SLC52A3 – Riboflavin Transporter Deficiency

Brown-Vialetto-Van Laere syndrome, also known as riboflavin transporter deficiency, is a rare autosomal recessive neurodegenerative disorder characterized by progressive pontobulbar palsy, sensorineural hearing loss (HP:0000407), respiratory insufficiency (HP:0002093), muscle weakness (HP:0001324), hypotonia (HP:0001252) and ataxia (HP:0001251). Mutations in SLC52A3, encoding the intestinal riboflavin transporter RFVT-3, underlie type 3 riboflavin transporter deficiency, leading to impaired flavin uptake and mitochondrial dysfunction.

Genetic evidence for SLC52A3 in riboflavin transporter deficiency is robust: over 100 patients from more than 30 unrelated families harbor biallelic SLC52A3 variants, including at least 8 loss-of-function alleles (nonsense, frameshift, splice) and multiple recurrent missense mutations. Variant spectrum spans c.1300del (p.Ala434fs), c.639C>G (p.Tyr213Ter), c.989G>T (p.Gly330Val) and c.106G>A (p.Glu36Lys), among others. High allelic heterogeneity with both private and founder mutations has been documented across diverse populations. Segregation of pathogenic alleles was demonstrated in consanguineous and nonconsanguineous pedigrees, including two affected siblings with compound heterozygous mutations (affected_relatives=2).(PMID:21110228)

Functional studies in Caco-2 intestinal epithelial cells show that clinical mutations such as p.Glu36Lys and p.Arg132Trp significantly impair riboflavin uptake without altering mRNA or total protein expression, due to aberrant membrane targeting and ER retention of hRFT-3.(PMID:22273710) Convergent evidence from patient fibroblasts and Drosophila models confirms downstream mitochondrial electron transport chain deficits (complex I/II), abnormal membrane potential and locomotor deficits, all rescuable by riboflavin esters.

Clinically, early high-dose riboflavin supplementation yields dramatic and often sustained neurological improvement, including reversal of diaphragmatic paralysis, bulbar dysfunction and motor deficits. Response predictably correlates with prompt diagnosis: all treated patients survived with functional gains, whereas untreated individuals face high mortality and morbidity.(PMID:21110228)

No conflicting evidence disputing the SLC52A3–riboflavin transporter deficiency association has been reported. The consolidated genetic and functional data support a definitive gene–disease relationship.

Key take-home: SLC52A3 testing should be performed in any infant or child presenting with pontobulbar palsy and sensorineural deafness, as early riboflavin replacement is a safe, effective, and potentially life-saving intervention.

References

• American journal of human genetics • 2010 • Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54 [PMID:20206331]
• Journal of inherited metabolic disease • 2011 • 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 [PMID:21110228]
• Molecular genetics and metabolism • 2012 • Effect of clinical mutations on functionality of the human riboflavin transporter-2 (hRFT-2). [PMID:22273710]

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