Longitudinal riboflavin response in homozygous SLC52A2 p.Pro134Leu: a Turkish kindred with riboflavin transporter deficiency type 2.

Riboflavin transporter deficiency (RTD) is a rare but treatable autosomal recessive neurodegenerative disorder caused by biallelic variants in SLC52A2 (RTD2) or SLC52A3 (RTD3). It typically presents with motor neuronopathy and sensorineural hearing loss. High-dose riboflavin is beneficial but does not halt disease progression, and the determinants of treatment response remain unclear. To describe the phenotype and longitudinal riboflavin response in a Turkish kindred with homozygous SLC52A2 p.Pro134Leu, and to relate reversibility to the timing of treatment. All four patients underwent clinical, neurophysiological, audiological, ophthalmological, and neuroimaging evaluations; the variant was identified by whole-exome sequencing and confirmed by Sanger sequencing and family segregation. Patients received high-dose riboflavin and were followed for five years. The response to riboflavin was related to the interval between symptom onset and treatment. Case 1, treated eight months after onset, achieved complete clinical recovery, with improved nerve conduction and resolution of neurogenic changes within a year. Case 2, treated approximately thirteen years after onset, showed clinical stabilization but no electrophysiological improvement after two years; she also had optic atrophy and severe hearing loss. Cases 3 and 4 were identified by cascade screening and treated presymptomatically; both had subtle signs on examination and normal baseline electrophysiology, and they remain asymptomatic with normal nerve conduction studies and needle EMG after approximately four years. Once age at assessment was taken into account, phenotypic variability within the family was limited, confined to the initial presentation and to early audiological involvement. In Case 2, the earliest hearing loss was confined to 8000 Hz and later extended to the speech frequencies. This is the second independent Turkish family with p.Pro134Leu, consistent with either a regional founder allele or a recurrent mutation. In this family, the outcome of riboflavin therapy tracked how early it was started. Cascade screening revealed affected relatives at a subclinical, electrophysiologically intact stage, and high-frequency audiometry detected hearing loss before it affected speech frequencies.