PRPS1 Gene Mutation Causes Complex X-Linked Adult-Onset Cerebellar Ataxia in Women

Discussion

PRPS1 is located in X chromosome and codes the enzyme phosphoribosyl pyrophosphate (PRPP) synthetase 1. This enzyme is involved in the synthesis of PRPP from ATP and ribose-5-phosphate, which is essential in the production of purines (adenine and guanine) and pyrimidines (cytosine, thymine, and uracil) nucleotides, the building blocks of life. Pathogenic variants in PRPS1 cause 4 distinct conditions in males: CMTX5, X-linked deafness 1 (DFNX1), Arts syndrome, and an inherited form of gout (PRPS-related gout). Sensorineural hearing loss is the only common manifestation of these disorders and the isolated finding of DFNX1. Patients with CMTX5 and Arts syndrome additionally have peripheral neuropathy, ataxia, and optic atrophy.^2,4 Severe cognitive decline, recurrent infections, and early death complicate the clinical course in Arts syndrome, the most severe phenotype.⁵ Individuals with PRPS-related gout, the most common form, have hyperuricemia, but some exhibit mental retardation, ataxia, and hypotonia.²

The variant found in our patient, c.359G>T(p.Gly120Val), is novel and was confirmed by Sanger sequencing. Also, it was absent in the parents characterizing a de novo mutation. Moreover, this variant is absent in 178,000 X chromosomes. It affects a highly conserved residue, and in silico prediction indicates a deleterious effect. The combination of the molecular mechanism, location, and the correlation with clinical features suggests that this variant is most likely pathogenic.

Female patients with PRPS1 mutations are usually asymptomatic and rarely present with neurologic symptoms.⁶ The female disease spectrum ranges from isolated sensorineural hearing loss to the combination of retinal dystrophy, optic atrophy, peripheral neuropathy, ataxia with cerebellar atrophy in MRI, and developmental delay.^3,4,7 Our patient presented early-onset hearing loss, retinal dystrophy, and cerebellar ataxia. Her phenotype is consistent with the one described in 2 women from a Spanish family.³ Fiorentino et al.⁷ reported similar phenotypic features in a Japanese mother and her daughter, who had retinal dystrophy, optic atrophy, sensorineural hearing loss, and gait ataxia. A pathophysiologic explanation for a late-onset phenotype in a woman related to PRPS1 is the X inactivation. De novo variants and skewed inactivation of X chromosome have been described.

The work by Fiorentino et al.⁷ demonstrated 7 of 9 patients with PRPS1-related retinal dystrophy had asymmetric retinal abnormalities. A high proportion of women with X-linked IRD have fundus changes, which are frequently asymmetric. This may be a consequence of skewed inactivation of X chromosomes in females, causing a higher proportion of retinal cells to express the pathogenic variant of PRPS1 gene, rather than the wild-type allele. The degree of skewed X-chromosome inactivation and PRPP synthetase residual activity are the likely determinants of phenotype severity in women with pathogenic variants of PRPS1.⁴

It is noteworthy that PRPS1-related disorders might be treatable. Dietary S-adenosylmethionine supplementation (SAM) exploits an alternative route of ATP biosynthesis, which may alleviate the shortage of adenosine-derived nucleotides. Of interest, in 2 individuals with Arts syndrome, SAM supplementation resulted in clinical improvement.²

In conclusion, this report illustrates the remarkable phenotypic variability of PRPS1 mutations, which may cause a rare form of X-linked adult-onset cerebellar ataxia. Asymmetric retinal dystrophy might represent a clue for the diagnosis of PRPS1 spectrum disease in women with hearing loss and cerebellar signs.