rs148234606 — SLC52A2 Leu339Pro

Pathogenic missense variant in the riboflavin transporter RFVT2 that abolishes cellular vitamin B2 uptake, causing Brown-Vialetto-Van Laere syndrome type 2; high-dose riboflavin supplementation can dramatically reverse neurological decline when started early.

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SLC52A2 Leu339Pro — When the Brain Cannot Import Vitamin B2

Inside the blood-brain barrier, a protein called RFVT2 (encoded by SLC52A2) works as the primary gate that moves riboflavin — vitamin B2 — from the bloodstream into neurons. Without it, brain and brainstem cells starve for the vitamin that powers FAD- and FMN-dependent enzymes at the core of cellular energy metabolism. The p.Leu339Pro variant is a missense mutation that abolishes riboflavin transport activity11 missense mutation that abolishes riboflavin transport activity
c.1016T>C substitutes leucine with proline at position 339, disrupting the transmembrane helix architecture of RFVT2. When two loss-of-function copies are inherited — in homozygosity or compound heterozygosity with a second SLC52A2 pathogenic variant — the result is Brown-Vialetto-Van Laere syndrome type 2 (BVVLS2/RTD2), a rare but treatable childhood neuronopathy.

The Mechanism

SLC52A2 encodes riboflavin transporter 2 (RFVT2/RFT3), one of three human riboflavin transporters. RFVT2 is expressed most highly in brain, brainstem, and spinal cord22 RFVT2 is expressed most highly in brain, brainstem, and spinal cord
GTEx data confirm SLC52A2 is enriched in CNS tissues relative to peripheral tissues; SLC52A3 handles intestinal riboflavin absorption. Riboflavin is the precursor to FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide), coenzymes required by dozens of enzymes including those in the mitochondrial respiratory chain and acyl-CoA dehydrogenases. When RFVT2 is lost, cranial and spinal motor neurons are selectively deprived of these cofactors, producing a cascade of metabolic dysfunction that manifests as progressive neuronopathy. Crucially, plasma riboflavin concentrations can be normal — the transport defect is at the tissue level, not absorption — making standard blood vitamin panels uninformative for diagnosis.

The L339P substitution changes a leucine residue within a predicted transmembrane domain to proline, a helix-breaking amino acid. Functional studies in HEK293 cells confirmed complete abolition of radiolabeled riboflavin uptake and a marked decrease in RFVT2 protein expression, indicating both loss of function and protein destabilisation.

The Evidence

Haack et al. (2012)33 Haack et al. (2012) identified p.Leu339Pro in compound heterozygosity with p.Leu123Pro in a girl who developed progressive hearing loss, optic atrophy, ataxia, and nystagmus from age 3. Within 4 weeks of starting riboflavin supplementation at 10 mg/kg/day, six of seven elevated acylcarnitine species normalised — a biochemical signature of restored FAD-dependent acyl-CoA dehydrogenase activity — accompanied by moderate motor improvement.

Foley et al. (2014)44 Foley et al. (2014) expanded the picture to 18 patients from 13 families. Every patient had sensorineural deafness; 94% had optic atrophy; 72% needed respiratory support. Riboflavin at 10–50 mg/kg/day produced biochemical improvements in 10 of 18 patients and clinical improvements in the majority, with the best outcomes in those treated earliest. L339P appeared among the recurring pathogenic variants in this cohort.

GeneReviews (Cali et al. 2015)55 GeneReviews (Cali et al. 2015) confirmed that untreated RTD2 has a median survival of 7.5 years, with most deaths from respiratory failure. Treatment with riboflavin is described as "possibly lifesaving" and should begin as soon as the diagnosis is suspected, even before genetic confirmation.

Practical Actions

For homozygous individuals (CC) — a genotype virtually undetectable in population databases — biallelic loss of RFVT2 is a medical emergency requiring immediate specialist evaluation, riboflavin loading, and investigation of the full phenotype. For heterozygous carriers (CT), current evidence does not demonstrate clinical symptoms; single-copy SLC52A2 function is sufficient for normal riboflavin transport. The primary clinical value of carrier status is reproductive counselling: two CT carriers face a 25% chance per pregnancy of an affected child.

Because riboflavin supplementation is safe, some practitioners recommend heterozygous carriers maintain dietary adequacy for riboflavin from animal products (liver, dairy, eggs) and consider supplementation during high-demand states (pregnancy, illness, caloric restriction). This is a conservative precaution rather than an evidence-based mandate.

