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Early Infantile Epileptic Encephalopathy via the SLC25A22 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
4241 SLC25A22 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4241SLC25A2281479 81479(x2) $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Li Fan, MD, PhD, FCCMG, FACMG

Clinical Features and Genetics

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).

Clinical Sensitivity - Sequencing with CNV PG-Select

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.

Testing Strategy

This test provides full coverage of all coding exons of the SLC25A22 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

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. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in SLC25A22.

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 AR 609304

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

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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1) Select Test Method (Backbone)


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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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