PRPS1 Superactivity

Genetic MONDO:0010395 Pathograph 23 Show in embeddings browser Inborn Error of Purine Metabolism

Phosphoribosylpyrophosphate synthetase (PRS-I) superactivity is an X-linked disorder of purine metabolism caused either by PRPS1 gain-of-function variants that disrupt allosteric regulation or by increased PRPS1 transcription with PRS-I overexpression. Both mechanisms increase phosphoribosylpyrophosphate (PRPP), purine nucleotide synthesis, and uric acid production. The core biochemical phenotype is hyperuricemia with hyperuricosuria, leading to uric acid crystalluria, nephrolithiasis, and gout; severe disease can also include developmental delay or intellectual disability, sensorineural hearing loss, hypotonia, and ataxia.

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1
Inheritance
6
Pathophys.
12
Phenotypes
23
Pathograph
1
Genes
2
Medical Actions
2
Subtypes
🏷

Classifications

👪

Inheritance

1
X-linked HP:0001417
X-linked inheritance
◆

Subtypes

2
PRS-I superactivity, mild phenotype
~75% of affected males
Later-onset phenotype, typically presenting in the second or third decade and usually limited to hyperuricemia and hyperuricosuria with urinary crystalluria or stones and later gout if serum urate is not controlled.
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"The mild phenotype (~75% of affected males) with onset in the second or third decade of life is typically limited to these biochemical findings, whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable..."
GeneReviews defines the mild PRS-I superactivity phenotype and its approximate proportion among affected males.
PRS-I superactivity, severe phenotype
~25% of affected males
Early-onset phenotype with hyperuricemia and hyperuricosuria plus variable neurodevelopmental, auditory, hypotonia, and ataxia findings.
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia."
GeneReviews defines the severe PRS-I superactivity phenotype and its approximate proportion among affected males.
⚙

