Cystinosis

Mendelian MONDO:0016239 Pathograph 76 Inborn disorder of lysosomal amino acid transport Lysosomal storage disease

Cystinosis is an autosomal recessive lysosomal amino-acid transport disorder caused by biallelic pathogenic variants in CTNS, which encodes cystinosin. Cystinosin dysfunction impairs lysosomal cystine export, producing intralysosomal cystine accumulation and multisystem tissue injury, especially renal Fanconi syndrome and kidney failure in nephropathic forms and corneal cystine crystal disease in ocular involvement.

Ask OpenScientist

Ask a research question about Cystinosis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
1
Definitions
1
Inheritance
7
Pathophys.
57
Phenotypes
76
Pathograph
1
Genes
7
Treatments
3
Subtypes
1
Trials
19
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0016239 cystinosis
skos:exactMatch Orphanet ORPHA:213
Orphanet ORPHA:213 lists MONDO:0016239 as an exact cross-reference for cystinosis.
📘

Definitions

1
Orphanet cystinosis definition
A rare lysosomal disease in which cystine accumulates inside lysosomes, damaging multiple organs and tissues, particularly the kidneys and eyes.
OTHER
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"A rare lysosomal disease characterized by an accumulation of cystine inside the lysosomes"
Orphanet supports the lysosomal cystine accumulation disease definition.
👪

Inheritance

1
Autosomal recessive HP:0000007
Cystinosis is caused by biallelic pathogenic variants in CTNS.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:213 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for cystinosis.
PMID:20301574 SUPPORT Human Clinical
"Cystinosis is inherited in an autosomal recessive manner."
GeneReviews confirms autosomal recessive inheritance.
◆

Subtypes

3
Nephropathic (infantile) cystinosis MONDO:0100151
95%
The classic severe nephropathic form, corresponding to OMIM:219800, presents in infancy with renal Fanconi syndrome, growth failure, rickets, progressive glomerular impairment, and extrarenal cystine storage.
Show evidence (2 references)
ORPHA:213 SUPPORT Other
"Three clinical forms have been described: nephropathic infantile, nephropathic juvenile and ocular."
Orphanet defines the three clinical forms and names nephropathic infantile cystinosis.
PMID:20301574 SUPPORT Human Clinical
"This is the most common form (95% of individuals with cystinosis)."
GeneReviews identifies nephropathic infantile cystinosis as the dominant cystinosis subtype.
Later-onset (juvenile) nephropathic cystinosis MONDO:0009066
5%
A later-onset nephropathic form, corresponding to OMIM:219900, with typical nephropathic manifestations but delayed onset and untreated renal failure usually in adolescence or young adulthood.
Show evidence (2 references)
ORPHA:213 SUPPORT Other
"Three clinical forms have been described: nephropathic infantile, nephropathic juvenile and ocular."
Orphanet defines nephropathic juvenile cystinosis as a distinct clinical form.
PMID:20301574 SUPPORT Human Clinical
"Renal glomerular failure occurs in untreated affected individuals, usually between ages 15 and 25 years."
GeneReviews distinguishes later-onset juvenile disease by delayed renal failure.
Non-nephropathic (ocular) cystinosis MONDO:0009064
<1%
The ocular non-nephropathic form, corresponding to OMIM:219750, is dominated by corneal cystine crystal disease and photophobia without the major renal Fanconi syndrome and kidney-failure course typical of nephropathic disease.
Show evidence (2 references)
ORPHA:213 SUPPORT Other
"Three clinical forms have been described: nephropathic infantile, nephropathic juvenile and ocular."
Orphanet defines ocular cystinosis as a distinct clinical form.
PMID:20301574 SUPPORT Human Clinical
"Non-nephropathic adult (ocular) cystinosis: Characterized by photophobia resulting from corneal cystine crystal accumulation."
GeneReviews distinguishes the non-nephropathic ocular phenotype from nephropathic disease.
⚙

