Cystinuria

Mendelian MONDO:0009067 Pathograph 28 inherited renal tubular disease inborn disorder of amino acid transport monogenic kidney stone disease

Cystinuria is an inherited renal tubular amino acid transport disorder caused by pathogenic variants in SLC3A1 or SLC7A9, the two subunits of the proximal tubular and intestinal b(0,+) cystine/dibasic amino acid transporter. Defective reabsorption causes high urinary cystine and dibasic amino acids; cystine is poorly soluble at physiologic urine pH and precipitates into recurrent cystine kidney stones, with risks of obstruction, recurrent procedures, chronic kidney disease, and hypertension.

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1
Mappings
1
Definitions
1
Inheritance
6
Pathophys.
15
Phenotypes
28
Pathograph
2
Genes
5
Treatments
2
Subtypes
2
Trials
15
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0009067 cystinuria
skos:exactMatch Orphanet ORPHA:214
Orphanet ORPHA:214 lists MONDO:0009067 as an exact cross-reference for cystinuria.
📘

Definitions

1
Orphanet cystinuria definition
A rare renal tubular amino acid transport disorder characterized by recurrent cystine kidney stone formation.
OTHER
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"A rare disorder of renal tubular amino acid transport characterized by recurrent formation of kidney cystine stones."
Orphanet defines cystinuria by the renal amino acid transport defect and recurrent cystine stone formation.
👪

Inheritance

1
Autosomal recessive and semi-dominant inheritance HP:0000007
Cystinuria is usually autosomal recessive, with incompletely dominant or semi-dominant expression recognized particularly for some SLC7A9 heterozygotes.
Autosomal recessive inheritance
Show evidence (3 references)
ORPHA:214 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance.
ORPHA:214 SUPPORT Other
"Semi-dominant"
Orphanet also records semi-dominant inheritance.
PMID:32066273 SUPPORT Human Clinical
"Cystinuria is a genetic disorder with both autosomal recessive and incompletely dominant inheritance."
Consensus statement confirms recessive and incompletely dominant inheritance patterns.
◆

Subtypes

2
Cystinuria type A MONDO:0019745
Etiological subtype caused by SLC3A1 variants affecting the rBAT heavy subunit of the cystine/dibasic amino acid transporter.
Show evidence (2 references)
ORPHA:93612 SUPPORT Other
"MONDO:0019745 | Exact"
Orphanet maps cystinuria type A to MONDO:0019745.
ORPHA:93612 SUPPORT Other
"SLC3A1 | solute carrier family 3 member 1 | hgnc:11025 | Disease-causing germline mutation(s) in"
Orphanet lists SLC3A1 as the disease-causing gene for cystinuria type A.
Cystinuria type B MONDO:0019746
Etiological subtype caused by SLC7A9 variants affecting the b(0,+)AT light subunit of the cystine/dibasic amino acid transporter.
Show evidence (2 references)
ORPHA:93613 SUPPORT Other
"MONDO:0019746 | Exact"
Orphanet maps cystinuria type B to MONDO:0019746.
ORPHA:93613 SUPPORT Other
"SLC7A9 | solute carrier family 7 member 9 | hgnc:11067 | Disease-causing germline mutation(s) in"
Orphanet lists SLC7A9 as the disease-causing gene for cystinuria type B.
⚙

Pathophysiology

6
Proximal Tubule Cystine Transport Defect
SLC3A1 or SLC7A9 dysfunction impairs b(0,+)-mediated proximal tubular reabsorption of filtered cystine and dibasic amino acids.
Epithelial cell of proximal tubule link
SLC3A1 link SLC7A9 link
L-cystine transport link ↓ DECREASED amino acid transmembrane transport link ↓ DECREASED
amino acid transmembrane transporter activity link ↓ DECREASED
Downstream
Urinary Cystine Supersaturation Failed proximal tubular cystine reabsorption raises urinary cystine to the poorly soluble range that drives cystine nephrolithiasis.
Cystinuria Defective proximal tubular reabsorption of filtered cystine produces the biochemical cystinuria phenotype.
Abnormal amino acid metabolism The same transporter defect disrupts renal handling of cystine and dibasic amino acids.
Stone-Risk Chemistry Modifiers Additional urinary and systemic stone-risk chemistry abnormalities are reported in cystinuria, but the cached evidence does not establish whether they are direct consequences of the cystine transporter defect or co-occurring modifiers.
Show evidence (2 references)
PMID:20517292 SUPPORT Other
"causes a failure in the reabsorption of filtered cystine and dibasic amino acids in the proximal tubule"
Review links cystinuria-causing transporter defects to impaired proximal tubular cystine and dibasic amino acid reabsorption.
PMID:30515543 SUPPORT Other
"The COLA transporter (b0,+) is a heterodimer consisting of the rBAT (encoded by SLC3A1, located on chromosome 2p16.3) and b0,+AT (encoded by SLC7A9, located on chromosome 19q13.1) subunits joined by a disulfide bridge."
Review describes the two-subunit transporter whose dysfunction causes the proximal tubule defect.
Urinary Cystine Supersaturation
High urinary cystine concentration exceeds cystine solubility, especially when urine volume is low or pH is not sufficiently alkaline, producing cystine crystalluria.
Downstream
Cystine Crystal Growth and Aggregation Poor cystine solubility permits crystallization in urine, initiating crystal nucleation and growth.
Cystine crystalluria Supersaturated urinary cystine crystallizes, producing cystine crystalluria.
Echogenic fetal colon Prenatal echogenic colon is an occasional cystinuria-associated finding; the cached evidence does not resolve the intermediate mechanism.
Show evidence (2 references)
PMID:36900678 SUPPORT Human Clinical
"increased urine levels of the poorly soluble amino acid result in recurrent cystine nephrolithiasis"
Guideline review summarizes the solubility-based mechanism connecting excess urinary cystine to recurrent stones.
PMID:30515543 SUPPORT Other
"Of the four amino acids, cystine is the least soluble and it can crystallize in the urinary tract, leading to cystine stone formation."
Review explains why urinary cystine, rather than the other dibasic amino acids, drives stone formation.
Stone-Risk Chemistry Modifiers
Co-occurring urinary stone-risk chemistries in cystinuria include low urinary citrate and elevated urinary calcium or uric acid, which may modify stone propensity alongside cystine supersaturation.
Downstream
Hypocitraturia Low urinary citrate is represented as a stone-risk chemistry modifier.
Hypercalciuria Elevated urinary calcium is represented as an occasional stone-risk chemistry modifier.
Hyperuricosuria Elevated urinary uric acid is represented as an occasional stone-risk chemistry modifier.
Hyperuricemia Elevated blood uric acid is represented as a reported systemic stone-risk chemistry feature of cystinuria.
Show evidence (3 references)
ORPHA:214 SUPPORT Other
"HP:0012405 | Hypocitraturia | Frequent (79-30%)"
Orphanet records hypocitraturia as a frequent cystinuria finding.
ORPHA:214 SUPPORT Other
"HP:0002150 | Hypercalciuria | Occasional (29-5%)"
Orphanet records hypercalciuria as an occasional cystinuria finding.
ORPHA:214 SUPPORT Other
"HP:0003149 | Hyperuricosuria | Occasional (29-5%)"
Orphanet records hyperuricosuria as an occasional cystinuria finding.
Cystine Crystal Growth and Aggregation
Cystine crystals nucleate, grow, and aggregate in urine, converting supersaturation and crystalluria into clinically significant stones.
Downstream
Recurrent Cystine Nephrolithiasis Crystal growth and aggregation convert cystine crystallization into clinically significant recurrent stones.
Show evidence (1 reference)
PMID:30515543 SUPPORT Other
"In addition to crystal nucleation and growth, crystal aggregation is required for stone formation"
Review identifies crystal aggregation as a required step beyond nucleation and growth.
Recurrent Cystine Nephrolithiasis
Cystine stones form repeatedly in the kidney and urinary tract, causing renal colic, hematuria, obstruction, and recurrent intervention.
Downstream
Chronic Kidney Injury from Recurrent Stones Recurrent stones damage the kidney through recurrent renal injury, obstructive uropathy, and repeated urologic intervention.
Nephrolithiasis Recurrent cystine stone formation manifests clinically as nephrolithiasis.
Hematuria Hematuria is reported as a very frequent phenotype in cystinuria stone disease, but the cached evidence does not specify the local injury mechanism.
Flank pain Flank pain is reported as a frequent phenotype in cystinuria stone disease, but the cached evidence does not specify the intermediate pain pathway.
Nausea and vomiting Nausea and vomiting are reported in cystinuria stone disease, but the cached evidence does not specify the intermediate pathway.
Abnormal urinary odor Abnormal urinary odor is reported in cystinuria, but the cached evidence does not define its intermediate mechanism.
Show evidence (1 reference)
PMID:20517292 SUPPORT Other
"The clinical symptoms of this disease are caused by the loss of poorly soluble cystine, which precipitates to form stones."
Review directly connects cystine precipitation to clinical stone disease.
Chronic Kidney Injury from Recurrent Stones
Recurrent stones, obstruction, and repeated urologic procedures can damage kidney tissue over time, contributing to chronic kidney disease and hypertension.
Epithelial cell of proximal tubule link
Downstream
Renal insufficiency Chronic kidney disease and cumulative renal injury reduce renal function, captured clinically as renal insufficiency.
Hypertension Chronic kidney disease and cumulative renal injury can contribute to high blood pressure in cystinuria cohorts.
Show evidence (1 reference)
PMID:30515543 SUPPORT Human Clinical
"CKD in patients with cystinuria may result from recurrent stones, repeated urologic interventions, or obstructive uropathy"
Review summarizes mechanisms of cumulative renal injury in cystinuria.
⬡