Pathophysiology

6
PRS-I allosteric gain of function
PRPS1 missense variants can make PRS-I resistant to normal purine nucleotide feedback inhibition and alter activation by inorganic phosphate. This allosteric gain of function increases effective PRS-I activity in patient cells and recombinant PRS1 models.
PRPS1 hgnc:9462
ribose phosphate diphosphokinase activity GO:0004749 ↑ INCREASED
Downstream
PRPP and purine nucleotide overproduction Feedback-resistant PRS-I increases PRPP availability and de novo purine nucleotide synthesis.
Neurodevelopmental and auditory involvement Severe PRS-I superactivity with allosteric variants can include neurodevelopmental and auditory findings through incompletely defined downstream mechanisms.
Show evidence (2 references)
PMID:7593598 SUPPORT In Vitro
"Kinetic analysis of recombinant mutant PRS1s showed that widely dispersed point mutations in the X chromosome-linked PRPS1 gene encoding the PRS1 isoform result in alteration of the allosteric mechanisms regulating both enzyme inhibition by purine nucleotides and activation by inorganic phosphate."
Shows that PRPS1 variants directly alter allosteric regulation of PRS-I, the proximal gain-of-function mechanism in severe PRS-I superactivity.
PMID:8253776 SUPPORT In Vitro
"recombinant N. B. and S. M. PRS1s showed the purine nucleotide feedback resistance phenotypes characteristic of PRS from patients' cells."
Recombinant PRS1 variants reproduce the feedback-resistance phenotype measured in patient cells.
PRPS1 transcriptional overactivity
In the mild overactivity-of-normal-PRS mechanism, patient cells have increased PRPS1 transcription and PRS1 isoform expression despite normal PRS-I allosteric regulation, increasing PRPP and purine synthesis.
PRPS1 hgnc:9462
Downstream
PRPP and purine nucleotide overproduction PRS1 overexpression increases PRPP and purine nucleotide synthesis in intact patient cells.
Show evidence (2 references)
PMID:10066814 SUPPORT In Vitro
"PRPS1 transcription was increased relative to GAPDH (3- to 4-fold normal in fibroblasts; 1.9- to 2.4-fold in lymphoblasts) and PRPS2."
Patient fibroblasts and lymphoblasts show increased PRPS1 transcription.
PMID:10066814 SUPPORT In Vitro
"accelerated PRPS1 transcription is the major aberration leading to PRS1 overexpression."
Identifies PRPS1 transcriptional up-regulation as the primary aberration in overactivity of structurally normal PRS-I.
PRPP and purine nucleotide overproduction
Excess PRS-I activity increases PRPP availability and drives de novo purine nucleotide biosynthesis beyond metabolic demand, creating the biochemical substrate for uric acid overproduction.
purine nucleotide biosynthetic process GO:0006164 ↑ INCREASED
Downstream
Urate Overproduction Increased purine nucleotide flux increases downstream uric acid production.
Show evidence (2 references)
PMID:7593598 SUPPORT In Vitro
"The functional consequences of these mutations provide a tenable basis for the enhanced production of phosphoribosylpyrophosphate, purine nucleotides, and uric acid that are the biochemical hallmarks of PRS superactivity."
Directly supports PRPP, purine nucleotide, and uric acid overproduction as biochemical hallmarks of PRS-I superactivity.
PMID:10066814 SUPPORT In Vitro
"Phosphoribosylpyrophosphate (PRPP) synthetase (PRS) superactivity is an X-linked disorder characterized by gout with overproduction of purine nucleotides and uric acid."
Confirms purine nucleotide and uric acid overproduction in PRS-I superactivity.
Urate Overproduction
Excess purine turnover increases uric acid production, causing hyperuricemia and hyperuricosuria. This is the biochemical state that precedes, but is distinct from, uric acid crystal deposition.
purine nucleobase catabolic process GO:0006145 ↑ INCREASED
Downstream
Hyperuricemia Serum urate rises because uric acid production exceeds clearance.
Hyperuricosuria Urinary uric acid excretion rises with urate overproduction.
Uric Acid Crystal Disease Sustained hyperuricemia and hyperuricosuria allow uric acid to crystallize when serum urate is not controlled.
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria."
GeneReviews identifies hyperuricemia and hyperuricosuria as shared biochemical features of both PRS-I superactivity phenotypes.
Uric Acid Crystal Disease
When urate overproduction is not controlled, uric acid crystallizes in urine, kidneys, and joints, driving crystalluria, stones, gouty arthritis, tophi, and crystal-related kidney injury.
Downstream
Gout Persistent hyperuricemia promotes urate crystal arthritis.
Uric Acid Nephrolithiasis Hyperuricosuria and uric acid crystalluria promote urinary stones.
Uric Acid Crystalluria Urate overproduction can first manifest as urinary uric acid crystals.
Acute kidney injury Severe urate crystal disease can cause acute kidney failure.
Show evidence (1 reference)
PMID:30423175 SUPPORT Human Clinical
"We describe a 16-year-old African American female who developed progressive tophi, nephrolithiasis and acute kidney failure due to urate overproduction."
Human case evidence links urate overproduction to crystal-deposition complications including tophi and nephrolithiasis.
Neurodevelopmental and auditory involvement
Severe PRS-I superactivity can involve the nervous system and hearing, including developmental delay or intellectual disability, sensorineural hearing loss, hypotonia, and ataxia. The connecting mechanism from purine dysregulation to these features is not fully defined.
Downstream
Neurodevelopmental Abnormality Severe PRS-I superactivity can include developmental delay or intellectual disability.
Sensorineural Hearing Impairment Severe PRS-I superactivity can include sensorineural hearing loss.
Hypotonia Severe PRS-I superactivity can include hypotonia.
Ataxia Severe PRS-I superactivity can include ataxia.
Show evidence (2 references)
PMID:20301734 SUPPORT Other
"whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia."
GeneReviews lists the neurologic and auditory manifestations of severe PRS-I superactivity.
PMID:26089585 SUPPORT Other
"The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment."
PRPS1 review summarizes neurological and hearing features reported in PRS-I superactivity.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PRPS1 Superactivity Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Ear 1
Sensorineural Hearing Impairment Sensorineural hearing impairment HP:0000407
Show evidence (2 references)
PMID:20301734 SUPPORT Other
"whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia."
GeneReviews lists sensorineural hearing loss among severe PRS-I superactivity manifestations.
PMID:26089585 SUPPORT Other
"The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment."
PRPS1 review lists postlingual hearing impairment among reported features of PRS-I superactivity.
Genitourinary 3
Uric Acid Nephrolithiasis Uric acid nephrolithiasis HP:0000791
Show evidence (2 references)
PMID:20301734 SUPPORT Other
"In the mild phenotype, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled."
GeneReviews identifies uric acid crystalluria or urinary stones as an early clinical feature.
PMID:30423175 SUPPORT Human Clinical
"We describe a 16-year-old African American female who developed progressive tophi, nephrolithiasis and acute kidney failure due to urate overproduction."
Human PRPS1 superactivity case data directly links urate overproduction to nephrolithiasis.
Acute kidney injury Acute kidney injury HP:0001919
Show evidence (1 reference)
PMID:30423175 SUPPORT Human Clinical
"We describe a 16-year-old African American female who developed progressive tophi, nephrolithiasis and acute kidney failure due to urate overproduction."
Human PRPS1 superactivity case data documents acute kidney failure due to urate overproduction.
End-Stage Renal Disease Stage 5 chronic kidney disease HP:0003774
Show evidence (1 reference)
PMID:30423175 SUPPORT Human Clinical
"Family history included a mother with tophaceous gout who developed end-stage kidney disease due to nephrolithiasis and an affected sister with polyarticular gout."
Human PRPS1 superactivity family data documents end-stage kidney disease secondary to nephrolithiasis in an affected female.
Metabolism 1
Hyperuricemia Hyperuricemia HP:0002149
Show evidence (2 references)
PMID:20301734 SUPPORT Other
"Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria."
GeneReviews states that both PRS-I superactivity phenotypes are characterized by hyperuricemia.
PMID:30423175 SUPPORT Human Clinical
"Clinical findings in previously reported females with PRPS1 superactivity showed a high clinical penetrance of this disorder with a mean serum urate level of 8.5 (4.1) mg/dl"
Female PRPS1 superactivity cases had elevated mean serum urate.
Musculoskeletal 2
Gout Gout HP:0001997
Show evidence (2 references)
PMID:20301734 SUPPORT Other
"In the mild phenotype, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled."
GeneReviews describes gouty arthritis as a downstream clinical feature when serum urate is not controlled.
PMID:30423175 SUPPORT Human Clinical
"Family history included a mother with tophaceous gout who developed end-stage kidney disease due to nephrolithiasis and an affected sister with polyarticular gout."
Human family data documents tophaceous and polyarticular gout in PRPS1 superactivity.
Hypotonia Hypotonia HP:0001252
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia."
GeneReviews lists hypotonia among severe PRS-I superactivity manifestations.
Nervous System 1
Ataxia Ataxia HP:0001251
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia."
GeneReviews lists ataxia among severe PRS-I superactivity manifestations.
Other 4
Hyperuricosuria Hyperuricosuria HP:0003149
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria."
GeneReviews identifies hyperuricosuria as a core biochemical feature.
Uric Acid Crystalluria Crystalluria HP:0020074
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"In the mild phenotype, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled."
GeneReviews identifies uric acid crystalluria as a common early clinical finding in the mild phenotype.
Neurodevelopmental Abnormality Neurodevelopmental abnormality HP:0012759
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia."
GeneReviews lists developmental delay and intellectual disability among severe PRS-I superactivity manifestations.
Urate Tophus Urate tophus HP:0033073
Show evidence (1 reference)
PMID:30423175 SUPPORT Human Clinical
"We describe a 16-year-old African American female who developed progressive tophi, nephrolithiasis and acute kidney failure due to urate overproduction."
Human PRPS1 superactivity case documents progressive tophi due to urate overproduction.
🧬

Genetic Associations

1
PRPS1 gain-of-function and overexpression mechanisms (Pathogenic Variants)
Gene: PRPS1 hgnc:9462
X-linked
Show evidence (4 references)
PMID:7593598 SUPPORT In Vitro
"each PRS1 cDNA contained a distinctive single base substitution predicting a corresponding amino acid substitution in the PRS1 isoform."
Identifies distinct PRPS1 missense variants in affected families.
PMID:10066814 SUPPORT In Vitro
"Study of the two X-linked PRS isoforms (PRS1 and PRS2) in cells from certain affected individuals has shown selectively increased concentrations of structurally normal PRS1 transcript and isoform, suggesting that this form of the disorder involves pretranslational dysregulation of PRPS1..."
Supports the non-coding/transcriptional overactivity mechanism of structurally normal PRS1 in a subset of affected individuals.
PMID:20301734 SUPPORT Other
"PRS superactivity caused by a pathogenic variant in PRPS1 is inherited in an X-linked manner."
GeneReviews confirms X-linked inheritance for PRPS1 variant-positive PRS-I superactivity.
+ 1 more reference
💊

