Atypical phenotypic characteristics, mutation analysis and treatment in a family of riboflavin transporter deficiency caused by SLC52A3 variants

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.