Pathograph

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

15
Cardiovascular 1
Hypertension FREQUENT Hypertension (HP:0000822)
Show evidence (2 references)
ORPHA:214 SUPPORT Other
"HP:0000822 | Hypertension | Frequent (79-30%)"
Orphanet classifies hypertension as frequent.
PMID:30515543 SUPPORT Human Clinical
"Hypertension was also common in this study, with 28.6% of patients having high blood pressure"
Review reports hypertension frequency in a retrospective cystinuria cohort.
Digestive 1
Nausea and vomiting FREQUENT Nausea and vomiting (HP:0002017)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0002017 | Nausea and vomiting | Frequent (79-30%)"
Orphanet classifies nausea and vomiting as frequent.
Genitourinary 4
Nephrolithiasis VERY_FREQUENT Nephrolithiasis (HP:0000787)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0000787 | Nephrolithiasis | Very frequent (99-80%)"
Orphanet classifies nephrolithiasis as very frequent.
Hematuria VERY_FREQUENT Hematuria (HP:0000790)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0000790 | Hematuria | Very frequent (99-80%)"
Orphanet classifies hematuria as very frequent.
Renal insufficiency FREQUENT Renal insufficiency (HP:0000083)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0000083 | Renal insufficiency | Frequent (79-30%)"
Orphanet classifies renal insufficiency as frequent.
Abnormal urinary odor FREQUENT Abnormal urinary odor (HP:0012088)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0012088 | Abnormal urinary odor | Frequent (79-30%)"
Orphanet classifies abnormal urinary odor as frequent.
Metabolism 1
Hyperuricemia FREQUENT Hyperuricemia (HP:0002149)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0002149 | Hyperuricemia | Frequent (79-30%)"
Orphanet classifies hyperuricemia as frequent.
Constitutional 1
Flank pain FREQUENT Flank pain (HP:0030157)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0030157 | Flank pain | Frequent (79-30%)"
Orphanet classifies flank pain as frequent.
Other 7
Cystinuria VERY_FREQUENT Cystinuria (HP:0003131)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0003131 | Cystinuria | Very frequent (99-80%)"
Orphanet classifies cystinuria as very frequent.
Abnormal amino acid metabolism VERY_FREQUENT Abnormality of amino acid metabolism (HP:0004337)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0004337 | Abnormality of amino acid metabolism | Very frequent (99-80%)"
Orphanet classifies abnormal amino acid metabolism as very frequent.
Cystine crystalluria FREQUENT Cystine crystalluria (HP:0033067)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0033067 | Cystine crystalluria | Frequent (79-30%)"
Orphanet classifies cystine crystalluria as frequent.
Hypocitraturia FREQUENT Hypocitraturia (HP:0012405)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0012405 | Hypocitraturia | Frequent (79-30%)"
Orphanet classifies hypocitraturia as frequent.
Hypercalciuria OCCASIONAL Hypercalciuria (HP:0002150)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0002150 | Hypercalciuria | Occasional (29-5%)"
Orphanet classifies hypercalciuria as occasional.
Hyperuricosuria OCCASIONAL Hyperuricosuria (HP:0003149)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:0003149 | Hyperuricosuria | Occasional (29-5%)"
Orphanet classifies hyperuricosuria as occasional.
Echogenic fetal colon OCCASIONAL Echogenic fetal colon (HP:6000916)
Show evidence (1 reference)
ORPHA:214 SUPPORT Other
"HP:6000916 | Echogenic fetal colon | Occasional (29-5%)"
Orphanet classifies echogenic fetal colon as occasional.
🧬

Genetic Associations

2
SLC3A1 (Causal loss-of-function variant)
Show evidence (4 references)
ORPHA:93612 SUPPORT Other
"SLC3A1 | solute carrier family 3 member 1 | hgnc:11025 | Disease-causing germline mutation(s) in"
Orphanet lists SLC3A1 as the disease-causing gene for cystinuria type A.
PMID:22480232 SUPPORT Other
"SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b(0,+) transporter"
Review identifies SLC3A1 as the rBAT heavy-subunit gene.
PMID:18752446 SUPPORT Human Clinical
"Twenty-four out of 62 are novel mutations, 9 in SLC3A1 and 15 in SLC7A9."
Patient cohort expands the SLC3A1 and SLC7A9 mutation spectrum.
+ 1 more reference
SLC7A9 (Causal loss-of-function variant)
Show evidence (4 references)
ORPHA:93613 SUPPORT Other
"SLC7A9 | solute carrier family 7 member 9 | hgnc:11067 | Disease-causing germline mutation(s) in"
Orphanet lists SLC7A9 as the disease-causing gene for cystinuria type B.
PMID:22480232 SUPPORT Other
"SLC7A9 (chromosome 19q12) encodes its interacting light subunit b(0,+)AT"
Review identifies SLC7A9 as the b(0,+)AT light-subunit gene.
PMID:24045899 SUPPORT Human Clinical
"Genetic analysis of both cystinuria genes may be necessary due to the synergistic effects of mutations in two genes."
Family study supports genetic heterogeneity and need to evaluate both cystinuria genes.
+ 1 more reference
💊