Pathophysiology

7
CTNS lysosomal cystine transporter deficiency
Biallelic pathogenic CTNS variants impair cystinosin, the lysosomal cystine transporter, reducing cystine export from lysosomes and disrupting intracellular cysteine homeostasis.
CTNS link
L-cystine transport link lysosomal transport link intracellular cysteine homeostasis link
L-cystine transmembrane transporter activity link transmembrane transporter activity link
lysosome link
Downstream
Intralysosomal cystine accumulation and lysosomal dysfunction Impaired cystinosin-mediated export produces intralysosomal cystine accumulation.
Show evidence (3 references)
PMID:11689434 SUPPORT In Vitro
"Cystinosis is an inherited lysosomal storage disease characterized by defective"
Defines cystinosis as a lysosomal storage disease with defective cystine transport.
PMID:11689434 SUPPORT In Vitro
"responsible for cystine export from lysosomes"
Directly identifies cystinosin as the lysosomal cystine export transporter.
PMID:29260317 SUPPORT Human Clinical
"caused by mutations in the CTNS gene that encodes"
Review evidence connects CTNS mutations to cystinosin deficiency in patients.
Intralysosomal cystine accumulation and lysosomal dysfunction
Failure to export cystine causes cystine accumulation in lysosomes throughout the body. Lysosomal storage is accompanied by broader abnormalities in endolysosomal trafficking, proteolysis, lysosomal clearance, autophagy, and cellular energy balance.
autophagy link
lysosome link
Downstream
Proximal tubule cell dysfunction and renal Fanconi syndrome Proximal tubule cells are especially vulnerable to cystinosin loss and lysosomal dysfunction.
Corneal cystine crystal deposition Cystine deposition in the cornea causes crystals and photophobia.
Extrarenal tissue cystine accumulation Multisystem cystine accumulation drives endocrine, myopathic, hepatic, pancreatic, and neurologic complications.
Elevated leukocyte cystine Lysosomal cystine storage is measured diagnostically as elevated cystine in leukocytes.
Show evidence (3 references)
ORPHA:213 SUPPORT Other
"A rare lysosomal disease characterized by an accumulation of cystine inside the lysosomes"
Orphanet summarizes the defining lysosomal cystine storage mechanism.
PMID:27990015 SUPPORT Human Clinical
"results in an accumulation of cystine in all organs"
Review evidence supports multisystem cystine accumulation from the transporter defect.
PMID:27990015 SUPPORT Human Clinical
"identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy"
Mechanistic review links cystinosin deficiency to broader lysosomal and autophagy abnormalities.
Proximal tubule cell dysfunction and renal Fanconi syndrome
Cystinosin deficiency causes early and severe proximal tubule dysfunction. This produces renal Fanconi syndrome with urinary losses of electrolytes, bicarbonate, minerals, glucose, amino acids, and low-molecular-weight proteins, leading to dehydration, acidosis, rickets, poor growth, and progressive renal impairment.
epithelial cell of proximal tubule link
proximal tubule link kidney link
Downstream
Progressive kidney failure Chronic glomerular damage and tubular disease progress to kidney failure when untreated.
Electrolyte wasting, rickets, and growth failure Tubular wasting drives mineral/electrolyte abnormalities, skeletal disease, and impaired growth.
Renal Fanconi syndrome Proximal tubular dysfunction presents clinically as renal Fanconi syndrome.
Renal tubular dysfunction The proximal tubular defect produces broader renal tubular dysfunction.
Renal tubular solute wasting Fanconi syndrome causes urinary wasting of electrolytes, minerals, glucose, amino acids, and low-molecular-weight solutes.
Decreased circulating carnitine concentration Fanconi-related tubular solute and nutrient wasting can contribute to reduced circulating carnitine.
Proteinuria Tubular injury includes urinary loss of low-molecular-weight proteins.
Glycosuria Impaired proximal tubular reabsorption causes urinary glucose loss.
Aminoaciduria Impaired proximal tubular reabsorption causes urinary amino-acid loss.
Hyperphosphaturia Impaired proximal tubular phosphate reabsorption causes phosphate wasting.
Aciduria Tubular bicarbonate and acid-base handling abnormalities contribute to aciduria.
Nephrogenic diabetes insipidus Proximal tubular disease and renal concentrating defects contribute to nephrogenic diabetes insipidus.
Polydipsia Tubular dysfunction with concentrating defects produces polydipsia.
Dehydration Polyuria and renal tubular wasting predispose affected children to dehydration.
Show evidence (3 references)
PMID:27990015 SUPPORT Human Clinical
"renal Fanconi syndrome is often the first manifestation of cystinosis"
Review evidence identifies Fanconi syndrome as the early clinical manifestation.
PMID:27990015 SUPPORT Human Clinical
"dysfunction of proximal tubule cells"
Supports proximal tubule cell dysfunction as the renal mechanism.
PMID:20301574 SUPPORT Human Clinical
"signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis)"
GeneReviews ties the renal tubular defect to characteristic clinical and biochemical losses.
Electrolyte wasting, rickets, and growth failure
Renal Fanconi syndrome causes urinary wasting of electrolytes, bicarbonate, minerals, glucose, and amino acids. These losses drive metabolic acidosis, hypophosphatemia, hypocalcemia, hypokalemia, hypophosphatemic/calcipenic rickets, and impaired growth.
monoatomic ion transport link phosphate ion transport link bicarbonate transport link neutral amino acid transport link
proximal tubule link
Downstream
Rickets Mineral wasting contributes to hypophosphatemic/calcipenic rickets.
Short stature Chronic Fanconi syndrome and mineral losses contribute to impaired growth.
Hypophosphatemia Phosphate wasting causes hypophosphatemia.
Hypokalemia Potassium wasting causes hypokalemia.
Metabolic acidosis Bicarbonate wasting contributes to metabolic acidosis.
Hypocalcemia Mineral wasting contributes to hypocalcemia.
Hyponatremia Sodium wasting can contribute to hyponatremia.
Elevated circulating alkaline phosphatase concentration Rickets and mineral bone disease are accompanied by elevated alkaline phosphatase.
Osteomalacia Chronic mineral wasting contributes to osteomalacia.
Failure to thrive Tubular wasting, acidosis, and mineral depletion impair weight gain.
Growth delay Chronic Fanconi syndrome and mineral losses impair growth.
Nephrocalcinosis Disturbed renal mineral handling can contribute to nephrocalcinosis.
Nephrolithiasis Disturbed renal mineral handling can contribute to nephrolithiasis.
Show evidence (3 references)
PMID:20301574 SUPPORT Human Clinical
"poor growth, hypophosphatemic/calcipenic rickets"
GeneReviews connects nephropathic cystinosis to poor growth and rickets.
PMID:20301574 SUPPORT Human Clinical
"increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals"
GeneReviews documents the renal tubular wasting mechanism.
PMID:20301574 SUPPORT Human Clinical
"elevated serum alkaline phosphatase; and hypocalcemia,"
GeneReviews supports downstream mineral and biochemical abnormalities from tubular wasting.
Progressive kidney failure
In untreated nephropathic cystinosis, renal Fanconi syndrome and glomerular impairment progress to end-stage kidney disease during childhood, although cysteamine and renal replacement therapy have improved survival.
kidney link
Downstream
Renal insufficiency Progressive glomerular impairment manifests as renal insufficiency and end-stage kidney disease.
Nephropathy Chronic tubular and glomerular injury produce nephropathic disease.
Show evidence (2 references)
PMID:20301574 SUPPORT Human Clinical
"within the first 12 years of life if untreated"
GeneReviews describes childhood progression to end-stage kidney disease without treatment.
PMID:29260317 SUPPORT Human Clinical
"develop end-stage renal disease (ESRD) by 10-12 years of age."
Treatment review confirms the natural-history timing of untreated kidney failure.
Corneal cystine crystal deposition
Cystine crystal deposition in the cornea is a hallmark ocular manifestation and causes photophobia; ocular cystinosis can present with photophobia from corneal cystine accumulation even without nephropathic disease.
cornea link
Downstream
Photophobia Corneal cystine crystal deposition causes photophobia.
Corneal opacity Corneal crystal disease contributes to corneal opacity.
Band keratopathy Chronic corneal involvement can present as band keratopathy.
Visual impairment Ocular cystine crystal disease can impair vision.
Show evidence (2 references)
PMID:20301574 SUPPORT Human Clinical
"resulting from corneal cystine crystal accumulation."
GeneReviews directly links ocular symptoms to corneal cystine crystal accumulation.
PMID:29260317 SUPPORT Human Clinical
"Early corneal cystine crystal deposition is a hallmark of the disease."
Review evidence supports corneal crystal deposition as a hallmark feature.
Extrarenal tissue cystine accumulation
Continued cystine storage affects multiple organs over time, including the eye, thyroid, gonads, pancreas, muscle, bone marrow, liver, nervous system, lungs, and bones, explaining the broad extrarenal phenotype burden.
Downstream
Retinopathy Eye involvement beyond the cornea can include retinopathy.
Hypothyroidism Thyroid involvement causes hypothyroidism.
Hypogonadism Gonadal involvement contributes to hypogonadism.
Delayed puberty Gonadal endocrine dysfunction can delay puberty.
Azoospermia Male gonadal involvement can result in azoospermia.
Glucose intolerance Pancreatic involvement can impair glucose handling.
Abnormality of endocrine pancreas physiology Pancreatic involvement can alter endocrine pancreas function.
Type I diabetes mellitus Pancreatic endocrine dysfunction can manifest as diabetes mellitus.
Myopathy Muscle involvement contributes to cystinotic myopathy.
Muscle weakness Myopathic involvement causes progressive muscle weakness.
EMG myopathic abnormalities Muscle involvement can produce myopathic abnormalities on electromyography.
Hypotonia Neuromuscular involvement can manifest as hypotonia.
Gait disturbance Neuromuscular involvement can impair gait.
Dysphagia Gastrointestinal and muscle involvement can produce swallowing difficulty.
Feeding difficulties Gastrointestinal involvement contributes to feeding difficulties.
Vomiting Gastrointestinal involvement contributes to vomiting.
Constipation Gastrointestinal dysmotility can contribute to constipation.
Malabsorption Gastrointestinal and pancreatic involvement can contribute to malabsorption.
Exocrine pancreatic insufficiency Pancreatic involvement can impair exocrine pancreatic function.
Hepatomegaly Liver involvement can manifest as hepatomegaly.
Splenomegaly Hepatic and portal-system involvement can manifest as splenomegaly.
Portal hypertension Hepatobiliary involvement can contribute to portal hypertension.
Mild intellectual disability Nervous-system involvement can affect neurocognitive development.
Aphasia Nervous-system involvement can contribute to language impairment.
Cranial nerve paralysis Nervous-system involvement can manifest as cranial nerve dysfunction.
Fatigue Multisystem cystinosis burden can contribute to fatigue.
Fever Multisystem cystinosis can include fever, with the specific storage-to-fever intermediate unresolved.
Show evidence (2 references)
PMID:20301574 SUPPORT Human Clinical
"accumulation of cystine in almost all cells, leading to cellular dysfunction"
GeneReviews connects widespread cystine accumulation to cellular and organ dysfunction.
PMID:29260317 SUPPORT Human Clinical
"may affect several other organs over time, including the eye, thyroid gland, gonads, pancreas, muscles"
Treatment review enumerates the multi-organ complications of cystinosis.
⬡

