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SLC52A2 encodes the human riboflavin transporter 2 (RFVT2), one of three solute carriers responsible for cellular uptake of riboflavin (vitamin B2). Riboflavin transporter deficiency (formerly Brown-Vialetto-Van Laere syndrome; MONDO:0008891) is an autosomal recessive neurodegenerative disorder characterized by sensorineural hearing loss, bulbar palsy, optic atrophy, and respiratory insufficiency. High-dose riboflavin supplementation has emerged as an effective treatment that can stabilize or reverse disease progression.
Autosomal recessive biallelic pathogenic variants in SLC52A2 cause riboflavin transporter deficiency, with at least 18 patients from 13 unrelated families reported to harbor compound heterozygous or homozygous mutations, consistently segregating with disease (PMID:24253200). Segregation analysis confirms cosegregation of SLC52A2 variants in multiple pedigrees. The core phenotype includes rapidly progressive axonal sensorimotor neuropathy manifesting as sensory ataxia and upper limb weakness; additional hallmarks are deafness, optic nerve degeneration, and ventilatory failure.
Over 22 distinct pathogenic SLC52A2 variants have been identified, predominantly missense and frameshift changes leading to loss of transporter function. A recurrent missense variant c.916G>A (p.Gly306Arg) has been detected in multiple unrelated patients and shown to abrogate riboflavin uptake (PMID:24253200). Variants range from early truncating alleles (e.g., p.Trp198Ter) to hypomorphic substitutions impacting membrane targeting and stability.
In vitro uptake assays in patient fibroblasts and overexpression systems demonstrate markedly reduced riboflavin transport for SLC52A2 missense and truncating mutations (PMID:23243084; PMID:24253200). Immunoblotting shows decreased RFVT2 expression, and confocal imaging confirms defective membrane localization. In Drosophila models with RFVT2 knockdown, flies exhibit reduced complex I activity, impaired locomotion, and shortened lifespan—phenotypes partially rescued by riboflavin esters, underscoring mechanism and therapeutic potential (PMID:29053833).
High-dose riboflavin supplementation initiated early leads to dramatic and sustained clinical and biochemical improvements, including stabilization of neuropathy, restoration of hearing thresholds, and prevention of respiratory failure. Riboflavin transporter deficiency should be considered in children with unexplained sensorimotor neuropathy or auditory neuropathy spectrum disorder, as timely genetic diagnosis directly informs life-saving therapy.
Key Take-home: SLC52A2-deficient riboflavin transporter deficiency is a treatable autosomal recessive neuropathy; early genetic testing and initiation of high-dose riboflavin can arrest or reverse disease progression.
Gene–Disease AssociationDefinitive18 patients from 13 families with biallelic SLC52A2 variants, consistent segregation and replication across cohorts Genetic EvidenceStrongCompound heterozygous or homozygous variants identified in 18 probands from 13 families with segregation and multiple variant classes ([PMID:24253200]) Functional EvidenceStrongRiboflavin uptake assays, protein expression and localization studies demonstrating loss of RFVT2 function and Drosophila model rescue with riboflavin esters ([PMID:23243084], [PMID:29053833]) |