Medical Actions

2
Urate-Lowering Therapy
Action: Urate-lowering therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: allopurinol CHEBI:40279 febuxostat CHEBI:31596
Xanthine oxidase inhibitor therapy with allopurinol or febuxostat reduces uric acid formation and helps control serum urate, urinary uric acid, gout, and stone risk. High daily fluid intake and urine alkalinization with potassium citrate are used as needed for urinary crystal prevention.
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"In all individuals, hyperuricemia and hyperuricosuria can be reduced by treatment with allopurinol or febuxostat to reduce uric acid formation and thus serum urate and urinary uric acid; high daily fluid intake; and, as needed, potassium citrate to alkalinize the urine."
GeneReviews recommends allopurinol or febuxostat plus hydration and urine alkalinization for the uric acid overproduction phenotype.
Genetic Counseling
Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling addresses X-linked inheritance, reproductive risks, heterozygote testing, and prenatal or preimplantation genetic testing when the familial PRPS1 variant is known.
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"If a PRPS1 pathogenic variant has been identified in the proband, heterozygote testing for at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible."
GeneReviews supports genetic counseling and familial testing when the PRPS1 variant is known.
🔬

Biochemical Markers

4
Increased PRS-I activity or impaired allosteric regulation (INCREASED)
Context: Enzyme testing can show high PRS-I activity or lack of allosteric regulation; the severe variant mechanism impairs purine nucleotide feedback inhibition.
Pathograph Readouts
Readout Of PRS-I allosteric gain of function Threshold Dependent Diagnostic
Increased PRS-I activity or abnormal allosteric regulation reports the proximal PRS-I superactivity mechanism.
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"detection of high activity or lack of allosteric regulation of the PRS-I enzyme (PRS-I enzyme assay) establishes the diagnosis."
GeneReviews identifies high PRS-I activity or loss of allosteric regulation as the diagnostic enzyme readout.
Show evidence (2 references)
PMID:20301734 SUPPORT Other
"detection of high activity or lack of allosteric regulation of the PRS-I enzyme (PRS-I enzyme assay) establishes the diagnosis."
GeneReviews identifies increased activity or impaired allosteric regulation as diagnostic biochemical evidence.
PMID:7593598 SUPPORT In Vitro
"Kinetic analysis of recombinant mutant PRS1s showed that widely dispersed point mutations in the X chromosome-linked PRPS1 gene encoding the PRS1 isoform result in alteration of the allosteric mechanisms regulating both enzyme inhibition by purine nucleotides and activation by inorganic phosphate."
Functional assays define altered allosteric regulation as the biochemical mechanism of gain-of-function variants.
Increased PRPP and purine nucleotide synthesis (INCREASED)
Context: Patient cells can show increased PRPP and purine nucleotide synthesis, reflecting enhanced entry of ribose into purine biosynthesis.
Pathograph Readouts
Readout Of PRPP and purine nucleotide overproduction Positive Diagnostic
Increased PRPP and purine nucleotide synthesis directly report the purine-overproduction node downstream of PRS-I superactivity.
Show evidence (1 reference)
PMID:10066814 SUPPORT In Vitro
"modulated relative increases in PRS activities at suboptimal Pi concentration and in rates of PRPP and purine nucleotide synthesis in intact patient fibroblasts indicate that despite an intact allosteric mechanism of regulation of PRS activity, PRPS1 transcription is a major determinant of PRPP..."
Patient fibroblast data directly support increased PRPP and purine synthesis as the readout of purine-overproduction biology.
Show evidence (1 reference)
PMID:10066814 SUPPORT In Vitro
"modulated relative increases in PRS activities at suboptimal Pi concentration and in rates of PRPP and purine nucleotide synthesis in intact patient fibroblasts indicate that despite an intact allosteric mechanism of regulation of PRS activity, PRPS1 transcription is a major determinant of PRPP..."
Patient fibroblast data shows increased PRPP and purine nucleotide synthesis downstream of PRPS1 transcriptional overactivity.
Elevated serum urate (INCREASED)
Context: Serum urate is elevated from uric acid overproduction and is monitored as a treatment target.
Pathograph Readouts
Readout Of Urate Overproduction Positive Monitoring
Elevated serum urate reports the urate-overproduction branch and is used to monitor crystal-disease risk.
Show evidence (1 reference)
PMID:30423175 SUPPORT Human Clinical
"Clinical findings in previously reported females with PRPS1 superactivity showed a high clinical penetrance of this disorder with a mean serum urate level of 8.5 (4.1) mg/dl"
Human case synthesis directly supports elevated serum urate as a clinical readout of PRPS1 superactivity.
Show evidence (1 reference)
PMID:30423175 SUPPORT Human Clinical
"Clinical findings in previously reported females with PRPS1 superactivity showed a high clinical penetrance of this disorder with a mean serum urate level of 8.5 (4.1) mg/dl"
Female PRPS1 superactivity cases had elevated mean serum urate.
Increased urinary uric acid excretion (INCREASED)
Context: Urinary uric acid excretion is increased and is used for screening and treatment surveillance.
Pathograph Readouts
Readout Of Urate Overproduction Positive Monitoring
Increased urinary uric acid excretion reports urate overproduction and the urinary crystal/stone-risk branch.
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"In male relatives at risk: measurement of serum urate concentration and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio."
GeneReviews identifies urinary uric acid excretion as a measured biochemical readout for PRS-I superactivity risk assessment.
Show evidence (1 reference)
PMID:20301734 SUPPORT Other
"In male relatives at risk: measurement of serum urate concentration and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio."
GeneReviews recommends urinary uric acid measurement for screening relatives at risk.
{ }

