Phosphoribosylpyrophosphate synthetase (PRS) superactivity is characterized by the overproduction and buildup of uric acid. Uric acid is a waste product of normal chemical processes. In people with PRS superactivity, uric acid builds up and can cause various health problems.

There are two forms of PRS superactivity:

• Mild PRS superactivity
• Severe PRS superactivity

Mild PRS superactivity typically appears in late adolescence or early adulthood. People with this condition often have a buildup of uric acid in the blood (hyperuricemia) and in the urine (hyperuricosuria). The first sign of mild PRS superactivity is usually kidney stones or bladder stones, which are caused by the buildup of uric acid. Prolonged and uncontrolled high uric acid levels can lead to gout, which is a form of arthritis caused by an accumulation of uric acid crystals in the joints.

Severe PRS superactivity often begins in infancy or early childhood. In addition to kidney or bladder stones and gout, people with severe PRS superactivity have neurological problems. These problems can include hearing loss caused by changes in the inner ear (sensorineural hearing loss), weak muscle tone (hypotonia), impaired muscle coordination (ataxia), and developmental delays. Some affected individuals have specific facial features, such as a prominent forehead, low-set ears, and skin folds that cover the inner corner of the eyes (epicanthal folds).

PRS superactivity is thought to be a very rare disorder. Most people with the condition have the mild form of the disease. PRS superactivity occurs most often in men and boys.

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the PRPS1 gene cause PRS superactivity. The PRPS1 gene provides instructions for making an enzyme called phosphoribosyl pyrophosphate synthetase 1, or PRPP synthetase 1. This enzyme helps produce phosphoribosyl pyrophosphate (PRPP). PRPP is involved in making molecules called nucleotides. Nucleotides are the building blocks of DNA, its chemical cousin RNA, and molecules such as ATP and GTP that serve as energy sources in the cell. Nucleotides are categorized into two groups: purines and pyrimidines. In addition to making new nucleotides, PRPP synthetase 1 and PRPP also play a key role in recycling purines, which is a faster and more efficient way of making purines available for the cell.

In people with severe PRS superactivity, pathogenic variants in the PRPS1 gene change single protein building blocks (amino acids) in the PRPP synthetase 1 enzyme. As a result, the enzyme is poorly regulated and cannot be turned off, leading to an overactive enzyme.

In people with mild PRS superactivity, the PRPS1 gene is overactive for reasons that are not well understood. PRPS1 gene overactivity increases the production of the PRPP synthetase 1 enzyme.

In both forms of the disorder, increased PRPP synthetase 1 enzyme activity leads to increased PRPP production, which causes the cell to make too many purines. When these excess purines are broken down, uric acid is produced and builds up in the body. A buildup of uric acid can cause kidney stones, bladder stones, and gout.

It is unclear how pathogenic variants in the PRPS1 gene are related to the neurological problems that are associated with severe PRS superactivity. It could be that the abnormal version of the enzyme is more likely to be broken down in nerve cells, causing these cells to produce fewer nucleotides.

Genetic Testing Information

• Genetic Testing Registry: Phosphoribosylpyrophosphate synthetase superactivity

Genetic and Rare Diseases Information Center

• Phosphoribosylpyrophosphate synthetase superactivity

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE SUPERACTIVITY

Scientific Articles on PubMed

• PubMed

• Almoguera B, He S, Corton M, Fernandez-San Jose P, Blanco-Kelly F, Lopez-Molina MI, Garcia-Sandoval B, Del Val J, Guo Y, Tian L, Liu X, Guan L, Torres RJ, Puig JG, Hakonarson H, Xu X, Keating B, Ayuso C. Expanding the phenotype of PRPS1 syndromes in females: neuropathy, hearing loss and retinopathy. Orphanet J Rare Dis. 2014 Dec 10;9:190. doi: 10.1186/s13023-014-0190-9. Citation on PubMed
• Camici M, Garcia-Gil M, Allegrini S, Pesi R, Bernardini G, Micheli V, Tozzi MG. Inborn Errors of Purine Salvage and Catabolism. Metabolites. 2023 Jun 24;13(7):787. doi: 10.3390/metabo13070787. Citation on PubMed
• de Brouwer APM, Christodoulou J. Phosphoribosylpyrophosphate Synthetase Superactivity. 2008 Sep 23 [updated 2022 Feb 17]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1973/ Citation on PubMed
• Nyhan WL. Disorders of purine and pyrimidine metabolism. Mol Genet Metab. 2005 Sep-Oct;86(1-2):25-33. doi: 10.1016/j.ymgme.2005.07.027. Citation on PubMed
• Porrmann J, Betcheva-Krajcir E, Di Donato N, Kahlert AK, Schallner J, Rump A, Schrock E, Dobritzsch D, Roelofsen J, van Kuilenburg ABP, Tzschach A. Novel PRPS1 gain-of-function mutation in a patient with congenital hyperuricemia and facial anomalies. Am J Med Genet A. 2017 Oct;173(10):2736-2742. doi: 10.1002/ajmg.a.38359. Epub 2017 Jul 25. Citation on PubMed
• Zikanova M, Wahezi D, Hay A, Stiburkova B, Pitts C 3rd, Musalkova D, Skopova V, Baresova V, Souckova O, Hodanova K, Zivna M, Stranecky V, Hartmannova H, Hnizda A, Bleyer AJ, Kmoch S. Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females. Rheumatology (Oxford). 2018 Jul 1;57(7):1180-1185. doi: 10.1093/rheumatology/key041. Citation on PubMed