PRPS1 mutations: four distinct syndromes and potential treatment

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Phosphoribosylpyrophosphate synthetases (PRSs) are crucial enzymes catalyzing the initial step in nucleotide synthesis, essential for cellular functions.
• Mutations in the ubiquitously expressed PRPS1 gene, encoding PRS-I, are compatible with life, leading to diverse clinical phenotypes.
• These phenotypes range from PRS-I superactivity to decreased activity, manifesting as distinct X-linked disorders.

Purpose of the Study:

• To elucidate the spectrum of PRPS1-related disorders and their underlying molecular mechanisms.
• To investigate the link between PRPS1 mutations, nucleotide synthesis, and neurological dysfunction.
• To explore potential therapeutic interventions for PRPS1-related diseases.

Main Methods:

• Analysis of missense mutations in the PRPS1 gene.
• Clinical characterization of patients with PRPS1-related disorders, including X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2).
• Assessment of nucleotide levels (GTP, ATP) and preliminary evaluation of S-adenosylmethionine (SAM) supplementation efficacy.

Main Results:

• PRPS1 mutations result in PRS-I superactivity or reduced activity, causing distinct clinical presentations.
• Patients exhibit symptoms including uric acid overproduction, intellectual disability, ataxia, hypotonia, hearing impairment, peripheral and central neuropathy, and optic atrophy.
• Neurological phenotypes are linked to reduced GTP and potentially other purine nucleotide levels, suggesting a shared disease spectrum.
• Preliminary data indicate that SAM supplementation may improve symptoms in Arts syndrome patients.

Conclusions:

• PRPS1-related disorders represent a spectrum of diseases primarily caused by impaired purine nucleotide synthesis.
• Reduced GTP and ATP levels are implicated in the neurological manifestations of these disorders.
• Dietary SAM supplementation presents a potential therapeutic strategy for alleviating symptoms in PRPS1 spectrum diseases by replenishing purine nucleotides.