Source YAML

click to show 
name: PRPS1 Superactivity
creation_date: "2026-04-04T00:00:00Z"
updated_date: "2026-05-21T04:37:25Z"
description: >-
  Phosphoribosylpyrophosphate synthetase (PRS-I) superactivity is an
  X-linked disorder of purine metabolism caused either by PRPS1
  gain-of-function variants that disrupt allosteric regulation or by
  increased PRPS1 transcription with PRS-I overexpression. Both mechanisms
  increase phosphoribosylpyrophosphate (PRPP), purine nucleotide synthesis,
  and uric acid production. The core biochemical phenotype is hyperuricemia
  with hyperuricosuria, leading to uric acid crystalluria, nephrolithiasis,
  and gout; severe disease can also include developmental delay or
  intellectual disability, sensorineural hearing loss, hypotonia, and ataxia.
category: Genetic
parents:
- Inborn Error of Purine Metabolism
classifications:
  icimd_category:
  - classification_value: purine_metabolism
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Disorders of
      purine metabolism" under category "Disorders of nucleobase, nucleotide
      and nucleic acid metabolism". PRS-I superactivity increases PRPP,
      purine nucleotide synthesis, and uric acid production.
disease_term:
  preferred_term: phosphoribosylpyrophosphate synthetase superactivity
  term:
    id: MONDO:0010395
    label: phosphoribosylpyrophosphate synthetase superactivity
prevalence:
- population: Global
  prevalence_class: RARE
  percentage: Rare
inheritance:
- name: X-linked
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
has_subtypes:
- name: Mild
  display_name: PRS-I superactivity, mild phenotype
  classification: clinical_phenotype
  subtype_frequency: "~75% of affected males"
  description: >-
    Later-onset phenotype, typically presenting in the second or third decade
    and usually limited to hyperuricemia and hyperuricosuria with urinary
    crystalluria or stones and later gout if serum urate is not controlled.
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mild phenotype (~75% of affected males) with onset in the second
      or third decade of life is typically limited to these biochemical
      findings, whereas the severe phenotype (~25% of affected males) with
      onset in the first decade of life has in addition to these biochemical
      findings variable combinations of developmental delay (DD) /
      intellectual disability (ID), sensorineural hearing loss, hypotonia,
      and ataxia.
    explanation: >-
      GeneReviews defines the mild PRS-I superactivity phenotype and its
      approximate proportion among affected males.
- name: Severe
  display_name: PRS-I superactivity, severe phenotype
  classification: clinical_phenotype
  subtype_frequency: "~25% of affected males"
  description: >-
    Early-onset phenotype with hyperuricemia and hyperuricosuria plus
    variable neurodevelopmental, auditory, hypotonia, and ataxia findings.
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      whereas the severe phenotype (~25% of affected males) with onset in
      the first decade of life has in addition to these biochemical findings
      variable combinations of developmental delay (DD) / intellectual
      disability (ID), sensorineural hearing loss, hypotonia, and ataxia.
    explanation: >-
      GeneReviews defines the severe PRS-I superactivity phenotype and its
      approximate proportion among affected males.
pathophysiology:
- name: PRS-I allosteric gain of function
  description: >-
    PRPS1 missense variants can make PRS-I resistant to normal purine
    nucleotide feedback inhibition and alter activation by inorganic
    phosphate. This allosteric gain of function increases effective PRS-I
    activity in patient cells and recombinant PRS1 models.
  genes:
  - preferred_term: PRPS1
    term:
      id: hgnc:9462
      label: PRPS1
  molecular_functions:
  - preferred_term: ribose phosphate diphosphokinase activity
    term:
      id: GO:0004749
      label: ribose phosphate diphosphokinase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:7593598
    reference_title: The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Kinetic analysis of recombinant mutant PRS1s showed that widely
      dispersed point mutations in the X chromosome-linked PRPS1 gene
      encoding the PRS1 isoform result in alteration of the allosteric
      mechanisms regulating both enzyme inhibition by purine nucleotides
      and activation by inorganic phosphate.
    explanation: >-
      Shows that PRPS1 variants directly alter allosteric regulation of
      PRS-I, the proximal gain-of-function mechanism in severe PRS-I
      superactivity.
  - reference: PMID:8253776
    reference_title: Human X-linked phosphoribosylpyrophosphate synthetase superactivity is associated with distinct point mutations in the PRPS1 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      recombinant N. B. and S. M. PRS1s showed the purine nucleotide
      feedback resistance phenotypes characteristic of PRS from patients'
      cells.
    explanation: >-
      Recombinant PRS1 variants reproduce the feedback-resistance phenotype
      measured in patient cells.
  downstream:
  - target: PRPP and purine nucleotide overproduction
    description: >-
      Feedback-resistant PRS-I increases PRPP availability and de novo purine
      nucleotide synthesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7593598
      reference_title: The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The functional consequences of these mutations provide a tenable
        basis for the enhanced production of phosphoribosylpyrophosphate,
        purine nucleotides, and uric acid that are the biochemical hallmarks
        of PRS superactivity.
      explanation: >-
        Directly links allosteric PRS1 variants to enhanced PRPP, purine
        nucleotide, and uric acid production.
  - target: Neurodevelopmental and auditory involvement
    description: >-
      Severe PRS-I superactivity with allosteric variants can include
      neurodevelopmental and auditory findings through incompletely defined
      downstream mechanisms.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301734
      reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        whereas the severe phenotype (~25% of affected males) with onset in
        the first decade of life has in addition to these biochemical findings
        variable combinations of developmental delay (DD) / intellectual
        disability (ID), sensorineural hearing loss, hypotonia, and ataxia.
      explanation: >-
        GeneReviews links the severe PRS-I superactivity phenotype to
        neurodevelopmental, auditory, and motor findings.
- name: PRPS1 transcriptional overactivity
  description: >-
    In the mild overactivity-of-normal-PRS mechanism, patient cells have
    increased PRPS1 transcription and PRS1 isoform expression despite normal
    PRS-I allosteric regulation, increasing PRPP and purine synthesis.
  genes:
  - preferred_term: PRPS1
    term:
      id: hgnc:9462
      label: PRPS1
  evidence:
  - reference: PMID:10066814
    reference_title: Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PRPS1 transcription was increased relative to GAPDH (3- to 4-fold
      normal in fibroblasts; 1.9- to 2.4-fold in lymphoblasts) and PRPS2.
    explanation: >-
      Patient fibroblasts and lymphoblasts show increased PRPS1
      transcription.
  - reference: PMID:10066814
    reference_title: Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      accelerated PRPS1 transcription is the major aberration leading to
      PRS1 overexpression.
    explanation: >-
      Identifies PRPS1 transcriptional up-regulation as the primary
