Association ofPRPS1Mutations with Disease Phenotypes

Abstract

Phosphoribosylpyrophosphate synthetase 1(PRPS1) codes for PRS-I enzyme that catalyzes the first step of nucleotide synthesis.PRPS1gene mutations have been implicated in a number of human diseases. Recently, new mutations inPRPS1have been identified that have been associated with novel phenotypes like diabetes insipidus expanding the spectrum ofPRPS1-related diseases. The purpose of this review is to evaluate current literature onPRPS1-related syndromes and summarize potential therapies. The overexpression ofPRPS1results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment. On the other hand, decreased activity leads to X-linked nonsyndromic sensorineural deafness (DFNX-2), Charcot-Marie-Tooth disease-5 (CMTX5), and Arts syndrome depending on the residual activity of PRS-I. Mild PRS-I deficiency (DFNX-2) results in non-syndromic progressive hearing loss whereas moderate PRS-I deficiency (CMTX5) and severe PRS-I deficiency (Arts syndrome) present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment. Currently, purine replacement via S-adenosylmethionine (SAM) supplementation in patients with Arts syndrome appears to improve their condition. This suggests that SAM supplementation can alleviate symptoms ofPRPS1deficient patients and open new avenues of therapeutic intervention.