Adenine Phosphoribosyltransferase Deficiency

Mendelian MONDO:0013869 Pathograph 31 Purine Metabolism Disorder Genetic Kidney Disease

Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive purine-salvage disorder caused by biallelic APRT loss of function. Reduced APRT activity diverts adenine to xanthine oxidoreductase, producing poorly soluble 2,8-dihydroxyadenine (2,8-DHA). Urinary 2,8-DHA crystals cause radiolucent nephrolithiasis, obstructive stone disease, acute kidney injury, chronic tubulointerstitial crystal nephropathy, and progressive chronic kidney disease unless xanthine oxidoreductase inhibitor therapy is recognized and maintained.

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1
Mappings
1
Definitions
1
Inheritance
7
Pathophys.
1
Histopath.
18
Phenotypes
31
Pathograph
1
Genes
3
Treatments
7
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0013869 adenine phosphoribosyltransferase deficiency
skos:exactMatch Orphanet ORPHA:976
Orphanet ORPHA:976 lists MONDO:0013869 as an exact cross-reference for adenine phosphoribosyltransferase deficiency.
📘

Definitions

1
Orphanet APRT deficiency definition
A rare genetic nephropathy secondary to disordered purine metabolism, characterized by urinary 2,8-dihydroxyadenine formation, urolithiasis, and crystalline nephropathy.
OTHER
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"A rare genetic nephropathy secondary to a disorder of purine metabolism characterized by the formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy."
Orphanet defines the core biochemical, stone, and crystal-nephropathy disease features.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"Autosomal recessive"
Orphanet lists autosomal recessive inheritance.
⚙

Pathophysiology

7
APRT molecular function deficiency
Biallelic APRT pathogenic variants reduce adenine phosphoribosyltransferase catalytic activity, impairing adenine salvage.
APRT link
purine-containing compound salvage link ↓ DECREASED
adenine phosphoribosyltransferase activity link ↓ DECREASED
Downstream
Adenine conversion to 2,8-dihydroxyadenine Loss of APRT activity leaves adenine available for oxidation by xanthine oxidoreductase.
Reduced APRT enzyme activity Biallelic APRT loss of function is measured diagnostically as absent or markedly reduced enzyme activity.
Abnormal APRT enzyme activity The proximal enzymatic defect is the biochemical phenotype recorded for APRT deficiency.
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"APRT | adenine phosphoribosyltransferase | hgnc:626 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet identifies APRT loss of function as the disease-causing gene mechanism.
PMID:33707627 SUPPORT Human Clinical
"Individuals homozygous for disease-causing variants have invariably been shown to have completely abolished enzyme activity"
Human variant data support abolished APRT enzyme activity in affected homozygotes.
Adenine conversion to 2,8-dihydroxyadenine
Xanthine oxidoreductase oxidizes adenine to 2,8-dihydroxyadenine when APRT salvage is absent.
purine nucleobase metabolic process link ⚠ ABNORMAL
Downstream
Urinary 2,8-dihydroxyadenine crystalluria Poorly soluble DHA is excreted in urine and precipitates as crystals.
Increased urinary 2,8-dihydroxyadenine XOR-mediated DHA generation produces excessive urinary DHA excretion.
Show evidence (2 references)
PMID:30443743 SUPPORT Human Clinical
"adenine is converted by xanthine oxidoreductase (XOR; xanthine dehydrogenase/oxidase) to the poorly soluble 2,8-dihydroxyadenine (DHA)"
Human APRT registry paper describes XOR-mediated production of poorly soluble DHA.
PMID:33707627 SUPPORT Human Clinical
"adenine is oxidized to 2,8-dihydroxyadenine (DHA) by xanthine oxidoreductase"
Human genetic study background confirms the biochemical conversion step.
Urinary 2,8-dihydroxyadenine crystalluria
Excess 2,8-DHA is excreted in urine, where its low solubility produces characteristic crystalluria and radiolucent stones.
Downstream
Obstructive DHA stone disease Urinary DHA precipitation produces urolithiasis and obstructive stone events.
Renal tubular crystal deposition and obstruction DHA crystals deposit within renal tubules and can obstruct tubular lumens.
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy"
Orphanet links urinary DHA overexcretion to stones and crystalline nephropathy.
PMID:22700886 SUPPORT Other
"formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine."
The review supports urinary DHA formation and hyperexcretion.
Obstructive DHA stone disease
Poorly soluble DHA forms urinary stones that can cause obstructive stone events, lower urinary tract symptoms, hematuria, pain, and obstructive AKI.
Downstream
Nephrolithiasis DHA stone formation manifests clinically as nephrolithiasis.
Uric acid-like radiolucent nephrolithiasis Radiolucent DHA stones may be misidentified as uric acid calculi.
Acute kidney injury Bilateral obstructive DHA stone disease can cause AKI episodes.
Recurrent urinary tract infections Stone disease and urinary tract obstruction can predispose to recurrent urinary tract infections.
Macroscopic hematuria DHA stone disease and urinary tract irritation can present with hematuria.
Dysuria Urinary tract irritation from DHA stones and crystalluria can produce painful urination.
Flank pain Obstructive stone events can present with flank pain.
Abdominal colic Colicky abdominal pain can accompany urinary tract stone events.
Urinary retention Obstructive urinary stone disease can contribute to urinary retention.
Urinary hesitancy Lower urinary tract obstruction and irritation can manifest as urinary hesitancy.
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy"
Orphanet supports urolithiasis as a direct consequence of urinary DHA hyperexcretion.
PMID:30443743 SUPPORT Human Clinical
"Reddish-brown diaper spots and kidney stones were the most common presenting features"
Human registry data support kidney stones as a major clinical presentation.
Renal tubular crystal deposition and obstruction
2,8-DHA crystals deposit in renal tubules. Small crystals can be taken up by tubular epithelial cells, while larger crystals obstruct whole tubules.
renal tubular epithelial cell link
endocytosis link ↑ INCREASED
Downstream
Tubular injury inflammation and fibrosis Crystal deposition drives tubular injury and chronic inflammatory-fibrotic repair.
Show evidence (3 references)
PMID:32086278 SUPPORT Model Organism
"The smallest crystals were endocytosed by tubular epithelial cells."
Mouse model data support crystal interaction with tubular epithelial cells.
PMID:32086278 SUPPORT Model Organism
"Large crystals obstructed whole tubules."
Mouse model data support direct tubular obstruction by large crystals.
PMID:32086278 SUPPORT Human Clinical
"Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury."
Patient-biopsy findings show that the model mechanisms are clinically relevant.
Tubular injury inflammation and fibrosis
Crystal-induced tubular injury triggers inflammation and fibrosis, producing chronic tubulointerstitial injury and nephron loss.
inflammatory response link ↑ INCREASED
Downstream
Progressive DHA crystal nephropathy and renal dysfunction Chronic crystal nephropathy causes CKD, AKI episodes, and kidney failure risk.
Proteinuria Biopsy-proven crystal nephropathy can present with elevated urine protein:creatinine ratio.
Show evidence (2 references)
PMID:32086278 SUPPORT Model Organism
"progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis."
Mouse model evidence supports inflammation and fibrosis downstream of crystal deposition.
PMID:30443743 SUPPORT Human Clinical
"chronic DHA crystal nephropathy which is characterized by chronic tubulointerstitial inflammation, fibrosis and progressive nephron loss."
Human registry discussion identifies chronic inflammation, fibrosis, and nephron loss in DHA nephropathy.
Progressive DHA crystal nephropathy and renal dysfunction
Ongoing crystal nephropathy manifests clinically as recurrent nephrolithiasis, acute obstructive kidney injury, chronic kidney disease, and kidney failure in a subset of untreated or late-treated individuals.
glomerular filtration link ↓ DECREASED
Downstream
Chronic kidney disease Progressive DHA crystal nephropathy reduces renal function and manifests as CKD.
Renal insufficiency Crystal nephropathy-associated renal dysfunction appears clinically as renal insufficiency.
Stage 5 chronic kidney disease Untreated or inadequately treated DHA crystal nephropathy can progress to ESRD.
Oliguria Advanced renal dysfunction or obstructive AKI can reduce urine output.
Hypertension Chronic kidney disease and renal dysfunction can contribute to hypertension.
Show evidence (2 references)
PMID:22934314 SUPPORT Other
"crystal-induced kidney damage (i.e., DHA crystal nephropathy) causing acute kidney injury episodes and progressive chronic kidney disease (CKD)."
GeneReviews supports the renal outcome mechanism.
PMID:30443743 SUPPORT Human Clinical
"Affected individuals develop kidney stones and/or progressive chronic kidney disease (CKD) due to DHA crystal nephropathy"
Human registry study links DHA nephropathy to stones and progressive CKD.
✶

Histopathology

1
Intratubular 2,8-DHA crystals with chronic tubulointerstitial injury
Kidney biopsy can show 2,8-DHA crystal deposits in renal tubules with tubular injury, inflammation, fibrosis, and progressive nephron loss.
Show evidence (2 references)
PMID:32086278 SUPPORT Human Clinical
"Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury."
Patient kidney biopsies support characteristic crystal nephropathy histopathology.
PMID:30443743 SUPPORT Human Clinical
"chronic DHA crystal nephropathy which is characterized by chronic tubulointerstitial inflammation, fibrosis and progressive nephron loss."
Human registry paper describes the chronic histopathologic injury pattern.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Adenine Phosphoribosyltransferase Deficiency 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