      aberration in overactivity of structurally normal PRS-I.
  downstream:
  - target: PRPP and purine nucleotide overproduction
    description: >-
      PRS1 overexpression increases PRPP and purine nucleotide synthesis in
      intact patient cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10066814
      reference_title: Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        modulated relative increases in PRS activities at suboptimal Pi
        concentration and in rates of PRPP and purine nucleotide synthesis in
        intact patient fibroblasts indicate that despite an intact allosteric
        mechanism of regulation of PRS activity, PRPS1 transcription is a
        major determinant of PRPP and purine synthesis.
      explanation: >-
        Links PRPS1 transcriptional overactivity to increased PRPP and purine
        synthesis in patient fibroblasts.
- name: PRPP and purine nucleotide overproduction
  description: >-
    Excess PRS-I activity increases PRPP availability and drives de novo
    purine nucleotide biosynthesis beyond metabolic demand, creating the
    biochemical substrate for uric acid overproduction.
  biological_processes:
  - preferred_term: purine nucleotide biosynthetic process
    term:
      id: GO:0006164
      label: purine nucleotide biosynthetic process
    modifier: INCREASED
  chemical_entities:
  - preferred_term: phosphoribosyl pyrophosphate
    term:
      id: CHEBI:17111
      label: 5-O-phosphono-alpha-D-ribofuranosyl diphosphate
    modifier: INCREASED
  evidence:
  - reference: PMID:7593598
    reference_title: The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The functional consequences of these mutations provide a tenable
      basis for the enhanced production of phosphoribosylpyrophosphate,
      purine nucleotides, and uric acid that are the biochemical hallmarks
      of PRS superactivity.
    explanation: >-
      Directly supports PRPP, purine nucleotide, and uric acid
      overproduction as biochemical hallmarks of PRS-I superactivity.
  - reference: PMID:10066814
    reference_title: Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Phosphoribosylpyrophosphate (PRPP) synthetase (PRS) superactivity is
      an X-linked disorder characterized by gout with overproduction of
      purine nucleotides and uric acid.
    explanation: >-
      Confirms purine nucleotide and uric acid overproduction in PRS-I
      superactivity.
  downstream:
  - target: Urate Overproduction
    description: >-
      Increased purine nucleotide flux increases downstream uric acid
      production.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:7593598
      reference_title: The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The functional consequences of these mutations provide a tenable
        basis for the enhanced production of phosphoribosylpyrophosphate,
        purine nucleotides, and uric acid that are the biochemical hallmarks
        of PRS superactivity.
      explanation: >-
        Directly ties increased PRPP and purine nucleotides to uric acid
        overproduction.
- name: Urate Overproduction
  description: >-
    Excess purine turnover increases uric acid production, causing
    hyperuricemia and hyperuricosuria. This is the biochemical state that
    precedes, but is distinct from, uric acid crystal deposition.
  biological_processes:
  - preferred_term: purine nucleobase catabolic process
    term:
      id: GO:0006145
      label: purine nucleobase catabolic process
    modifier: INCREASED
  chemical_entities:
  - preferred_term: uric acid
    term:
      id: CHEBI:27226
      label: uric acid
    modifier: INCREASED
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises
      two phenotypes, both characterized by hyperuricemia and hyperuricosuria.
    explanation: >-
      GeneReviews identifies hyperuricemia and hyperuricosuria as shared
      biochemical features of both PRS-I superactivity phenotypes.
  downstream:
  - target: Hyperuricemia
    description: Serum urate rises because uric acid production exceeds clearance.
    causal_link_type: DIRECT
  - target: Hyperuricosuria
    description: Urinary uric acid excretion rises with urate overproduction.
    causal_link_type: DIRECT
  - target: Uric Acid Crystal Disease
    description: >-
      Sustained hyperuricemia and hyperuricosuria allow uric acid to
      crystallize when serum urate is not controlled.
    causal_link_type: DIRECT
- name: Uric Acid Crystal Disease
  description: >-
    When urate overproduction is not controlled, uric acid crystallizes in
    urine, kidneys, and joints, driving crystalluria, stones, gouty arthritis,
    tophi, and crystal-related kidney injury.
  chemical_entities:
  - preferred_term: uric acid
    term:
      id: CHEBI:27226
      label: uric acid
    modifier: INCREASED
  evidence:
  - reference: PMID:30423175
    reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a 16-year-old African American female who developed
      progressive tophi, nephrolithiasis and acute kidney failure due to
      urate overproduction.
    explanation: >-
      Human case evidence links urate overproduction to crystal-deposition
      complications including tophi and nephrolithiasis.
  downstream:
  - target: Gout
    description: Persistent hyperuricemia promotes urate crystal arthritis.
    causal_link_type: DIRECT
  - target: Uric Acid Nephrolithiasis
    description: Hyperuricosuria and uric acid crystalluria promote urinary stones.
    causal_link_type: DIRECT
  - target: Uric Acid Crystalluria
    description: Urate overproduction can first manifest as urinary uric acid crystals.
    causal_link_type: DIRECT
  - target: Acute kidney injury
    description: Severe urate crystal disease can cause acute kidney failure.
    causal_link_type: DIRECT
- name: Neurodevelopmental and auditory involvement
  description: >-
    Severe PRS-I superactivity can involve the nervous system and hearing,
    including developmental delay or intellectual disability, sensorineural
    hearing loss, hypotonia, and ataxia. The connecting mechanism from purine
    dysregulation to these features is not fully defined.
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      whereas the severe phenotype (~25% of affected males) with onset in
      the first decade of life has in addition to these biochemical findings
      variable combinations of developmental delay (DD) / intellectual
      disability (ID), sensorineural hearing loss, hypotonia, and ataxia.
    explanation: >-
      GeneReviews lists the neurologic and auditory manifestations of severe
      PRS-I superactivity.
  - reference: PMID:26089585
    reference_title: Association of PRPS1 Mutations with Disease Phenotypes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The overexpression of PRPS1 results in PRS-I superactivity resulting
      in purine overproduction. Patients with PRS-I superactivity demonstrate
      uric acid overproduction, hypotonia, ataxia, neurodevelopment
      abnormalities, and postlingual hearing impairment.
    explanation: >-
      PRPS1 review summarizes neurological and hearing features reported in
      PRS-I superactivity.
  downstream:
  - target: Neurodevelopmental Abnormality
    description: Severe PRS-I superactivity can include developmental delay or intellectual disability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensorineural Hearing Impairment
    description: Severe PRS-I superactivity can include sensorineural hearing loss.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    description: Severe PRS-I superactivity can include hypotonia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ataxia
