SLC52A2 – Brown-Vialetto-van Laere syndrome type 2

SLC52A2 encodes the riboflavin transporter 2 (RFVT2), which mediates cellular uptake of riboflavin critical for FMN and FAD synthesis. Biallelic pathogenic variants in SLC52A2 cause Brown-Vialetto-van Laere syndrome type 2 (BVVL2), a rare autosomal recessive neurodegenerative disorder characterized by infancy-onset sensorineural hearing loss, progressive bulbar palsy, ataxia, visual impairment, and muscle weakness (PMID:23243084).

Autosomal recessive inheritance is supported by multiple unrelated cases. A Chinese patient with paternal uniparental disomy of chromosome 8 harbored a homozygous c.1255G>A (p.Gly419Ser) variant with early bulbar palsy and ataxia, responsive to riboflavin supplementation (PMID:36186484). A 13-month-old girl presented with hyporegenerative macrocytic anemia and classical bulbar and motor deficits carrying compound heterozygous SLC52A2 mutations (PMID:35441393).

To date, 32 distinct SLC52A2 mutations—predominantly missense but including frameshift and splice variants—have been reported across the gene excluding the N-terminus (PMID:36186484). A novel compound heterozygous pair (c.1328G>A [p.Cys443Tyr] and c.1022_1023insC [p.Leu341ProfsTer103]) was identified in a Chinese pedigree with improved bulbar and motor function following high-dose riboflavin therapy (PMID:31064337).

Functional assays demonstrate that missense variants such as c.155C>T (p.Ser52Phe) and c.1255G>A (p.Gly419Ser) significantly reduce riboflavin transport in cell models (PMID:23243084). Drosophila knockdown of the RFVT2 homologue and patient fibroblast studies reveal impaired mitochondrial complex I and II activity, abnormal membrane potential, and reduced locomotion—phenotypes partially rescued by riboflavin esters (PMID:29053833).

A Slc52a2 knockout mouse model exhibits embryonic lethality, underscoring the essential role of RFVT2 in development and supporting a loss-of-function mechanism (PMID:33518683).

Emerging therapeutics include high-dose riboflavin supplementation, which correlates with improved neurological and hematological outcomes, and AAV9-mediated SLC52A2 gene augmentation in patient‐derived motoneurons, which restores neurite outgrowth, pointing to future in vivo gene therapy potential (PMID:40134705).

Collectively, SLC52A2 meets ClinGen criteria for a Strong gene-disease association based on multiple probands, consistent autosomal recessive segregation, diverse pathogenic variant spectrum, and concordant functional models. Early genetic diagnosis enables timely riboflavin therapy and informs prognosis.

References

• Journal of medical genetics • 2013 • Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations PMID:23243084
• Frontiers in genetics • 2022 • First report of paternal uniparental disomy of chromosome 8 with SLC52A2 mutation in Brown-vialetto-van Laere syndrome type 2 and an analysis of genotype-phenotype correlations PMID:36186484
• American journal of hematology • 2022 • Thirteen-month-old girl with hyporegenerative macrocytic anemia due to Brown-Vialetto-Van Laere syndrome 2 PMID:35441393
• BMC medical genetics • 2019 • A Chinese pedigree with Brown-Vialetto-Van Laere syndrome due to two novel mutations of SLC52A2 gene: clinical course and response to riboflavin PMID:31064337
• Brain : a journal of neurology • 2017 • Clinical, pathological and functional characterization of riboflavin-responsive neuropathy PMID:29053833
• Biological & pharmaceutical bulletin • 2021 • Complete Deletion of Slc52a2 Causes Embryonic Lethality in Mice PMID:33518683
• Frontiers in cellular neuroscience • 2025 • Riboflavin transporter deficiency: AAV9-SLC52A2 gene therapy as a new therapeutic strategy PMID:40134705

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