Treatments

5
High fluid intake and dietary sodium/protein moderation
Action: dietary intervention MAXO:0000088
High urine volume plus sodium and animal-protein moderation are first-line conservative measures to reduce cystine concentration and stone recurrence.
Mechanism Target:
INHIBITS Urinary Cystine Supersaturation — Increased urine volume lowers cystine concentration relative to its solubility threshold.
Show evidence (1 reference)
PMID:30515543 SUPPORT Other
"Medical treatment for cystinuria involves increasing cystine solubility by increasing urine volume and pH."
The review explains the fluid-volume component of conservative therapy as increasing urinary cystine solubility.
Show evidence (1 reference)
PMID:32066273 SUPPORT Human Clinical
"conservative measures: fluid intake and dietary modification"
Consensus statement places fluid intake and dietary modification at the start of stepwise therapy.
Urinary alkalinization with potassium citrate
Action: Pharmacotherapy NCIT:C15986
Agent: potassium citrate ↗
Alkali therapy, commonly potassium citrate, raises urine pH to improve cystine solubility when conservative measures are insufficient.
Mechanism Target:
INHIBITS Urinary Cystine Supersaturation — Alkalinization increases cystine solubility and lowers supersaturation.
Show evidence (1 reference)
PMID:30515543 SUPPORT Other
"Cystine solubility increases with pH but only at values greater than 7.0"
Increased cystine solubility at alkaline pH supports the mechanism targeted by potassium citrate.
Show evidence (2 references)
PMID:32066273 SUPPORT Human Clinical
"first alkalinizing the urine and then using cystine-binding thiol drugs"
Consensus statement supports urinary alkalinization before cystine-binding thiol therapy.
PMID:30515543 SUPPORT Other
"Cystine solubility increases with pH but only at values greater than 7.0"
Review explains the solubility rationale for alkalinization.
Cystine-binding thiol drugs
Action: Pharmacotherapy NCIT:C15986
Agent: tiopronin ↗ D-penicillamine ↗
Tiopronin or D-penicillamine can form more soluble mixed disulfides and are used for severe or recurrent stone disease not controlled by conservative measures and alkalinization.
Mechanism Target:
INHIBITS Urinary Cystine Supersaturation — Thiol drugs convert cystine into more soluble mixed disulfides.
Show evidence (1 reference)
PMID:30515543 SUPPORT Other
"These sulfhydryl drugs convert cystine to the more soluble mixed disulfides of cysteine-penicillamine or cysteine-tiopronin, respectively."
Formation of more soluble mixed disulfides explains how thiol drugs lower the supersaturation mechanism.
Show evidence (2 references)
PMID:32066273 SUPPORT Human Clinical
"using cystine-binding thiol drugs"
Consensus statement supports cystine-binding thiol drugs after fluid, diet, and alkalinization when stone formation recurs.
PMID:30515543 SUPPORT Other
"These sulfhydryl drugs convert cystine to the more soluble mixed disulfides of cysteine-penicillamine or cysteine-tiopronin, respectively."
Review explains the biochemical mechanism of D-penicillamine and tiopronin.
Calculi removal for symptomatic or large cystine stones
Action: calculi removal MAXO:0000890
Endoscopic or surgical stone removal, including ureteroscopic management and lithotripsy when appropriate, treats symptomatic or large cystine stones but does not correct the underlying transport defect.
Target Phenotypes: Nephrolithiasis ↗
Show evidence (1 reference)
PMID:38814457 SUPPORT Human Clinical
"The management protocol consisted of (i) treating symptomatic or > 7 mm stones, (ii) multi-staged URS for voluminous stones"
Long-term cohort supports ureteroscopic management for symptomatic, large, or voluminous cystine stones.
Alpha-lipoic acid investigational therapy
Action: Pharmacotherapy NCIT:C15986
Agent: alpha-lipoic acid ↗
Alpha-lipoic acid is an investigational approach supported by mouse-model evidence and a clinical trial evaluating daily supplementation for cystine stone recurrence.
Mechanism Target:
MODULATES Urinary Cystine Supersaturation — Alpha-lipoic acid increased urinary cystine solubility in a Slc3a1 knockout mouse model.
Show evidence (1 reference)
PMID:28165480 SUPPORT Model Organism
"α-lipoic acid inhibits cystine stone formation in the Slc3a1-/- mouse model of cystinuria by increasing the solubility of urinary cystine."
Mouse-model data directly supports alpha-lipoic acid as a urinary cystine-solubility modifier.
Show evidence (2 references)
PMID:28165480 SUPPORT Model Organism
"α-lipoic acid inhibits cystine stone formation in the Slc3a1-/- mouse model of cystinuria by increasing the solubility of urinary cystine."
Mouse-model study supports alpha-lipoic acid as an investigational solubility-modifying therapy.
clinicaltrials:NCT02910531 SUPPORT Human Clinical
"This study evaluates how daily alpha lipoic acid supplementation affects cystine kidney stone recurrence."
ClinicalTrials.gov documents a human clinical trial evaluating alpha-lipoic acid supplementation in cystinuria.
🔬

Clinical Trials

2
NCT02910531 PHASE_II COMPLETED
Randomized placebo-controlled study evaluating daily alpha-lipoic acid supplementation for cystine kidney stone recurrence over three years.
Target Phenotypes: Nephrolithiasis ↗
Show evidence (1 reference)
clinicaltrials:NCT02910531 SUPPORT Human Clinical
"Half of the subjects will receive 1200 mg alpha lipoic acid orally daily for three years, while the other half will receive a placebo."
ClinicalTrials.gov record describes the alpha-lipoic acid intervention and comparator.
NCT03663855 PHASE_II COMPLETED
Study evaluating increasing tiopronin doses and urine cystine capacity to guide cystine-binding thiol drug therapy and minimize side effects.
Target Phenotypes: Cystinuria ↗
Show evidence (1 reference)
clinicaltrials:NCT03663855 SUPPORT Human Clinical
"The purpose of this study is to determine the minimum effective dose of the cysteine binding thiol drug (CBTD) Tiopronin on urine cystine capacity"
ClinicalTrials.gov record documents tiopronin dose evaluation using urine cystine capacity.
{ }

