{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:32:32Z","timestamp":1786440752511,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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\u2013Marie\u2013Tooth 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&gt;G) presenting a 15-year diagnostic delay. Kaplan\u2013Meier analysis revealed sensorineural hearing loss manifested acutely (median 0 years; 95% CI: 0\u20131). In contrast, neurological deficits demonstrated a prolonged latency (median 3 years; 95% CI: 1\u20138), 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.<\/jats:p>","DOI":"10.3390\/biom16081164","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:09:36Z","timestamp":1786435776000},"page":"1164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Age-Dependent Progression of Neurological Involvement in PRPP Deficiency: Insights from a Four-Generation Family and Systematic Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1925-9952","authenticated-orcid":false,"given":"Bartosz","family":"Rodziewicz","sequence":"first","affiliation":[{"name":"Department of Developmental Neurology, Medical University of Gdansk, 80-952 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5921-7324","authenticated-orcid":false,"given":"Miko\u0142aj","family":"Kacperski","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurology, Medical University of Gdansk, 80-952 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kacper","family":"Kisi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurology, Medical University of Gdansk, 80-952 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4562-1882","authenticated-orcid":false,"given":"Marta","family":"Zawadzka","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurology, Medical University of Gdansk, 80-952 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kalicka","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Rare Diseases Centre, University Clinical Center, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Sawicka","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurology, Medical University of Gdansk, 80-952 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Lipska-Zi\u0119tkiewicz","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Rare Diseases Centre, University Clinical Center, 80-210 Gdansk, Poland"},{"name":"Clinical Genetics Unit, Department of Biology and Medical Genetics, Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Mazurkiewicz-Be\u0142dzi\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurology, Medical University of Gdansk, 80-952 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41572-025-00679-2","article-title":"Charcot-Marie-Tooth disease and related neuropathies","volume":"12","author":"Burns","year":"2026","journal-title":"Nat. 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