Age-Dependent Progression of Neurological Involvement in PRPP Deficiency: Insights from a Four-Generation Family and...

Loss-of-function (LoF) variants in the PRPS1 gene, encoding the phosphoribosyl pyrophosphate (PRPP) synthetase 1 enzyme, cause rare neurometabolic disorders historically viewed as discrete entities: nonsyndromic deafness (DFNX1), Charcot-Marie-Tooth disease type X5 (CMTX5), and Arts syndrome. A major clinical challenge is the temporal dissociation between early auditory failure and subsequent neurodegeneration, causing fragmented diagnostics. We systematically quantified this diagnostic latency and reconceptualized the disease spectrum through a molecular lens. A PRISMA-compliant systematic review identified 19 patients with genetically confirmed PRPS1 LoF variants, including our index case (c.362C>G) presenting a 15-year diagnostic delay. Kaplan-Meier analysis revealed sensorineural hearing loss manifested acutely (median 0 years; 95% CI: 0-1). In contrast, neurological deficits demonstrated a prolonged latency (median 3 years; 95% CI: 1-8), followed by ophthalmological signs (median 11.5 years). The median symptomatic delay was 3 years (range up to 19). We posit that this temporal dissociation reflects differential tissue vulnerability to intracellular ATP/GTP and NAD+ depletion caused by the primary enzymatic defect. Ultimately, DFNX1, CMTX5, and Arts syndrome represent a continuous PRPS1-related neurometabolic spectrum. Because targeted metabolic interventions (such as S-adenosylmethionine or nicotinamide riboside) have limited efficacy on advanced structural nerve damage, recognizing this early diagnostic window to initiate biochemical rescue prior to irreversible axonal degeneration is critical.