Pathograph

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

57
Cardiovascular 2
Portal hypertension OCCASIONAL Portal hypertension (HP:0001409)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001409 | Portal hypertension | Occasional (29-5%)"
Orphanet phenotype table lists portal hypertension as occasional in cystinosis.
Splenomegaly FREQUENT Splenomegaly (HP:0001744)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001744 | Splenomegaly | Frequent (79-30%)"
Orphanet phenotype table lists splenomegaly as frequent in cystinosis.
Digestive 7
Exocrine pancreatic insufficiency OCCASIONAL Exocrine pancreatic insufficiency (HP:0001738)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001738 | Exocrine pancreatic insufficiency | Occasional (29-5%)"
Orphanet phenotype table lists exocrine pancreatic insufficiency as occasional in cystinosis.
Vomiting VERY_FREQUENT Vomiting (HP:0002013)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002013 | Vomiting | Very frequent (99-80%)"
Orphanet phenotype table lists vomiting as very frequent in cystinosis.
Dysphagia FREQUENT Dysphagia (HP:0002015)
Show evidence (1 reference)
DOI:10.1007/s00467-023-06211-6 SUPPORT Human Clinical
"vomiting, hyperacidity, dysphagia, dysmotility, and diarrhea, are nearly universal among patients with nephropathic cystinosis."
Gastrointestinal review evidence supports dysphagia as a common sequela of nephropathic cystinosis.
Constipation OCCASIONAL Constipation (HP:0002019)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002019 | Constipation | Occasional (29-5%)"
Orphanet phenotype table lists constipation as occasional in cystinosis.
Malabsorption OCCASIONAL Malabsorption (HP:0002024)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002024 | Malabsorption | Occasional (29-5%)"
Orphanet phenotype table lists malabsorption as occasional in cystinosis.
Hepatomegaly FREQUENT Hepatomegaly (HP:0002240)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002240 | Hepatomegaly | Frequent (79-30%)"
Orphanet phenotype table lists hepatomegaly as frequent in cystinosis.
Feeding difficulties FREQUENT Feeding difficulties (HP:0011968)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0011968 | Feeding difficulties | Frequent (79-30%)"
Orphanet phenotype table lists feeding difficulties as frequent in cystinosis.
Endocrine 3
Hypogonadism FREQUENT Hypogonadism (HP:0000135)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000135 | Hypogonadism | Frequent (79-30%)"
Orphanet phenotype table lists hypogonadism as frequent in cystinosis.
Hypothyroidism VERY_FREQUENT Hypothyroidism (HP:0000821)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000821 | Hypothyroidism | Very frequent (99-80%)"
Orphanet phenotype table lists hypothyroidism as very frequent in cystinosis.
Delayed puberty VERY_FREQUENT Delayed puberty (HP:0000823)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000823 | Delayed puberty | Very frequent (99-80%)"
Orphanet phenotype table lists delayed puberty as very frequent in cystinosis.
Eye 4
Retinopathy FREQUENT Retinopathy (HP:0000488)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000488 | Retinopathy | Frequent (79-30%)"
Orphanet phenotype table lists retinopathy as frequent in cystinosis.
Visual impairment OCCASIONAL Visual impairment (HP:0000505)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000505 | Visual impairment | Occasional (29-5%)"
Orphanet phenotype table lists visual impairment as occasional in cystinosis.
Photophobia VERY_FREQUENT Photophobia (HP:0000613)
Show evidence (2 references)
ORPHA:213 SUPPORT Other
"HP:0000613 | Photophobia | Very frequent (99-80%)"
Orphanet phenotype table lists photophobia as very frequent in cystinosis.
PMID:20301574 SUPPORT Human Clinical
"photophobia resulting from corneal cystine crystal accumulation."
GeneReviews links photophobia directly to corneal cystine crystal accumulation.
Corneal opacity VERY_FREQUENT Corneal opacity (HP:0007957)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0007957 | Corneal opacity | Very frequent (99-80%)"
Orphanet phenotype table lists corneal opacity as very frequent in cystinosis.
Genitourinary 8
Azoospermia OCCASIONAL Azoospermia (HP:0000027)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000027 | Azoospermia | Occasional (29-5%)"
Orphanet phenotype table lists azoospermia as occasional in cystinosis.
Renal insufficiency FREQUENT Renal insufficiency (HP:0000083)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000083 | Renal insufficiency | Frequent (79-30%)"
Orphanet phenotype table lists renal insufficiency as frequent in cystinosis.
Proteinuria VERY_FREQUENT Proteinuria (HP:0000093)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000093 | Proteinuria | Very frequent (99-80%)"
Orphanet phenotype table lists proteinuria as very frequent in cystinosis.
Nephropathy VERY_FREQUENT Nephropathy (HP:0000112)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000112 | Nephropathy | Very frequent (99-80%)"
Orphanet phenotype table lists nephropathy as very frequent in cystinosis.
Renal tubular dysfunction VERY_FREQUENT Renal tubular dysfunction (HP:0000124)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000124 | Renal tubular dysfunction | Very frequent (99-80%)"
Orphanet phenotype table lists renal tubular dysfunction as very frequent in cystinosis.
Nephrolithiasis FREQUENT Nephrolithiasis (HP:0000787)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000787 | Nephrolithiasis | Frequent (79-30%)"
Orphanet phenotype table lists nephrolithiasis as frequent in cystinosis.
Renal Fanconi syndrome VERY_FREQUENT Renal Fanconi syndrome (HP:0001994)
Show evidence (2 references)
ORPHA:213 SUPPORT Other
"HP:0001994 | Renal Fanconi syndrome | Very frequent (99-80%)"
Orphanet phenotype table lists renal Fanconi syndrome as very frequent in cystinosis.
PMID:29260317 SUPPORT Human Clinical
"present with renal Fanconi syndrome by 6-12 months of age"
Review evidence supports early renal Fanconi syndrome in nephropathic cystinosis.
Glycosuria FREQUENT Glycosuria (HP:0003076)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0003076 | Glycosuria | Frequent (79-30%)"
Orphanet phenotype table lists glycosuria as frequent in cystinosis.
Metabolism 8
Metabolic acidosis OCCASIONAL Metabolic acidosis (HP:0001942)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001942 | Metabolic acidosis | Occasional (29-5%)"
Orphanet phenotype table lists metabolic acidosis as occasional in cystinosis.
Dehydration VERY_FREQUENT Dehydration (HP:0001944)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001944 | Dehydration | Very frequent (99-80%)"
Orphanet phenotype table lists dehydration as very frequent in cystinosis.
Fever OCCASIONAL Fever (HP:0001945)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001945 | Fever | Occasional (29-5%)"
Orphanet phenotype table lists fever as occasional in cystinosis.
Glucose intolerance OCCASIONAL Glucose intolerance (HP:0001952)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001952 | Glucose intolerance | Occasional (29-5%)"
Orphanet phenotype table lists glucose intolerance as occasional in cystinosis.
