Title: Unique retinal findings in a case of riboflavin transporter deficiency
Abstract:
Riboflavin Transporter Deficiency (RTD), also known as Brown-Vialetto-Van Laere syndrome, is a rare autosomal recessive neurodegenerative disorder caused by pathogenic variants in SLC52A2 and SLC52A3, which encode the riboflavin transporters RFVT2 and RFVT3 (5). Riboflavin is essential for generating the flavin cofactors FMN and FAD, central to mitochondrial oxidative metabolism and redox homeostasis (2,3). Defective riboflavin transport leads to mitochondrial dysfunction and a multisystem neurological disease, often responsive to high-dose riboflavin therapy (10). While optic atrophy is the most described ocular manifestation (1,6,7,8,9)—with prevalence reported as 46% in a cohort of 109 patients (1) and up to 70% in smaller studies (8)—retinal changes remain poorly characterized.
We report a 9-year-old boy with genetically confirmed RTD (SLC52A2 variant) who exhibited progressive systemic and ocular involvement. His symptoms began at age 2 with delayed motor milestones and failure to achieve independent ambulation. By age 3, he developed bulbar dysfunction with recurrent aspiration, necessitating fundoplication and gastrostomy feeding. Given the high clinical suspicion of RTD, riboflavin supplementation was initiated at age 3, resulting in improvements in agitation and gross motor function. His multisystem course continued with the development of sensorineural hearing loss requiring bilateral cochlear implantation and neuromuscular scoliosis.
Ocular features emerged early and progressed over time. Pendular horizontal and vertical nystagmus was noted from 3 months of age and improved partially with riboflavin therapy. Brain MRI at age 2 demonstrated mild bilateral optic nerve hypoplasia. After a two-year lapse in ophthalmic follow-up due to social circumstances, he re-presented with worsening visual function, including difficulty recognizing faces and frequent collisions. Optos imaging showed persistent optic nerve hypoplasia and new bilateral pigmentary changes. Testing revealed little visual interest beyond a central 15 cm field. Electroretinography revealed minimally delayed scotopic responses but excluded a primary photoreceptor dystrophy. Examination under anaesthesia identified persistent hyaloid remnants, pale optic nerves, and peripheral speckled pigmentation bilaterally. FAF demonstrated a 360-degree window defect with early choroidal flush outside the arcades but no leakage or neovascularization. Over the subsequent three years, follow-up imaging showed progression to widespread 360-degree retinal atrophy with macular sparing and more extensive pigmentary changes, with functional vision restricted to the central 10 degrees.
These findings tentatively suggest that RTD may involve retinal changes more extensively than previously recognized, although further data are required to clarify if there is a true association. Riboflavin’s roles in retinal structure and metabolism (4,11,12) and anterior segment homeostasis (13) are well documented and may be relevant to the unique findings seen in this in case given the largely normal ERG findings.
In conclusion, this unique case highlights a progressive pigmentary retinopathy and retinal atrophy in a child with genetically confirmed RTD, possibly expanding the currently recognized ocular phenotype. Comprehensive ophthalmic evaluation and longitudinal monitoring may be essential for understanding the full visual impact of this rare disorder.
