(mentions CMT X5) PRPS1 mutations: four distinct syndromes and potential treatme

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Am J Hum Genet. 2010 Apr 9;86(4):506-18.

PRPS1 mutations: four distinct syndromes and potential treatment.

de Brouwer AP, van Bokhoven H, Nabuurs SB, Arts WF, Christodoulou J, Duley J.

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and

Institute of Genetic and Metabolic Diseases, Radboud University Nijmegen Medical

Centre, 6500 HB Nijmegen, The Netherlands. a.debrouwer@...

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.