Hypophosphatemia VERY_FREQUENT Hypophosphatemia (HP:0002148)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002148 | Hypophosphatemia | Very frequent (99-80%)"
Orphanet phenotype table lists hypophosphatemia as very frequent in cystinosis.
Hypokalemia VERY_FREQUENT Hypokalemia (HP:0002900)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002900 | Hypokalemia | Very frequent (99-80%)"
Orphanet phenotype table lists hypokalemia as very frequent in cystinosis.
Hypocalcemia FREQUENT Hypocalcemia (HP:0002901)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002901 | Hypocalcemia | Frequent (79-30%)"
Orphanet phenotype table lists hypocalcemia as frequent in cystinosis.
Hyponatremia OCCASIONAL Hyponatremia (HP:0002902)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002902 | Hyponatremia | Occasional (29-5%)"
Orphanet phenotype table lists hyponatremia as occasional in cystinosis.
Musculoskeletal 5
Hypotonia OCCASIONAL Hypotonia (HP:0001252)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001252 | Hypotonia | Occasional (29-5%)"
Orphanet phenotype table lists hypotonia as occasional in cystinosis.
Muscle weakness VERY_FREQUENT Muscle weakness (HP:0001324)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001324 | Muscle weakness | Very frequent (99-80%)"
Orphanet phenotype table lists muscle weakness as very frequent in cystinosis.
Rickets FREQUENT Rickets (HP:0002748)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002748 | Rickets | Frequent (79-30%)"
Orphanet phenotype table lists rickets as frequent in cystinosis.
Osteomalacia FREQUENT Osteomalacia (HP:0002749)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002749 | Osteomalacia | Frequent (79-30%)"
Orphanet phenotype table lists osteomalacia as frequent in cystinosis.
Myopathy VERY_FREQUENT Myopathy (HP:0003198)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0003198 | Myopathy | Very frequent (99-80%)"
Orphanet phenotype table lists myopathy as very frequent in cystinosis.
Nervous System 5
Mild intellectual disability OCCASIONAL Mild intellectual disability (HP:0001256)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001256 | Intellectual disability, mild | Occasional (29-5%)"
Orphanet phenotype table lists mild intellectual disability as occasional in cystinosis.
Gait disturbance OCCASIONAL Gait disturbance (HP:0001288)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001288 | Gait disturbance | Occasional (29-5%)"
Orphanet phenotype table lists gait disturbance as occasional in cystinosis.
Polydipsia VERY_FREQUENT Polydipsia (HP:0001959)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001959 | Polydipsia | Very frequent (99-80%)"
Orphanet phenotype table lists polydipsia as very frequent in cystinosis.
Aphasia OCCASIONAL Aphasia (HP:0002381)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0002381 | Aphasia | Occasional (29-5%)"
Orphanet phenotype table lists aphasia as occasional in cystinosis.
Cranial nerve paralysis OCCASIONAL Cranial nerve paralysis (HP:0006824)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0006824 | Cranial nerve paralysis | Occasional (29-5%)"
Orphanet phenotype table lists cranial nerve paralysis as occasional in cystinosis.
Cellular 1
Decreased circulating carnitine concentration OCCASIONAL Decreased circulating carnitine concentration (HP:0003234)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0003234 | Decreased circulating carnitine concentration | Occasional (29-5%)"
Orphanet phenotype table lists decreased circulating carnitine as occasional in cystinosis.
Constitutional 1
Fatigue VERY_FREQUENT Fatigue (HP:0012378)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0012378 | Fatigue | Very frequent (99-80%)"
Orphanet phenotype table lists fatigue as very frequent in cystinosis.
Growth 3
Failure to thrive VERY_FREQUENT Failure to thrive (HP:0001508)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001508 | Failure to thrive | Very frequent (99-80%)"
Orphanet phenotype table lists failure to thrive as very frequent in cystinosis.
Growth delay FREQUENT Growth delay (HP:0001510)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0001510 | Growth delay | Frequent (79-30%)"
Orphanet phenotype table lists growth delay as frequent in cystinosis.
Short stature VERY_FREQUENT Short stature (HP:0004322)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0004322 | Short stature | Very frequent (99-80%)"
Orphanet phenotype table lists short stature as very frequent in cystinosis.
Other 10
Nephrocalcinosis FREQUENT Nephrocalcinosis (HP:0000121)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000121 | Nephrocalcinosis | Frequent (79-30%)"
Orphanet phenotype table lists nephrocalcinosis as frequent in cystinosis.
Band keratopathy FREQUENT Band keratopathy (HP:0000585)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0000585 | Band keratopathy | Frequent (79-30%)"
Orphanet phenotype table lists band keratopathy as frequent in cystinosis.
Hyperphosphaturia FREQUENT Hyperphosphaturia (HP:0003109)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0003109 | Hyperphosphaturia | Frequent (79-30%)"
Orphanet phenotype table lists hyperphosphaturia as frequent in cystinosis.
Elevated circulating alkaline phosphatase concentration FREQUENT Elevated circulating alkaline phosphatase concentration (HP:0003155)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0003155 | Elevated circulating alkaline phosphatase concentration | Frequent (79-30%)"
Orphanet phenotype table lists elevated circulating alkaline phosphatase as frequent in cystinosis.
Aminoaciduria VERY_FREQUENT Aminoaciduria (HP:0003355)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0003355 | Aminoaciduria | Very frequent (99-80%)"
Orphanet phenotype table lists aminoaciduria as very frequent in cystinosis.
EMG myopathic abnormalities FREQUENT EMG: myopathic abnormalities (HP:0003458)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0003458 | EMG: myopathic abnormalities | Frequent (79-30%)"
Orphanet phenotype table lists EMG myopathic abnormalities as frequent in cystinosis.
Nephrogenic diabetes insipidus VERY_FREQUENT Nephrogenic diabetes insipidus (HP:0009806)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0009806 | Nephrogenic diabetes insipidus | Very frequent (99-80%)"
Orphanet phenotype table lists nephrogenic diabetes insipidus as very frequent in cystinosis.
Aciduria FREQUENT Aciduria (HP:0012072)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0012072 | Aciduria | Frequent (79-30%)"
Orphanet phenotype table lists aciduria as frequent in cystinosis.
Abnormality of endocrine pancreas physiology OCCASIONAL Abnormality of endocrine pancreas physiology (HP:0012093)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0012093 | Abnormality of endocrine pancreas physiology | Occasional (29-5%)"
Orphanet phenotype table lists abnormal endocrine pancreas physiology as occasional in cystinosis.
Type I diabetes mellitus VERY_FREQUENT Type I diabetes mellitus (HP:0100651)
Show evidence (1 reference)
ORPHA:213 SUPPORT Other
"HP:0100651 | Type I diabetes mellitus | Very frequent (99-80%)"
Orphanet phenotype table lists type I diabetes mellitus as very frequent in cystinosis.
🧬