18
Cardiovascular 2
Hypertension FREQUENT Hypertension (HP:0000822)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0000822 | Hypertension | Frequent (79-30%)"
Orphanet records hypertension as frequent.
Atrial fibrillation OCCASIONAL Atrial fibrillation (HP:0005110)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0005110 | Atrial fibrillation | Occasional (29-5%)"
Orphanet records atrial fibrillation as occasional.
Genitourinary 10
Nephrolithiasis FREQUENT Nephrolithiasis (HP:0000787)
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"HP:0000787 | Nephrolithiasis | Frequent (79-30%)"
Orphanet records nephrolithiasis as frequent.
PMID:22934314 SUPPORT Other
"Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age;"
GeneReviews supports kidney stones as a major clinical manifestation.
Uric acid-like radiolucent nephrolithiasis OCCASIONAL Uric acid nephrolithiasis (HP:0000791)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0000791 | Uric acid nephrolithiasis | Occasional (29-5%)"
Orphanet records uric acid nephrolithiasis as occasional.
Chronic kidney disease FREQUENT Chronic kidney disease (HP:0012622)
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"HP:0012622 | Chronic kidney disease | Frequent (79-30%)"
Orphanet records chronic kidney disease as frequent.
PMID:30443743 SUPPORT Human Clinical
"Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary purine metabolism disorder that causes kidney stones and chronic kidney disease (CKD)."
Human cohort paper supports CKD as a disease manifestation.
Renal insufficiency FREQUENT Renal insufficiency (HP:0000083)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0000083 | Renal insufficiency | Frequent (79-30%)"
Orphanet records renal insufficiency as frequent.
Acute kidney injury FREQUENT Acute kidney injury (HP:0001919)
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"HP:0001919 | Acute kidney injury | Frequent (79-30%)"
Orphanet records acute kidney injury as frequent.
PMID:30443743 SUPPORT Human Clinical
"Six of these patients had experienced kidney stone events and three had developed acute kidney injury (AKI) prior to allopurinol treatment."
Registry data document AKI before treatment in pediatric-presenting patients.
Stage 5 chronic kidney disease OCCASIONAL Stage 5 chronic kidney disease (HP:0003774)
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"HP:0003774 | Stage 5 chronic kidney disease | Occasional (29-5%)"
Orphanet records stage 5 chronic kidney disease as occasional.
PMID:22934314 SUPPORT Other
"approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD)"
GeneReviews supports kidney failure risk when treatment is inadequate.
Proteinuria FREQUENT Proteinuria (HP:0000093)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0000093 | Proteinuria | Frequent (79-30%)"
Orphanet records proteinuria as frequent.
Dysuria FREQUENT Dysuria (HP:0100518)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0100518 | Dysuria | Frequent (79-30%)"
Orphanet records dysuria as frequent.
Urinary retention OCCASIONAL Urinary retention (HP:0000016)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0000016 | Urinary retention | Occasional (29-5%)"
Orphanet records urinary retention as occasional.
Oliguria OCCASIONAL Oliguria (HP:0100520)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0100520 | Oliguria | Occasional (29-5%)"
Orphanet records oliguria as occasional.
Constitutional 1
Flank pain OCCASIONAL Flank pain (HP:0030157)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0030157 | Flank pain | Occasional (29-5%)"
Orphanet records flank pain as occasional.
Other 5
Abnormal APRT enzyme activity VERY_FREQUENT Abnormal circulating enzyme concentration or activity (HP:0012379)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"
Orphanet reports abnormal enzyme/coenzyme activity as very frequent.
Recurrent urinary tract infections OCCASIONAL Recurrent urinary tract infections (HP:0000010)
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"HP:0000010 | Recurrent urinary tract infections | Occasional (29-5%)"
Orphanet records recurrent urinary tract infections as occasional.
PMID:30443743 SUPPORT Human Clinical
"Other well-known clinical features in children include reddish-brown diaper stains in young children, acute kidney injury (AKI) due to bilateral obstructive DHA calculi, recurrent urinary tract infections and hematuria"
Pediatric APRT registry paper describes recurrent urinary tract infections among clinical features.
Macroscopic hematuria OCCASIONAL Macroscopic hematuria (HP:0012587)
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"HP:0012587 | Macroscopic hematuria | Occasional (29-5%)"
Orphanet records macroscopic hematuria as occasional.
PMID:30443743 SUPPORT Human Clinical
"recurrent urinary tract infections and hematuria"
Pediatric registry background supports hematuria as a clinical feature.
Urinary hesitancy OCCASIONAL Urinary hesitancy (HP:0000019)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0000019 | Urinary hesitancy | Occasional (29-5%)"
Orphanet records urinary hesitancy as occasional.
Abdominal colic OCCASIONAL Abdominal colic (HP:0011848)
Show evidence (1 reference)
ORPHA:976 SUPPORT Other
"HP:0011848 | Abdominal colic | Occasional (29-5%)"
Orphanet records abdominal colic as occasional.
🧬

Genetic Associations

1
APRT variants (Causative)
Autosomal recessive
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"APRT | adenine phosphoribosyltransferase | hgnc:626 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists APRT loss-of-function germline variants as disease causing.
PMID:30443743 SUPPORT Human Clinical
"The diagnosis is confirmed by absent APRT enzyme activity in red cell lysates and/or the identification of biallelic pathogenic variants in the APRT gene"
Human registry paper supports biallelic APRT variants and absent enzyme activity as diagnostic.
💊

Treatments

3
Xanthine oxidoreductase inhibitor pharmacotherapy
Action: Pharmacotherapy NCIT:C15986
Agent: allopurinol ↗ febuxostat ↗
Allopurinol or febuxostat inhibits xanthine oxidoreductase, reducing conversion of adenine to 2,8-DHA, lowering urinary DHA burden, and reducing stone recurrence and kidney injury risk when taken at adequate dose.
Mechanism Target:
INHIBITS Adenine conversion to 2,8-dihydroxyadenine — XOR inhibition reduces the biochemical conversion of adenine to 2,8-DHA.
Show evidence (1 reference)
PMID:33707627 SUPPORT Human Clinical
"Treatment with the xanthine oxidoreductase inhibitors allopurinol and febuxostat reduces DHA synthesis and excretion"
Human genetic study background states the treatment mechanism.
Target Phenotypes: Nephrolithiasis ↗ Chronic kidney disease ↗
Show evidence (4 references)
PMID:22934314 SUPPORT Other
"Treatment with the xanthine oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase) allopurinol or febuxostat can improve kidney function"
GeneReviews supports allopurinol or febuxostat therapy for kidney outcomes.
PMID:30443743 SUPPORT Human Clinical
"Timely diagnosis and treatment of APRT deficiency decreases renal complications and preserves kidney function."
Registry data support clinical benefit from early treatment.
PMID:30443743 SUPPORT Human Clinical
"Timely pharmacologic therapy appears to reduce stone burden and slow or possibly prevent the progression of CKD"
Registry data support reduced stone burden and slower CKD progression.
+ 1 more reference
High fluid intake
Action: dietary intervention MAXO:0000088
Ample fluid intake is advised to dilute urinary solutes and support stone prevention alongside XOR inhibitor pharmacotherapy.
Mechanism Target:
INHIBITS Urinary 2,8-dihydroxyadenine crystalluria — Higher fluid intake dilutes urinary DHA and complements pharmacologic DHA suppression.
Show evidence (1 reference)
PMID:22934314 SUPPORT Other
"Ample fluid intake is advised."
GeneReviews recommends ample fluid intake as part of management.
Target Phenotypes: Nephrolithiasis ↗
Show evidence (1 reference)
PMID:22934314 SUPPORT Other
"Ample fluid intake is advised."
GeneReviews advises high fluid intake in APRT deficiency management.
Kidney replacement therapy for ESRD
Action: organ transplantation MAXO:0010039
Dialysis and kidney transplantation are used for ESRD, but XOR inhibitor therapy remains recommended after transplantation to prevent recurrent DHA nephropathy in the allograft.
Target Phenotypes: Stage 5 chronic kidney disease ↗
Show evidence (2 references)
PMID:22934314 SUPPORT Other
"ESRD is treated with dialysis and kidney transplantation."
GeneReviews supports dialysis and kidney transplantation for ESRD management.
PMID:22934314 SUPPORT Other
"Even after kidney transplantation, treatment with an XOR is recommended."
GeneReviews supports continuing XOR inhibition after transplant.
🔬

Biochemical Markers

2
Reduced APRT enzyme activity (DECREASED)
Context: Absent or markedly reduced APRT activity in red cell lysates is the diagnostic biochemical defect.
Pathograph Readouts
Readout Of APRT molecular function deficiency Negative Diagnostic
Absent red-cell APRT activity directly reports the proximal APRT molecular function deficiency.
Show evidence (1 reference)
PMID:22934314 SUPPORT Other
"The diagnosis of APRT deficiency is established in a proband by absence of APRT enzyme activity in red cell lysates"
GeneReviews identifies absent APRT enzyme activity as the diagnostic biochemical readout.
Show evidence (2 references)
PMID:22934314 SUPPORT Other
"The diagnosis of APRT deficiency is established in a proband by absence of APRT enzyme activity in red cell lysates"
GeneReviews identifies absent APRT enzyme activity as diagnostic.
ORPHA:976 SUPPORT Other
"APRT | adenine phosphoribosyltransferase | hgnc:626 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet supports APRT loss of function as the proximal biochemical defect.
Increased urinary 2,8-dihydroxyadenine (INCREASED)
Context: 2,8-DHA is formed and hyperexcreted in urine, where crystalluria and stone formation provide diagnostic and treatment-monitoring readouts.
Pathograph Readouts
Readout Of Adenine conversion to 2,8-dihydroxyadenine Positive Diagnostic
Increased urinary 2,8-DHA reports the abnormal XOR-mediated adenine conversion caused by APRT loss.
Show evidence (1 reference)
PMID:30443743 SUPPORT Human Clinical
"In the absence of APRT activity, adenine is converted by xanthine oxidoreductase (XOR; xanthine dehydrogenase/oxidase) to the poorly soluble 2,8-dihydroxyadenine (DHA) which is excreted in the urine in excessive amounts."
Human registry evidence identifies urinary 2,8-DHA excess as a biochemical readout of the abnormal conversion step.
Show evidence (2 references)
ORPHA:976 SUPPORT Other
"formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine"
Orphanet identifies urinary DHA hyperexcretion as the core biochemical abnormality.
PMID:30443743 SUPPORT Human Clinical
"In the absence of APRT activity, adenine is converted by xanthine oxidoreductase (XOR; xanthine dehydrogenase/oxidase) to the poorly soluble 2,8-dihydroxyadenine (DHA) which is excreted in the urine in excessive amounts."
Human registry paper describes urinary excess of DHA downstream of absent APRT activity.
{ }

