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replenishing purine nucleotides (J.C., unpublished data).