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Biotin-Thiamine-Responsive Basal Ganglia Disease via the SLC19A3 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
2087 SLC19A3$680.00 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

Biotin-thiamine-responsive basal ganglia disease is a rare disorder, and clinical sensitivity cannot yet be estimated. Analytical sensitivity should be high because the great majority of pathogenic variants thus far reported are detectable by sequencing genomic DNA.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 SLC19A3$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

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a neurological disorder characterized by encephalopathy and neurological decline. BTBGD represents a clinical spectrum of disorders resulting from loss of the neuronal thiamine transporter hTHTR2. Disease onset can occur anytime between infancy and adulthood, with the preponderance of cases showing childhood onset. The first symptoms are often seen following febrile illness or mild trauma and include: subacute episodes of encephalopathy, seizures, ataxia, and/or confusion (Alfadhel et al. 2013; Tabarki et al. 2013). At onset, seizures are generally well controlled with medication. Additional variable symptoms include dystonia, dysarthria, dysphagia, somnolence, external ophthalmoplegia, quadriparesis, and hyperreflexia. If left untreated, severe neurodegeneration is seen, ultimately leading to severe intellectual disability, coma, respiratory insufficiency, and death. In severe cases of BTBGD, patients present during infancy with hypotonia or hyptertonia, difficulty feeding, infantile spasms, and severe psychomotor delay (Kevelam et al. 2013). In these reported cases, EEG readings showed mutlifocal spikes without hypsarrhythmia. Not only is there high phenotypic variability among patients with different SLC19A3 variants, but there can also be considerable variability in disease onset within members of the same family (Alfadhel et al. 2013).

MRI findings reveal bilateral hyperintensity of the basal ganglia (caudate nucleus and putamen) on T2-weighted sequences. Vasogenic edema is also seen on MRI during acute neurometabolic crisis. Involvement of the brain stem and cerebellar cortex and vermis has also been reported (Distelmaier et al. 2013). As the disease progresses, MRI reveals significant brain atrophy and bilateral lesions in the thalami and basal ganglia (Kevelam et al. 2013).

BTBGD is often misdiagnosed as Leigh syndrome as it shares many symptoms with this mitochondrial disorder. BTBGD patients may have lactic acidemia and a lactate peak on magnetic resonance spectroscopy, which further supports a diagnosis of Leigh syndrome (Gerards et al. 2013). However, metabolic screening in BTBGD patients is normal and there is no evidence of respiratory chain deficiency (Debs et al. 2010; Serrano et al. 2012).  In addition, MRI in BTBGD patients may show vasogenic edema and diffuse cortical and subcortical changes that are not typical of Leigh syndrome (Distelmaier et al. 2013).

The BTBGD phenotype has also been likened to Wernicke's encephalopathy (WE), thiamine deficiency described in alcoholics, due to the presence of ophthalmoplegia, ataxia, and confusion.

Treatment with a high dose of biotin and additional thiamine has been shown to be effective in BTBGD patients (Tabarki et al. 2013). Patients treated shortly after onset of symptoms showed partial to complete improvement within days, whereas patients treated later into disease progression did not show a complete reversal of symptoms, but did exhibit marked improvement (Alfadhel et al. 2013). Continuous biotin-thiamine therapy is required; symptoms recur upon removal of treatment.

Genetics

BTBGD is inherited in an autosomal recessive manner and is caused by pathogenic variants in the SLC19A3 gene. Pathogenic nonsense, missense, frameshift, and splice site variants in the SLC19A3 gene have been reported (Debs et al. 2010; Kevelam et al. 2013). Currently there is no clear genotype-phenotype correlation to explain why some patients with pathogenic SLC19A3 variants show a more severe course of disease than others.

SLC19A3 encodes hTHTR2, one of two thiamine transporters localized to the plasma membrane (Gerards et al. 2013). hTHTR2 is a high-affinity low capacity transporter that is expressed in neurons. Once thiamine is imported into the cell it is converted to its active form thiamine pyrophosphate, which is a cofactor for a range of enzymatic reactions.

Combined treatment with biotin and thiamine reverses disease progression in BTBGD patients with pathogenic missense and loss-of-function variants (Haack et al. 2014; Alfadhel et al. 2013). Biotin is not a known substrate of hTHTR2 and the molecular mechanism by which treatment with biotin helps compensate for defective thiamine transport is unclear.

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the SLC19A3 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

SLC19A3 sequencing should be considered in patients with symptoms of BTBGD and in patients diagnosed with Leigh syndrome, but for which no impairment of mitochondrial metabolism was detected. SLC19A3 testing is also warranted in patients with childhood encephalopathy that responded to treatment with biotin and thiamine.

Gene

Official Gene Symbol OMIM ID
SLC19A3 606152
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Basal Ganglia Disease, Biotin-Responsive 607483

Related Test

Name
Early Infantile Epileptic Encephalopathy, Recessive Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Alfadhel M, Almuntashri M, Jadah RH, Bashiri FA, Rifai MT Al, Shalaan H Al, Balwi M Al, Rumayan A Al, Eyaid W, Al-Twaijri W. 2013. Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J Rare Dis 8: 83. PubMed ID: 23742248
  • Debs R, Depienne C, Rastetter A, Bellanger A, Degos B, Galanaud D, Keren B, Lyon-Caen O, Brice A, Sedel F. 2010. Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations. Archives of neurology 67: 126–130. PubMed ID: 20065143
  • Distelmaier F, Huppke P, Pieperhoff P, Amunts K, Schaper J, Morava E, Mayatepek E, Kohlhase J, Karenfort M. 2013. Biotin-Responsive Basal Ganglia Disease: A Treatable Differential Diagnosis of Leigh Syndrome. In: Zschocke J, Gibson KM, Brown G, Morava E, and Peters V, editors. JIMD Reports - Case and Research Reports, Volume 13, Berlin, Heidelberg: Springer Berlin Heidelberg, p 53–57. PubMed ID: 24166474
  • Gerards M, Kamps R, Oevelen J van, Boesten I, Jongen E, Koning B de, Scholte HR, Angst I de, Schoonderwoerd K, Sefiani A, Ratbi I, Coppieters W, Karim L, de Coo R, van den Bosch B, Smeets H. 2013. Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Brain 136: 882–890. PubMed ID: 23423671
  • Haack TB, Klee D, Strom TM, Mayatepek E, Meitinger T, Prokisch H, Distelmaier F. 2014. Infantile Leigh-like syndrome caused by SLC19A3 mutations is a treatable disease. Brain 137: e295–e295. PubMed ID: 24878502
  • Kevelam SH, Bugiani M, Salomons GS, Feigenbaum A, Blaser S, Prasad C, Haberle J, Baric I, Bakker IMC, Postma NL, Kanhai WA, Wolf NI, Abbink TE, Waisfisz Q, Heutink P, van der Knaap MS. 2013. Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy. Brain 136: 1534–1543. PubMed ID: 23482991
  • Serrano M, Rebollo M, Depienne C, Rastetter A, Fernández-Álvarez E, Muchart J, Martorell L, Artuch R, Obeso JA, Pérez-Dueñas B. 2012. Reversible generalized dystonia and encephalopathy from thiamine transporter 2 deficiency. Movement Disorders 27: 1295–1298. PubMed ID: 22777947
  • Tabarki B, Al-Shafi S, Al-Shahwan S, Azmat Z, Al-Hashem A, Al-Adwani N, Biary N, Al-Zawahmah M, Khan S, Zuccoli G. 2013. Biotin-responsive basal ganglia disease revisited: Clinical, radiologic, and genetic findings. Neurology 80: 261–267. PubMed ID: 23269594
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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