Source YAML

click to show 
name: Adenine Phosphoribosyltransferase Deficiency
category: Mendelian
creation_date: "2026-05-10T09:34:20Z"
updated_date: "2026-05-21T08:27:02Z"
synonyms:
- APRT deficiency
- 2,8-dihydroxyadenine urolithiasis
description: >
  Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive
  purine-salvage disorder caused by biallelic APRT loss of function. Reduced
  APRT activity diverts adenine to xanthine oxidoreductase, producing poorly
  soluble 2,8-dihydroxyadenine (2,8-DHA). Urinary 2,8-DHA crystals cause
  radiolucent nephrolithiasis, obstructive stone disease, acute kidney injury,
  chronic tubulointerstitial crystal nephropathy, and progressive chronic
  kidney disease unless xanthine oxidoreductase inhibitor therapy is recognized
  and maintained.
disease_term:
  preferred_term: adenine phosphoribosyltransferase deficiency
  term:
    id: MONDO:0013869
    label: adenine phosphoribosyltransferase deficiency
parents:
- Purine Metabolism Disorder
- Genetic Kidney Disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0013869
      label: adenine phosphoribosyltransferase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:976
    mapping_justification: >
      Orphanet ORPHA:976 lists MONDO:0013869 as an exact cross-reference for
      adenine phosphoribosyltransferase deficiency.
external_assertions:
- name: Orphanet adenine phosphoribosyltransferase deficiency disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:976
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=976
  description: >
    Orphanet's ORPHA:976 structured record provides the exact MONDO mapping,
    definition, inheritance, disease gene, prevalence, and HPO phenotype rows
    used as structured evidence for this entry.
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0013869 | Exact"
    explanation: Orphanet maps ORPHA:976 exactly to MONDO:0013869.
definitions:
- name: Orphanet APRT deficiency definition
  definition_type: OTHER
  description: >
    A rare genetic nephropathy secondary to disordered purine metabolism,
    characterized by urinary 2,8-dihydroxyadenine formation, urolithiasis, and
    crystalline nephropathy.
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare genetic nephropathy secondary to a disorder of purine metabolism characterized by the formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy."
    explanation: Orphanet defines the core biochemical, stone, and crystal-nephropathy disease features.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet lists autosomal recessive inheritance.
prevalence:
- population: Europe
  percentage: 1-9 per 100,000
  notes: >
    Orphanet reports point prevalence in Europe in the one-to-nine per 100,000
    range, with founder-effect populations also noted in Iceland and Japan.
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Europe | Point prevalence | ORPHANET"
    explanation: Orphanet reports European point prevalence in this range.
- population: Iceland and Japan founder populations
  percentage: 1-9 per 100,000
  notes: >
    Orphanet separately records the same point-prevalence class for Iceland and
    Japan; population-genetic data support founder effects in both countries.
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Iceland | Point prevalence | EXPERT"
    explanation: Orphanet records point prevalence for Iceland.
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Japan | Point prevalence | EXPERT"
    explanation: Orphanet records point prevalence for Japan.
  - reference: PMID:33707627
    reference_title: "Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The large number of cases in Japan and Iceland is consistent with a founder effect in these populations."
    explanation: Human population-genetic data support founder effects in Japan and Iceland.
progression:
- phase: Variable onset with delayed recognition
  notes: >
    APRT deficiency can present from infancy to adulthood, and many patients are
    diagnosed only after stones, incidental crystalluria, family screening, or
    advanced kidney disease.
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infancy among onset categories.
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: Orphanet records adult onset among onset categories.
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age;"
    explanation: GeneReviews supports broad age variability of clinical presentation.
- phase: Preventable progression to kidney failure
  notes: >
    Untreated or delayed diagnosis can progress to ESRD, whereas early
    pharmacologic treatment reduces stone burden and helps preserve kidney
    function.
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If adequate treatment is not provided, approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD), usually in adult life."
    explanation: GeneReviews summarizes the untreated risk of kidney failure.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Timely diagnosis and treatment of APRT deficiency decreases renal complications and preserves kidney function."
    explanation: Longitudinal registry data support improved outcomes after early treatment.
  - reference: PMID:27994857
    reference_title: "Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Outcome is poor in late diagnosis and there is a high prevalence of ESRD."
    explanation: UK cross-sectional survey supports poor late-diagnosis outcomes and ESRD burden.
pathophysiology:
- name: APRT molecular function deficiency
  description: >
    Biallelic APRT pathogenic variants reduce adenine phosphoribosyltransferase
    catalytic activity, impairing adenine salvage.
  genes:
  - preferred_term: APRT
    term:
      id: hgnc:626
      label: APRT
  molecular_functions:
  - preferred_term: adenine phosphoribosyltransferase activity
    term:
      id: GO:0003999
      label: adenine phosphoribosyltransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: purine-containing compound salvage
    term:
      id: GO:0043101
      label: purine-containing compound salvage
    modifier: DECREASED
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "APRT | adenine phosphoribosyltransferase | hgnc:626 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet identifies APRT loss of function as the disease-causing gene mechanism.
  - reference: PMID:33707627
    reference_title: "Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals homozygous for disease-causing variants have invariably been shown to have completely abolished enzyme activity"
    explanation: Human variant data support abolished APRT enzyme activity in affected homozygotes.
  downstream:
  - target: Adenine conversion to 2,8-dihydroxyadenine
    description: Loss of APRT activity leaves adenine available for oxidation by xanthine oxidoreductase.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30443743
      reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the absence of APRT activity, adenine is converted by xanthine oxidoreductase"
      explanation: Human registry background directly links absent APRT activity to XOR-mediated adenine conversion.
  - target: Reduced APRT enzyme activity
    description: Biallelic APRT loss of function is measured diagnostically as absent or markedly reduced enzyme activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22934314
      reference_title: "Adenine Phosphoribosyltransferase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "absence of APRT enzyme activity in red cell lysates"
      explanation: GeneReviews identifies absent APRT enzyme activity as the diagnostic biochemical defect.
  - target: Abnormal APRT enzyme activity
    description: The proximal enzymatic defect is the biochemical phenotype recorded for APRT deficiency.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"
      explanation: Orphanet records abnormal enzyme activity as a very frequent APRT deficiency phenotype.
- name: Adenine conversion to 2,8-dihydroxyadenine
  description: >
    Xanthine oxidoreductase oxidizes adenine to 2,8-dihydroxyadenine when APRT
    salvage is absent.
  chemical_entities:
  - preferred_term: adenine
    term:
      id: CHEBI:16708
      label: adenine
    modifier: INCREASED
  - preferred_term: 2,8-dihydroxyadenine
    term:
      id: CHEBI:183641
      label: 2,8-dihydroxyadenine
    modifier: INCREASED
  biological_processes:
  - preferred_term: purine nucleobase metabolic process
    term:
      id: GO:0006144
      label: purine nucleobase metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "adenine is converted by xanthine oxidoreductase (XOR; xanthine dehydrogenase/oxidase) to the poorly soluble 2,8-dihydroxyadenine (DHA)"
    explanation: Human APRT registry paper describes XOR-mediated production of poorly soluble DHA.
  - reference: PMID:33707627
    reference_title: "Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "adenine is oxidized to 2,8-dihydroxyadenine (DHA) by xanthine oxidoreductase"
    explanation: Human genetic study background confirms the biochemical conversion step.
  downstream:
  - target: Urinary 2,8-dihydroxyadenine crystalluria
    description: Poorly soluble DHA is excreted in urine and precipitates as crystals.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22700886
      reference_title: "Adenine phosphoribosyltransferase deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The low solubility of DHA results in precipitation of this compound and the formation of urinary crystals and stones."
      explanation: Review evidence links DHA low solubility to urinary crystals and stones.
  - target: Increased urinary 2,8-dihydroxyadenine
    description: XOR-mediated DHA generation produces excessive urinary DHA excretion.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30443743
      reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the absence of APRT activity, adenine is converted by xanthine oxidoreductase (XOR; xanthine dehydrogenase/oxidase) to the poorly soluble 2,8-dihydroxyadenine (DHA) which is excreted in the urine in excessive amounts."
      explanation: Human registry evidence directly links absent APRT activity to excessive urinary DHA excretion.
- name: Urinary 2,8-dihydroxyadenine crystalluria
  description: >
    Excess 2,8-DHA is excreted in urine, where its low solubility produces
    characteristic crystalluria and radiolucent stones.
  chemical_entities:
  - preferred_term: 2,8-dihydroxyadenine
    term:
      id: CHEBI:183641
      label: 2,8-dihydroxyadenine
    modifier: INCREASED
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy"
    explanation: Orphanet links urinary DHA overexcretion to stones and crystalline nephropathy.
  - reference: PMID:22700886
    reference_title: "Adenine phosphoribosyltransferase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine."
    explanation: The review supports urinary DHA formation and hyperexcretion.
  downstream:
  - target: Obstructive DHA stone disease
    description: Urinary DHA precipitation produces urolithiasis and obstructive stone events.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy"
      explanation: Orphanet directly links urinary DHA hyperexcretion to urolithiasis.
  - target: Renal tubular crystal deposition and obstruction
    description: DHA crystals deposit within renal tubules and can obstruct tubular lumens.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32086278
      reference_title: "Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "formation of 2,8-DHA crystals within renal tubules"
      explanation: Patient-biopsy and model study supports intratubular crystal formation.
- name: Obstructive DHA stone disease
  description: >
    Poorly soluble DHA forms urinary stones that can cause obstructive stone
    events, lower urinary tract symptoms, hematuria, pain, and obstructive AKI.
  chemical_entities:
  - preferred_term: 2,8-dihydroxyadenine
    term:
      id: CHEBI:183641
      label: 2,8-dihydroxyadenine
    modifier: INCREASED
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine, causing urolithiasis and crystalline nephropathy"
    explanation: Orphanet supports urolithiasis as a direct consequence of urinary DHA hyperexcretion.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reddish-brown diaper spots and kidney stones were the most common presenting features"
    explanation: Human registry data support kidney stones as a major clinical presentation.
  downstream:
  - target: Nephrolithiasis
    description: DHA stone formation manifests clinically as nephrolithiasis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22934314
      reference_title: "Adenine Phosphoribosyltransferase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "kidney stone formation and crystal-induced kidney damage"
      explanation: GeneReviews directly links excessive DHA to kidney stone formation.
  - target: Uric acid-like radiolucent nephrolithiasis
    description: Radiolucent DHA stones may be misidentified as uric acid calculi.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Radiolucent DHA stone misidentification
    evidence:
    - reference: PMID:30443743
      reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "misidentification of radiolucent kidney stones as uric acid calculi"
      explanation: Human registry discussion describes radiolucent DHA stones being mistaken for uric acid stones.
  - target: Acute kidney injury
    description: Bilateral obstructive DHA stone disease can cause AKI episodes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30443743
      reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three patients presented with AKI due to obstructive stone disease"
      explanation: Human registry data directly link obstructive stone disease to AKI at presentation.
  - target: Recurrent urinary tract infections
    description: Stone disease and urinary tract obstruction can predispose to recurrent urinary tract infections.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30443743
      reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other well-known clinical features in children include reddish-brown diaper stains in young children, acute kidney injury (AKI) due to bilateral obstructive DHA calculi, recurrent urinary tract infections and hematuria"
      explanation: Pediatric registry evidence lists recurrent urinary tract infections with obstructive DHA calculi among known clinical features.
  - target: Macroscopic hematuria
    description: DHA stone disease and urinary tract irritation can present with hematuria.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012587 | Macroscopic hematuria | Occasional (29-5%)"
      explanation: Orphanet records macroscopic hematuria as an occasional phenotype in APRT deficiency.
    - reference: PMID:30443743
      reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "recurrent urinary tract infections and hematuria"
      explanation: Pediatric registry evidence supports hematuria as a clinical feature accompanying APRT stone disease.
  - target: Dysuria
    description: Urinary tract irritation from DHA stones and crystalluria can produce painful urination.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100518 | Dysuria | Frequent (79-30%)"
      explanation: Orphanet records dysuria as a frequent phenotype in APRT deficiency.
  - target: Flank pain
    description: Obstructive stone events can present with flank pain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0030157 | Flank pain | Occasional (29-5%)"
      explanation: Orphanet records flank pain as an APRT deficiency phenotype.
  - target: Abdominal colic
    description: Colicky abdominal pain can accompany urinary tract stone events.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0011848 | Abdominal colic | Occasional (29-5%)"
