SLC52A2-Related Riboflavin Transporter Deficiency in Non-Isolated Auditory Neuropathy: Evidence from a Chinese Cohort and a Global Variant Review

Background/Objectives: Riboflavin transporter deficiency type 2 (RTD2), caused by biallelic pathogenic variants in SLC52A2, is a treatable neurodegenerative disorder in which auditory neuropathy may be an early manifestation. This study characterized the clinical and genetic spectrum of SLC52A2-related RTD2, with emphasis on auditory findings and geographic variation in the reported variant spectrum. Methods: We screened unrelated probands with clinically diagnosed auditory neuropathy from a multicenter cohort for SLC52A2-related disease. Clinical, audiological, genetic, treatment, and follow-up data were reviewed. PubMed, Web of Science, and Embase were searched from inception through Feb 2026 to summarize reported SLC52A2 variants. Results: Four patients carried eight distinct SLC52A2 variants, four of which were previously unreported. Audiological testing identified an auditory neuropathy phenotype, with onset between 0.5 and 4 years of age and severity ranging from mild or moderate to profound. In two patients, hearing loss was the first or a concurrent initial manifestation. Riboflavin treatment improved anemia, ataxia, muscle strength, and motor function, whereas established auditory and visual impairment showed limited recovery. The Chinese cohort showed a dispersed variant distribution across SLC52A2, without clustering at known hotspots. In the global dataset, p.G306R was the most frequent variant, accounting for 41.6% (74/178) of reported variant alleles. Conclusions: SLC52A2-related RTD2 should be considered in children with early-onset or progressive auditory neuropathy and multisystem manifestations. Early molecular diagnosis may permit timely riboflavin treatment before irreversible neural injury develops. The four previously unreported variants expand the SLC52A2 variant spectrum, while the geographic patterns identified in published cases require validation in larger cohorts.