Source YAML

click to show 
name: Cystinuria
category: Mendelian
creation_date: '2026-05-05T15:29:06Z'
updated_date: '2026-05-19T09:45:30Z'
synonyms:
- Cystinuria-lysinuria syndrome
description: >
  Cystinuria is an inherited renal tubular amino acid transport disorder caused
  by pathogenic variants in SLC3A1 or SLC7A9, the two subunits of the proximal
  tubular and intestinal b(0,+) cystine/dibasic amino acid transporter. Defective
  reabsorption causes high urinary cystine and dibasic amino acids; cystine is
  poorly soluble at physiologic urine pH and precipitates into recurrent cystine
  kidney stones, with risks of obstruction, recurrent procedures, chronic kidney
  disease, and hypertension.
disease_term:
  preferred_term: cystinuria
  term:
    id: MONDO:0009067
    label: cystinuria
parents:
- inherited renal tubular disease
- inborn disorder of amino acid transport
- monogenic kidney stone disease
references:
- reference: ORPHA:214
  title: Cystinuria
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: ORPHA:93612
  title: Cystinuria type A
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: ORPHA:93613
  title: Cystinuria type B
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:22480232
  title: "Cystinuria: an inborn cause of urolithiasis."
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:20517292
  title: Pathophysiology and treatment of cystinuria.
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:18752446
  title: Twenty-four novel mutations identified in a cohort of 85 patients by direct sequencing of the SLC3A1 and SLC7A9 cystinuria genes.
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:24045899
  title: "Synergistic mutations in SLC3A1 and SLC7A9 leading to heterogeneous cystinuria phenotypes: pitfalls in the diagnostic workup."
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:30515543
  title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:32066273
  title: "Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement."
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:36900678
  title: A Summary of Current Guidelines and Future Directions for Medical Management and Monitoring of Patients with Cystinuria.
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:28165480
  title: alpha-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria.
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:35822468
  title: "Cystinuria: An Overview of Diagnosis and Medical Management."
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: PMID:38814457
  title: "Ureteroscopic management in cystinuric patients: long-term results from a tertiary care referral center."
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: clinicaltrials:NCT02910531
  title: The Effect of Lipoic Acid Natural Supplement on Cystine Stone Formation
  found_in:
  - Cystinuria-deep-research-fallback.md
- reference: clinicaltrials:NCT03663855
  title: Effect of Increasing Doses of Tiopronin on Cystine Capacity in Patients With Cystinuria
  found_in:
  - Cystinuria-deep-research-fallback.md
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009067
      label: cystinuria
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:214
    mapping_justification: >
      Orphanet ORPHA:214 lists MONDO:0009067 as an exact cross-reference for
      cystinuria.
external_assertions:
- name: Orphanet cystinuria record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:214
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=214
  description: >
    Orphanet's ORPHA:214 structured record provides the definition, inheritance,
    prevalence bands, exact MONDO and OMIM mappings, and HPO annotations used as
    structured assertions in this curation.
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0009067 | Exact"
    explanation: Orphanet maps ORPHA:214 exactly to the MONDO identifier used here.
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:220100 | Exact"
    explanation: Orphanet lists OMIM:220100 as an exact external cross-reference.
definitions:
- name: Orphanet cystinuria definition
  definition_type: OTHER
  description: >
    A rare renal tubular amino acid transport disorder characterized by
    recurrent cystine kidney stone formation.
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare disorder of renal tubular amino acid transport characterized by recurrent formation of kidney cystine stones."
    explanation: Orphanet defines cystinuria by the renal amino acid transport defect and recurrent cystine stone formation.
inheritance:
- name: Autosomal recessive and semi-dominant inheritance
  description: >
    Cystinuria is usually autosomal recessive, with incompletely dominant or
    semi-dominant expression recognized particularly for some SLC7A9
    heterozygotes.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance.
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Semi-dominant"
    explanation: Orphanet also records semi-dominant inheritance.
  - reference: PMID:32066273
    reference_title: "Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystinuria is a genetic disorder with both autosomal recessive and incompletely dominant inheritance."
    explanation: Consensus statement confirms recessive and incompletely dominant inheritance patterns.
has_subtypes:
- name: Cystinuria type A
  display_name: Cystinuria type A
  subtype_term:
    preferred_term: cystinuria type A
    term:
      id: MONDO:0019745
      label: cystinuria type A
  description: >
    Etiological subtype caused by SLC3A1 variants affecting the rBAT heavy
    subunit of the cystine/dibasic amino acid transporter.
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0019745
        label: cystinuria type A
      mapping_predicate: skos:exactMatch
      mapping_source: Orphanet ORPHA:93612
      mapping_justification: Orphanet ORPHA:93612 lists MONDO:0019745 as an exact cross-reference.
  evidence:
  - reference: ORPHA:93612
    reference_title: "Cystinuria type A (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0019745 | Exact"
    explanation: Orphanet maps cystinuria type A to MONDO:0019745.
  - reference: ORPHA:93612
    reference_title: "Cystinuria type A (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC3A1 | solute carrier family 3 member 1 | hgnc:11025 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SLC3A1 as the disease-causing gene for cystinuria type A.
- name: Cystinuria type B
  display_name: Cystinuria type B
  subtype_term:
    preferred_term: cystinuria type B
    term:
      id: MONDO:0019746
      label: cystinuria type B
  description: >
    Etiological subtype caused by SLC7A9 variants affecting the b(0,+)AT light
    subunit of the cystine/dibasic amino acid transporter.
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0019746
        label: cystinuria type B
      mapping_predicate: skos:exactMatch
      mapping_source: Orphanet ORPHA:93613
      mapping_justification: Orphanet ORPHA:93613 lists MONDO:0019746 as an exact cross-reference.
  evidence:
  - reference: ORPHA:93613
    reference_title: "Cystinuria type B (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0019746 | Exact"
    explanation: Orphanet maps cystinuria type B to MONDO:0019746.
  - reference: ORPHA:93613
    reference_title: "Cystinuria type B (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC7A9 | solute carrier family 7 member 9 | hgnc:11067 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SLC7A9 as the disease-causing gene for cystinuria type B.
prevalence:
- population: Worldwide
  notes: >
    Orphanet records a worldwide point-prevalence band of 1-5 per 10,000,
    while population studies show substantial regional variation.
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Worldwide | Point prevalence | PMID:22480232,EXPERT"
    explanation: Orphanet provides the worldwide point-prevalence band.
  - reference: PMID:19096983
    reference_title: "Prevalence of cystinuria among elementary schoolchildren in Eskisehir, Turkey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of cystinuria in this study was 1:2065."
    explanation: School-screening study illustrates higher regional prevalence in a Turkish cohort.
progression:
- phase: Early and recurrent stone disease
  age_range: All ages, commonly childhood to adolescence
  notes: >
    Cystine stones can occur at any age but often begin in childhood or
    adolescence, recur frequently, and may require repeated procedures.
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: All ages"
    explanation: Orphanet records onset across all ages.
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "approximately 50% of patients developing their first stone in the first decade of life and 25% to 40% during their teenage years"
    explanation: Review summarizes early age of first stone formation.
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "untreated patients experience one new stone every year and undergo a surgical procedure to remove the stones every three years"
    explanation: Review describes recurrence and procedure burden in untreated disease.
- phase: Cumulative renal injury
  age_range: Childhood to adulthood
  notes: >
    Recurrent cystine stones, obstruction, and repeated urologic interventions
    can contribute to chronic kidney disease and hypertension.
  evidence:
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Up to 70% of patients with cystinuria may develop chronic kidney disease (CKD)"
    explanation: Review summarizes CKD risk in cystinuria.
  - reference: PMID:38814457
    reference_title: "Ureteroscopic management in cystinuric patients: long-term results from a tertiary care referral center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CKD is a not neglectable event that potentially occurs at an early stage of life."
    explanation: Long-term ureteroscopic cohort reinforces early CKD risk in cystinuric patients.
genetic:
- name: SLC3A1
  association: Causal loss-of-function variant
  gene_term:
    preferred_term: SLC3A1
    term:
      id: hgnc:11025
      label: SLC3A1
  notes: >
    Pathogenic SLC3A1 variants impair the rBAT heavy subunit of the b(0,+)
    cystine/dibasic amino acid transporter and cause type A cystinuria.
  evidence:
  - reference: ORPHA:93612
    reference_title: "Cystinuria type A (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC3A1 | solute carrier family 3 member 1 | hgnc:11025 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SLC3A1 as the disease-causing gene for cystinuria type A.
  - reference: PMID:22480232
    reference_title: "Cystinuria: an inborn cause of urolithiasis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b(0,+) transporter"
    explanation: Review identifies SLC3A1 as the rBAT heavy-subunit gene.
  - reference: PMID:18752446
    reference_title: Twenty-four novel mutations identified in a cohort of 85 patients by direct sequencing of the SLC3A1 and SLC7A9 cystinuria genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-four out of 62 are novel mutations, 9 in SLC3A1 and 15 in SLC7A9."
    explanation: Patient cohort expands the SLC3A1 and SLC7A9 mutation spectrum.
  - reference: CGGV:assertion_fbde8280-d4bc-47e8-8f3d-aed8bb05e22e-2020-06-29T174347.853Z
    reference_title: "SLC3A1 / cystinuria (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC3A1 | HGNC:11025 | cystinuria | MONDO:0009067 | AR | Definitive"
    explanation: ClinGen classifies the SLC3A1-cystinuria gene-disease relationship as definitive with autosomal recessive inheritance.
- name: SLC7A9
  association: Causal loss-of-function variant
  gene_term:
    preferred_term: SLC7A9
    term:
      id: hgnc:11067
      label: SLC7A9
  notes: >
    Pathogenic SLC7A9 variants impair the b(0,+)AT light subunit of the
    cystine/dibasic amino acid transporter and cause type B cystinuria, with
    semi-dominant or incompletely dominant expression in some heterozygotes.
  evidence:
  - reference: ORPHA:93613
