Genes Included

ETFA, ETFB, ETFDH, SLC52A2, SLC52A3

Diseases Included

Brown-Vialetto-Van Laere syndrome (also known as riboflavin transporter deficiency); Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia type II

Description

Brown-Vialetto-Van Laere syndrome and multiple acyl-CoA dehydrogenase deficiency (MADD) can have overlapping clinical and biochemical presentations (elevated C4 and C5 acylcarnitine profile). Brown-Vialetto-Van Laere syndrome (also known as riboflavin transporter deficiency) is caused by pathogenic variants in SLC52A2 and SLC52A3, and may present from infancy through adolescence with respiratory insufficiency, sensorineural deafness and pontobulbar palsy. MADD (also known as glutaric acidemia type II) is caused by pathogenic variants in ETFA, ETFB, and ETFDH. MADD is a disorder of fatty acid, amino acid, and choline metabolism. Patients can present with a severe neonatal form with metabolic acidosis, cardiomyopathy, and liver disease or with a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness and respiratory failure. For both of these conditions, some patients may benefit from high-dose riboflavin supplementation. 

Indications

Metabolic acidosis
Nonketotic hypoglycemia
Hepatomegaly
Elevated levels of amino acids and fatty acids in urine
Hypotonia and muscle weakness
Cardiomyopathy 

Testing Methodology 

This test is performed by enrichment of the coding exons, flanking intronic and untranslated regions (5’ and 3’), as well as known pathogenic variants (HGMD 2017.3) in the promoter and deep intronic regions of the genes specified above using oligonucleotide probe hybridization followed by next-generation sequencing with >50X coverage at every target base. All pathogenic and novel variants, as well as variants of unknown (indeterminate) significance, as determined bioinformatically, are confirmed by Sanger sequencing. Regions with <50X will be filled in by Sanger sequencing. A detailed non-coding variant list is available upon request.

Sensitivity and Limitations

The analytical sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed. Variants in regulatory regions and non-reported variants in untranslated regions may not be detected by this test. Large deletions/ duplications, large insertions and other complex genetic events will not be identified using sequencing methodology.

Turn-Around Time

28 days

CPT Codes

81479 x3

How to Order

These genes are also included as part of the Metaboseq panel. A “Reflex to Metaboseq Panel” can be ordered with the Riboflavin Disorders panel. If primary test results are negative or do not fully explain the patient’s clinical symptoms, the Metaboseq panel will automatically be performed when “Reflex to Metaboseq panel” is also ordered. Download Inborn Errors of Metabolism requisition.

References

Foley, AR, Menezes, MP, et al. (2014) Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 137: 44-56.

Frerman, FE and Goodman, SI. (2001) Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric acidemia type II. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. (8th ed.) New York: McGraw-Hill (pub.). Pp. 2357-2365.

Green, P, Wiseman, M, et al. (2010) Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in C20ORF54. Am. J. Hum. Genet. 86: 485-489.

Johnson, JO, Gibbs, JR, et al. (2012) Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 135: 2875-2882.

Liang, WC, Ohkuma, A, et al. (2009) ETFDH mutations, CoQ-10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromusc. Disord. 19: 212-216.

Olsen, RKJ, Andresen, BS, et al. (2003) Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum. Mutat. 22: 12-23.