rs397514538 — SLC52A2

Pathogenic missense variant in riboflavin transporter RFVT2 (p.Leu123Pro) causing Brown-Vialetto-Van Laere syndrome type 2, a rare autosomal recessive neurodegenerative disorder; high-dose riboflavin supplementation is the primary disease-modifying treatment

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SLC52A2 Leu123Pro — Riboflavin Transporter Deficiency and BVVLS2

Riboflavin (vitamin B2) is the molecular precursor to FAD and FMN11 FAD and FMN
Flavin adenine dinucleotide and flavin mononucleotide — the two active coenzyme forms of riboflavin that serve as electron carriers in over 100 cellular oxidoreduction reactions, including the mitochondrial electron transport chain, fatty acid oxidation, and amino acid metabolism. Unlike many vitamins that diffuse freely across cell membranes, riboflavin is a polar molecule that cannot enter most cells without help. The brain and peripheral nervous system are especially dependent on dedicated transport proteins to maintain adequate intracellular riboflavin. The SLC52A2 gene encodes one of those proteins — RFVT2 (riboflavin transporter 2), the principal riboflavin transporter expressed in neurons and intestinal epithelium.

When SLC52A2 is non-functional, riboflavin cannot enter nerve cells efficiently, FAD and FMN are depleted, and neuronal energy metabolism collapses. The clinical consequence is Brown-Vialetto-Van Laere syndrome type 222 Brown-Vialetto-Van Laere syndrome type 2
BVVLS2 (OMIM #614707) — named for the three clinicians who independently described the phenotype between 1894 and 1959. The molecular cause was not identified until 2010 when mutations in SLC52A3 were found; SLC52A2 was implicated in 2012. (BVVLS2), a rare progressive neuronopathy with sensorineural deafness, bulbar palsy, and respiratory compromise that is fatal without treatment. Crucially, it is one of very few inherited neurodegenerative disorders that responds dramatically to supplementation.

The Mechanism

The c.368T>C variant substitutes a leucine for a proline at position 123 of the RFVT2 protein (p.Leu123Pro). Proline is structurally unique — its side chain loops back to form a ring with the backbone nitrogen, introducing rigidity and a kink into a polypeptide chain. Replacing a flexible leucine with proline at position 123 disrupts the local fold of the transmembrane domain.

Functional transport assays33 Functional transport assays
Haack TB et al. Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. J Inherit Metab Dis, 2012 demonstrated that cells overexpressing the p.Leu123Pro mutant showed significantly reduced [³H]riboflavin uptake compared to wild-type RFVT2, confirming that the structural change directly impairs transport activity. The same study also identified p.Leu339Pro in the same patient as a compound heterozygous partner, illustrating the typical presentation: most BVVLS2 patients carry two different pathogenic SLC52A2 alleles rather than two identical ones.

The Evidence

BVVLS2 is rare but the treatment response is among the most striking in all of metabolic genetics. Foley et al. 201444 Foley et al. 2014
Foley AR et al. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain, 2014 described 18 patients from 13 families with SLC52A2 mutations, demonstrating "significant and sustained clinical and biochemical improvements" with high-dose oral riboflavin, including improvements in motor function, respiratory capacity, and acylcarnitine profiles in 10 of 13 patients with preliminary data.

The natural history data makes the treatment case starkly. Bosch et al. 201255 Bosch et al. 2012
Bosch AM et al. The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis, 2012 reviewed 74 BVVLS and Fazio-Londe patients across all published cases: all 13 riboflavin-treated patients survived, while 28 of 61 untreated patients died — most before age 4 if onset was in infancy. Without treatment, children typically progress to ventilator dependence.

The standard dosing is established by clinical practice: Cali et al. GeneReviews 201566 Cali et al. GeneReviews 2015
Cali E et al. Riboflavin Transporter Deficiency. GeneReviews, University of Washington, 2015 (updated 2021) specifies 10–50 mg/kg/day of oral riboflavin for riboflavin transporter deficiency, with early initiation producing substantially better outcomes than late treatment.

ClinVar lists this variant (VCV000039576) as pathogenic for Brown-Vialetto-Van Laere syndrome 2 with five independent submitters including Cambridge Genomics Laboratory, OMIM, PreventionGenetics, and the Solve-RD Consortium.