      explanation: Orphanet records abdominal colic as an APRT deficiency phenotype.
  - target: Urinary retention
    description: Obstructive urinary stone disease can contribute to urinary retention.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000016 | Urinary retention | Occasional (29-5%)"
      explanation: Orphanet records urinary retention as an occasional phenotype in APRT deficiency.
  - target: Urinary hesitancy
    description: Lower urinary tract obstruction and irritation can manifest as urinary hesitancy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000019 | Urinary hesitancy | Occasional (29-5%)"
      explanation: Orphanet records urinary hesitancy as an occasional phenotype in APRT deficiency.
- name: Renal tubular crystal deposition and obstruction
  description: >
    2,8-DHA crystals deposit in renal tubules. Small crystals can be taken up by
    tubular epithelial cells, while larger crystals obstruct whole tubules.
  chemical_entities:
  - preferred_term: 2,8-dihydroxyadenine
    term:
      id: CHEBI:183641
      label: 2,8-dihydroxyadenine
    modifier: INCREASED
  cell_types:
  - preferred_term: renal tubular epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: endocytosis
    term:
      id: GO:0006897
      label: endocytosis
    modifier: INCREASED
  evidence:
  - reference: PMID:32086278
    reference_title: "Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The smallest crystals were endocytosed by tubular epithelial cells."
    explanation: Mouse model data support crystal interaction with tubular epithelial cells.
  - reference: PMID:32086278
    reference_title: "Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Large crystals obstructed whole tubules."
    explanation: Mouse model data support direct tubular obstruction by large crystals.
  - reference: PMID:32086278
    reference_title: "Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury."
    explanation: Patient-biopsy findings show that the model mechanisms are clinically relevant.
  downstream:
  - target: Tubular injury inflammation and fibrosis
    description: Crystal deposition drives tubular injury and chronic inflammatory-fibrotic repair.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32086278
      reference_title: "Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis."
      explanation: Mouse data directly connect crystal deposits to tubular injury, inflammation, and fibrosis.
- name: Tubular injury inflammation and fibrosis
  description: >
    Crystal-induced tubular injury triggers inflammation and fibrosis, producing
    chronic tubulointerstitial injury and nephron loss.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:32086278
    reference_title: "Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis."
    explanation: Mouse model evidence supports inflammation and fibrosis downstream of crystal deposition.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic DHA crystal nephropathy which is characterized by chronic tubulointerstitial inflammation, fibrosis and progressive nephron loss."
    explanation: Human registry discussion identifies chronic inflammation, fibrosis, and nephron loss in DHA nephropathy.
  downstream:
  - target: Progressive DHA crystal nephropathy and renal dysfunction
    description: Chronic crystal nephropathy causes CKD, AKI episodes, and kidney failure risk.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22934314
      reference_title: "Adenine Phosphoribosyltransferase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "DHA crystal nephropathy) causing acute kidney injury episodes and progressive chronic kidney disease (CKD)."
      explanation: GeneReviews directly links DHA crystal nephropathy to AKI and progressive CKD.
  - target: Proteinuria
    description: Biopsy-proven crystal nephropathy can present with elevated urine protein:creatinine ratio.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27994857
      reference_title: "Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "urine protein:creatinine ratio 55.1 mg/mmol], no formal urine microscopy for crystals was undertaken at any stage and CT KUB was unremarkable. The renal team was aware that he was the brother of the index case. A renal biopsy showed a crystal nephropathy with interstitial nephritis and tubular deposition of crystals"
      explanation: Human case-series evidence links proteinuria-range urine protein:creatinine elevation with biopsy-confirmed DHA crystal nephropathy.
- name: Progressive DHA crystal nephropathy and renal dysfunction
  description: >
    Ongoing crystal nephropathy manifests clinically as recurrent
    nephrolithiasis, acute obstructive kidney injury, chronic kidney disease,
    and kidney failure in a subset of untreated or late-treated individuals.
  biological_processes:
  - preferred_term: glomerular filtration
    term:
      id: GO:0003094
      label: glomerular filtration
    modifier: DECREASED
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "crystal-induced kidney damage (i.e., DHA crystal nephropathy) causing acute kidney injury episodes and progressive chronic kidney disease (CKD)."
    explanation: GeneReviews supports the renal outcome mechanism.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals develop kidney stones and/or progressive chronic kidney disease (CKD) due to DHA crystal nephropathy"
    explanation: Human registry study links DHA nephropathy to stones and progressive CKD.
  downstream:
  - target: Chronic kidney disease
    description: Progressive DHA crystal nephropathy reduces renal function and manifests as CKD.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30443743
      reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary purine metabolism disorder that causes kidney stones and chronic kidney disease (CKD)."
      explanation: Human registry paper directly states that APRT deficiency causes CKD.
  - target: Renal insufficiency
    description: Crystal nephropathy-associated renal dysfunction appears clinically as renal insufficiency.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic kidney disease
    evidence:
    - reference: PMID:27994857
      reference_title: "Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with unexplained renal stone disease or deterioration in kidney function should be considered for screening."
      explanation: Human cross-sectional survey evidence supports kidney-function deterioration as part of the APRT deficiency renal presentation.
  - target: Stage 5 chronic kidney disease
    description: Untreated or inadequately treated DHA crystal nephropathy can progress to ESRD.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Progressive chronic kidney disease
    evidence:
    - reference: PMID:22934314
      reference_title: "Adenine Phosphoribosyltransferase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD)"
      explanation: GeneReviews supports progression to ESRD when treatment is inadequate.
  - target: Oliguria
    description: Advanced renal dysfunction or obstructive AKI can reduce urine output.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100520 | Oliguria | Occasional (29-5%)"
      explanation: Orphanet records oliguria as an occasional renal phenotype in APRT deficiency.
  - target: Hypertension
    description: Chronic kidney disease and renal dysfunction can contribute to hypertension.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000822 | Hypertension | Frequent (79-30%)"
      explanation: Orphanet records hypertension as a frequent phenotype in APRT deficiency, consistent with downstream renal dysfunction.
phenotypes:
- category: Biochemical
  name: Abnormal APRT enzyme activity
  frequency: VERY_FREQUENT
  description: APRT enzyme activity is absent or markedly reduced in affected individuals.
  phenotype_term:
    preferred_term: Abnormal enzyme/coenzyme activity
    term:
      id: HP:0012379
      label: Abnormal circulating enzyme concentration or activity
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent (99-80%)"
    explanation: Orphanet reports abnormal enzyme/coenzyme activity as very frequent.
- category: Renal
  name: Nephrolithiasis
  frequency: FREQUENT
  description: Radiolucent DHA stones are a common presenting manifestation.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000787 | Nephrolithiasis | Frequent (79-30%)"
    explanation: Orphanet records nephrolithiasis as frequent.
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age;"
    explanation: GeneReviews supports kidney stones as a major clinical manifestation.
- category: Renal
  name: Uric acid-like radiolucent nephrolithiasis
  frequency: OCCASIONAL
  description: DHA stones may be misidentified clinically as uric acid stones.
  phenotype_term:
    preferred_term: Uric acid nephrolithiasis
    term:
      id: HP:0000791
      label: Uric acid nephrolithiasis
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000791 | Uric acid nephrolithiasis | Occasional (29-5%)"
    explanation: Orphanet records uric acid nephrolithiasis as occasional.
- category: Renal
  name: Chronic kidney disease
  frequency: FREQUENT
  description: Crystal nephropathy can cause progressive chronic kidney disease.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012622 | Chronic kidney disease | Frequent (79-30%)"
    explanation: Orphanet records chronic kidney disease as frequent.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary purine metabolism disorder that causes kidney stones and chronic kidney disease (CKD)."
    explanation: Human cohort paper supports CKD as a disease manifestation.
- category: Renal
  name: Renal insufficiency
  frequency: FREQUENT
  description: Reduced renal function is frequent in APRT deficiency.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000083 | Renal insufficiency | Frequent (79-30%)"
    explanation: Orphanet records renal insufficiency as frequent.
- category: Renal
  name: Acute kidney injury
  frequency: FREQUENT
  description: Bilateral obstructive DHA calculi and crystal nephropathy can cause AKI episodes.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001919 | Acute kidney injury | Frequent (79-30%)"
    explanation: Orphanet records acute kidney injury as frequent.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six of these patients had experienced kidney stone events and three had developed acute kidney injury (AKI) prior to allopurinol treatment."
    explanation: Registry data document AKI before treatment in pediatric-presenting patients.
- category: Renal
  name: Stage 5 chronic kidney disease
  frequency: OCCASIONAL
  description: A subset of untreated or late-treated individuals develop kidney failure.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003774 | Stage 5 chronic kidney disease | Occasional (29-5%)"
    explanation: Orphanet records stage 5 chronic kidney disease as occasional.
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD)"
    explanation: GeneReviews supports kidney failure risk when treatment is inadequate.
- category: Renal
  name: Proteinuria
  frequency: FREQUENT
  description: Proteinuria is a frequent renal manifestation in Orphanet's structured phenotype table.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000093 | Proteinuria | Frequent (79-30%)"
    explanation: Orphanet records proteinuria as frequent.
- category: Genitourinary
  name: Dysuria
  frequency: FREQUENT
  description: Painful urination can accompany urinary tract stones and irritation.
  phenotype_term:
    preferred_term: Dysuria
    term:
      id: HP:0100518
      label: Dysuria
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100518 | Dysuria | Frequent (79-30%)"
    explanation: Orphanet records dysuria as frequent.
- category: Genitourinary
  name: Recurrent urinary tract infections
  frequency: OCCASIONAL
  description: Recurrent urinary tract infections occur in a subset of affected individuals.
  phenotype_term:
    preferred_term: Recurrent urinary tract infections
    term:
      id: HP:0000010
      label: Recurrent urinary tract infections
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000010 | Recurrent urinary tract infections | Occasional (29-5%)"
    explanation: Orphanet records recurrent urinary tract infections as occasional.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other well-known clinical features in children include reddish-brown diaper stains in young children, acute kidney injury (AKI) due to bilateral obstructive DHA calculi, recurrent urinary tract infections and hematuria"
    explanation: Pediatric APRT registry paper describes recurrent urinary tract infections among clinical features.
- category: Genitourinary
  name: Macroscopic hematuria
  frequency: OCCASIONAL
  description: Gross hematuria can accompany DHA stone disease.
  phenotype_term:
    preferred_term: Macroscopic hematuria
    term:
      id: HP:0012587
      label: Macroscopic hematuria
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012587 | Macroscopic hematuria | Occasional (29-5%)"
    explanation: Orphanet records macroscopic hematuria as occasional.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent urinary tract infections and hematuria"
    explanation: Pediatric registry background supports hematuria as a clinical feature.
- category: Genitourinary
  name: Urinary retention
  frequency: OCCASIONAL
  description: Urinary retention occurs in a subset of affected individuals.
  phenotype_term:
    preferred_term: Urinary retention
    term:
      id: HP:0000016
      label: Urinary retention
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000016 | Urinary retention | Occasional (29-5%)"
    explanation: Orphanet records urinary retention as occasional.
- category: Genitourinary
  name: Urinary hesitancy
  frequency: OCCASIONAL
  description: Urinary hesitancy occurs in a subset of affected individuals.
  phenotype_term:
    preferred_term: Urinary hesitancy
    term:
      id: HP:0000019
      label: Urinary hesitancy
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000019 | Urinary hesitancy | Occasional (29-5%)"
    explanation: Orphanet records urinary hesitancy as occasional.
- category: Renal
  name: Oliguria
  frequency: OCCASIONAL
  description: Oliguria occurs in a subset of affected individuals, especially with obstructive or acute kidney injury.
  phenotype_term:
    preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100520 | Oliguria | Occasional (29-5%)"
    explanation: Orphanet records oliguria as occasional.
- category: Pain
  name: Flank pain
  frequency: OCCASIONAL
  description: Flank pain can occur during stone passage or obstruction.
  phenotype_term:
    preferred_term: Flank pain
    term:
      id: HP:0030157
      label: Flank pain
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030157 | Flank pain | Occasional (29-5%)"
    explanation: Orphanet records flank pain as occasional.
- category: Pain
  name: Abdominal colic
  frequency: OCCASIONAL
  description: Colicky abdominal pain may accompany urinary tract stones.
  phenotype_term:
    preferred_term: Abdominal colic
    term:
      id: HP:0011848
      label: Abdominal colic
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011848 | Abdominal colic | Occasional (29-5%)"
    explanation: Orphanet records abdominal colic as occasional.
- category: Cardiovascular
  name: Hypertension
  frequency: FREQUENT
  description: Hypertension is frequent in Orphanet's phenotype table, plausibly secondary to renal disease.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000822 | Hypertension | Frequent (79-30%)"
    explanation: Orphanet records hypertension as frequent.
- category: Cardiovascular
  name: Atrial fibrillation
  frequency: OCCASIONAL
