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Early Infantile Epileptic Encephalopathy via the SLC25A22 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
2263 SLC25A22$780.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

EIEE3 is a rare disorder and clinical sensitivity cannot yet be estimated. Analytical sensitivity should be high because all pathogenic variants thus far reported are expected to be detected by sequencing methods.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 SLC25A22$690.00 81479 Add to Order
Pricing Comment

# of Genes Ordered

Total Price

1

$690

2

$730

3

$770

4-10

$840

11-30

$1,290

31-100

$1,670

Over 100

Call for quote

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Early infantile epileptic encephalopathy-3 (EIEE3) is an infantile onset seizure disorder defined by focal myoclonic seizures and burst suppression pattern on EEG. EIEE3 likely represents a spectrum of phenotypes, with two distinct phenotypes already having been attributed to SLC25A22 variants: early myoclonic encephalopathy (EME) and malignant migrating partial seizures of infancy (MMPSI) (Cohen et al. 2014; Poduri et al. 2013).

EIEE3 is characterized by seizure onset within the first weeks of life. Patients present with erratic myoclonus and focal seizures and may later develop tonic seizures. Seizures may manifest as: hemiconvulsions on one side of the body, myoclonus involving the hands, legs, and face, and/or eye deviation and lip smacking. Seizures are generally refractory to treatment with antieplileptic drugs. Other features commonly seen include hypotonia and microcephaly. EEG reveals a burst suppression pattern that is more pronounced during sleep (Cohen et al. 2014). Some patients may also experience a transient evolution to hypsarrhythmia on EEG, with an eventual return to a burst suppression pattern. MRI at early stages may appear normal, but as the disease progresses common findings include: thin corpus callosum, cerebellar hypoplasia, and general brain atrophy (Molinari et al. 2009). Prognosis is poor for EIEE3 patients; psychomotor development may be severely delayed or absent, resulting in a vegetative state and early death.

EIEE3 overlaps phenotypically with Ohtahara syndrome, another infantile onset epileptic encephalopathy. Two features that can help distinguish these disorders are:  1. EIEE3 patients typically present with erratic myoclonus rather than tonic spasms and 2. the burst suppression pattern of EIEE3 is more pronounced during sleep, whereas in OS patients there is no wake/sleep differential (Cohen et al. 2014). Interestingly, visual deficits and abnormal ERG readings indicating loss of macular and peripheral photoresponses were reported in a number of EIEE3 patients with SLC25A22 variants (Molinari et al. 2009). More studies will be needed to determine if retinal phenotypes are another hallmark of EIEE3.

One report described two patients with pathogenic SLC25A22 variants that were diagnosed with malignant migrating partial seizures of infancy (MMPSI); the patients had infantile onset partial seizures without myoclonus, and EEG revealed migrating seizures and no burst suppression pattern (Poduri et al. 2013).

Genetics

EIEE3 is inherited in an autosomal recessive manner, and is caused by pathogenic variants in the SLC25A22 gene. All reported pathogenic SLC25A22 variants have been missense variants, which have been identified in the homozygous state in consanguineous families.

SLC25A22 encodes GC1, a mitochondrial carrier that catalyzes the transport of glutamate into the mitochondrial matrix (Fiermonte 2002). GC1 is highly expressed in astrocytes in areas of the brain controlling motor coordination (Berkich et al. 2007). Glutamate is an important neurotransmitter required for neuronal signaling. Glutamate is released by pre-synaptic neurons to signal post-synaptic neurons. Glutamate from the synapse is then taken up by astrocytes where it is converted to glutamine and recycled back to pre-synaptic neurons. It is hypothesized that loss of GC1 function leads to accumulation of glutamate in the cytosol of astrocytes and in the synaptic cleft. Dysregulation of extracellular glutamate could lead to inappropriate activation of post-synaptic glutamate receptors, impairing signaling in the brain and resulting in epilepsy (Cohen 2014).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the SLC25A22 gene plus ~20 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

SLC25A22 sequencing should be considered in patients who present with myoclonic seizures during the first few weeks of life and who exhibit a burst suppression pattern on EEG.

Gene

Official Gene Symbol OMIM ID
SLC25A22 609302
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Epileptic Encephalopathy, Early Infantile, 3 609304

Related Tests

Name
Early Infantile Epileptic Encephalopathy, Recessive Sequencing Panel
Epilepsy: Ohtahara Syndrome Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Berkich DA, Ola MS, Cole J, Sweatt AJ, Hutson SM, LaNoue KF. 2007. Mitochondrial transport proteins of the brain. Journal of Neuroscience Research 85: 3367–3377. PubMed ID: 17847082
  • Cohen R, Basel-Vanagaite L, Goldberg-Stern H, Halevy A, Shuper A, Feingold-Zadok M, Behar DM, Straussberg R. 2014. Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22. European Journal of Paediatric Neurology 18: 801–805. PubMed ID: 25033742
  • Fiermonte G. 2002. Identification of the Mitochondrial Glutamate Transporter. Bacterial Expression, Reconstitution, Functional Characterization, and Tissue Distribution of Two Human Isoforms. Journal of Biological Chemistry 277: 19289-19294. PubMed ID: 11897791
  • Molinari F et al. 2009. Clinical Genetics. 76: 188-94.
    PubMed ID: 19780765
  • Poduri A, Heinzen EL, Chitsazzadeh V, Lasorsa FM, Elhosary PC, LaCoursiere CM, Martin E, Yuskaitis CJ, Hill RS, Atabay KD, Barry B, Partlow JN, Bashiri FA, Zeidan RM, Elmalik SA, Kabiraj MM, Kothare S, Stödberg T, McTague A, Kurian MA, Scheffer IE, Barkovich AJ, Palmieri F, Salih MA, Walsh CA. 2013. SLC25A22 is a novel gene for migrating partial seizures in infancy: Poduri et al: SLC25A22 Mutation in MPSI. Annals of Neurology 74: 873–882. PubMed ID: 24596948
Order Kits
TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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