PRPS1 Gene Mutation Causes Complex X-Linked Adult-Onset Cerebellar Ataxia in Women
Citation Manager Formats
Make Comment
See Comments

Inherited retinal dystrophies (IRD) comprise a heterogeneous group of disorders that affect visual function. IRD occur in isolated forms or in association with systemic abnormalities.1 Over 300 disease-causing genes have been identified in IRD.
We report an unusual form of syndromic IRD with a complex neurologic phenotype caused by a mutation in PRPS1 gene. Pathogenic variants in PRPS1 lead to Arts syndrome, X-linked deafness 1, PRPS-related gout, or Charcot-Marie-Tooth 5 (CMTX5) in boys,2 but it has been recently shown that women may also be symptomatic and display hearing loss, ophthalmologic abnormalities, and neurologic manifestations.3
Case Report
A 30-year-old woman, born from nonconsanguineous parents, presented with a 5-year history of progressive ataxia. She also had congenital strabismus, infantile-onset hearing loss, and a retinal dystrophy with progressive visual loss for the past 10 years. The visual acuity was 20/200 on the right eye and 20/40 on the left eye. Fundus examination revealed pale optic discs, attenuated vessels, and atrophic areas containing whitish fine dots, reticular pigmentation, and bone spicules bilaterally. Examination showed cerebellar ataxia, dysarthria, and gaze-evoked nystagmus. Audiometry confirmed bilateral sensorineural hearing loss. Brain MRI showed atrophy in the pons, middle cerebellar peduncles, vermis, and cerebellar hemispheres (figure). The genetic test for Friedreich ataxia was negative. Alpha-fetoprotein, albumin, vitamin E, creatine kinase, and lactate were normal. Whole-exome sequencing disclosed a heterozygous missense variant c.359G>T(p.Gly120Val) in one of her PRPS1 alleles.
Color fundus photographs of both eyes depicting pale optic discs, attenuated retinal vessels, and atrophic areas containing whitish fine dots with reticular pigmentation (A). The pattern of retinal dystrophy is remarkably asymmetric and more severe on the right eye, in which the macula is affected. Axial T2-weighted sequence of brain MRI shows atrophy in the cerebellar peduncles and pons (B) and in cerebellar hemispheres (C) (white arrows).
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.
Study Funding
This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (grant number: 2019/15298-1).
Disclosure
F.M. Rezende Filho and M.M. Palma report no disclosures relevant to the manuscript. J.L. Pedroso received grant from FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo). O.G.P. Barsottini and J.M.F. Sallum report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures.
Acknowledgment
The authors thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for have funded this study.
Appendix Authors


Footnotes
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).
- Received September 7, 2020.
- Accepted in final form December 8, 2020.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
References
- 1.↵
- Ellingford JM,
- Barton S,
- Bhaskar S, et al
- 2.↵
- de Brouwer APM,
- van Bokhoven H,
- Nabuurs SB,
- Arts WF,
- Christodoulou J,
- Duley J
- 3.↵
- Almoguera B,
- He S,
- Corton M, et al
- 4.↵
- 5.↵
- 6.↵
- 7.↵
- Fiorentino A,
- Fujinami K,
- Arno G, et al
Letters: Rapid online correspondence
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Related Articles
- No related articles found.