  description: Atrial fibrillation is listed as an occasional Orphanet phenotype.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005110 | Atrial fibrillation | Occasional (29-5%)"
    explanation: Orphanet records atrial fibrillation as occasional.
histopathology:
- name: Intratubular 2,8-DHA crystals with chronic tubulointerstitial injury
  description: >
    Kidney biopsy can show 2,8-DHA crystal deposits in renal tubules with
    tubular injury, inflammation, fibrosis, and progressive nephron loss.
  diagnostic: true
  evidence:
  - reference: PMID:32086278
    reference_title: "Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury."
    explanation: Patient kidney biopsies support characteristic crystal nephropathy histopathology.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic DHA crystal nephropathy which is characterized by chronic tubulointerstitial inflammation, fibrosis and progressive nephron loss."
    explanation: Human registry paper describes the chronic histopathologic injury pattern.
biochemical:
- name: Reduced APRT enzyme activity
  presence: DECREASED
  context: >
    Absent or markedly reduced APRT activity in red cell lysates is the
    diagnostic biochemical defect.
  readouts:
  - target: APRT molecular function deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Absent red-cell APRT activity directly reports the proximal APRT molecular function deficiency.
    evidence:
    - reference: PMID:22934314
      reference_title: "Adenine Phosphoribosyltransferase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The diagnosis of APRT deficiency is established in a proband by absence of APRT enzyme activity in red cell lysates"
      explanation: GeneReviews identifies absent APRT enzyme activity as the diagnostic biochemical readout.
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of APRT deficiency is established in a proband by absence of APRT enzyme activity in red cell lysates"
    explanation: GeneReviews identifies absent APRT enzyme activity as diagnostic.
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "APRT | adenine phosphoribosyltransferase | hgnc:626 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet supports APRT loss of function as the proximal biochemical defect.
- name: Increased urinary 2,8-dihydroxyadenine
  presence: INCREASED
  context: >
    2,8-DHA is formed and hyperexcreted in urine, where crystalluria and stone
    formation provide diagnostic and treatment-monitoring readouts.
  biomarker_term:
    preferred_term: 2,8-dihydroxyadenine
    term:
      id: CHEBI:183641
      label: 2,8-dihydroxyadenine
  readouts:
  - target: Adenine conversion to 2,8-dihydroxyadenine
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary 2,8-DHA reports the abnormal XOR-mediated adenine conversion caused by APRT loss.
    evidence:
    - reference: PMID:30443743
      reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the absence of APRT activity, adenine is converted by xanthine oxidoreductase (XOR; xanthine dehydrogenase/oxidase) to the poorly soluble 2,8-dihydroxyadenine (DHA) which is excreted in the urine in excessive amounts."
      explanation: Human registry evidence identifies urinary 2,8-DHA excess as a biochemical readout of the abnormal conversion step.
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "formation and hyperexcretion of 2,8-dihydroxyadenine (2,8-DHA) in urine"
    explanation: Orphanet identifies urinary DHA hyperexcretion as the core biochemical abnormality.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the absence of APRT activity, adenine is converted by xanthine oxidoreductase (XOR; xanthine dehydrogenase/oxidase) to the poorly soluble 2,8-dihydroxyadenine (DHA) which is excreted in the urine in excessive amounts."
    explanation: Human registry paper describes urinary excess of DHA downstream of absent APRT activity.
diagnosis:
- name: Urine microscopy for DHA crystals
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >
    Detection of characteristic round brown DHA crystals by urine microscopy is
    highly suggestive and also helps monitor pharmacotherapy.
  markers: DHA crystalluria
  results: Round brown 2,8-DHA crystals in urine.
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The detection of the characteristic round, brown DHA crystals by urine microscopy is highly suggestive of the disorder."
    explanation: GeneReviews supports urine microscopy for characteristic DHA crystals as a diagnostic test.
- name: APRT enzyme activity assay
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >
    APRT enzyme activity measurement in red cell lysates establishes the
    enzymatic diagnosis when absent.
  markers: APRT enzyme activity in red cell lysates
  results: Absent APRT enzyme activity.
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "absence of APRT enzyme activity in red cell lysates"
    explanation: GeneReviews identifies red-cell lysate enzyme activity testing as diagnostic.
  - reference: PMID:22700886
    reference_title: "Adenine phosphoribosyltransferase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "stone analysis, crystalluria, and APRT activity measurement"
    explanation: Review lists APRT activity measurement among available diagnostic tools.
- name: APRT molecular genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >
    Molecular diagnosis is made by identifying biallelic pathogenic APRT
    variants, especially in family screening or when enzymatic testing is not
    immediately available.
  markers: biallelic APRT pathogenic variants
  results: Biallelic pathogenic variants in APRT.
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "identification of biallelic pathogenic variants in APRT."
    explanation: GeneReviews includes biallelic APRT pathogenic variants in diagnostic testing.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis was confirmed by genetic testing (n=20) and/or absent APRT activity (n=4) in all cases."
    explanation: Registry data support genetic testing as a common confirmatory method.
- name: Stone analysis and kidney biopsy for DHA nephropathy
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >
    Stone analysis, crystalluria assessment, and biopsy recognition of DHA
    crystal nephropathy can distinguish APRT deficiency from uric acid stones
    and other crystal nephropathies.
  markers: DHA stone composition; DHA crystal nephropathy
  results: DHA crystals or stones, often radiolucent and easily misidentified.
  evidence:
  - reference: PMID:22700886
    reference_title: "Adenine phosphoribosyltransferase deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnostic tools available-including stone analysis, crystalluria, and APRT activity measurement-make the diagnosis easy to confirm when APRT deficiency is suspected."
    explanation: Review supports stone analysis and crystalluria in diagnostic confirmation.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of APRT deficiency was initially suggested by detection of urinary DHA crystals in 18 patients and by stone analysis in two."
    explanation: Registry data document diagnostic suggestion by crystalluria or stone analysis.
  - reference: PMID:27994857
    reference_title: "Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with unexplained renal stone disease or deterioration in kidney function should be considered for screening."
    explanation: UK survey supports screening in unexplained renal stone disease or kidney-function deterioration.
genetic:
- name: APRT variants
  gene_term:
    preferred_term: APRT
    term:
      id: hgnc:626
      label: APRT
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: ORPHA:976
      reference_title: "Adenine phosphoribosyltransferase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Autosomal recessive"
      explanation: Orphanet reports autosomal recessive inheritance.
  variants:
  - name: Biallelic APRT loss-of-function variants
    description: >
      Pathogenic APRT variants include missense, nonsense, frameshift, deletion,
      start-loss, and splice variants; affected homozygotes or compound
      heterozygotes have absent enzyme activity.
    evidence:
    - reference: PMID:33707627
      reference_title: "Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sixty-two pathogenic APRT variants were identified, including six novel variants."
      explanation: Human genetic study summarizes the known pathogenic variant spectrum.
    - reference: PMID:33707627
      reference_title: "Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Individuals homozygous for disease-causing variants have invariably been shown to have completely abolished enzyme activity"
      explanation: Human genetic study connects causative genotype with enzyme loss.
  features: >
    APRT encodes adenine phosphoribosyltransferase. Biallelic germline
    loss-of-function variants abolish APRT activity, divert adenine to 2,8-DHA,
    and produce the renal stone and crystal nephropathy phenotype.
  evidence:
  - reference: ORPHA:976
    reference_title: "Adenine phosphoribosyltransferase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "APRT | adenine phosphoribosyltransferase | hgnc:626 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists APRT loss-of-function germline variants as disease causing.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is confirmed by absent APRT enzyme activity in red cell lysates and/or the identification of biallelic pathogenic variants in the APRT gene"
    explanation: Human registry paper supports biallelic APRT variants and absent enzyme activity as diagnostic.
treatments:
- name: Xanthine oxidoreductase inhibitor pharmacotherapy
  description: >
    Allopurinol or febuxostat inhibits xanthine oxidoreductase, reducing
    conversion of adenine to 2,8-DHA, lowering urinary DHA burden, and reducing
    stone recurrence and kidney injury risk when taken at adequate dose.
  treatment_term:
    preferred_term: Pharmacotherapy
    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
  target_mechanisms:
  - target: Adenine conversion to 2,8-dihydroxyadenine
    treatment_effect: INHIBITS
    description: XOR inhibition reduces the biochemical conversion of adenine to 2,8-DHA.
    evidence:
    - reference: PMID:33707627
      reference_title: "Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment with the xanthine oxidoreductase inhibitors allopurinol and febuxostat reduces DHA synthesis and excretion"
      explanation: Human genetic study background states the treatment mechanism.
  target_phenotypes:
  - preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment with the xanthine oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase) allopurinol or febuxostat can improve kidney function"
    explanation: GeneReviews supports allopurinol or febuxostat therapy for kidney outcomes.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Timely diagnosis and treatment of APRT deficiency decreases renal complications and preserves kidney function."
    explanation: Registry data support clinical benefit from early treatment.
  - reference: PMID:30443743
    reference_title: "Long-term renal outcomes of APRT deficiency presenting in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Timely pharmacologic therapy appears to reduce stone burden and slow or possibly prevent the progression of CKD"
    explanation: Registry data support reduced stone burden and slower CKD progression.
  - reference: PMID:27994857
    reference_title: "Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment is with a xanthine dehydrogenase inhibitor such as allopurinol"
    explanation: UK survey supports allopurinol as xanthine dehydrogenase inhibitor treatment.
- name: High fluid intake
  description: >
    Ample fluid intake is advised to dilute urinary solutes and support stone
    prevention alongside XOR inhibitor pharmacotherapy.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Urinary 2,8-dihydroxyadenine crystalluria
    treatment_effect: INHIBITS
    description: Higher fluid intake dilutes urinary DHA and complements pharmacologic DHA suppression.
    evidence:
    - reference: PMID:22934314
      reference_title: "Adenine Phosphoribosyltransferase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Ample fluid intake is advised."
      explanation: GeneReviews recommends ample fluid intake as part of management.
  target_phenotypes:
  - preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ample fluid intake is advised."
    explanation: GeneReviews advises high fluid intake in APRT deficiency management.
- name: Kidney replacement therapy for ESRD
  description: >
    Dialysis and kidney transplantation are used for ESRD, but XOR inhibitor
    therapy remains recommended after transplantation to prevent recurrent DHA
    nephropathy in the allograft.
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  target_phenotypes:
  - preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ESRD is treated with dialysis and kidney transplantation."
    explanation: GeneReviews supports dialysis and kidney transplantation for ESRD management.
  - reference: PMID:22934314
    reference_title: "Adenine Phosphoribosyltransferase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Even after kidney transplantation, treatment with an XOR is recommended."
    explanation: GeneReviews supports continuing XOR inhibition after transplant.
references:
- reference: ORPHA:976
  title: Adenine phosphoribosyltransferase deficiency
  found_in:
  - Orphanet structured cache ORPHA:976
  findings:
  - statement: Orphanet provides disease identity, definition, inheritance, gene, prevalence, and phenotype rows.
- reference: PMID:22700886
  title: Adenine phosphoribosyltransferase deficiency.
  found_in:
  - PubMed evidence curation
  findings:
  - statement: Review summarizes DHA formation, urinary precipitation, diagnostic tools, and treatment importance.
- reference: PMID:22934314
  title: Adenine Phosphoribosyltransferase Deficiency.
  tags:
  - GeneReviews
  found_in:
  - PubMed evidence curation
  findings:
  - statement: GeneReviews summarizes clinical characteristics, diagnosis, management, surveillance, and inheritance.
- reference: PMID:27994857
  title: "Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey."
  found_in:
  - Adenine_Phosphoribosyltransferase_Deficiency-deep-research-asta.md
  findings:
  - statement: Asta retrieval surfaced a UK cross-sectional survey supporting late-diagnosis outcomes, screening, and allopurinol treatment.
- reference: PMID:30443743
  title: Long-term renal outcomes of APRT deficiency presenting in childhood.
  found_in:
  - PubMed evidence curation
  findings:
  - statement: Registry cohort supports clinical presentations, diagnostic confirmation, and treatment-associated renal outcomes.
- reference: PMID:32086278
  title: Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.
  found_in:
  - PubMed evidence curation
  findings:
  - statement: Patient biopsy and mouse data support crystal deposition, tubular obstruction, inflammation, fibrosis, and renal injury.
- reference: PMID:33707627
  title: Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency.
  found_in:
  - PubMed evidence curation
  findings:
  - statement: Human population-genetic study supports pathogenic APRT variant spectrum, founder effects, and treatment mechanism.
notes: >-
  This entry integrates ORPHA:976 structured rows with GeneReviews, Clin JASN,
  Pediatric Nephrology, JASN, and European Journal of Human Genetics evidence.
  Falcon deep research was launched but terminated after a quiet wait without
  producing an artifact. Asta completed and was used for bounded literature
  retrieval; it surfaced the UK cross-sectional survey integrated above. The
  remaining curated evidence was selected from cached PubMed and ORPHA sources.
📚

