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GLUT1 Deficiency Syndrome via the SLC2A1 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
1446 SLC2A1$750.00 81405 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 has been reported to be 40-65% when patients are identified based solely on clinical features or a combination of clinical features, CSF glucose and lactate concentrations and blood glucose concentration (Leen et al. 2010; Yang et al. 2011). Out of 132 patients with GLUT1-DS suspected based solely on clinical features, Leen and colleagues identified pathogenic sequence changes in 57 individuals (Leen et al. 2010). Of those 57 individuals, 51 harbored DNA variants that were detectable via DNA sequencing, suggesting a clinical sensitivity of ~89% in patients with confirmed GLUT1-DS. 

Yang and colleagues examined 109 patients for GLUT1-DS (Yang et al. 2011). This group of patients had clinical features consistent with the classical phenotype, as well as expected results for CSF glucose and lactate concentrations and blood glucose concentration. Prior to molecular genetic analysis, the patient samples were further stratified based on the results of the 3-O-methyl-D-Glucose (3-OMG) uptake assay. Of the 109 initial patients, 74 were found to have decreased 3-OMG uptake, while 35 had normal 3-OMG uptake. Of those with decreased 3-OMG uptake, 70 patients were found to harbor pathogenic SLC2A1 variants, of which ~81% were variants detectable via DNA sequencing.

Overall, these results suggest a clinical sensitivity of ~80-90% in individuals with GLUT1-DS who exhibit typical clinical features, laboratory results and decreased 3-OMG uptake assay results. It should be noted Yang et al. (2011) identified one individual with a pathogenic SLC2A1 missense variant that had normal 3-OMG uptake results, so patients with such results should not necessarily be ruled out for molecular genetic testing if other clinical features fit a diagnosis of GLUT1-DS.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 SLC2A1$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 Sensitivity
While the majority of SLC2A1 variants are expected to be detected via gene sequencing, greater than 10% of reported variants in this gene are exonic or whole-gene deletions, not detectable via sequencing. Out of 57 individuals with pathogenic molecular variations in the SLC2A1 gene, Leen and colleagues identified six with deletions encompassing multiple exons (~11%) (Leen et al. 2010). Similarly, Yang et al. identified five individuals with large intragenic deletions and five with whole-gene deletions in a group of 74 patients with decreased 3-OMG uptake (~14%) (Yang et al. 2011). These types of copy number changes are expected to be detectable via gene-specific array CGH, suggesting a clinical sensitivity of approximately 11-14%.

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Clinical Features
GLUT1 Deficiency Syndrome (GLUT1-DS, also known as De Vivo Syndrome) is a disorder caused by defective glucose transport into the brain. The classical phenotype is characterized by infantile onset seizures which are often refractory, delayed neurological development, acquired microcephaly, and complex movement disorders, which generally consist of ataxia, dystonia and chorea. In approximately 90% of classic GLUT1-DS individuals, seizures begin before two years of age, while they first begin later in life in the remaining 10%. Cognitive impairment is often observed, and may range from mild learning disabilities to severe intellectual disability. The complex movement disorder may be continuous or paroxysmal, and the severity may be influenced by environmental factors, such as hunger, fever, exercise or anxiety (De Giorgis and Veggiotti 2013; Wang et al. 2015).

The clinical definition of GLUT1-DS has been expanded to include non-classical presentations, which includes, but may not be limited to, atypical childhood absence epilepsy, myoclonic epilepsy, intermittent ataxia, choreoathetosis, sleep disturbances, limb dystonia, alternating hemiplegia of childhood with or without epilepsy, paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18) and choreoathetosis and spasticity (previously known as dystonia 9) (De Giorgis and Veggiotti 2013; Wang et al. 2015).

Aside from clinical features, certain biomarkers are helpful in diagnosing GLUT1-DS. All individuals with GLUT1-DS have a lower than normal ratio of cerebrospinal fluid (CSF) glucose concentration to blood glucose concentration. Individuals with this syndrome typically have a ratio of less than or equal to ~0.5, while normal individuals have a ratio of 0.6 or greater (De Giorgis and Veggiotti 2013). Additionally, the concentration of CSF lactate is found to be in the low to normal range, and has never been observed to be elevated in a GLUT1-DS individual (De Giorgis and Veggiotti 2013; Wang et al. 2015). Lastly, the majority of individuals with GLUT1-DS have a decreased rate of 3-O-methyl-D-Glucose (3-OMG) uptake in erythrocytes (Yang et al. 2011).

The generally recommended treatment for GLUT1-DS individuals is to be placed on some variation of a ketogenic diet, which is a high-fat, adequate-protein, low-carbohydrate diet. As individuals with GLUT1-DS are unable to transport an adequate amount of glucose into the brain, the ketogenic diet results in a higher than normal level of ketone bodies being generated. These are able to be transported into the brain for use as an alternative fuel source. For the majority of GLUT1-DS patients, such dietary control helps to greatly decrease the frequency of seizures, and often helps decrease the severity of the movement disorder as well (De Giorgis and Veggiotti 2013; Wang et al. 2015).