Genetic Associations

1
CTNS variants (Causative)
Autosomal recessive
Show evidence (4 references)
PMID:20301574 SUPPORT Human Clinical
"caused by pathogenic variants in CTNS."
GeneReviews identifies CTNS pathogenic variants as causative.
PMID:29260317 SUPPORT Human Clinical
"It is caused by mutations in the CTNS gene that encodes"
Review evidence confirms CTNS encodes cystinosin and causes cystinosis.
url:https://www.ncbi.nlm.nih.gov/books/NBK1400/ SUPPORT Other
"Founder variants have been identified in several populations"
GeneReviews supports founder-variant considerations for CTNS molecular testing.
+ 1 more reference
💊

Treatments

7
Oral cysteamine bitartrate therapy
Action: Pharmacotherapy NCIT:C15986
Agent: cysteamine ↗
Oral cysteamine bitartrate is disease-directed cystine-depleting therapy. Early and lifelong treatment lowers lysosomal cystine burden, delays glomerular damage and ESRD, improves growth, and reduces extrarenal complications, although it does not fully correct the Fanconi syndrome.
Mechanism Target:
INHIBITS Intralysosomal cystine accumulation and lysosomal dysfunction — Cysteamine facilitates cystine depletion from lysosomes.
Show evidence (1 reference)
PMID:27990015 SUPPORT Human Clinical
"cysteamine, facilitates lysosomal cystine clearance"
Review evidence directly supports lysosomal cystine clearance as the treatment mechanism.
Show evidence (2 references)
PMID:20301574 SUPPORT Human Clinical
"cystine depletion therapy (cysteamine bitartrate) significantly delays progression of glomerular damage."
GeneReviews supports cysteamine bitartrate as disease-directed therapy that delays kidney damage.
PMID:29260317 SUPPORT Human Clinical
"long-term cysteamine treatment delays progression to ESRD"
Treatment review supports long-term clinical benefit of cysteamine.
Cysteamine ophthalmic drops
Action: Pharmacotherapy NCIT:C15986
Agent: cysteamine ↗
Cysteamine eye drops are used for corneal disease involvement and can relieve photophobia caused by corneal cystine crystals.
Mechanism Target:
INHIBITS Corneal cystine crystal deposition — Topical cysteamine treats corneal cystine crystal disease.
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"Cysteamine ophthalmic drops can relieve photophobia."
GeneReviews supports topical cysteamine for symptoms caused by corneal cystine crystal disease.
Target Phenotypes: Photophobia ↗ Corneal opacity ↗
Show evidence (2 references)
PMID:20301574 SUPPORT Human Clinical
"Cysteamine ophthalmic drops can relieve photophobia."
GeneReviews supports ophthalmic cysteamine for photophobia.
PMID:29260317 SUPPORT Human Clinical
"needs to be combined with cysteamine eye drops for"
Treatment review supports combining oral cysteamine with eye drops for corneal involvement.
Fanconi syndrome replacement therapy
Action: supportive care MAXO:0000950
Replacement of renal tubular losses includes electrolytes, bicarbonate, minerals, and other small-molecular-weight nutrients, with free access to water and additional fluid/nutrient replacement during dehydration.
Mechanism Target:
MODULATES Proximal tubule cell dysfunction and renal Fanconi syndrome — Replacement therapy mitigates consequences of renal tubular wasting.
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"Renal Fanconi syndrome is treated by replacement of tubular losses of electrolytes"
GeneReviews supports replacement therapy as management for renal tubular wasting downstream of Fanconi syndrome.
Target Phenotypes: Renal Fanconi syndrome ↗ Hypophosphatemia ↗ Hypokalemia ↗ Dehydration ↗
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"Renal Fanconi syndrome is treated by replacement of tubular losses of electrolytes"
GeneReviews supports replacement of tubular losses as Fanconi syndrome management.
Growth hormone therapy
Action: human growth hormone replacement therapy MAXO:0000780
Growth hormone therapy is supportive endocrine management used as needed for impaired growth in cystinosis.
Mechanism Target:
MODULATES Electrolyte wasting, rickets, and growth failure — Growth hormone is supportive management for impaired growth downstream of the Fanconi-syndrome growth-failure mechanism.
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"growth hormone therapy as needed"
GeneReviews lists growth hormone therapy for growth problems in cystinosis.
Target Phenotypes: Short stature ↗ Failure to thrive ↗
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"growth hormone therapy as needed"
GeneReviews lists growth hormone therapy as supportive management when needed for growth problems.
L-thyroxine therapy
Action: Pharmacotherapy NCIT:C15986
L-thyroxine is used as needed for cystinosis-associated hypothyroidism.
Mechanism Target:
MODULATES Extrarenal tissue cystine accumulation — L-thyroxine is supportive endocrine management for hypothyroidism downstream of extrarenal thyroid involvement.
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"L-thyroxine as needed for hypothyroidism"
GeneReviews lists thyroid hormone replacement for cystinosis-associated hypothyroidism.
Target Phenotypes: Hypothyroidism ↗
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"L-thyroxine as needed for hypothyroidism"
GeneReviews lists L-thyroxine as supportive treatment for hypothyroidism.
Renal dialysis
Action: renal dialysis MAXO:0000601
Dialysis is used as renal replacement therapy when renal glomerular disease progresses despite medical treatment.
Mechanism Target:
MODULATES Progressive kidney failure — Dialysis manages kidney failure rather than correcting cystinosin deficiency.
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"additional treatment of renal glomerular disease include dialysis and kidney transplant"
GeneReviews lists dialysis as renal replacement management once cystinosis progresses to glomerular kidney disease.
Target Phenotypes: Renal insufficiency ↗
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"additional treatment of renal glomerular disease include dialysis and kidney transplant"
GeneReviews lists dialysis as additional treatment for renal glomerular disease.
Kidney transplantation
Action: whole kidney transplantation MAXO:0010043
Kidney transplantation is indicated when medical treatment is no longer effective for progressive kidney failure in cystinosis.
Mechanism Target:
MODULATES Progressive kidney failure — Transplantation replaces failed kidney function without reversing systemic cystine storage.
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"Kidney transplantation is indicated when other medical treatments are no longer effective."
GeneReviews supports kidney transplantation as management for progressive renal disease not controlled by medical therapy.
Target Phenotypes: Renal insufficiency ↗
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"Kidney transplantation is indicated when other medical treatments are no longer effective."
GeneReviews supports kidney transplantation for refractory renal disease.
🔬