    description: Severe PRS-I superactivity can include ataxia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Metabolic
  name: Hyperuricemia
  description: >-
    Elevated serum urate from PRS-I-driven uric acid overproduction. This is
    a defining biochemical feature in both mild and severe PRS-I
    superactivity.
  phenotype_term:
    preferred_term: Hyperuricemia
    term:
      id: HP:0002149
      label: Hyperuricemia
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises
      two phenotypes, both characterized by hyperuricemia and hyperuricosuria.
    explanation: >-
      GeneReviews states that both PRS-I superactivity phenotypes are
      characterized by hyperuricemia.
  - reference: PMID:30423175
    reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in previously reported females with PRPS1
      superactivity showed a high clinical penetrance of this disorder with
      a mean serum urate level of 8.5 (4.1) mg/dl
    explanation: >-
      Female PRPS1 superactivity cases had elevated mean serum urate.
- category: Metabolic
  name: Hyperuricosuria
  description: >-
    Increased urinary uric acid excretion accompanies hyperuricemia and
    contributes to uric acid crystalluria and urinary stones.
  phenotype_term:
    preferred_term: Hyperuricosuria
    term:
      id: HP:0003149
      label: Hyperuricosuria
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises
      two phenotypes, both characterized by hyperuricemia and hyperuricosuria.
    explanation: >-
      GeneReviews identifies hyperuricosuria as a core biochemical feature.
- category: Musculoskeletal
  name: Gout
  description: >-
    Gouty arthritis develops when serum urate is not adequately controlled,
    and can be severe or tophaceous in affected females and males.
  phenotype_term:
    preferred_term: Gout
    term:
      id: HP:0001997
      label: Gout
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the mild phenotype, uric acid crystalluria or a urinary stone is
      commonly the first clinical finding, followed later by gouty arthritis
      if serum urate concentration is not controlled.
    explanation: >-
      GeneReviews describes gouty arthritis as a downstream clinical feature
      when serum urate is not controlled.
  - reference: PMID:30423175
    reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family history included a mother with tophaceous gout who developed
      end-stage kidney disease due to nephrolithiasis and an affected sister
      with polyarticular gout.
    explanation: >-
      Human family data documents tophaceous and polyarticular gout in
      PRPS1 superactivity.
- category: Renal
  name: Uric Acid Nephrolithiasis
  description: >-
    Uric acid urinary stones and nephrolithiasis arise from increased
    urinary uric acid excretion and crystalluria.
  phenotype_term:
    preferred_term: Uric acid nephrolithiasis
    term:
      id: HP:0000791
      label: Uric acid nephrolithiasis
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the mild phenotype, uric acid crystalluria or a urinary stone is
      commonly the first clinical finding, followed later by gouty arthritis
      if serum urate concentration is not controlled.
    explanation: >-
      GeneReviews identifies uric acid crystalluria or urinary stones as an
      early clinical feature.
  - reference: PMID:30423175
    reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a 16-year-old African American female who developed
      progressive tophi, nephrolithiasis and acute kidney failure due to
      urate overproduction.
    explanation: >-
      Human PRPS1 superactivity case data directly links urate
      overproduction to nephrolithiasis.
- category: Renal
  name: Uric Acid Crystalluria
  subtype: Mild
  description: >-
    Uric acid crystalluria can be the first clinical finding in the mild
    phenotype, reflecting urinary uric acid supersaturation before overt gout.
  phenotype_term:
    preferred_term: Crystalluria
    term:
      id: HP:0020074
      label: Crystalluria
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the mild phenotype, uric acid crystalluria or a urinary stone is
      commonly the first clinical finding, followed later by gouty arthritis
      if serum urate concentration is not controlled.
    explanation: >-
      GeneReviews identifies uric acid crystalluria as a common early
      clinical finding in the mild phenotype.
- category: Renal
  name: Acute kidney injury
  description: >-
    Severe urate overproduction with nephrolithiasis can precipitate acute
    kidney failure.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:30423175
    reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a 16-year-old African American female who developed
      progressive tophi, nephrolithiasis and acute kidney failure due to
      urate overproduction.
    explanation: >-
      Human PRPS1 superactivity case data documents acute kidney failure due
      to urate overproduction.
- category: Neurological
  name: Neurodevelopmental Abnormality
  subtype: Severe
  description: >-
    Severe PRS-I superactivity can include developmental delay or
    intellectual disability.
  phenotype_term:
    preferred_term: Neurodevelopmental abnormality
    term:
      id: HP:0012759
      label: Neurodevelopmental abnormality
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      whereas the severe phenotype (~25% of affected males) with onset in
      the first decade of life has in addition to these biochemical findings
      variable combinations of developmental delay (DD) / intellectual
      disability (ID), sensorineural hearing loss, hypotonia, and ataxia.
    explanation: >-
      GeneReviews lists developmental delay and intellectual disability
      among severe PRS-I superactivity manifestations.
- category: Neurological
  name: Ataxia
  subtype: Severe
  description: >-
    Ataxia occurs in the severe phenotype as part of neurologic involvement.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      whereas the severe phenotype (~25% of affected males) with onset in
      the first decade of life has in addition to these biochemical findings
      variable combinations of developmental delay (DD) / intellectual
      disability (ID), sensorineural hearing loss, hypotonia, and ataxia.
    explanation: >-
      GeneReviews lists ataxia among severe PRS-I superactivity
      manifestations.
- category: Neurological
  name: Hypotonia
  subtype: Severe
  description: >-
    Hypotonia occurs in the severe phenotype as part of neurologic
    involvement.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      whereas the severe phenotype (~25% of affected males) with onset in
      the first decade of life has in addition to these biochemical findings
      variable combinations of developmental delay (DD) / intellectual
      disability (ID), sensorineural hearing loss, hypotonia, and ataxia.
    explanation: >-
      GeneReviews lists hypotonia among severe PRS-I superactivity
      manifestations.
- category: Hearing
  name: Sensorineural Hearing Impairment
  subtype: Severe
  description: >-
    Sensorineural hearing loss is a severe-phenotype manifestation and may
    be postlingual in PRS-I superactivity.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      whereas the severe phenotype (~25% of affected males) with onset in
      the first decade of life has in addition to these biochemical findings
      variable combinations of developmental delay (DD) / intellectual
      disability (ID), sensorineural hearing loss, hypotonia, and ataxia.
    explanation: >-
      GeneReviews lists sensorineural hearing loss among severe PRS-I