Practical Actions

Because BVVLS2 is autosomal recessive, a single heterozygous copy of the p.Leu123Pro variant does not cause disease. Heterozygous carriers have one functional RFVT2 allele, which is sufficient for normal riboflavin transport under typical conditions. The clinical significance of carrier status is primarily reproductive: if both parents carry pathogenic SLC52A2 variants, each child has a 25% chance of inheriting biallelic mutations and developing BVVLS2.

For homozygous or compound heterozygous individuals, high-dose riboflavin is the only established disease-modifying treatment. It must be started immediately and continued lifelong — riboflavin supplementation does not cure the underlying transporter defect but compensates for it by driving passive diffusion through mass action. Sensorineural hearing loss, once established, is typically not recovered with treatment even when motor and respiratory function improve.

Interactions

Compound heterozygosity is the rule in BVVLS2: most patients carry p.Leu123Pro on one chromosome and a different pathogenic SLC52A2 variant on the other. The related gene SLC52A3 (RFVT3) causes BVVLS type 3 with an overlapping phenotype; both conditions respond to riboflavin. SLC52A1 (RFVT1) causes Fazio-Londe syndrome. When a patient presents with bulbar palsy and hearing loss, all three SLC52A genes should be sequenced to determine the causative gene, as the treatment (riboflavin) is the same for all three.

Nutrient Interactions

riboflavin increased_need

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-Carrier Normal

Normal RFVT2 function — standard riboflavin transport

With no copies of the Leu123Pro variant, your SLC52A2 gene produces fully functional RFVT2 transporter. Riboflavin enters nerve cells and epithelial cells normally, and your cells can generate the FAD and FMN coenzymes required for mitochondrial energy production at standard dietary riboflavin intakes.

Standard dietary riboflavin intake (1.1–1.3 mg/day for adults) is sufficient for this genotype. No additional supplementation is warranted based on this variant alone.

CC Homozygous Deficient

Homozygous Leu123Pro — absent RFVT2 function; consistent with Brown-Vialetto-Van Laere syndrome type 2

With two copies of Leu123Pro, neither RFVT2 allele can transport riboflavin effectively into neurons and intestinal epithelial cells. Functional assays confirmed that the p.Leu123Pro variant significantly reduces cellular riboflavin uptake (Haack et al. 2012). As a result, intracellular riboflavin falls, and consequently so do the FAD and FMN coenzyme levels required for the mitochondrial electron transport chain and dozens of other flavoenzyme reactions.

Motor neurons of the brainstem and anterior horn are particularly vulnerable because they have high energy demands and limited metabolic reserves. The clinical phenotype — cranial nerve palsies, hearing loss, and sensorimotor neuropathy — reflects this vulnerability.

High-dose riboflavin (10–50 mg/kg/day orally) compensates for absent RFVT2 by driving passive diffusion through mass action: at very high luminal concentrations, enough riboflavin enters cells via concentration-dependent passive mechanisms even without a functional transporter. Treatment must begin immediately upon diagnosis and continue lifelong; stopping supplementation results in rapid clinical deterioration.

Response to treatment is substantial but incomplete. Motor function, respiratory capacity, and biochemical markers (acylcarnitine profiles, riboflavin-responsive enzyme activities) typically improve. Sensorineural hearing loss, once established, generally does not recover even with treatment. Early treatment before significant neurological damage is essential for the best outcomes.

Plasma riboflavin levels may appear normal in BVVLS2 (unlike BVVLS3 due to SLC52A3 mutations, which show reduced plasma levels), because RFVT2 is the major transporter into neurons, not into blood. Normal plasma riboflavin does not rule out RFVT2 deficiency.

CT Carrier Carrier

Heterozygous carrier of Leu123Pro — single-allele status, normal riboflavin transport

One functional RFVT2 allele produces enough transporter protein to sustain normal riboflavin uptake into neurons and intestinal cells under typical dietary conditions. There is no published evidence of clinical riboflavin deficiency or neurological symptoms in heterozygous SLC52A2 carriers.

The biological significance of carrier status is autosomal recessive inheritance: BVVLS2 requires biallelic loss of function. A carrier coupled with a non-carrier partner cannot produce an affected child. A carrier coupled with another carrier (of any pathogenic SLC52A2 variant, not necessarily the same one) faces a 25% chance of an affected pregnancy per conception.

Genetic counseling is the primary actionable recommendation for carriers who are planning a family, particularly if there is any family history of bulbar palsy, sensorineural deafness, or progressive neuropathy in childhood.