References & Deep Research

References

7
ORPHA:976
Adenine phosphoribosyltransferase deficiency
1 finding
Orphanet provides disease identity, definition, inheritance, gene, prevalence, and phenotype rows.
PMID:22700886
Adenine phosphoribosyltransferase deficiency.
1 finding
Review summarizes DHA formation, urinary precipitation, diagnostic tools, and treatment importance.
PMID:22934314
Adenine Phosphoribosyltransferase Deficiency.
1 finding
GeneReviews summarizes clinical characteristics, diagnosis, management, surveillance, and inheritance.
PMID:27994857
Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey.
1 finding
Asta retrieval surfaced a UK cross-sectional survey supporting late-diagnosis outcomes, screening, and allopurinol treatment.
PMID:30443743
Long-term renal outcomes of APRT deficiency presenting in childhood.
1 finding
Registry cohort supports clinical presentations, diagnostic confirmation, and treatment-associated renal outcomes.
PMID:32086278
Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.
1 finding
Patient biopsy and mouse data support crystal deposition, tubular obstruction, inflammation, fibrosis, and renal injury.
PMID:33707627
Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency.
1 finding
Human population-genetic study supports pathogenic APRT variant spectrum, founder effects, and treatment mechanism.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Adenine Phosphoribosyltransferase Deficiency. Core disease mechanisms, mol...
Asta Scientific Corpus Retrieval 20 citations 2026-05-10T03:03:13.231290

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Adenine Phosphoribosyltransferase Deficiency. Core disease mechanisms, mol...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Yeast Models for the Study of Amyloid-Associated Disorders and Development of Future Therapy

  • Authors: Sigal Rencus-Lazar, Yasmin DeRowe, Hanaa Adsi, E. Gazit, Dana Laor
  • Year: 2019
  • Venue: Frontiers in Molecular Biosciences
  • URL: https://www.semanticscholar.org/paper/8080662b575308ff2b2bcc7704a060c8f04f5af6
  • DOI: 10.3389/fmolb.2019.00015
  • PMID: 30968029
  • PMCID: 6439353
  • Citations: 37
  • Influential citations: 2
  • Summary: Currently available yeast models of diverse amyloid-associated disorders of neurodegenerative disorders are described, as well as their impact on the understanding of disease mechanisms and contribution to future potential drug development.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Inborn error of metabolism (IEM) disorders result from mutations in genes encoding for various metabolic enzymes. Consequently, the corresponding metabolite substrate accumulates, leading to diverse symptoms (Ferreira et al., 2018). However, the molecular mechanisms underlying the development of the specific symptoms of each of these disorders in specific organs are still mostly unknown. Recently, a new paradigm for metabolite accumulation and their putative roles in metabolic disorders was established. Several amino acids and nucleobases, including adenine, have been shown to form archetypical nanofibrils, displaying amyloid-like properties, in vitro (Adler-Abramovich et al., 2012;Shaham-Niv et al., 2015). These amyloid-like structures were suggested to be associated with the pathology that underlies several genetic metabolic disorders, thus postulating IEM conditions to constitute yet another group of amyloid-associated disorders (Gazit, 2016). However, studies exploring the formation of amyloid-like assemblies by various metabolites were so far performed mostly in vitro. Hence, evidence for the role of metabolite assemblies in an in vivo model has been lacking. > Given the high degree of conservation of metabolic pathways across all branches of life, simple models can be established to study the devastating disorders observed upon metabolites accumulation. Thus, aiming to understand the biological relevance and consequences of this metabolite self-assembly, we set out to establish the first in vivo yeast model for studying adenine accumulation. In humans, inborn mutations in genes involved in the adenine salvage pathway can lead to the development of several metabolic disorders. Among these, mutations in adenine phosphoribosyltransferase (APRT) and adenosine deaminase (ADA) lead to APRT and ADA deficiency, respectively. The pathology of these disorders involves the accumulation of adenine and its derivatives, which can be toxic or interfere with the normal function of different organs, such as the kidneys and the urinary tract, as well as lead to developmental delays and to severe combined immunodeficiency.