Biochemical Markers

2
Elevated leukocyte cystine (Elevated)
Context: Elevated cystine concentration in polymorphonuclear leukocytes is a diagnostic biochemical finding and reflects the lysosomal cystine storage mechanism.
Pathograph Readouts
Readout Of Intralysosomal cystine accumulation and lysosomal dysfunction Positive Diagnostic
Elevated cystine in polymorphonuclear leukocytes reports the systemic lysosomal cystine storage mechanism caused by CTNS/cystinosin deficiency.
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"elevated cystine concentration in polymorphonuclear leukocytes"
GeneReviews lists elevated leukocyte cystine as a diagnostic criterion.
Renal tubular solute wasting (Present)
Context: Fanconi syndrome causes urinary wasting of electrolytes, bicarbonate, minerals, glucose, amino acids, and low-molecular-weight proteins.
Pathograph Readouts
Readout Of Proximal tubule cell dysfunction and renal Fanconi syndrome Positive Diagnostic
Increased urinary losses of electrolytes, minerals, glucose, amino acids, and low-molecular-weight solutes report the proximal-tubule Fanconi syndrome mechanism.
Show evidence (1 reference)
PMID:20301574 SUPPORT Human Clinical
"increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals"
GeneReviews describes the characteristic renal tubular losses.
🔬

Clinical Trials

1
NCT03897361 PHASE_I COMPLETED
Phase 1/2 study of autologous human CD34+ hematopoietic stem cells from cystinosis patients modified ex vivo with CTNS lentiviral vector, evaluating safety and efficacy of gene-corrected hematopoietic stem cells.
Show evidence (1 reference)
clinicaltrials:NCT03897361 SUPPORT Human Clinical
"This study is a Phase 1/2 clinical trial that will assess the safety and efficacy of enriched gene-corrected hematopoietic stem cells isolated from patients affected with cystinosis."
ClinicalTrials.gov documents the cystinosis CTNS lentiviral HSC gene-therapy trial.
{ }

