Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease

Abstract

Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.

Hyperprolinemia in Type 2 Glutaric Aciduria and MADD-Like Profiles

“…Cases of secondary MADD related to riboflavin deficiency have been described in neonates of mothers carrying heterozygous mutations in a riboflavin transporter (deficiency for GPR172B/SLC52A1) and showed a good response to transient riboflavin supplementation (Chiong et al 2007;Harpey et al 1983;Ho et al 2011). A different entity with later presentation, Brown-Vialetto-Van Laere syndrome, is caused by mutations in two related riboflavin transporters SLC52A2 and SLC52A3 (Bosch et al 2011;Green et al 2010;Johnson et al 2012).…”

Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2)

“…3,15,16 In order to investigate the discrepancy brought by the identification of the causative mutation by whole-exome sequencing in SLC52A2 localized in qter of chromosome 8, we verified the genotype of the four closest 8q markers from the initial ABI PRISM Linkage Mapping Set 10 (D8S285, D8S270, D8S284 and D8S272) plus one additional marker closer to SLC52A2 (D8S1836).…”

A Commentary on ‘Four novel C20ORF54 mutations identified in Brown–Vialetto–Van Laere syndrome patients.’

“…5,6 In humans there are three members of the riboflavin transporter gene family, recently mutations in a second transporter, SLC52A2 or GPR172A gene was identified in BVVL families from Lebanon and England with a similar clinical phenotype but a slightly later age at onset. 7 The identification of mutations in BVVL have been important in the diagnosis of patients, but of far greater importance has been the treatment of BVVL patients with riboflavin supplements, which has shown clinical benefit in children with C20ORF54 and SLC52A2 genetic defects. 7 Here, Mitra Ansari Dezfouli and colleagues 8 report the identification of four novel mutations in the C20ORF54 gene in three unrelated Iranian BVVL patients.…”

“…7 The identification of mutations in BVVL have been important in the diagnosis of patients, but of far greater importance has been the treatment of BVVL patients with riboflavin supplements, which has shown clinical benefit in children with C20ORF54 and SLC52A2 genetic defects. 7 Here, Mitra Ansari Dezfouli and colleagues 8 report the identification of four novel mutations in the C20ORF54 gene in three unrelated Iranian BVVL patients. This expands the geographical distribution and mutation spectrum of C20ORF54 defects in BVVL.…”