    reference_title: "Cystinuria type B (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC7A9 | solute carrier family 7 member 9 | hgnc:11067 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SLC7A9 as the disease-causing gene for cystinuria type B.
  - reference: PMID:22480232
    reference_title: "Cystinuria: an inborn cause of urolithiasis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC7A9 (chromosome 19q12) encodes its interacting light subunit b(0,+)AT"
    explanation: Review identifies SLC7A9 as the b(0,+)AT light-subunit gene.
  - reference: PMID:24045899
    reference_title: "Synergistic mutations in SLC3A1 and SLC7A9 leading to heterogeneous cystinuria phenotypes: pitfalls in the diagnostic workup."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis of both cystinuria genes may be necessary due to the synergistic effects of mutations in two genes."
    explanation: Family study supports genetic heterogeneity and need to evaluate both cystinuria genes.
  - reference: CGGV:assertion_a8e706c5-4b10-4c8a-b5ab-dda8545f464a-2020-06-29T174426.491Z
    reference_title: "SLC7A9 / cystinuria (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC7A9 | HGNC:11067 | cystinuria | MONDO:0009067 | AR | Definitive"
    explanation: ClinGen classifies the SLC7A9-cystinuria gene-disease relationship as definitive with autosomal recessive inheritance.
pathophysiology:
- name: Proximal Tubule Cystine Transport Defect
  description: >
    SLC3A1 or SLC7A9 dysfunction impairs b(0,+)-mediated proximal tubular
    reabsorption of filtered cystine and dibasic amino acids.
  genes:
  - preferred_term: SLC3A1
    term:
      id: hgnc:11025
      label: SLC3A1
  - preferred_term: SLC7A9
    term:
      id: hgnc:11067
      label: SLC7A9
  cell_types:
  - preferred_term: Epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  biological_processes:
  - preferred_term: L-cystine transport
    term:
      id: GO:0015811
      label: L-cystine transport
    modifier: DECREASED
  - preferred_term: amino acid transmembrane transport
    term:
      id: GO:0003333
      label: amino acid transmembrane transport
    modifier: DECREASED
  molecular_functions:
  - preferred_term: amino acid transmembrane transporter activity
    term:
      id: GO:0015171
      label: amino acid transmembrane transporter activity
    modifier: DECREASED
  chemical_entities:
  - preferred_term: cystine
    term:
      id: CHEBI:17376
      label: cystine
    modifier: INCREASED
  - preferred_term: L-lysine
    term:
      id: CHEBI:18019
      label: L-lysine
    modifier: INCREASED
  - preferred_term: L-arginine
    term:
      id: CHEBI:16467
      label: L-arginine
    modifier: INCREASED
  - preferred_term: ornithine
    term:
      id: CHEBI:18257
      label: ornithine
    modifier: INCREASED
  evidence:
  - reference: PMID:20517292
    reference_title: Pathophysiology and treatment of cystinuria.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "causes a failure in the reabsorption of filtered cystine and dibasic amino acids in the proximal tubule"
    explanation: Review links cystinuria-causing transporter defects to impaired proximal tubular cystine and dibasic amino acid reabsorption.
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The COLA transporter (b0,+) is a heterodimer consisting of the rBAT (encoded by SLC3A1, located on chromosome 2p16.3) and b0,+AT (encoded by SLC7A9, located on chromosome 19q13.1) subunits joined by a disulfide bridge."
    explanation: Review describes the two-subunit transporter whose dysfunction causes the proximal tubule defect.
  downstream:
  - target: Urinary Cystine Supersaturation
    description: >
      Failed proximal tubular cystine reabsorption raises urinary cystine to the
      poorly soluble range that drives cystine nephrolithiasis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36900678
      reference_title: A Summary of Current Guidelines and Future Directions for Medical Management and Monitoring of Patients with Cystinuria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As the result of a genetic defect in proximal tubular reabsorption of filtered cystine, increased urine levels of the poorly soluble amino acid result in recurrent cystine nephrolithiasis."
      explanation: Guideline review directly links proximal tubular reabsorption defects to increased urinary cystine levels.
  - target: Cystinuria
    description: >
      Defective proximal tubular reabsorption of filtered cystine produces the
      biochemical cystinuria phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20517292
      reference_title: Pathophysiology and treatment of cystinuria.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "causes a failure in the reabsorption of filtered cystine and dibasic amino acids in the proximal tubule"
      explanation: Failed filtered-cystine reabsorption is the mechanism represented by the cystinuria phenotype.
  - target: Abnormal amino acid metabolism
    description: >
      The same transporter defect disrupts renal handling of cystine and dibasic
      amino acids.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20517292
      reference_title: Pathophysiology and treatment of cystinuria.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "causes a failure in the reabsorption of filtered cystine and dibasic amino acids in the proximal tubule"
      explanation: The proximal tubule defect affects cystine and dibasic amino acid handling, matching the amino acid metabolism phenotype.
  - target: Stone-Risk Chemistry Modifiers
    description: >
      Additional urinary and systemic stone-risk chemistry abnormalities are
      reported in cystinuria, but the cached evidence does not establish whether
      they are direct consequences of the cystine transporter defect or
      co-occurring modifiers.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012405 | Hypocitraturia | Frequent (79-30%)"
      explanation: Orphanet records hypocitraturia as a frequent biochemical finding in cystinuria.
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002150 | Hypercalciuria | Occasional (29-5%)"
      explanation: Orphanet records hypercalciuria as an occasional biochemical finding in cystinuria.
- name: Urinary Cystine Supersaturation
  description: >
    High urinary cystine concentration exceeds cystine solubility, especially
    when urine volume is low or pH is not sufficiently alkaline, producing
    cystine crystalluria.
  chemical_entities:
  - preferred_term: cystine
    term:
      id: CHEBI:17376
      label: cystine
    modifier: INCREASED
  evidence:
  - reference: PMID:36900678
    reference_title: A Summary of Current Guidelines and Future Directions for Medical Management and Monitoring of Patients with Cystinuria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased urine levels of the poorly soluble amino acid result in recurrent cystine nephrolithiasis"
    explanation: Guideline review summarizes the solubility-based mechanism connecting excess urinary cystine to recurrent stones.
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Of the four amino acids, cystine is the least soluble and it can crystallize in the urinary tract, leading to cystine stone formation."
    explanation: Review explains why urinary cystine, rather than the other dibasic amino acids, drives stone formation.
  downstream:
  - target: Cystine Crystal Growth and Aggregation
    description: >
      Poor cystine solubility permits crystallization in urine, initiating
      crystal nucleation and growth.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Of the four amino acids, cystine is the least soluble and it can crystallize in the urinary tract, leading to cystine stone formation."
      explanation: The review directly connects cystine's low solubility with urinary crystallization.
  - target: Cystine crystalluria
    description: >
      Supersaturated urinary cystine crystallizes, producing cystine
      crystalluria.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Of the four amino acids, cystine is the least soluble and it can crystallize in the urinary tract, leading to cystine stone formation."
      explanation: Low cystine solubility and crystallization support the cystine crystalluria phenotype link.
  - target: Echogenic fetal colon
    description: >
      Prenatal echogenic colon is an occasional cystinuria-associated finding;
      the cached evidence does not resolve the intermediate mechanism.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:6000916 | Echogenic fetal colon | Occasional (29-5%)"
      explanation: Orphanet records echogenic fetal colon as an occasional prenatal phenotype in cystinuria.
- name: Stone-Risk Chemistry Modifiers
  description: >
    Co-occurring urinary stone-risk chemistries in cystinuria include low urinary
    citrate and elevated urinary calcium or uric acid, which may modify stone
    propensity alongside cystine supersaturation.
  chemical_entities:
  - preferred_term: citrate
    term:
      id: CHEBI:16947
      label: citrate(3-)
    modifier: DECREASED
  - preferred_term: calcium
    term:
      id: CHEBI:29108
      label: calcium(2+)
    modifier: INCREASED
  - preferred_term: uric acid
    term:
      id: CHEBI:27226
      label: uric acid
    modifier: INCREASED
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012405 | Hypocitraturia | Frequent (79-30%)"
    explanation: Orphanet records hypocitraturia as a frequent cystinuria finding.
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002150 | Hypercalciuria | Occasional (29-5%)"
    explanation: Orphanet records hypercalciuria as an occasional cystinuria finding.
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003149 | Hyperuricosuria | Occasional (29-5%)"
    explanation: Orphanet records hyperuricosuria as an occasional cystinuria finding.
  downstream:
  - target: Hypocitraturia
    description: >
      Low urinary citrate is represented as a stone-risk chemistry modifier.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012405 | Hypocitraturia | Frequent (79-30%)"
      explanation: Orphanet records hypocitraturia as a frequent biochemical finding in cystinuria.
  - target: Hypercalciuria
    description: >
      Elevated urinary calcium is represented as an occasional stone-risk
      chemistry modifier.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002150 | Hypercalciuria | Occasional (29-5%)"
      explanation: Orphanet records hypercalciuria as an occasional biochemical finding in cystinuria.
  - target: Hyperuricosuria
    description: >
      Elevated urinary uric acid is represented as an occasional stone-risk
      chemistry modifier.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003149 | Hyperuricosuria | Occasional (29-5%)"
      explanation: Orphanet records hyperuricosuria as an occasional biochemical finding in cystinuria.
  - target: Hyperuricemia
    description: >
      Elevated blood uric acid is represented as a reported systemic stone-risk
      chemistry feature of cystinuria.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002149 | Hyperuricemia | Frequent (79-30%)"
      explanation: Orphanet records hyperuricemia as a frequent biochemical finding in cystinuria.
- name: Cystine Crystal Growth and Aggregation
  description: >
    Cystine crystals nucleate, grow, and aggregate in urine, converting
    supersaturation and crystalluria into clinically significant stones.
  evidence:
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In addition to crystal nucleation and growth, crystal aggregation is required for stone formation"
    explanation: Review identifies crystal aggregation as a required step beyond nucleation and growth.
  downstream:
  - target: Recurrent Cystine Nephrolithiasis
    description: >
      Crystal growth and aggregation convert cystine crystallization into
      clinically significant recurrent stones.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In addition to crystal nucleation and growth, crystal aggregation is required for stone formation"
