Brown-Vialetto-van Laere Syndrome and Fazio-Londe Disease Panel

Brown-Vialetto-van Laere syndrome 1 and 2 are rare neurologic disorders with a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy. The major symptoms include bulbar palsy, neurological deterioration, muscle weakness, optic atrophy, respiratory insufficiency, and early death. Onset of symptoms has been reported in the first decade of life (Manole et al. 2017. PubMed ID: 29053833; Green et al. 2010. PubMed ID: 20206331). Sensorineural deafness was also found to be a common feature, but more often in patients with later onset. High-dose oral riboflavin supplementation therapy has been shown to decrease symptoms (Foley et al. 2014. PubMed ID: 24253200).

Fazio-Londe disease is a progressive bulbar palsy with onset in childhood that presents with hypotonia and respiratory insufficiency due to diaphragmatic paralysis (Bosch et al. 2011. PubMed ID: 21110228).

Brown-Vialetto-van Laere syndrome and Fazio-Londe disease are believed to represent variable presentations of a single disorder (Dipti et al. 2005. PubMed ID: 16122634).

Brown-Vialetto-van Laere syndrome 1 and 2, and Fazio-Londe disease, are inherited as autosomal recessive disorders. Pathogenic variants in SLC52A3 and SLC52A2 cause Brown-Vialetto-van Laere syndrome 1 and 2 as well as Fazio-Londe disease (Johnson et al. 2010. PubMed ID: 20920669; Green et al. 2010. PubMed ID: 20206331; Haack et al. 2012. PubMed ID: 22864630; Johnson et al. 2012. PubMed ID: 22740598).

The SLC52A3 gene encodes solute carrier family 52 member 3 which is a riboflavin transporter (Green et al. 2010. PubMed ID: 20206331; Bosch et al. 2011. PubMed ID: 21110228). SLC52A3 pathogenic variants reported include missense, nonsense, splicing, and small frameshift deletions and duplications. No large deletions and duplications have been reported (Human Gene Mutation Database).

The SLC52A2 gene encodes solute carrier family 52, member 2 which is also a riboflavin transporter (Yonezawa and Inui. 2013. PubMed ID: 23506902). SLC52A2 pathogenic variants include missense, nonsense, splicing and small frameshift deletions. No large deletions and duplications have been reported (HGMD).

Functional studies have shown that pathogenic variants in SLC52A3 and SLC52A2 result in reduced riboflavin transporter expression, and therefore, decreased uptake of riboflavin. As riboflavin metabolites are critical components of the mitochondrial electron transport chain, mitochondrial dysfunction is a downstream consequence of the riboflavin transporter gene defects (Haack et al. 2012. PubMed ID: 22864630; Foley et al. 2014. PubMed ID: 24253200; Manole et al. 2017. PubMed ID: 29053833).

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 pathogenic variants thus far reported are expected to be detected by sequencing genomic DNA.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).