      superactivity manifestations.
  - reference: PMID:26089585
    reference_title: Association of PRPS1 Mutations with Disease Phenotypes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The overexpression of PRPS1 results in PRS-I superactivity resulting
      in purine overproduction. Patients with PRS-I superactivity demonstrate
      uric acid overproduction, hypotonia, ataxia, neurodevelopment
      abnormalities, and postlingual hearing impairment.
    explanation: >-
      PRPS1 review lists postlingual hearing impairment among reported
      features of PRS-I superactivity.
- category: Musculoskeletal
  name: Urate Tophus
  description: >-
    Deposition of monosodium urate crystals as tophi, which can be
    progressive when serum urate is not controlled in PRS-I superactivity.
  phenotype_term:
    preferred_term: Urate tophus
    term:
      id: HP:0033073
      label: Urate tophus
  evidence:
  - reference: PMID:30423175
    reference_title: "Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a 16-year-old African American female who developed
      progressive tophi, nephrolithiasis and acute kidney failure due to
      urate overproduction.
    explanation: >-
      Human PRPS1 superactivity case documents progressive tophi due to
      urate overproduction.
- category: Renal
  name: End-Stage Renal Disease
  description: >-
    Severe urate crystal nephropathy and nephrolithiasis can progress to
    end-stage kidney disease in affected individuals with PRS-I superactivity.
  phenotype_term:
    preferred_term: End-stage renal disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:30423175
    reference_title: "Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family history included a mother with tophaceous gout who developed
      end-stage kidney disease due to nephrolithiasis and an affected sister
      with polyarticular gout.
    explanation: >-
      Human PRPS1 superactivity family data documents end-stage kidney
      disease secondary to nephrolithiasis in an affected female.
biochemical:
- name: Increased PRS-I activity or impaired allosteric regulation
  presence: INCREASED
  context: >-
    Enzyme testing can show high PRS-I activity or lack of allosteric
    regulation; the severe variant mechanism impairs purine nucleotide
    feedback inhibition.
  readouts:
  - target: PRS-I allosteric gain of function
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: DIAGNOSTIC
    interpretation: Increased PRS-I activity or abnormal allosteric regulation reports the proximal PRS-I superactivity mechanism.
    evidence:
    - reference: PMID:20301734
      reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        detection of high activity or lack of allosteric regulation of the
        PRS-I enzyme (PRS-I enzyme assay) establishes the diagnosis.
      explanation: GeneReviews identifies high PRS-I activity or loss of allosteric regulation as the diagnostic enzyme readout.
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      detection of high activity or lack of allosteric regulation of the
      PRS-I enzyme (PRS-I enzyme assay) establishes the diagnosis.
    explanation: >-
      GeneReviews identifies increased activity or impaired allosteric
      regulation as diagnostic biochemical evidence.
  - reference: PMID:7593598
    reference_title: The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Kinetic analysis of recombinant mutant PRS1s showed that widely
      dispersed point mutations in the X chromosome-linked PRPS1 gene
      encoding the PRS1 isoform result in alteration of the allosteric
      mechanisms regulating both enzyme inhibition by purine nucleotides
      and activation by inorganic phosphate.
    explanation: >-
      Functional assays define altered allosteric regulation as the
      biochemical mechanism of gain-of-function variants.
- name: Increased PRPP and purine nucleotide synthesis
  biomarker_term:
    preferred_term: phosphoribosyl pyrophosphate
    term:
      id: CHEBI:17111
      label: 5-O-phosphono-alpha-D-ribofuranosyl diphosphate
  presence: INCREASED
  context: >-
    Patient cells can show increased PRPP and purine nucleotide synthesis,
    reflecting enhanced entry of ribose into purine biosynthesis.
  readouts:
  - target: PRPP and purine nucleotide overproduction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased PRPP and purine nucleotide synthesis directly report the purine-overproduction node downstream of PRS-I superactivity.
    evidence:
    - reference: PMID:10066814
      reference_title: Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        modulated relative increases in PRS activities at suboptimal Pi
        concentration and in rates of PRPP and purine nucleotide synthesis in
        intact patient fibroblasts indicate that despite an intact allosteric
        mechanism of regulation of PRS activity, PRPS1 transcription is a
        major determinant of PRPP and purine synthesis.
      explanation: Patient fibroblast data directly support increased PRPP and purine synthesis as the readout of purine-overproduction biology.
  evidence:
  - reference: PMID:10066814
    reference_title: Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      modulated relative increases in PRS activities at suboptimal Pi
      concentration and in rates of PRPP and purine nucleotide synthesis in
      intact patient fibroblasts indicate that despite an intact allosteric
      mechanism of regulation of PRS activity, PRPS1 transcription is a
      major determinant of PRPP and purine synthesis.
    explanation: >-
      Patient fibroblast data shows increased PRPP and purine nucleotide
      synthesis downstream of PRPS1 transcriptional overactivity.
- name: Elevated serum urate
  biomarker_term:
    preferred_term: Serum urate
    term:
      id: CHEBI:27226
      label: uric acid
  presence: INCREASED
  context: >-
    Serum urate is elevated from uric acid overproduction and is monitored
    as a treatment target.
  readouts:
  - target: Urate Overproduction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Elevated serum urate reports the urate-overproduction branch and is used to monitor crystal-disease risk.
    evidence:
    - reference: PMID:30423175
      reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical findings in previously reported females with PRPS1
        superactivity showed a high clinical penetrance of this disorder with
        a mean serum urate level of 8.5 (4.1) mg/dl
      explanation: Human case synthesis directly supports elevated serum urate as a clinical readout of PRPS1 superactivity.
  evidence:
  - reference: PMID:30423175
    reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings in previously reported females with PRPS1
      superactivity showed a high clinical penetrance of this disorder with
      a mean serum urate level of 8.5 (4.1) mg/dl
    explanation: >-
      Female PRPS1 superactivity cases had elevated mean serum urate.
- name: Increased urinary uric acid excretion
  biomarker_term:
    preferred_term: Urinary uric acid
    term:
      id: CHEBI:27226
      label: uric acid
  presence: INCREASED
  context: >-
    Urinary uric acid excretion is increased and is used for screening and
    treatment surveillance.
  readouts:
  - target: Urate Overproduction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Increased urinary uric acid excretion reports urate overproduction and the urinary crystal/stone-risk branch.
    evidence:
    - reference: PMID:20301734
      reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In male relatives at risk: measurement of serum urate concentration
