PRPS1 – Charcot-Marie-Tooth Disease X-linked Recessive 5 (CMTX5)

X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) is characterized by early-onset prelingual sensorineural hearing loss, peripheral neuropathy with steppage gait, and optic neuropathy. The causative gene, PRPS1 (HGNC:9462), encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-I), a critical enzyme in purine nucleotide biosynthesis. Affected males typically present in infancy or early childhood with auditory and motor deficits progressing to visual involvement. Female carriers may be asymptomatic or show mild hearing loss due to skewed X-inactivation.

Initial evidence came from two unrelated families (European and Asian descent) harboring the missense mutations c.344T>C (p.Met115Thr) and c.129A>T (p.Glu43Asp) in PRPS1, respectively, with 2 male probands demonstrating sensorineural hearing loss, peripheral neuropathy, and visual loss, and patient erythrocyte assays confirming reduced PRS-I activity ([PMID:17701900]). This X-linked recessive inheritance was supported by co-segregation in multiple affected males across pedigrees.

Subsequent case reports expanded the variant and phenotypic spectrum. A Korean family with a novel hemizygous c.362C>G (p.Ala121Gly) variant in PRPS1 presented with early hearing loss at 5 months, steppage gait by age 6, and peripheral neuropathy but without optic atrophy; segregation in two additional male relatives provided further support ([PMID:24285972]).

Additional hemizygous missense variants have been reported in single CMTX5 patients: c.202A>T (p.Met68Leu) in a French patient with neuropathy, deafness, and optic neuropathy ([PMID:31338985]); c.319A>G (p.Ile107Val) in two siblings with recurrent transient proximal weakness after febrile illness ([PMID:30177296]); and c.82G>C (p.Gly28Arg) in a Japanese patient with typical CMTX5 but milder enzyme deficiency ([PMID:34803094]). No recurrent or founder variants have been described to date.

Functional studies consistently demonstrate a loss-of-function mechanism. Patient-derived enzyme assays show markedly reduced PRS-I activity in erythrocytes and fibroblasts ([PMID:17701896]). A zebrafish prps1a/prps1b double-mutant model recapitulates phenotypes of reduced eye size, decreased hair cell numbers, primary motor neuron defects, and leukopenia, mirroring optic atrophy, hearing impairment, neuropathy, and immunodeficiency seen in human PRPS1-deficient syndromes ([PMID:27425195]).

Overall, the PRPS1–CMTX5 association meets a Strong ClinGen gene–disease validity classification: 7 unrelated male probands, documented X-linked recessive segregation, and concordant functional data. Genetic testing for PRPS1 should be considered in male patients presenting with the triad of early sensorineural hearing loss, peripheral neuropathy, and optic involvement. Identification of PRPS1 mutations enables definitive molecular diagnosis, carrier detection, genetic counseling, and potential exploration of purine replacement therapies.

References

• American Journal of Human Genetics • 2007 • Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5) PMID:17701900
• Journal of Clinical Neurology • 2013 • Exome Sequencing Reveals a Novel PRPS1 Mutation in a Family with CMTX5 without Optic Atrophy. PMID:24285972
• Brain & Development • 2019 • X-linked Charcot-Marie-Tooth disease type 5 with recurrent weakness after febrile illness. PMID:30177296
• Molecular Genetics & Genomic Medicine • 2019 • New PRPS1 variant p.(Met68Leu) located in the dimerization area identified in a French CMTX5 patient. PMID:31338985
• Internal Medicine (Tokyo, Japan) • 2022 • A Novel PRPS1 Mutation in a Japanese Patient with CMTX5. PMID:34803094
• American Journal of Human Genetics • 2007 • Arts syndrome is caused by loss-of-function mutations in PRPS1. PMID:17701896
• Scientific Reports • 2016 • Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases. PMID:27425195

Evidence Based Scoring (AI generated)