SUCLA2 Pathogenic Variants Referenced in This GeneReview

Chapter Notes

Author Notes

Dr Ayman El-Hattab (moc.oohay@wabattahle) is actively involved in clinical research regarding individuals with mitochondrial disorders. He would be happy to communicate with persons who have any questions regarding diagnosis of mitochondrial disorders or other considerations.

Dr El-Hattab is also interested in hearing from clinicians treating families affected by mitochondrial disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr El-Hattab to inquire about review of SUCLA2 variants of uncertain significance.

Author History

Ayman W El-Hattab, MD, FAAP, FACMG (2016-present)

Elsebet Ostergaard, MD, PhD; National University Hospital Rigshospitalet (2009-2016)

Fernando Scaglia, MD, FAAP, FACMG (2016-present)

Revision History

  • 28 September 2023 (bp) Comprehensive update posted live
  • 30 June 2016 (ma) Comprehensive update posted live
  • 26 May 2009 (et) Review posted live
  • 16 January 2009 (eo) Original submission

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