      explanation: The review identifies crystal aggregation as a required step in stone formation.
- name: Recurrent Cystine Nephrolithiasis
  description: >
    Cystine stones form repeatedly in the kidney and urinary tract, causing
    renal colic, hematuria, obstruction, and recurrent intervention.
  evidence:
  - reference: PMID:20517292
    reference_title: Pathophysiology and treatment of cystinuria.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical symptoms of this disease are caused by the loss of poorly soluble cystine, which precipitates to form stones."
    explanation: Review directly connects cystine precipitation to clinical stone disease.
  downstream:
  - target: Chronic Kidney Injury from Recurrent Stones
    description: >
      Recurrent stones damage the kidney through recurrent renal injury,
      obstructive uropathy, and repeated urologic intervention.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - recurrent renal injury
    - obstructive uropathy
    - repeated urologic interventions
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CKD in patients with cystinuria may result from recurrent stones, repeated urologic interventions, or obstructive uropathy"
      explanation: The review lists recurrent stones, procedures, and obstruction as intermediates leading to CKD.
  - target: Nephrolithiasis
    description: >
      Recurrent cystine stone formation manifests clinically as nephrolithiasis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36900678
      reference_title: A Summary of Current Guidelines and Future Directions for Medical Management and Monitoring of Patients with Cystinuria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "increased urine levels of the poorly soluble amino acid result in recurrent cystine nephrolithiasis"
      explanation: Guideline review supports the nephrolithiasis phenotype as the clinical result of cystine stone formation.
  - target: Hematuria
    description: >
      Hematuria is reported as a very frequent phenotype in cystinuria stone
      disease, but the cached evidence does not specify the local injury
      mechanism.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000790 | Hematuria | Very frequent (99-80%)"
      explanation: Orphanet records hematuria as a very frequent cystinuria phenotype.
    - reference: PMID:20517292
      reference_title: Pathophysiology and treatment of cystinuria.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The clinical symptoms of this disease are caused by the loss of poorly soluble cystine, which precipitates to form stones."
      explanation: Review supports cystine stones as the source of clinical manifestations.
  - target: Flank pain
    description: >
      Flank pain is reported as a frequent phenotype in cystinuria stone disease,
      but the cached evidence does not specify the intermediate pain pathway.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0030157 | Flank pain | Frequent (79-30%)"
      explanation: Orphanet records flank pain as a frequent cystinuria phenotype.
    - reference: PMID:20517292
      reference_title: Pathophysiology and treatment of cystinuria.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The clinical symptoms of this disease are caused by the loss of poorly soluble cystine, which precipitates to form stones."
      explanation: Review supports cystine stones as the source of clinical manifestations.
  - target: Nausea and vomiting
    description: >
      Nausea and vomiting are reported in cystinuria stone disease, but the
      cached evidence does not specify the intermediate pathway.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002017 | Nausea and vomiting | Frequent (79-30%)"
      explanation: Orphanet records nausea and vomiting as a frequent cystinuria phenotype.
    - reference: PMID:20517292
      reference_title: Pathophysiology and treatment of cystinuria.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The clinical symptoms of this disease are caused by the loss of poorly soluble cystine, which precipitates to form stones."
      explanation: Review supports cystine stones as the source of clinical manifestations.
  - target: Abnormal urinary odor
    description: >
      Abnormal urinary odor is reported in cystinuria, but the cached evidence
      does not define its intermediate mechanism.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:214
      reference_title: "Cystinuria (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012088 | Abnormal urinary odor | Frequent (79-30%)"
      explanation: Orphanet records abnormal urinary odor as a frequent cystinuria phenotype.
- name: Chronic Kidney Injury from Recurrent Stones
  description: >
    Recurrent stones, obstruction, and repeated urologic procedures can damage
    kidney tissue over time, contributing to chronic kidney disease and
    hypertension.
  cell_types:
  - preferred_term: Epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  evidence:
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CKD in patients with cystinuria may result from recurrent stones, repeated urologic interventions, or obstructive uropathy"
    explanation: Review summarizes mechanisms of cumulative renal injury in cystinuria.
  downstream:
  - target: Renal insufficiency
    description: >
      Chronic kidney disease and cumulative renal injury reduce renal function,
      captured clinically as renal insufficiency.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Up to 70% of patients with cystinuria may develop chronic kidney disease (CKD)"
      explanation: CKD in cystinuria supports the downstream renal insufficiency phenotype link.
  - target: Hypertension
    description: >
      Chronic kidney disease and cumulative renal injury can contribute to high
      blood pressure in cystinuria cohorts.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic kidney disease
    - reduced renal function
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypertension was also common in this study, with 28.6% of patients having high blood pressure"
      explanation: Review reports hypertension in a cystinuria cohort with CKD burden.
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CKD in patients with cystinuria may result from recurrent stones, repeated urologic interventions, or obstructive uropathy"
      explanation: Recurrent stones, procedures, and obstruction are known intermediates for chronic kidney disease.
phenotypes:
- name: Cystinuria
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >
    Increased urinary cystine is the biochemical hallmark of cystinuria.
  phenotype_term:
    preferred_term: Cystinuria
    term:
      id: HP:0003131
      label: Cystinuria
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003131 | Cystinuria | Very frequent (99-80%)"
    explanation: Orphanet classifies cystinuria as very frequent.
- name: Nephrolithiasis
  category: Renal
  frequency: VERY_FREQUENT
  description: >
    Recurrent cystine kidney stones are the defining clinical manifestation.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000787 | Nephrolithiasis | Very frequent (99-80%)"
    explanation: Orphanet classifies nephrolithiasis as very frequent.
- name: Hematuria
  category: Renal
  frequency: VERY_FREQUENT
  description: >
    Blood in the urine occurs with cystine stones and stone passage.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000790 | Hematuria | Very frequent (99-80%)"
    explanation: Orphanet classifies hematuria as very frequent.
- name: Abnormal amino acid metabolism
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >
    Cystinuria disrupts renal handling of cystine and dibasic amino acids.
  phenotype_term:
    preferred_term: Abnormality of amino acid metabolism
    term:
      id: HP:0004337
      label: Abnormality of amino acid metabolism
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004337 | Abnormality of amino acid metabolism | Very frequent (99-80%)"
    explanation: Orphanet classifies abnormal amino acid metabolism as very frequent.
- name: Cystine crystalluria
  category: Biochemical
  frequency: FREQUENT
  description: >
    Hexagonal cystine crystals can be detected in urine when cystine exceeds its
    solubility threshold.
  phenotype_term:
    preferred_term: Cystine crystalluria
    term:
      id: HP:0033067
      label: Cystine crystalluria
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0033067 | Cystine crystalluria | Frequent (79-30%)"
    explanation: Orphanet classifies cystine crystalluria as frequent.
- name: Flank pain
  category: Renal
  frequency: FREQUENT
  description: >
    Cystine stones commonly cause flank pain or renal colic.
  phenotype_term:
    preferred_term: Flank pain
    term:
      id: HP:0030157
      label: Flank pain
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030157 | Flank pain | Frequent (79-30%)"
    explanation: Orphanet classifies flank pain as frequent.
- name: Renal insufficiency
  category: Renal
  frequency: FREQUENT
  description: >
    Recurrent stones, obstruction, procedures, and chronic injury can reduce
    renal function.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000083 | Renal insufficiency | Frequent (79-30%)"
    explanation: Orphanet classifies renal insufficiency as frequent.
- name: Hypertension
  category: Cardiovascular
  frequency: FREQUENT
  description: >
    Hypertension can accompany chronic renal injury in cystinuria cohorts.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000822 | Hypertension | Frequent (79-30%)"
    explanation: Orphanet classifies hypertension as frequent.
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertension was also common in this study, with 28.6% of patients having high blood pressure"
    explanation: Review reports hypertension frequency in a retrospective cystinuria cohort.
- name: Nausea and vomiting
  category: Gastrointestinal
  frequency: FREQUENT
  description: >
    Nausea and vomiting can occur during symptomatic stone episodes.
  phenotype_term:
    preferred_term: Nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002017 | Nausea and vomiting | Frequent (79-30%)"
    explanation: Orphanet classifies nausea and vomiting as frequent.
- name: Hyperuricemia
  category: Biochemical
  frequency: FREQUENT
  description: >
    Elevated blood uric acid is listed among frequent biochemical findings in
    the Orphanet cystinuria record.
  phenotype_term:
    preferred_term: Hyperuricemia
    term:
      id: HP:0002149
      label: Hyperuricemia
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002149 | Hyperuricemia | Frequent (79-30%)"
    explanation: Orphanet classifies hyperuricemia as frequent.
- name: Abnormal urinary odor
  category: Renal
  frequency: FREQUENT
  description: >
    Abnormal urinary odor is listed among frequent urinary findings.
  phenotype_term:
    preferred_term: Abnormal urinary odor
    term:
      id: HP:0012088
      label: Abnormal urinary odor
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012088 | Abnormal urinary odor | Frequent (79-30%)"
    explanation: Orphanet classifies abnormal urinary odor as frequent.
- name: Hypocitraturia
  category: Biochemical
  frequency: FREQUENT
  description: >
    Reduced urinary citrate is a frequent stone-risk modifier in the Orphanet
    cystinuria phenotype table.
  phenotype_term:
    preferred_term: Hypocitraturia
    term:
      id: HP:0012405
      label: Hypocitraturia
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012405 | Hypocitraturia | Frequent (79-30%)"
    explanation: Orphanet classifies hypocitraturia as frequent.
- name: Hypercalciuria
  category: Biochemical
  frequency: OCCASIONAL
  description: >
    Elevated urinary calcium is an occasional metabolic finding.
  phenotype_term:
    preferred_term: Hypercalciuria
    term:
      id: HP:0002150
      label: Hypercalciuria
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002150 | Hypercalciuria | Occasional (29-5%)"