[2] Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

  • Authors: G. del Favero, A. Bonifacio, T. Rowland, Shanshan Gao, Kunhua Song et al.
  • Year: 2020
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/98c99997015d4b753548454628875ce01936b442
  • DOI: 10.3390/jcm9082457
  • PMID: 32751926
  • PMCID: 7465084
  • Citations: 17
  • Influential citations: 1
  • Summary: Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.409) > Because Danon disease is very rare, with <100 clinical reports and <200 families reported in the literature [12], there is poor availability of material for diagnosis and characterization [13]. Hence, research toward the creation of reliable models, such as animal models [14] or iPSC-CMs, enabling the study of this complex pathology even in a limited manner are essential and constantly evolving. > To determine the molecular and cellular mechanisms by which LAMP-2 deficiency results in metabolic changes, here we combined Raman spectroscopy, transcriptomics, and metabolomics approaches on cardiac tissue and cellular models derived from Danon patients. Analyses were performed on cardiac tissue biopsies from Danon patients, as well as from patient-derived hiPSC-CMs. Even with limited patient cardiac tissue, we were able to identify pathways that were similarly impacted in our cellular models, supportive of these pathways being significantly affected in Danon disease. LAMP-2 deficiency appeared to promote specific metabolic switch in cardiomyocytes, possibly adaptive, given that cardiomyocytes have a high metabolic need. The pathway analyses suggest that LAMP-2 deficiency favors glycolysis to oxidative phosphorylation (OXPHOS) and promotes alternative metabolic pathways, such as with the mobilization of tryptophan. This contributes to preserving high nicotinamide adenine dinucleotide (NAD + ) levels despite mitochondrial aging. Similarly, fibroblasts respond to LAMP-2 deficiency with a stress-associated phenotype pointing toward fibrosis progression. This was accompanied by impairment of biomechanical properties, which retraces the clinical phenotype of Danon disease.

[3] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 4
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.408) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[4] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

  • Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
  • Year: 2024
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
  • DOI: 10.3390/metabo14100515
  • PMID: 39452896
  • PMCID: 11509386
  • Citations: 2
  • Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
  • Evidence snippets:
  • Snippet 1 (score: 0.403) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[5] Uncovering Proteomic and Biochemical Alterations in Plasma from Lesch–Nyhan Disease Patients

  • Authors: Sundas Javed, D. Braconi, Haidara Nadwa, A. Paffetti, G. Jacomelli et al.
  • Year: 2025
  • Venue: Cellular and Molecular Neurobiology
  • URL: https://www.semanticscholar.org/paper/9a62a3d01ad7438fe1e7bf6587725c4c9a576bfa
  • DOI: 10.1007/s10571-025-01644-z
  • PMID: 41398526
  • PMCID: 12804513
  • Summary: It is suggested that plasma proteomics might be a potential tool in LND for monitoring disease progression and therapeutic response, potentially paving the way for targeted treatment strategies that extend beyond the purine salvage pathway to address the currently unmet clinical needs of LND patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.401) > Lesch–Nyhan disease (LND) is an ultra-rare X-linked inborn error of metabolism caused by complete or partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), a key enzyme in the purine salvage pathway. This defect leads to uric acid overproduction and a broad spectrum of neurological and behavioral manifestations, whose severity depends on the degree of residual enzymatic activity. Although emerging evidence implicates HPRT deficiency in widespread cellular dysfunctions, particularly within midbrain dopaminergic neurons, the molecular mechanisms underlying the neurobehavioral phenotype of HPRT deficiency remain poorly understood and are not adequately explained by purine metabolism dysfunctions alone. Although proteomics represents a powerful approach for elucidating molecular alterations underlying disease, it has so far found only limited application in LND research. To address this gap, we provide here the first proteomic study combined with clinical biochemistry data and pro-inflammatory cytokines profiling of plasma samples from 29 HPRT deficient individuals (21 with classic LND and 8 with Lesch–Nyhan variants – LNV). We suggest that plasma proteomics might be a potential tool in LND for monitoring disease progression and therapeutic response, potentially paving the way for targeted treatment strategies that extend beyond the purine salvage pathway to address the currently unmet clinical needs of LND patients.

[6] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 38
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[7] Inborn Errors of Purine Salvage and Catabolism

  • Authors: M. Camici, M. Garcia-Gil, S. Allegrini, R. Pesi, G. Bernardini et al.
  • Year: 2023
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/d148bf0d5fd4f6a8eca5ba4751391963e98d9f69
  • DOI: 10.3390/metabo13070787
  • PMID: 37512494
  • PMCID: 10383617
  • Citations: 20
  • Summary: Diagnostic tools are suggested that may indicate to clinicians that the inborn errors of purine metabolism may not be very rare diseases after all and are offered new points of view on this topic.
  • Evidence snippets:
  • Snippet 1 (score: 0.396) > Mutations may affect different aspects of the enzyme functions, such as the kinetic parameters, or the binding of other regulating proteins or small molecules, leading to a panel of alterations in enzymatic activity and therefore to different symptoms. A complete lack of an enzyme activity may compromise vital functions resulting in life threatening diseases. Partial enzyme dysfunction may result in symptoms easily misdiagnosed as one of the many infantile syndromes characterized by neuropsychiatric, neuromotor, and neurosensorial impairments. In this regard, using metabolomic and transcriptomic approaches, dysfunctions of purine metabolism, other than the well-known ADSL deficiency, have been reported in autism spectrum disorders [304,305], such as a significant increase in ADA activity, with a reduction in UA [304], and an increase in hypoxanthine, inosine, and xanthosine [305]. Another reason for misdiagnosis is the occurrence of compensatory mechanisms, which may differ among individuals and may attenuate the effects of the purine inborn error, giving rise to various phenotypes that do not completely correlate with the genotype. > Over the years, several cell models have been developed and employed to explore the metabolic features and investigate the molecular mechanisms underpinning these rare diseases. Most studies have been initially conducted using easily available cells, such as erythrocytes and cultured fibroblasts, isolated from patients for diagnostic purposes. Other cellular models were also studied, but they quickly revealed their limitations: failing to recapitulate the different enzymatic expression or activity in different tissues or cell types, in different stages of development, or lacking several relevant pathways (e.g., protein synthesis machinery in erythrocytes). Furthermore, most of the pathologies of still unknown etiology, associated with purine inborn errors, concern the nervous system. The pathophysiology of neurological defects cannot be studied directly in the patients, because of the ethical implications of obtaining samples of brain tissue. Therefore, animal models were developed as an alternative approach, which, unfortunately, often did not completely reflect the human phenotype and failed to address many of the unresolved neurological features.

[8] Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in Drosophila

  • Authors: Céline Petitgas, Laurent Seugnet, Amina Dulac, Giorgio Matassi, Ali Mteyrek et al.
  • Year: 2023
  • Venue: eLife
  • URL: https://www.semanticscholar.org/paper/834a539d0f9c7ef8b4762a6c4f31c14c3e610898
  • DOI: 10.1101/2023.06.23.546306
  • PMID: 38700995
  • PMCID: 11068357
  • Citations: 2
  • Summary: Drosophila could be used in different ways to better understand Lesch-Nyhan disease and seek a cure for this dramatic disease, as well as suggest that the fruit fly could be a suitable animal model for this cure.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > The purine salvage pathway is an essential component of cellular metabolism that allows the recovery of free purine bases derived from the diet or from the degradation of nucleic acids and nucleotides, thus avoiding the energy cost of de novo purine biosynthesis (Nyhan, 2014). Energy-intensive tissues, such as cardiac muscle and brain cells, extensively use this pathway to maintain their purine levels (Ipata, 2011;Johnson et al., 2019). The two main recycling enzymes involved in the salvage pathway in mammals are hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which converts hypoxanthine and guanine into IMP and GMP, respectively, and adenine phosphoribosyltransferase (APRT), which converts adenine into AMP. > APRT and HGPRT deficiencies induce very different disorders in humans. Loss of APRT seems to have only metabolic consequences, leading to the formation of 2,8-dihydroxyadenine crystals in kidney, which can be fatal but is readily prevented by allopurinol treatment (Bollée et al., 2012;Harambat et al., 2012). In contrast, highly inactivating mutations in HGPRT trigger Lesch-Nyhan disease (LND), a rare neurometabolic X-linked recessive disorder with dramatic consequences for child neurodevelopment (Lesch and Nyhan, 1964;Seegmiller et al., 1967). The metabolic consequence of HGPRT deficiency is an overproduction of uric acid in the blood (hyperuricemia) that can lead to gout and tophi, or nephrolithiasis (Sass et al., 1965;Kelley et al., 1967). Affected children also develop severe neurological impairments, such as dystonia, choreoathetosis, spasticity, and a dramatic compulsive self-injurious behavior (Nyhan, 1997;Jinnah et al., 2006;Torres et al., 2007a;Schretlen et al., 2005;Madeo et al., 2019).

