To report three Chinese pediatric cases of Brown-Vialetto-Van Laere syndrome type 2 (BVVLS2) presenting with pure red cell aplasia (PRCA) as the core manifestation, and to analyze their clinical features, molecular basis, and response to riboflavin therapy. We conducted a retrospective analysis of three pediatric cases, integrating detailed clinical phenotyping with comprehensive genetic analysis (including whole-exome/targeted sequencing, Sanger validation, and ACMG-based variant interpretation). To elucidate genotype-phenotype correlations, we interpreted these findings in the context of a literature review. All three patients carried compound heterozygous variants in the SLC52A2 gene. Each exhibited early-onset PRCA (onset age: 2 days to 6 months; hemoglobin: 29-67 g/L) and progressive neurodegeneration, including motor regression, axonal peripheral neuropathy, and sensorineural hearing loss. Riboflavin supplementation led to normalization of hemoglobin levels within four weeks and marked improvement in neurological function. This case series provides detailed longitudinal data on riboflavin-responsive PRCA as a core presenting feature of BVVLS2 and reports rare SLC52A2 variants in the Chinese population. Early riboflavin treatment effectively reversed anemia and partially improved neurological deficits, which may inform a new diagnostic and therapeutic approach for unexplained PRCA accompanied by neurodegenerative features.

Riboflavin transporter deficiency Type 2 (RTD2, OMIM #614707), formerly known as Brown-Vialetto-Van Laere Syndrome 2 (BVVLS 2), is a rare autosomal recessive neurodegenerative disorder caused by biallelic variants in the SLC52A2 gene, encoding for riboflavin transporter 2 (RFVT2). This transporter plays a critical role in flavin cofactor delivery, particularly in the brain. Clinically, RTD2 presents with progressive hearing loss, optic atrophy, muscle weakness, respiratory issues, and pontobulbar palsy. Current treatment involves high-dose riboflavin and other supplements. In this study we explored the molecular mechanisms behind RTD2, focusing on the dimerization of RFVT2 and the associated cellular stress mechanisms in patient-specific models. We demonstrated that RFVT2 exists as a homodimer and that pathogenic variants significantly impair its dimerization, which may contribute to the induction of ER stress. This hypothesis was supported by elevated levels of BiP, an ER stress marker, in patient iPSC-derived motor neurons. Similar findings were confirmed in patient-derived fibroblasts, where we also observed mitochondrial dysfunction and disrupted calcium signaling. Interestingly, no significant changes in FAD content were detected in both cell models, suggesting that proteotoxic stress may be a crucial pathogenic mechanism in RTD2, even in the absence of signs of FAD deficiency. FAD autofluorescence and FLIM measurements reinforce the occurrence of mitochondrial dysfunction in patient MNs. These findings provide insight into the pathogenic mechanisms of RTD2, highlighting the critical role of RFVT2 misfolding, ER stress, and mitochondrial dysfunction in this neurodegenerative disorder.

Variants in the SLC52A3 gene have been associated with riboflavin transporter deficiency type 3 (RTD3), a severe neurodegenerative disorder, typically inherited in an autosomal recessive manner. In this study, two SLC52A3 variants (NM_033409.4: c.62A > G [p.Asn21Ser] and c.161G > A [p.Gly54Glu]) were identified in a family with hereditary hearing loss through whole-exome sequencing. The compound heterozygous proband exhibited only late-onset, progressive, and symmetric sensorineural hearing loss over 23 yr, along with unilateral facial muscle spasm. A heterozygous carrier of the c.62A > G variant also exhibited optic nerve dysfunction, while no other neurological abnormalities were observed in the family. Although the proband's decreased serum riboflavin level has been improved through supplementation, no significant clinical improvement was observed. These findings further support the phenotypic variability, incomplete penetrance, and a potential autosomal dominant inheritance pattern of RTD3. We also underscore the importance of early genetic testing, timely and sustained riboflavin supplementation, and long-term follow-up in affected individuals.

Riboflavin (vitamin B2), a precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), is essential for mitochondrial function, redox balance, and neuronal viability. Impairments in riboflavin transport and metabolism contribute to a growing spectrum of neurological diseases. This review provides a comprehensive update on the therapeutic applications, metabolic mechanisms, and gene-based strategies involving riboflavin in neurological disorders. We systematically analyzed clinical and experimental studies published between 2012 and 2025, focusing on riboflavin-responsive conditions and molecular mechanisms relevant to neurological pathology. Riboflavin supplementation-particularly in high doses-has demonstrated substantial efficacy in conditions such as riboflavin transporter deficiency (RTD), multiple acyl-CoA dehydrogenase deficiency (MADD), and migraine. Emerging data suggest potential benefit in Parkinson's disease, Alzheimer's disease, multiple sclerosis, and acute brain injury. Mechanistically, riboflavin supports mitochondrial bioenergetics, antioxidant systems, and epigenetic regulation. Recent advances in gene therapy and pharmacological chaperones targeting riboflavin-dependent pathways offer promising therapeutic directions. Riboflavin is evolving from a conventional micronutrient into a multifaceted therapeutic agent in neurology. Integration of gene-based approaches, targeted delivery systems, and biomarker-guided interventions may establish riboflavin as a key component of precision medicine strategies for neurological disorders.

BVVLS (Brown-Vialetto-Van Laere syndrome), a rare genetic condition characterized by progressive neuropathy, is caused by defects in SLC52A2 and SLC52A3 genes coding for hRFVT-2 and hRFVT-3. Five BVVLS cases were screened for disease-causing variants using exome sequencing and their functional contributions were evaluated by in silico analysis, riboflavin transport assay and confocal imaging. Probands enrolled in this study were presented with unusual phenotypes like syndactyly, polydactyly, pedal edema and chronic osteomyelitis. Genetic testing disclosed heterozygous variants in all five cases including c.229G>A p.E77K, c.384G>A p.S128S, c.1245C>T p.G415G and c.843del p.L282Cfs*8 in SLC52A2 gene and c.833C>T p.T278M, c.907A>G p.I303V and c.62A>G p.N21S in SLC52A3 gene. Among them, p.L282Cfs*8 was diagnosed here for first-time, whereas p.E77K and p.S128S were reported previously with a variation at nucleotide position. Functional analysis of the variant p.E77K, p.S128S, p.T278M and p.I303V evidenced impairment in riboflavin transport, whereas p.G415G and p.L282Cfs*8 showed no significant changes. Despite of having reduction in riboflavin uptake, the presence of same polymorphic variant (p.T278M and p.I303V) in asymptomatic father suggests it as not likely associated with disease phenotypes. Meantime, membranous expression of hRFVT-2 variants p.S128S and p.E77K were abrogated and mostly internalized in cytoplasmic regions of transfected cells, whereas no change was observed with other variants than wild-type. These results show for the first-time that BVVLS associated hRFVT-2 variants p.S128S and p.E77K affected riboflavin transport function due to abrogation in membranous localization and/or activity of the transporter. The polymorphic variants p.T278M and p.I303V of hRFVT-3 are unlikely to be implicated functionally in the pathogenesis of the disease.