Broadening the phenotypic and molecular spectrum of PRS deficiency in females

Phosphoribosylpyrophosphate synthase deficiency is a rare X-linked disorder caused by variants in the PRPS1 gene. While males typically exhibit severe phenotypes, heterozygous females may or may not be affected, likely explained by skewed X-chromosome inactivation and the impact on enzyme activity. In this study, we describe and study both unique and previously described variants in PRPS1 in female patients. We provide detailed molecular and phenotypic information for two pediatric patients possessing unique variants in PRPS1, one of whom presents with bilateral tongue fasciculations, extending the cranial neuropathy spectrum described in these conditions. We summarize and compare published cases of females with PRPS1 deficiency to establish common phenotypic features and demonstrate that all disease causing variants are missense variants scattered across the protein. In silico modelling was performed for all variants causing PRS deficiency in females to highlight different unique impacts on the protein. Altogether these findings expand the molecular and phenotypic spectrum of PRS deficiency in females, demonstrate that heterozygous females can manifest significant neurological and sensory impairment early in life, and highlight cranial nerve XII involvement. Continued functional and clinical studies are required to refine genotype-phenotype correlations and inform targeted diagnostic and therapeutic strategies.