[9] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

  • Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
  • Year: 2025
  • Venue: Pathophysiology
  • URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
  • DOI: 10.3390/pathophysiology32010009
  • PMID: 39982365
  • PMCID: 12077258
  • Citations: 30
  • Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[10] The Housekeeping Gene Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) Regulates Multiple Developmental and Metabolic Pathways of Murine Embryonic Stem Cell Neuronal Differentiation

  • Authors: T. Kang, Yongjin P. Park, J. Bader, T. Friedmann
  • Year: 2013
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/54edcbc1319338d7301bde981da800eba378740d
  • DOI: 10.1371/journal.pone.0074967
  • PMID: 24130677
  • PMCID: 3794013
  • Citations: 49
  • Influential citations: 3
  • Summary: Results of gene expression studies during neuronal differentiation of HPRT-deficient murine ESD3 embryonic stem cells are described and it is predicted that some of these systems defects play similar neuropathogenic roles in diverse neurodevelopmental and neurodegenerative diseases in common and may provide new experimental opportunities for clarifying pathogenesis.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > Lesch-Nyhan Disease (LND) is a monogenic neurodevelopmental disease caused by mutations in the X-linked gene encoding the purine salvage biosynthetic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) [1]. The clinical disorder is characterized by dystonia, choreoathetosis, cognitive deficits and self-injurious behavior, the hallmark feature of LND. The most prominent and well-recognized neurophysiological consequence of HPRT deficiency in the human central nervous system is dysfunction of basal ganglia dopaminergic (DA) neurons and defective development of DA signaling pathways [2][3][4][5] that in turn are thought at least partially to cause the aberrant neurological phenotype. The mechanisms connecting the defective purine pathways with neurological defects are not well understood, although most current models of LND pathogenesis assume that aberrant purine metabolism is the proximate cause of the neurological dysfunction through a direct effect of aberrant purine levels on early neural development or on neural function. > Recent studies in our laboratories have identified molecular neural dysregulatory mechanisms associated with HPRT deficiency that are likely to underlie defective neural development and aberrant function of dopaminergic and possibly other classes of neural cells. These findings point to a complex set of dysregulated functions and pathways that constitute a multi-systems set of pathogenic mechanisms responsible for this monogenic disease. Most relevant have been demonstrations of aberrant expression of key neuronal transcription factors, microRNA expression and defects in purinergic and other cellular signaling functions in a variety of mouse and human cell culture systems including human iPS cells. These defects have included aberrant canonical Wnt/bcatenin signaling and defective presenilin-1 expression [6], dysregulated expression of purinergic receptors with resulting aberrant expression of phospho-CREB and phospho-ERK signal-ing [7] and aberrant expression of microRNA expression [8].

[11] Rescuing compounds for Lesch-Nyhan disease identified using stem cell-based phenotypic screening.

  • Authors: Valentin Ruillier, Johana Tournois, Claire Boissart, Marie Lasbareilles, Gurvan Mahé et al.
  • Year: 2020
  • Venue: JCI insight
  • URL: https://www.semanticscholar.org/paper/406026bae064ce7f3e3e9df828b6bc7a2cc4890f
  • DOI: 10.1172/jci.insight.132094
  • PMID: 31990683
  • Citations: 21
  • Influential citations: 1
  • Summary: 6 pharmacological compounds are identified that corrected HGPRT deficiency-associated neuronal phenotypes by promoting metabolism compensations in an HG PRT-independent manner and can be provided to LND patients via simple food supplementation.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > In addition to these purely metabolic actions, purines activate a plethora of cell signalling pathways via membrane receptors that can act additively, synergistically, or antagonistically (2). Related to this mechanistic complexity, the precise measurement of purine intermediate concentrations requires complex techniques, such as HPLC, that are not Lesch-Nyhan disease (LND) is a rare monogenic disease caused by deficiency of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). LND is characterized by severe neuropsychiatric symptoms that currently cannot be treated. Predictive in vivo models are lacking for screening and evaluating candidate drugs because LND-associated neurological symptoms are not recapitulated in HGPRT-deficient animals. Here, we used human neural stem cells and neurons derived from induced pluripotent stem cells (iPSCs) of children affected with LND to identify neural phenotypes of interest associated with HGPRT deficiency to develop a targetagnostic-based drug screening system. We screened more than 3000 molecules and identified 6 pharmacological compounds, all possessing an adenosine moiety, that corrected HGPRT deficiencyassociated neuronal phenotypes by promoting metabolism compensations in an HGPRTindependent manner. This included S-adenosylmethionine, a compound that had already been used as a compassionate approach to ease the neuropsychiatric symptoms in LND. Interestingly, these compounds compensate abnormal metabolism in a manner complementary to the gold standard allopurinol and can be provided to patients with LND via simple food supplementation. This experimental paradigm can be easily adapted to other metabolic disorders affecting normal brain development and functioning in the absence of a relevant animal model. insight.jci.org https://doi.org/10.1172/jci.insight.132094

[12] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

  • Authors: Tian-Guang Zhang, Chaoyu Miao
  • Year: 2022
  • Venue: Acta Pharmaceutica Sinica. B
  • URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
  • DOI: 10.1016/j.apsb.2022.10.008
  • PMID: 36970208
  • PMCID: 10031255
  • Citations: 85
  • Influential citations: 1
  • Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[13] Oxidative Stress in Healthy and Pathological Red Blood Cells

  • Authors: Florencia Orrico, Sandrine Laurance, Ana C. Lopez, S. Lefevre, L. Thomson et al.
  • Year: 2023
  • Venue: Biomolecules
  • URL: https://www.semanticscholar.org/paper/5ea67232d5288f7e47b3304da16c315738a09419
  • DOI: 10.3390/biom13081262
  • PMID: 37627327
  • PMCID: 10452114
  • Citations: 124
  • Influential citations: 3
  • Summary: The most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and the role of oxidative stress in different red cell diseases are discussed, highlighting the underlying mechanisms leading to pathological RBC phenotypes are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.380) > Red cell diseases encompass a group of inherited or acquired erythrocyte disorders that affect the structure, function, or production of red blood cells (RBCs). These disorders can lead to various clinical manifestations, including anemia, hemolysis, inflammation, and impaired oxygen-carrying capacity. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms, plays a significant role in the pathophysiology of red cell diseases. In this review, we discuss the most relevant oxidant species involved in RBC damage, the enzymatic and low molecular weight antioxidant systems that protect RBCs against oxidative injury, and finally, the role of oxidative stress in different red cell diseases, including sickle cell disease, glucose 6-phosphate dehydrogenase deficiency, and pyruvate kinase deficiency, highlighting the underlying mechanisms leading to pathological RBC phenotypes.

[14] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.379) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[15] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

  • Authors: R. Ragusa, P. Bufano, A. Tognetti, M. Laurino, Chiara Caselli
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
  • DOI: 10.3390/ijms26062571
  • PMID: 40141213
  • PMCID: 11942187
  • Citations: 6
  • Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[16] Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey

  • Authors: G. Balasubramaniam, Monica Arenas-Hernandez, E. Escuredo, L. Fairbanks, T. Marinaki et al.
  • Year: 2016
  • Venue: Clinical Kidney Journal
  • URL: https://www.semanticscholar.org/paper/f23d722e643960918e52e56484c1ecfc4544a46d
  • DOI: 10.1093/ckj/sfw093
  • PMID: 27994857
  • PMCID: 5162415
  • Citations: 4
  • Summary: An inborn error of metabolism that can cause kidney disease from crystalline nephropathy or kidney stones presents in a wide spectrum in all age groups and patients can be completely asymptomatic and kidney disease may be incorrectly attributed to other conditions.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey

[17] mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node

  • Authors: Laura Mantoan Ritter, N. M. P. Annear, E. Baple, Leila Y. Ben-Chaabane, Istvan Bodi et al.
  • Year: 2025
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/f30b2504a3b3bbb7264847da72e690aebd2919d7
  • DOI: 10.1186/s13023-025-03740-1
  • PMID: 40426219
  • PMCID: 12107773
  • Citations: 6
  • Summary: How mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients is expound.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

[18] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.375) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[19] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 10
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[20] Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes

  • Authors: Carly S. Pontifex, Mashiat Zaman, R. Fanganiello, T. Shutt, G. Pfeffer
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/a0717d977acc61d9c08343d1ac6aed94c33f2138
  • DOI: 10.3390/ijms25115633
  • PMID: 38891822
  • PMCID: 11172259
  • Citations: 15
  • Summary: In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mito...
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Although the major roles of VCP in protein quality control are presumed to be the major mechanisms implicated in MSP, the incredible functional diversity and pleiotropic effects of VCP also imply that other mechanisms may be relevant and require further study.VCP cooperates with the 26S proteasome, the main pathway for protein degradation, to manage the protein quality control system.In the nucleus, VCP regulates cell cycle control and the DNA damage response by coordinating proteins at DNA damage sites.In the cytosol, VCP regulates responses to cellular stress by forming and clearing stress granules, facilitating ERAD, autophagy, mitophagy and lysophagy, and VCP may also be involved in apoptosis.The complexity of VCP's diverse molecular functions is also mirrored by the variability in clinical dysfunction caused by pathogenic variants in VCP.The relationship between specific molecular functions of VCP and the spectrum of clinical presentations remains poorly understood, and, in general, genotype-phenotype correlation is still difficult to demonstrate.Certainly, VCP plays many yet-to-be-identified roles in different cellular systems.Given that the role of VCP extends to so many cellular systems, it makes it difficult to ascertain which dysfunction leads to which clinical phenotype.The majority of MSP cases are related to variants at positions 155 and 159, but the phenotypic variability is extensive, suggesting that other genetic or epigenetic factors and/or environmental factors may interact.To better narrow down a causative mechanism in a given tissue, we advise that, when possible, experiments should include one or two other MSP genes such as SQSTM1 or HNRNPA2B1, as this may help identify common mechanisms of dysfunction in MSP.Studies of large cohorts of patients who have common variants in VCP may allow for the identification of genetic modifiers or other factors that contribute to phenotypic variability.Even though pathogenic variants in VCP typically lead to multisystem disease, in general, the affected systems predictably include certain tissue types (primarily skeletal muscle, the cerebrum, motor neurons and osteoclasts).Even though VCP is ubiquitously expressed and participates in numerous crucial cellular functions, pan-systemic disease is not observed.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.