Source YAML

click to show 
name: Cystinosis
category: Mendelian
creation_date: "2026-05-03T00:00:00Z"
updated_date: "2026-05-21T15:52:21Z"
synonyms:
- Protein defect of cystin transport
- Cystine storage disease
description: >
  Cystinosis is an autosomal recessive lysosomal amino-acid transport disorder
  caused by biallelic pathogenic variants in CTNS, which encodes cystinosin.
  Cystinosin dysfunction impairs lysosomal cystine export, producing
  intralysosomal cystine accumulation and multisystem tissue injury, especially
  renal Fanconi syndrome and kidney failure in nephropathic forms and corneal
  cystine crystal disease in ocular involvement.
disease_term:
  preferred_term: cystinosis
  term:
    id: MONDO:0016239
    label: cystinosis
parents:
- Inborn disorder of lysosomal amino acid transport
- Lysosomal storage disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016239
      label: cystinosis
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:213
    mapping_justification: >
      Orphanet ORPHA:213 lists MONDO:0016239 as an exact cross-reference for
      cystinosis.
has_subtypes:
- name: Nephropathic infantile cystinosis
  display_name: Nephropathic (infantile) cystinosis
  classification: clinical_phenotype
  subtype_term:
    preferred_term: nephropathic cystinosis
    term:
      id: MONDO:0100151
      label: nephropathic cystinosis
  subtype_frequency: "95%"
  description: >
    The classic severe nephropathic form, corresponding to OMIM:219800, presents
    in infancy with renal Fanconi syndrome, growth failure, rickets, progressive
    glomerular impairment, and extrarenal cystine storage.
  evidence:
  - reference: ORPHA:213
    reference_title: "Cystinosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Three clinical forms have been described: nephropathic infantile, nephropathic juvenile and ocular."
    explanation: Orphanet defines the three clinical forms and names nephropathic infantile cystinosis.
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the most common form (95% of individuals with cystinosis)."
    explanation: GeneReviews identifies nephropathic infantile cystinosis as the dominant cystinosis subtype.
- name: Nephropathic juvenile cystinosis
  display_name: Later-onset (juvenile) nephropathic cystinosis
  classification: clinical_phenotype
  subtype_term:
    preferred_term: juvenile nephropathic cystinosis
    term:
      id: MONDO:0009066
      label: juvenile nephropathic cystinosis
  subtype_frequency: "5%"
  description: >
    A later-onset nephropathic form, corresponding to OMIM:219900, with typical
    nephropathic manifestations but delayed onset and untreated renal failure
    usually in adolescence or young adulthood.
  evidence:
  - reference: ORPHA:213
    reference_title: "Cystinosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Three clinical forms have been described: nephropathic infantile, nephropathic juvenile and ocular."
    explanation: Orphanet defines nephropathic juvenile cystinosis as a distinct clinical form.
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal glomerular failure occurs in untreated affected individuals, usually between ages 15 and 25 years."
    explanation: GeneReviews distinguishes later-onset juvenile disease by delayed renal failure.
- name: Non-nephropathic ocular cystinosis
  display_name: Non-nephropathic (ocular) cystinosis
  classification: clinical_phenotype
  subtype_term:
    preferred_term: ocular cystinosis
    term:
      id: MONDO:0009064
      label: ocular cystinosis
  subtype_frequency: "<1%"
  description: >
    The ocular non-nephropathic form, corresponding to OMIM:219750, is dominated
    by corneal cystine crystal disease and photophobia without the major renal
    Fanconi syndrome and kidney-failure course typical of nephropathic disease.
  evidence:
  - reference: ORPHA:213
    reference_title: "Cystinosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Three clinical forms have been described: nephropathic infantile, nephropathic juvenile and ocular."
    explanation: Orphanet defines ocular cystinosis as a distinct clinical form.
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-nephropathic adult (ocular) cystinosis: Characterized by photophobia resulting from corneal cystine crystal accumulation."
    explanation: GeneReviews distinguishes the non-nephropathic ocular phenotype from nephropathic disease.
external_assertions:
- name: Orphanet Cystinosis disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:213
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=213
  description: >
    Orphanet's ORPHA:213 structured record for Cystinosis includes the exact
    MONDO cross-reference, definition, autosomal recessive inheritance,
    epidemiology, and HPO phenotype annotations used in this entry.
  evidence:
  - reference: ORPHA:213
    reference_title: "Cystinosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0016239 | Exact"
    explanation: Orphanet maps ORPHA:213 exactly to the MONDO identifier used by this entry.
definitions:
- name: Orphanet cystinosis definition
  definition_type: OTHER
  description: >
    A rare lysosomal disease in which cystine accumulates inside lysosomes,
    damaging multiple organs and tissues, particularly the kidneys and eyes.
  evidence:
  - reference: ORPHA:213
    reference_title: "Cystinosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare lysosomal disease characterized by an accumulation of cystine inside the lysosomes"
    explanation: Orphanet supports the lysosomal cystine accumulation disease definition.
inheritance:
- name: Autosomal recessive
  description: Cystinosis is caused by biallelic pathogenic variants in CTNS.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:213
    reference_title: "Cystinosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for cystinosis.
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cystinosis is inherited in an autosomal recessive manner."
    explanation: GeneReviews confirms autosomal recessive inheritance.
pathophysiology:
- name: CTNS lysosomal cystine transporter deficiency
  description: >
    Biallelic pathogenic CTNS variants impair cystinosin, the lysosomal cystine
    transporter, reducing cystine export from lysosomes and disrupting
    intracellular cysteine homeostasis.
  genes:
  - preferred_term: CTNS
    term:
      id: hgnc:2518
      label: CTNS
  molecular_functions:
  - preferred_term: L-cystine transmembrane transporter activity
    term:
      id: GO:0015184
      label: L-cystine transmembrane transporter activity
  - preferred_term: transmembrane transporter activity
    term:
      id: GO:0022857
      label: transmembrane transporter activity
  biological_processes:
  - preferred_term: L-cystine transport
    term:
      id: GO:0015811
      label: L-cystine transport
  - preferred_term: lysosomal transport
    term:
      id: GO:0007041
      label: lysosomal transport
  - preferred_term: intracellular cysteine homeostasis
    term:
      id: GO:0080145
      label: intracellular cysteine homeostasis
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:11689434
    reference_title: "Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cystinosis is an inherited lysosomal storage disease characterized by defective"
    explanation: Defines cystinosis as a lysosomal storage disease with defective cystine transport.
  - reference: PMID:11689434
    reference_title: "Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "responsible for cystine export from lysosomes"
    explanation: Directly identifies cystinosin as the lysosomal cystine export transporter.
  - reference: PMID:29260317
    reference_title: Effects of long-term cysteamine treatment in patients with cystinosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "caused by mutations in the CTNS gene that encodes"
    explanation: Review evidence connects CTNS mutations to cystinosin deficiency in patients.
  downstream:
  - target: Intralysosomal cystine accumulation and lysosomal dysfunction
    description: Impaired cystinosin-mediated export produces intralysosomal cystine accumulation.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      reference_title: Cystinosis (Orphanet structured-database record)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: A rare lysosomal disease characterized by an accumulation of cystine inside the lysosomes
      explanation: This evidence supports Intralysosomal cystine accumulation and lysosomal dysfunction as a cystinosis consequence represented by the CTNS lysosomal cystine transporter deficiency edge.
- name: Intralysosomal cystine accumulation and lysosomal dysfunction
  description: >
    Failure to export cystine causes cystine accumulation in lysosomes throughout
    the body. Lysosomal storage is accompanied by broader abnormalities in
    endolysosomal trafficking, proteolysis, lysosomal clearance, autophagy, and
    cellular energy balance.
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  chemical_entities:
  - preferred_term: cystine
    term:
      id: CHEBI:17376
      label: cystine
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: ORPHA:213
    reference_title: "Cystinosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare lysosomal disease characterized by an accumulation of cystine inside the lysosomes"
    explanation: Orphanet summarizes the defining lysosomal cystine storage mechanism.
  - reference: PMID:27990015
    reference_title: "The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "results in an accumulation of cystine in all organs"
    explanation: Review evidence supports multisystem cystine accumulation from the transporter defect.
  - reference: PMID:27990015
    reference_title: "The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy"
    explanation: Mechanistic review links cystinosin deficiency to broader lysosomal and autophagy abnormalities.
  downstream:
  - target: Proximal tubule cell dysfunction and renal Fanconi syndrome
    description: Proximal tubule cells are especially vulnerable to cystinosin loss and lysosomal dysfunction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27990015
      reference_title: 'The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: renal Fanconi syndrome is often the first manifestation of cystinosis
      explanation: This evidence supports Proximal tubule cell dysfunction and renal Fanconi syndrome as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Intralysosomal cystine accumulation and lysosomal dysfunction to this target are not fully resolved.
  - target: Corneal cystine crystal deposition
    description: Cystine deposition in the cornea causes crystals and photophobia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301574
      reference_title: Cystinosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: resulting from corneal cystine crystal accumulation.
      explanation: This evidence supports Corneal cystine crystal deposition as a cystinosis consequence represented by the Intralysosomal cystine accumulation and lysosomal dysfunction edge.
  - target: Extrarenal tissue cystine accumulation
    description: Multisystem cystine accumulation drives endocrine, myopathic, hepatic, pancreatic, and neurologic complications.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301574
      reference_title: Cystinosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: accumulation of cystine in almost all cells, leading to cellular dysfunction
      explanation: This evidence supports Extrarenal tissue cystine accumulation as a cystinosis consequence represented by the Intralysosomal cystine accumulation and lysosomal dysfunction edge.
  - target: Elevated leukocyte cystine
    description: Lysosomal cystine storage is measured diagnostically as elevated cystine in leukocytes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301574
      reference_title: Cystinosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: elevated cystine concentration in polymorphonuclear leukocytes
      explanation: This evidence supports Elevated leukocyte cystine as a cystinosis consequence represented by the Intralysosomal cystine accumulation and lysosomal dysfunction edge.
- name: Proximal tubule cell dysfunction and renal Fanconi syndrome
  description: >
    Cystinosin deficiency causes early and severe proximal tubule dysfunction.