        and 24-hour urinary uric acid excretion or spot urinary
        urate-to-creatinine ratio.
      explanation: GeneReviews identifies urinary uric acid excretion as a measured biochemical readout for PRS-I superactivity risk assessment.
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In male relatives at risk: measurement of serum urate concentration
      and 24-hour urinary uric acid excretion or spot urinary
      urate-to-creatinine ratio.
    explanation: >-
      GeneReviews recommends urinary uric acid measurement for screening
      relatives at risk.
genetic:
- name: PRPS1 gain-of-function and overexpression mechanisms
  association: Pathogenic Variants
  gene_term:
    preferred_term: PRPS1
    term:
      id: hgnc:9462
      label: PRPS1
  inheritance:
  - name: X-linked
    inheritance_term:
      preferred_term: X-linked inheritance
      term:
        id: HP:0001417
        label: X-linked inheritance
  features: >-
    Severe PRS-I superactivity is caused by PRPS1 pathogenic variants that
    alter allosteric regulation. Mild PRS-I superactivity in affected males
    can result from increased PRPS1 transcription with no detectable PRPS1
    coding variant. PRPS1 variant-positive disease is inherited in an
    X-linked manner, and heterozygous females can be clinically affected.
  evidence:
  - reference: PMID:7593598
    reference_title: The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      each PRS1 cDNA contained a distinctive single base substitution
      predicting a corresponding amino acid substitution in the PRS1 isoform.
    explanation: >-
      Identifies distinct PRPS1 missense variants in affected families.
  - reference: PMID:10066814
    reference_title: Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Study of the two X-linked PRS isoforms (PRS1 and PRS2) in cells from
      certain affected individuals has shown selectively increased
      concentrations of structurally normal PRS1 transcript and isoform,
      suggesting that this form of the disorder involves pretranslational
      dysregulation of PRPS1 expression and might be more appropriately
      termed overactivity of normal PRS.
    explanation: >-
      Supports the non-coding/transcriptional overactivity mechanism of
      structurally normal PRS1 in a subset of affected individuals.
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PRS superactivity caused by a pathogenic variant in PRPS1 is inherited
      in an X-linked manner.
    explanation: >-
      GeneReviews confirms X-linked inheritance for PRPS1 variant-positive
      PRS-I superactivity.
  - reference: CGGV:assertion_76dc3f8d-e1c9-4506-9381-d2b5ab3df300-2020-02-14T170000.000Z
    reference_title: PRPS1 / phosphoribosylpyrophosphate synthetase superactivity (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PRPS1 | HGNC:9462 | phosphoribosylpyrophosphate synthetase superactivity | MONDO:0010395 | XL | Limited"
    explanation: ClinGen records a limited gene-disease validity assertion for PRPS1 and phosphoribosylpyrophosphate synthetase superactivity.
  variants:
  - name: PRPS1 missense gain-of-function variants
    description: >-
      Missense variants alter PRS-I allosteric regulation, including reduced
      inhibition by purine nucleotides such as ADP/GDP.
    evidence:
    - reference: PMID:30423175
      reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutational analysis revealed a new c.520 G > A (p.G174R) mutation in
        the PRPS1 gene.
      explanation: >-
        Human female PRPS1 superactivity cases had a PRPS1 variant.
    - reference: PMID:30423175
      reference_title: Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The mutation resulted in decreased PRPS1 inhibition by ADP.
      explanation: >-
        Functional testing showed reduced ADP inhibition of the PRPS1
        p.G174R variant.
    - reference: PMID:7593598
      reference_title: The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Kinetic analysis of recombinant mutant PRS1s showed that widely
        dispersed point mutations in the X chromosome-linked PRPS1 gene
        encoding the PRS1 isoform result in alteration of the allosteric
        mechanisms regulating both enzyme inhibition by purine nucleotides
        and activation by inorganic phosphate.
      explanation: >-
        Recombinant PRS1 studies define the allosteric gain-of-function
        effect of PRPS1 missense variants.
  - name: PRPS1 transcriptional overactivity with structurally normal PRS1
    description: >-
      Some affected males have increased PRPS1 transcription and PRS1
      overexpression without a detectable PRPS1 coding variant.
    evidence:
    - reference: PMID:10066814
      reference_title: Accelerated transcription of PRPS1 in X-linked overactivity of normal human phosphoribosylpyrophosphate synthetase.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Neither PRPS1 amplification nor altered stability or processing of
        PRS1 mRNA was identified, but PRPS1 transcription was increased
        relative to GAPDH (3- to 4-fold normal in fibroblasts; 1.9- to
        2.4-fold in lymphoblasts) and PRPS2.
      explanation: >-
        Patient cells show increased PRPS1 transcription without gene
        amplification or mRNA stability changes.
    - reference: PMID:20301734
      reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        PRS superactivity caused by elevated PRPS1 mRNA levels is also
        inherited in an X-linked manner; however, because the underlying
        genetic alteration has not been characterized, the mode of
        inheritance cannot be confirmed with certainty.
      explanation: >-
        GeneReviews summarizes the elevated-PRPS1-mRNA mechanism and its
        unresolved genetic basis.
treatments:
- name: Urate-Lowering Therapy
  description: >-
    Xanthine oxidase inhibitor therapy with allopurinol or febuxostat reduces
    uric acid formation and helps control serum urate, urinary uric acid,
    gout, and stone risk. High daily fluid intake and urine alkalinization
    with potassium citrate are used as needed for urinary crystal prevention.
  treatment_term:
    preferred_term: Urate-lowering therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: allopurinol
      term:
        id: CHEBI:40279
        label: allopurinol
    - preferred_term: febuxostat
      term:
        id: CHEBI:31596
        label: febuxostat
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In all individuals, hyperuricemia and hyperuricosuria can be reduced
      by treatment with allopurinol or febuxostat to reduce uric acid
      formation and thus serum urate and urinary uric acid; high daily fluid
      intake; and, as needed, potassium citrate to alkalinize the urine.
    explanation: >-
      GeneReviews recommends allopurinol or febuxostat plus hydration and
      urine alkalinization for the uric acid overproduction phenotype.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses X-linked inheritance, reproductive risks,
    heterozygote testing, and prenatal or preimplantation genetic testing when
    the familial PRPS1 variant is known.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301734
    reference_title: Phosphoribosylpyrophosphate Synthetase Superactivity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If a PRPS1 pathogenic variant has been identified in the proband,
      heterozygote testing for at-risk female relatives, prenatal testing for
      a pregnancy at increased risk, and preimplantation genetic testing are
      possible.
    explanation: >-
      GeneReviews supports genetic counseling and familial testing when the
      PRPS1 variant is known.
datasets: