Riboflavin Transporter Deficiency: Effectiveness of High Dose Riboflavin Therapy and Clinical Trial Readiness

Abstract

Riboflavin Transporter Deficiency (RTD) is a progressive inherited neuropathy of childhood onset characterised clinically by bulbar palsy, limb muscle weakness, sensorineural hearing loss, visual impairment, sensory ataxia and respiratory compromise. Without treatment, the condition progresses relentlessly resulting in early death due to respiratory compromise. High dose oral riboflavin supplementation has been shown to be life saving and to improve functional outcomes.

94 genetically confirmed cases of RTD who received riboflavin supplementation were identified and had follow-up assessments. Information on the clinical and functional status before and after riboflavin supplementation was collected and analysed. Seventy-six of the 94 individuals (80.9%) showed an overall improvement after riboflavin supplementation, and the remaining (19.1%) were stable, though some individuals had deterioration in individual domains, with no reported deaths. Despite treatment, affected individuals were left with residual disability in multiple domains.

A longitudinal case series study was conducted during the period 1991 to 2022 at the Children’s Hospital at Westmead. Affected individuals had commenced high-dose oral riboflavin supplementation from the time of genetic diagnosis. Individuals for whom riboflavin supplementation was initiated early after disease onset had better outcomes compared to those in whom diagnosis was delayed. Overall, riboflavin supplementation slowed, but did not stop, disease progression.

An RTD-specific functional outcome measure, the Riboflavin Transporter Deficiency Pediatric Scale (RTDPedS), was developed by modifying the CMTPedS to account for phenotypic differences between children with CMT and RTD identified during the prior studies. This outcome measure aims to assess disease severity and progression in clinical trials and cohort studies.