    explanation: Orphanet classifies hypercalciuria as occasional.
- name: Hyperuricosuria
  category: Biochemical
  frequency: OCCASIONAL
  description: >
    Elevated urinary uric acid is an occasional metabolic finding.
  phenotype_term:
    preferred_term: Hyperuricosuria
    term:
      id: HP:0003149
      label: Hyperuricosuria
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003149 | Hyperuricosuria | Occasional (29-5%)"
    explanation: Orphanet classifies hyperuricosuria as occasional.
- name: Echogenic fetal colon
  category: Prenatal
  frequency: OCCASIONAL
  description: >
    Echogenic fetal colon has been observed prenatally in a minority of cases.
  phenotype_term:
    preferred_term: Echogenic fetal colon
    term:
      id: HP:6000916
      label: Echogenic fetal colon
  evidence:
  - reference: ORPHA:214
    reference_title: "Cystinuria (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6000916 | Echogenic fetal colon | Occasional (29-5%)"
    explanation: Orphanet classifies echogenic fetal colon as occasional.
diagnosis:
- name: Stone composition and 24-hour urinary cystine evaluation
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  description: >
    Diagnosis is supported by cystine stone analysis, urine cystine screening,
    and 24-hour urinary cystine assessment in patients with recurrent or early
    nephrolithiasis.
  evidence:
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is usually made by confirming the stone composition as cystine."
    explanation: Review supports cystine stone composition analysis as a diagnostic confirmation step.
- name: SLC3A1 and SLC7A9 genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >
    Molecular testing of both cystinuria genes helps classify type A, type B,
    mixed, or complex families and avoids missing synergistic variants.
  evidence:
  - reference: PMID:24045899
    reference_title: "Synergistic mutations in SLC3A1 and SLC7A9 leading to heterogeneous cystinuria phenotypes: pitfalls in the diagnostic workup."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis of both cystinuria genes may be necessary due to the synergistic effects of mutations in two genes."
    explanation: Family study supports testing both SLC3A1 and SLC7A9 in diagnostic workup.
treatments:
- name: High fluid intake and dietary sodium/protein moderation
  description: >
    High urine volume plus sodium and animal-protein moderation are first-line
    conservative measures to reduce cystine concentration and stone recurrence.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Urinary Cystine Supersaturation
    treatment_effect: INHIBITS
    description: Increased urine volume lowers cystine concentration relative to its solubility threshold.
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Medical treatment for cystinuria involves increasing cystine solubility by increasing urine volume and pH."
      explanation: The review explains the fluid-volume component of conservative therapy as increasing urinary cystine solubility.
  evidence:
  - reference: PMID:32066273
    reference_title: "Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "conservative measures: fluid intake and dietary modification"
    explanation: Consensus statement places fluid intake and dietary modification at the start of stepwise therapy.
- name: Urinary alkalinization with potassium citrate
  description: >
    Alkali therapy, commonly potassium citrate, raises urine pH to improve
    cystine solubility when conservative measures are insufficient.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: potassium citrate
      term:
        id: CHEBI:64733
        label: potassium citrate (anhydrous)
  target_mechanisms:
  - target: Urinary Cystine Supersaturation
    treatment_effect: INHIBITS
    description: Alkalinization increases cystine solubility and lowers supersaturation.
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cystine solubility increases with pH but only at values greater than 7.0"
      explanation: Increased cystine solubility at alkaline pH supports the mechanism targeted by potassium citrate.
  evidence:
  - reference: PMID:32066273
    reference_title: "Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "first alkalinizing the urine and then using cystine-binding thiol drugs"
    explanation: Consensus statement supports urinary alkalinization before cystine-binding thiol therapy.
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cystine solubility increases with pH but only at values greater than 7.0"
    explanation: Review explains the solubility rationale for alkalinization.
- name: Cystine-binding thiol drugs
  description: >
    Tiopronin or D-penicillamine can form more soluble mixed disulfides and are
    used for severe or recurrent stone disease not controlled by conservative
    measures and alkalinization.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tiopronin
      term:
        id: NCIT:C47758
        label: Tiopronin
    - preferred_term: D-penicillamine
      term:
        id: CHEBI:7959
        label: D-penicillamine
  target_mechanisms:
  - target: Urinary Cystine Supersaturation
    treatment_effect: INHIBITS
    description: Thiol drugs convert cystine into more soluble mixed disulfides.
    evidence:
    - reference: PMID:30515543
      reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "These sulfhydryl drugs convert cystine to the more soluble mixed disulfides of cysteine-penicillamine or cysteine-tiopronin, respectively."
      explanation: Formation of more soluble mixed disulfides explains how thiol drugs lower the supersaturation mechanism.
  evidence:
  - reference: PMID:32066273
    reference_title: "Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "using cystine-binding thiol drugs"
    explanation: Consensus statement supports cystine-binding thiol drugs after fluid, diet, and alkalinization when stone formation recurs.
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These sulfhydryl drugs convert cystine to the more soluble mixed disulfides of cysteine-penicillamine or cysteine-tiopronin, respectively."
    explanation: Review explains the biochemical mechanism of D-penicillamine and tiopronin.
- name: Calculi removal for symptomatic or large cystine stones
  description: >
    Endoscopic or surgical stone removal, including ureteroscopic management and
    lithotripsy when appropriate, treats symptomatic or large cystine stones but
    does not correct the underlying transport defect.
  treatment_term:
    preferred_term: calculi removal
    term:
      id: MAXO:0000890
      label: calculi removal
  target_phenotypes:
  - preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: PMID:38814457
    reference_title: "Ureteroscopic management in cystinuric patients: long-term results from a tertiary care referral center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The management protocol consisted of (i) treating symptomatic or > 7 mm stones, (ii) multi-staged URS for voluminous stones"
    explanation: Long-term cohort supports ureteroscopic management for symptomatic, large, or voluminous cystine stones.
- name: Alpha-lipoic acid investigational therapy
  description: >
    Alpha-lipoic acid is an investigational approach supported by mouse-model
    evidence and a clinical trial evaluating daily supplementation for cystine
    stone recurrence.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alpha-lipoic acid
      term:
        id: CHEBI:16494
        label: lipoic acid
  target_mechanisms:
  - target: Urinary Cystine Supersaturation
    treatment_effect: MODULATES
    description: Alpha-lipoic acid increased urinary cystine solubility in a Slc3a1 knockout mouse model.
    evidence:
    - reference: PMID:28165480
      reference_title: alpha-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "α-lipoic acid inhibits cystine stone formation in the Slc3a1-/- mouse model of cystinuria by increasing the solubility of urinary cystine."
      explanation: Mouse-model data directly supports alpha-lipoic acid as a urinary cystine-solubility modifier.
  evidence:
  - reference: PMID:28165480
    reference_title: alpha-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "α-lipoic acid inhibits cystine stone formation in the Slc3a1-/- mouse model of cystinuria by increasing the solubility of urinary cystine."
    explanation: Mouse-model study supports alpha-lipoic acid as an investigational solubility-modifying therapy.
  - reference: clinicaltrials:NCT02910531
    reference_title: The Effect of Lipoic Acid Natural Supplement on Cystine Stone Formation
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study evaluates how daily alpha lipoic acid supplementation affects cystine kidney stone recurrence."
    explanation: ClinicalTrials.gov documents a human clinical trial evaluating alpha-lipoic acid supplementation in cystinuria.
animal_models:
- species: Mouse
  genotype: Slc3a1 knockout
  description: >
    Slc3a1 knockout mice model type A cystinuria with crystalluria and
    stone formation, enabling testing of cystine solubility and crystal-growth
    therapies such as alpha-lipoic acid.
  genes:
  - preferred_term: SLC3A1
    term:
      id: hgnc:11025
      label: SLC3A1
  evidence:
  - reference: PMID:28165480
    reference_title: alpha-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the Slc3a1-/- mouse model which develops cystine urolithiasis"
    explanation: Study uses Slc3a1 knockout mice as a cystinuria model with cystine urolithiasis.
- species: Mouse
  genotype: Slc7a9 knockout
  description: >
    Slc7a9 knockout mice model type B cystinuria and show elevated cystine and
    dibasic amino acid excretion with cystine stone formation.
  genes:
  - preferred_term: SLC7A9
    term:
      id: hgnc:11067
      label: SLC7A9
  evidence:
  - reference: PMID:30515543
    reference_title: "Cystinuria: genetic aspects, mouse models, and a new approach to therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Slc7a9 knockout mice also showed elevated excretion of COLA"
    explanation: Review summarizes Slc7a9 knockout mouse biochemical phenotype.
clinical_trials:
- name: NCT02910531
  phase: PHASE_II
  status: COMPLETED
  description: >
    Randomized placebo-controlled study evaluating daily alpha-lipoic acid
    supplementation for cystine kidney stone recurrence over three years.
  target_phenotypes:
  - preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: clinicaltrials:NCT02910531
    reference_title: The Effect of Lipoic Acid Natural Supplement on Cystine Stone Formation
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of the subjects will receive 1200 mg alpha lipoic acid orally daily for three years, while the other half will receive a placebo."
    explanation: ClinicalTrials.gov record describes the alpha-lipoic acid intervention and comparator.
- name: NCT03663855
  phase: PHASE_II
  status: COMPLETED
  description: >
    Study evaluating increasing tiopronin doses and urine cystine capacity to
    guide cystine-binding thiol drug therapy and minimize side effects.
  target_phenotypes:
  - preferred_term: Cystinuria
    term:
      id: HP:0003131
      label: Cystinuria
  evidence:
  - reference: clinicaltrials:NCT03663855
    reference_title: Effect of Increasing Doses of Tiopronin on Cystine Capacity in Patients With Cystinuria
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The purpose of this study is to determine the minimum effective dose of the cysteine binding thiol drug (CBTD) Tiopronin on urine cystine capacity"
    explanation: ClinicalTrials.gov record documents tiopronin dose evaluation using urine cystine capacity.
notes: >-
  Provider-generated deep research was attempted with Falcon, OpenAI, and
  OpenScientist. Falcon and OpenScientist were interrupted after bounded silent
  waits, and OpenAI failed with a connection error. The fallback research
  artifact documents these failures and the cached literature scope used for
  curation.
📚

