PRPS1 – Arts syndrome

Arts syndrome is a severe X-linked recessive disorder caused by loss-of-function variants in PRPS1, characterized by early-onset hypotonia, ataxia, intellectual disability, congenital sensorineural hearing loss, optic atrophy, and recurrent infections. Initial linkage and sequencing studies in Dutch and Australian families identified pathogenic missense variants c.398A>C (p.Gln133Pro) and c.455T>C (p.Leu152Pro) segregating with Arts syndrome in multiple affected males ([PMID:17701896]). Subsequent independent reports described additional hemizygous variants, including c.367C>G (p.His123Asp) in a pedigree with three affected maternal uncles ([PMID:27256512]), and c.130A>G (p.Ile44Val) in a sporadic case lacking congenital hearing loss ([PMID:33294372]).

Functional assays demonstrate that these PRPS1 variants result in markedly reduced phosphoribosyl-pyrophosphate synthetase 1 activity in patient erythrocytes and fibroblasts ([PMID:17701896]), and zebrafish prps1a/prps1b double mutants recapitulate key human phenotypes—optic atrophy, hearing impairment, peripheral neuropathy, and leukocyte deficiency—supporting a loss-of-function mechanism ([PMID:27425195]). A recent case series of four Arts syndrome patients receiving S-adenosylmethionine and nicotinamide riboside supplementation showed stabilization or improvement of neurologic and immunologic features, suggesting a potential metabolic rescue strategy ([PMID:37927483]).

Collectively, genetic evidence from at least five unrelated families and concordant experimental data establish a definitive association between PRPS1 loss-of-function variants and Arts syndrome. PRPS1 sequencing should be pursued in male infants presenting with hypotonia, developmental delay, sensorineural hearing loss, optic atrophy, and recurrent infections. Early molecular diagnosis enables family counseling for X-linked inheritance and consideration of S-adenosylmethionine-based therapy.

References

• American journal of human genetics • 2007 • Arts syndrome is caused by loss-of-function mutations in PRPS1. PMID:17701896
• Brain & development • 2016 • Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report. PMID:27256512
• Molecular genetics and metabolism reports • 2020 • Atypical presentation of Arts syndrome due to a novel hemizygous loss-of-function variant in the PRPS1 gene. PMID:33294372
• Scientific reports • 2016 • Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases. PMID:27425195
• JIMD reports • 2023 • S-adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review. PMID:37927483

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