Forms

Brown-Vialetto-Van Laere Syndrome 2 and Fazio-Londe Disease (Progressive Bulbar Palsy With or Without Sensorineural Deafness) via the SLC52A2 Gene

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

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
920 SLC52A2$440.00 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

Brown-Vialetto-van Laere syndrome and Fazio-Londe disease are both rare disorders, and clinical sensitivity cannot yet be estimated.  Analytical sensitivity should be high because all mutations thus far reported are expected to be detected by sequencing genomic DNA.

See More

See Less

Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 SLC52A2$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

Brown-Vialetto-van Laere syndrome (BVVLS) and Fazio-Londe disease are rare neurologic disorders caused by mutations in genes belonging to the RFVT/SLC52 riboflavin transporter gene family. BVVLS1 (OMIM 211530) and BVVLS2 (OMIM 614707) are rare autosomal recessive disorders with clinically similar findings of bulbar palsy, neurological deterioration, muscle weakness, respiratory insufficiency, and early death. Onset of symptoms has been reported in the first decade of life (Green et al. 2010). Sensorineural deafness was also found to be a common feature, but more often in patients with later onset. Fazio-Londe disease (OMIM 211500) is a progressive bulbar palsy with onset in childhood that presents with hypotonia and respiratory insufficiency due to diaphragmatic paralysis (Bosch et al. 2011). The Fazio-Londe disease patients described by Bosch et al. (2011) displayed plasma acylcarnitine and urine organic acid profiles suggestive of a mild form of the multiple acylCoA dehydrogenation defect (MADD). However, further biochemical testing revealed a profound flavin deficiency in spite of a normal dietary riboflavin intake. Brown-Vialetto-van Laere syndrome and Fazio-Londe disease are believed to represent variable presentations of a single disorder (Dipti et al. 2005). High-dose oral riboflavin supplementation therapy has recently been shown to decrease symptoms in patients with BVVLS (Foley et al. 2014). Brown-Vialetto-van Laere syndrome and Fazio-Londe disease are believed to represent variable presentations of a single disorder (Dipti et al. 2005).

Genetics

Brown-Vialetto-van-Laere syndrome-2 (BVVLS2) and Fazio-Londe Disease are inherited in an autosomal recessive manner. The SLC52A2 gene was identified as the cause of BVVLS2 (Johnson et al. 2012; Haack et al. 2012). The SLC52A2 gene (also known as RFVT2 and RFT3) is a member of the three gene riboflavin transporter gene family SLC52/RFVT (Yonezawa and Inui 2013). Functional studies have shown that mutations in SLC52A2 results in decreased uptake of riboflavin (Haack et al. 2012; Foley et al. 2014). A small number of patients worldwide have thus far been documented. SLC52A2 mutation types reported in patients include missense and nonsense.

Testing Strategy

The SLC52A2 gene is composed of 4 coding exons encoding a protein of 445 amino acids. Testing is accomplished by amplifying each coding exon and ~20 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard dideoxy Sanger 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

Patients with clinical features consistent with Brown-Vialetto-van Laere syndrome or Fazio-Londe disease and demonstrated autosomal recessive inheritance.

Gene

Official Gene Symbol OMIM ID
SLC52A2 607882
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Brown-Vialetto-Van Laere syndrome 2 614707

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Bosch AM, Abeling NGGM, IJlst L, Knoester H, Pol WL, Stroomer AEM, Wanders RJ, Visser G, Wijburg FA, Duran M, Waterham HR. 2010. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. Journal of Inherited Metabolic Disease 34: 159–164. PubMed ID: 21110228
  • Dipti S, Childs A-M, Livingston JH, Aggarwal AK, Miller M, Williams C, Crow YJ. 2005. Brown–Vialetto–Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease. Brain and Development 27: 443–446. PubMed ID: 16122634
  • Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ, Sugano K, Yonezawa A, Manzur AY, Burns J, Hughes I, McCullagh BG, et al. 2014. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 137: 44–56. PubMed ID: 24253200
  • Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin J-P, Raymond FL, Childs A-M, Sheridan E, Edwards S, Josifova DJ. 2010. Brown-Vialetto-Van Laere Syndrome, a Ponto-Bulbar Palsy with Deafness, Is Caused by Mutations in C20orf54. The American Journal of Human Genetics 86: 485–489. PubMed ID: 20206331
  • Haack TB, Makowski C, Yao Y, Graf E, Hempel M, Wieland T, Tauer U, Ahting U, Mayr JA, Freisinger P, Yoshimatsu H, Inui K, et al. 2012. Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. J Inherit Metab Dis 35: 943–948. PubMed ID: 22864630
  • Johnson JO, Gibbs JR, Megarbane A, Urtizberea JA, Hernandez DG, Foley AR, Arepalli S, Pandraud A, Simon-Sanchez J, Clayton P, Reilly MM, Muntoni F, et al. 2012. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 135: 2875–2882. PubMed ID: 22740598
  • Yonezawa A, Inui K. 2013. Novel riboflavin transporter family RFVT/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52. Mol. Aspects Med. 34: 693–701. PubMed ID: 23506902
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.
loading Loading... ×