PRPS1 mutations: Four distinct syndromes and potential treatment

de Brouwer, Arjan P. M., van Bokhoven, H., Nabuurs, S. B., Arts, W. F., Christodoulou, J. and Duley, John (2010) PRPS1 mutations: Four distinct syndromes and potential treatment. American Journal of Human Genetics, 86 4: 506-518. doi:10.1016/j.ajhg.2010.02.024

Author de Brouwer, Arjan P. M.
van Bokhoven, H.
Nabuurs, S. B.
Arts, W. F.
Christodoulou, J.
Duley, John
Title PRPS1 mutations: Four distinct syndromes and potential treatment
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2010-04-09
Year available 2011
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1016/j.ajhg.2010.02.024
Volume 86
Issue 4
Start page 506
End page 518
Total pages 13
Editor C. C. Morton
E. Marcus
Place of publication Cambridge, MA, U.S.A.
Publisher Cell Press
Collection year 2011
Language eng
Subject C1
110904 Neurology and Neuromuscular Diseases
920110 Inherited Diseases (incl. Gene Therapy)
Abstract Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in phosphoribosylpyrophosphate synthetase 1 (PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data). © 2010 The American Society of Human Genetics.
Keyword Human phosphoribosylpyrophosphate synthetase
Hereditary orotic aciduria
Linked mental-retardation
Lesch-Nyhan disease
Pyrophosphate synthetase
Purine metabolism
Sensorineural deafness
Genetic heterogeneity
Enzymatic synthesis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Official 2011 Collection
School of Pharmacy Publications
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Created: Sun, 02 May 2010, 00:09:57 EST