Pathogenic variants in the SLC2A1 gene have also been reported in two patients with cryohydrocytosis. Clinical findings have included hemolytic anemia upon exposure to cold, hepatosplenomegaly, cataracts, seizures, intellectual disability and movement disorder (Flatt et al. 2011).
Genetics
GLUT1-DS is only known to be caused by defects in the SLC2A1 gene. This disorder is most commonly inherited in an autosomal dominant fashion, although autosomal recessive inheritance has been reported in two unrelated families (Klepper et al. 2009; Rotstein et al. 2010; Wang et al. 2015). Of those with autosomal dominant GLUT1-DS, approximately 90% are found to have a de novo heterozygous pathogenic variant, while approximately 10% inherit a pathogenic variant from a parent. Heterozygous parents tend to have a mild phenotype or be asymptomatic, suggestive of mosaicism. Penetrance of autosomal dominant GLUT1-DS is considered to be complete (De Giorgis and Veggiotti 2013; Wang et al. 2015).

To date, over 160 pathogenic variants have been reported in the SLC2A1 gene, including missense, nonsense, splice site, translation initiation, small insertions, deletions and indels, and multi-exonic and whole gene deletions (Human Gene Mutation Database). The variants are generally spread throughout the gene, although a few mutation “hot spots” have been reported. These include residues p.Arg126, p.Arg333, and the entirety of exon 4 (De Giorgis and Veggiotti 2013; Leen et al. 2010; Wang et al. 2015). A few studies have shown a potential correlation between the type of variant and severity of the disease, with missense variants being most commonly associated with mild to moderate presentation, protein truncating variants being associated primarily with moderate to severe presentations, and exonic or whole gene deletions being associated with severe presentations (Leen et al. 2010; Yang et al. 2011).

The SLC2A1 gene encodes the GLUT1 glucose transporter, which is the fundamental transporter that aids in the facilitated diffusion of glucose across the blood-brain barrier to supply the brain with glucose (De Giorgis and Veggiotti 2013; Wang et al. 2015). The GLUT1 transporter is an integral membrane protein, with twelve transmembrane helices and a pore through which glucose is transported. Pathogenic missense variants have been found to cluster in the regions of the protein involved in substrate binding, pore gating, and lining the transport path (Deng et al. 2014). As glucose is the primary energy source for brain metabolism, defects in the GLUT1 transporter can lead to profound neurological effects (De Giorgis and Veggiotti 2013).
Testing Strategy
This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the SLC2A1 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
Patients with clinical symptoms of GLUT1 Deficiency Syndrome are good candidates for this test, particularly if they have been shown to have a low concentration of glucose in their CSF and a low CSF to blood glucose concentration ratio (De Giorgis and Veggiotti 2013). Patients who, in addition, have demonstrated decreased erythrocyte glucose uptake in the 3-O-methyl-D-Glucose (3-OMG) assay are especially good candidates (Yang et al. 2011). Family members of patients who have known SLC2A1 variants are good candidates for this test. We will also sequence the SLC2A1 gene to determine carrier status and to confirm research results.

Gene

Official Gene Symbol OMIM ID
SLC2A1 138140
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

CONTACTS

Genetic Counselors
Geneticist
Citations
  • De Giorgis V, Veggiotti P. 2013. GLUT1 deficiency syndrome 2013: current state of the art. Seizure 22: 803–811. PubMed ID: 23890838
  • Deng D, Xu C, Sun P, Wu J, Yan C, Hu M, Yan N. 2014. Crystal structure of the human glucose transporter GLUT1. Nature 510: 121–125. PubMed ID: 24847886
  • Flatt JF, Guizouarn H, Burton NM, Borgese F, Tomlinson RJ, Forsyth RJ, Baldwin SA, Levinson BE, Quittet P, Aguilar-Martinez P, Delaunay J, Stewart GW, et al. 2011. Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome. Blood 118: 5267–5277. PubMed ID: 21791420
  • Human Gene Mutation Database (Bio-base).
  • Klepper J, Scheffer H, Elsaid MF, Kamsteeg E-J, Leferink M, Ben-Omran T. 2009. Autosomal recessive inheritance of GLUT1 deficiency syndrome. Neuropediatrics 40: 207–210. PubMed ID: 20221955
  • Leen WG, Klepper J, Verbeek MM, Leferink M, Hofste T, Engelen BG van, Wevers RA, Arthur T, Bahi-Buisson N, Ballhausen D, Bekhof J, Bogaert P van, Carrilho I, Chabrol B, Champion MP, Coldwell J, Clayton P, Donner E, Evangeliou A, Ebinger F, Farrell K, Forsyth RJ, de Goede CG, Gross S, Grunewald S, Holthausen H, Jayawant S, Lachlan K, Laugel V, Leppig K, Lim MJ, Mancini G, Marina AD, Martorell L, McMenamin J, Meuwissen ME, Mundy H, Nilsson NO, Panzer A, Poll-The BT, Rauscher C, Rouselle CM, Sandvig I, Scheffner T, Sheridan E, Simpson N, Sykora P, Tomlinson R, Trounce J, Webb D, Weschke B, Scheffer H, Willemsen MA. 2010. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 133: 655–670. PubMed ID: 20129935
  • Rotstein M, Engelstad K, Yang H, Wang D, Levy B, Chung WK, Vivo DC De. 2010. Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann. Neurol. 68: 955–958. PubMed ID: 20687207
  • Wang D, Pascual JM, De Vivo D. 2015. Glucose Transporter Type 1 Deficiency Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301603
  • Yang H, Wang D, Engelstad K, Bagay L, Wei Y, Rotstein M, Aggarwal V, Levy B, Ma L, Chung WK, Vivo DC De. 2011. Glut1 deficiency syndrome and erythrocyte glucose uptake assay. Ann. Neurol. 70: 996–1005. PubMed ID: 22190371
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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