Interactions

SLC52A2 and SLC52A3 (encoding intestinal riboflavin transporter RFVT3) operate in series: SLC52A3 governs gut absorption, SLC52A2 governs CNS uptake. Compound heterozygosity across both genes — one pathogenic SLC52A2 variant and one SLC52A3 variant in the same individual — has been documented and can cause BVVLS66 Compound heterozygosity across both genes — one pathogenic SLC52A2 variant and one SLC52A3 variant in the same individual — has been documented and can cause BVVLS, though such cases are exceedingly rare. Within SLC52A2, multiple pathogenic variants have been described; compound heterozygosity (two different pathogenic alleles, one per chromosome) is the most common disease configuration. Homozygosity for a single variant is rarer and typically reflects a founder effect, most notably the p.Gly306Arg allele (rs398124641) enriched in Lebanese populations.

Nutrient Interactions

riboflavin impaired_conversion
vitamin B2 increased_need

Genotype Interpretations

What each possible genotype means for this variant.

TT Non-Carrier Normal

No SLC52A2 Leu339Pro variant detected

You carry two copies of the common reference allele at rs148234606 and do not carry the Leu339Pro pathogenic variant in the riboflavin transporter gene SLC52A2. Your RFVT2 protein is expected to function normally, supporting adequate vitamin B2 uptake into brain and spinal cord neurons. This is the genotype found in essentially the entire global population; the C (Leu339Pro) allele has been observed at a frequency of approximately 0.007% in European exomes and is absent from East Asian, African, South Asian, and Latino gnomAD populations.

CC RFVT2 Deficiency Deficient

Homozygous Leu339Pro — biallelic SLC52A2 loss consistent with riboflavin transporter deficiency type 2

Brown-Vialetto-Van Laere syndrome type 2 (RTD2) is a rare autosomal recessive progressive neuronopathy caused by biallelic pathogenic variants in SLC52A2. The gene encodes RFVT2, the primary transporter that moves riboflavin from blood into CNS tissues. Loss of function depletes FAD and FMN cofactors from neurons, impairing mitochondrial respiratory chain enzymes and acyl-CoA dehydrogenases. Clinically, this manifests as a characteristic triad: progressive sensorineural deafness (present in 100% of patients in the Foley 2014 cohort), optic atrophy (94%), and sensorimotor neuropathy (100%), often complicated by respiratory insufficiency (72%) due to diaphragm and intercostal muscle weakness.

The disease typically presents in infancy or early childhood, though adult-onset cases are documented. First symptom is usually sensorineural deafness, with other deficits emerging over months to years. Without treatment, median survival is 7.5 years, with death usually from respiratory failure. Plasma riboflavin can be normal — the defect is at the tissue transport level — so standard blood vitamin panels do not rule out this condition.

The Leu339Pro substitution has been shown to completely abolish radiolabeled riboflavin uptake in HEK293 cells and markedly reduce RFVT2 protein levels (Haack et al. 2012). Homozygosity for this allele, versus compound heterozygosity with a second SLC52A2 variant, is rare; the variant is found predominantly in European exomes at ~0.007% heterozygous frequency.

Treatment is highly effective especially when started early: riboflavin 10–50 mg/kg/day normalizes acylcarnitine species within weeks, and the majority of patients show clinical stabilisation or improvement. Hearing and optic atrophy may be partially reversible with early intervention; irreversible damage accumulates with delay. Because riboflavin is safe at high doses and the diagnostic test (genetic sequencing) takes time, guidelines recommend starting supplementation as soon as RTD2 is clinically suspected rather than waiting for molecular confirmation.

CT Carrier Carrier

Heterozygous carrier of SLC52A2 Leu339Pro — one functional copy retained

SLC52A2 encodes riboflavin transporter 2 (RFVT2), the principal carrier that moves vitamin B2 from blood into brain and spinal cord cells. The p.Leu339Pro substitution (c.1016T>C) replaces a leucine in a transmembrane domain with proline — a structural amino acid that breaks alpha-helices — and has been shown in cellular studies to abolish riboflavin uptake and reduce RFVT2 protein levels.

Biallelic loss-of-function (homozygous or compound heterozygous with another SLC52A2 pathogenic variant) causes BVVLS2/RTD2, a progressive neuronopathy. With a single functional copy, riboflavin transport to the CNS is presumed adequate — no published study has identified clinical neurological findings in confirmed heterozygous carriers of L339Pro.

Precautionary note: some clinicians advise carriers to ensure dietary riboflavin adequacy and consider supplementation during states of increased demand (pregnancy, illness, prolonged caloric restriction), as any reduction in transport capacity may theoretically be more consequential when overall riboflavin availability is low. This recommendation is precautionary and not supported by controlled evidence in carriers.