References & Deep Research

References

15
ORPHA:214
Cystinuria
No top-level findings curated for this source.
ORPHA:93612
Cystinuria type A
No top-level findings curated for this source.
ORPHA:93613
Cystinuria type B
No top-level findings curated for this source.
PMID:22480232
Cystinuria: an inborn cause of urolithiasis.
No top-level findings curated for this source.
PMID:20517292
Pathophysiology and treatment of cystinuria.
No top-level findings curated for this source.
PMID:18752446
Twenty-four novel mutations identified in a cohort of 85 patients by direct sequencing of the SLC3A1 and SLC7A9 cystinuria genes.
No top-level findings curated for this source.
PMID:24045899
Synergistic mutations in SLC3A1 and SLC7A9 leading to heterogeneous cystinuria phenotypes: pitfalls in the diagnostic workup.
No top-level findings curated for this source.
PMID:30515543
Cystinuria: genetic aspects, mouse models, and a new approach to therapy.
No top-level findings curated for this source.
PMID:32066273
Evaluation and Medical Management of Patients with Cystine Nephrolithiasis: A Consensus Statement.
No top-level findings curated for this source.
PMID:36900678
A Summary of Current Guidelines and Future Directions for Medical Management and Monitoring of Patients with Cystinuria.
No top-level findings curated for this source.
PMID:28165480
alpha-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria.
No top-level findings curated for this source.
PMID:35822468
Cystinuria: An Overview of Diagnosis and Medical Management.
No top-level findings curated for this source.
PMID:38814457
Ureteroscopic management in cystinuric patients: long-term results from a tertiary care referral center.
No top-level findings curated for this source.
clinicaltrials:NCT02910531
The Effect of Lipoic Acid Natural Supplement on Cystine Stone Formation
No top-level findings curated for this source.
clinicaltrials:NCT03663855
Effect of Increasing Doses of Tiopronin on Cystine Capacity in Patients With Cystinuria
No top-level findings curated for this source.

Deep Research

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Fallback ▸
Cystinuria Deep Research Fallback

Cystinuria Deep Research Fallback

Provider Attempts

  • 2026-05-05T15:30Z: just research-disorder falcon Cystinuria produced no artifact after a bounded silent wait and was interrupted.
  • 2026-05-05T16:00Z: just research-disorder openai Cystinuria failed with an OpenAI connection error and produced no artifact.
  • 2026-05-05T16:05Z: just research-disorder openscientist Cystinuria produced no artifact after a bounded silent wait and was interrupted.

No provider-generated deep-research narrative was available within the bounded runtime. Curation therefore proceeded from generated structured Orphanet evidence and fetched PubMed/ClinicalTrials.gov caches, without hand-editing any references_cache/*.md files.

Evidence Scope Used For Curation

  • ORPHA:214 structured record for definition, inheritance, exact MONDO/OMIM mapping, prevalence bands, and HPO phenotype frequencies.
  • ORPHA:93612 and ORPHA:93613 structured subtype records for Cystinuria type A and type B, including MONDO mappings, inheritance, and SLC3A1/SLC7A9 gene assertions.
  • PMID:22480232 and PMID:20517292 for the renal b(0,+) transporter mechanism, SLC3A1/SLC7A9 subunits, proximal-tubule reabsorption failure, cystine precipitation, inheritance patterns, and clinical framing.
  • PMID:18752446 and PMID:24045899 for human mutation cohorts, genetic heterogeneity, and synergistic/digenic diagnostic complexity.
  • PMID:30515543 for detailed clinical burden, pediatric stone contribution, CKD risk, recurrence/procedure burden, transporter structure, current therapies, mouse models, crystal growth/aggregation, and investigational cystine-analog approaches.
  • PMID:32066273 and PMID:36900678 for consensus/guideline treatment pathways: high fluid intake, dietary modification, urinary alkalinization, cystine-binding thiol drugs, and monitoring with cystine capacity.
  • PMID:28165480 for alpha-lipoic acid model evidence increasing urinary cystine solubility and suppressing stone growth in Slc3a1 knockout mice.
  • PMID:35822468 for pediatric overview, monogenic stone-disease burden, CKD framing, and alpha-lipoic acid as an emerging medical option.
  • PMID:38814457 for long-term ureteroscopic/endoscopic management outcomes.
  • ClinicalTrials.gov NCT02910531 and NCT03663855 for alpha-lipoic acid and tiopronin clinical trial context.

Curation Conclusions

Cystinuria is a monogenic renal tubular aminoaciduria caused primarily by pathogenic variants in SLC3A1 or SLC7A9, which encode the rBAT heavy subunit and b(0,+)AT light subunit of the cystine/dibasic amino acid transporter. Loss or reduction of transporter function impairs proximal tubular reabsorption of filtered cystine, ornithine, lysine, and arginine. Cystine is the least soluble of these amino acids, so high urinary cystine drives cystine crystalluria and recurrent cystine nephrolithiasis. Recurrent stones and procedures can cause obstruction, renal injury, chronic kidney disease, and hypertension.

Disease-directed management focuses on lowering urinary cystine supersaturation: high urine volume, dietary sodium/protein moderation, urinary alkalinization, and cystine-binding thiol drugs such as tiopronin or D-penicillamine when conservative measures fail. Surgical/endoscopic stone removal remains necessary for symptomatic or large stones. Alpha-lipoic acid and cystine crystal-growth inhibitors remain investigational in the cited evidence.