Early Infantile Epileptic Encephalopathy or Kohlschütter-Tönz Syndrome via the SLC13A5 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
2157 SLC13A5$840.00 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

Clinical sensitivity of SLC13A5 testing in a large cohort of patients with early infantile epileptic encephalopathy is unavailable in the literature, because only a limited number of cases have been reported. For Kohlschütter-Tönz syndrome, SLC13A5 pathogenic variants were identified in all 10 patients with ROGDI-negative Kohlschütter-Tönz syndrome (Schossig et al. 2016). All reported SLC13A5 pathogenic variants are detectable by sequencing.

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Clinical Features

Early infantile epileptic encephalopathy 25 is characterized by neonatal seizures as early as the first hours and first week of life. Symptoms include focal chronic seizures, hemiconvulsions and generalized tonic-clonic seizures. Almost all patients have severe developmental delay and absence of speech. Other clinical manifestations include mild to severe intellectual disability, tooth dysplasia, plus variable combinations of ataxia, axial hypotonia, peripheral hypertonia, choreoathetosis, spasticity, and microcephaly. The frequency and severity of seizures tend to improve with age. A few patients can be even seizure-free between 3 and 7 years of age. EEG studies show mostly focal abnormalities. Experiments with a ketogenic diet have produced conflicting results (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016). Some antiepileptic drugs targeting the γ-aminobutyric acid system may reduce seizure frequency (Klotz et al. 2016). 

SLC13A5-related Kohlschütter-Tönz syndrome is characterized by neonatal epileptic encephalopathy and hypoplastic amelogenesis imperfecta (Schossig et al. 2016).


Early infantile epileptic encephalopathy 25 is inherited in an autosomal recessive manner and is caused by pathogenic variants in SLC13A5 encoding solute carrier family 13, member 5, which is a sodium/citrate cotransporter. Pathogenic variants in SLC13A5 include missense, nonsense, small deletion/insertion and splice pathogenic variants. No large deletions/duplications in the SLC13A5 locus have been reported (Thevenon et a.l 2014; Hardies et al. 2015; Klotz et al. 2016; Human Gene Mutation Database). Pathogenic variants produce inactive sodium/citrate transporter due to affected helix packing and substrate binding (Klotz et al. 2016). However, the mechanisms by which pathogenic variants in SLC13A5 cause epilepsy are not understood (Klotz et al. 2016).

Kohlschütter-Tönz syndrome is also inherited in an autosomal-recessive manner and is frequently caused by biallelic pathogenic variants in ROGDI. Recently, SLC13A5 was discovered as the second major gene associated with Kohlschütter-Tönz syndrome (Schossig et al. 2016).

Testing Strategy

Testing is accomplished by amplifying each coding exon of the SLC13A5 gene and ~10 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard Sanger dideoxy sequencing methods and a capillary electrophoresis instrument. 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

SLC13A5 sequencing is recommended for patients who are suspected to have early infantile epileptic encephalopathy 25 or ROGDI-negative Kohlschütter-Tönz syndrome.


Official Gene Symbol OMIM ID
SLC13A5 608305
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Epileptic Encephalopathy, Early Infantile, 25 AR 615905


Genetic Counselors
  • Hardies K. et al. 2015. Brain. 138: 3238-50. PubMed ID: 26384929
  • Human Gene Mutation Database (Bio-base).
  • Klotz J. et al. 2016. Molecular Medicine. 22: 310-321. PubMed ID: 27261973
  • Schossig A. et al. 2016. Journal of Medical Genetics. PubMed ID: 27600704
  • Thevenon J. et al. 2014. American Journal of Human Genetics. 95: 113-20. PubMed ID: 24995870
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  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 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

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 10 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.

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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.
  • 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.


(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.


(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.


(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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