    This produces renal Fanconi syndrome with urinary losses of electrolytes,
    bicarbonate, minerals, glucose, amino acids, and low-molecular-weight
    proteins, leading to dehydration, acidosis, rickets, poor growth, and
    progressive renal impairment.
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:27990015
    reference_title: "The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "renal Fanconi syndrome is often the first manifestation of cystinosis"
    explanation: Review evidence identifies Fanconi syndrome as the early clinical manifestation.
  - reference: PMID:27990015
    reference_title: "The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysfunction of proximal tubule cells"
    explanation: Supports proximal tubule cell dysfunction as the renal mechanism.
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis)"
    explanation: GeneReviews ties the renal tubular defect to characteristic clinical and biochemical losses.
  downstream:
  - target: Progressive kidney failure
    description: Chronic glomerular damage and tubular disease progress to kidney failure when untreated.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301574
      reference_title: Cystinosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: within the first 12 years of life if untreated
      explanation: This evidence supports Progressive kidney failure as a cystinosis consequence; the edge is indirect because known clinical intermediates connect it to Proximal tubule cell dysfunction and renal Fanconi syndrome.
  - target: Electrolyte wasting, rickets, and growth failure
    description: Tubular wasting drives mineral/electrolyte abnormalities, skeletal disease, and impaired growth.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301574
      reference_title: Cystinosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: poor growth, hypophosphatemic/calcipenic rickets
      explanation: This evidence supports Electrolyte wasting, rickets, and growth failure as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Renal Fanconi syndrome
    description: Proximal tubular dysfunction presents clinically as renal Fanconi syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001994 | Renal Fanconi syndrome | Very frequent (99-80%)
      explanation: This evidence supports Renal Fanconi syndrome as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Renal tubular dysfunction
    description: The proximal tubular defect produces broader renal tubular dysfunction.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000124 | Renal tubular dysfunction | Very frequent (99-80%)
      explanation: This evidence supports Renal tubular dysfunction as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Renal tubular solute wasting
    description: Fanconi syndrome causes urinary wasting of electrolytes, minerals, glucose, amino acids, and low-molecular-weight solutes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301574
      reference_title: Cystinosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals
      explanation: This evidence supports Renal tubular solute wasting as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Decreased circulating carnitine concentration
    description: Fanconi-related tubular solute and nutrient wasting can contribute to reduced circulating carnitine.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0003234 | Decreased circulating carnitine concentration | Occasional (29-5%)
      explanation: This evidence supports Decreased circulating carnitine concentration as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Proteinuria
    description: Tubular injury includes urinary loss of low-molecular-weight proteins.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000093 | Proteinuria | Very frequent (99-80%)
      explanation: This evidence supports Proteinuria as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Glycosuria
    description: Impaired proximal tubular reabsorption causes urinary glucose loss.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0003076 | Glycosuria | Frequent (79-30%)
      explanation: This evidence supports Glycosuria as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Aminoaciduria
    description: Impaired proximal tubular reabsorption causes urinary amino-acid loss.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0003355 | Aminoaciduria | Very frequent (99-80%)
      explanation: This evidence supports Aminoaciduria as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Hyperphosphaturia
    description: Impaired proximal tubular phosphate reabsorption causes phosphate wasting.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0003109 | Hyperphosphaturia | Frequent (79-30%)
      explanation: This evidence supports Hyperphosphaturia as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Aciduria
    description: Tubular bicarbonate and acid-base handling abnormalities contribute to aciduria.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0012072 | Aciduria | Frequent (79-30%)
      explanation: This evidence supports Aciduria as a cystinosis consequence represented by the Proximal tubule cell dysfunction and renal Fanconi syndrome edge.
  - target: Nephrogenic diabetes insipidus
    description: Proximal tubular disease and renal concentrating defects contribute to nephrogenic diabetes insipidus.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0009806 | Nephrogenic diabetes insipidus | Very frequent (99-80%)
      explanation: This evidence supports Nephrogenic diabetes insipidus as a cystinosis consequence; the edge is indirect because known clinical intermediates connect it to Proximal tubule cell dysfunction and renal Fanconi syndrome.
  - target: Polydipsia
    description: Tubular dysfunction with concentrating defects produces polydipsia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001959 | Polydipsia | Very frequent (99-80%)
      explanation: This evidence supports Polydipsia as a cystinosis consequence; the edge is indirect because known clinical intermediates connect it to Proximal tubule cell dysfunction and renal Fanconi syndrome.
  - target: Dehydration
    description: Polyuria and renal tubular wasting predispose affected children to dehydration.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001944 | Dehydration | Very frequent (99-80%)
      explanation: This evidence supports Dehydration as a cystinosis consequence; the edge is indirect because known clinical intermediates connect it to Proximal tubule cell dysfunction and renal Fanconi syndrome.
- name: Electrolyte wasting, rickets, and growth failure
  description: >
    Renal Fanconi syndrome causes urinary wasting of electrolytes, bicarbonate,
    minerals, glucose, and amino acids. These losses drive metabolic acidosis,
    hypophosphatemia, hypocalcemia, hypokalemia, hypophosphatemic/calcipenic
    rickets, and impaired growth.
  biological_processes:
  - preferred_term: monoatomic ion transport
    term:
      id: GO:0006811
      label: monoatomic ion transport
  - preferred_term: phosphate ion transport
    term:
      id: GO:0006817
      label: phosphate ion transport
  - preferred_term: bicarbonate transport
    term:
      id: GO:0015701
      label: bicarbonate transport
  - preferred_term: neutral amino acid transport
    term:
      id: GO:0015804
      label: neutral amino acid transport
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "poor growth, hypophosphatemic/calcipenic rickets"
    explanation: GeneReviews connects nephropathic cystinosis to poor growth and rickets.
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals"
    explanation: GeneReviews documents the renal tubular wasting mechanism.
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated serum alkaline phosphatase; and hypocalcemia,"
    explanation: GeneReviews supports downstream mineral and biochemical abnormalities from tubular wasting.
  downstream:
  - target: Rickets
    description: Mineral wasting contributes to hypophosphatemic/calcipenic rickets.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002748 | Rickets | Frequent (79-30%)
      explanation: This evidence supports Rickets as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Short stature
    description: Chronic Fanconi syndrome and mineral losses contribute to impaired growth.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0004322 | Short stature | Very frequent (99-80%)
      explanation: This evidence supports Short stature as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Hypophosphatemia
    description: Phosphate wasting causes hypophosphatemia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002148 | Hypophosphatemia | Very frequent (99-80%)
      explanation: This evidence supports Hypophosphatemia as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Hypokalemia
    description: Potassium wasting causes hypokalemia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002900 | Hypokalemia | Very frequent (99-80%)
      explanation: This evidence supports Hypokalemia as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Metabolic acidosis
    description: Bicarbonate wasting contributes to metabolic acidosis.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001942 | Metabolic acidosis | Occasional (29-5%)
      explanation: This evidence supports Metabolic acidosis as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Hypocalcemia
    description: Mineral wasting contributes to hypocalcemia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002901 | Hypocalcemia | Frequent (79-30%)
      explanation: This evidence supports Hypocalcemia as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Hyponatremia
    description: Sodium wasting can contribute to hyponatremia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002902 | Hyponatremia | Occasional (29-5%)
      explanation: This evidence supports Hyponatremia as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Elevated circulating alkaline phosphatase concentration
    description: Rickets and mineral bone disease are accompanied by elevated alkaline phosphatase.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0003155 | Elevated circulating alkaline phosphatase concentration | Frequent (79-30%)
      explanation: This evidence supports Elevated circulating alkaline phosphatase concentration as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Osteomalacia
    description: Chronic mineral wasting contributes to osteomalacia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002749 | Osteomalacia | Frequent (79-30%)
      explanation: This evidence supports Osteomalacia as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Failure to thrive
    description: Tubular wasting, acidosis, and mineral depletion impair weight gain.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001508 | Failure to thrive | Very frequent (99-80%)
      explanation: This evidence supports Failure to thrive as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Growth delay
    description: Chronic Fanconi syndrome and mineral losses impair growth.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001510 | Growth delay | Frequent (79-30%)
      explanation: This evidence supports Growth delay as a cystinosis consequence represented by the Electrolyte wasting, rickets, and growth failure edge.
  - target: Nephrocalcinosis
    description: Disturbed renal mineral handling can contribute to nephrocalcinosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000121 | Nephrocalcinosis | Frequent (79-30%)
      explanation: This evidence supports Nephrocalcinosis as a cystinosis consequence; the edge is indirect because known clinical intermediates connect it to Electrolyte wasting, rickets, and growth failure.
  - target: Nephrolithiasis
    description: Disturbed renal mineral handling can contribute to nephrolithiasis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000787 | Nephrolithiasis | Frequent (79-30%)
      explanation: This evidence supports Nephrolithiasis as a cystinosis consequence; the edge is indirect because known clinical intermediates connect it to Electrolyte wasting, rickets, and growth failure.
- name: Progressive kidney failure
  description: >
    In untreated nephropathic cystinosis, renal Fanconi syndrome and glomerular
    impairment progress to end-stage kidney disease during childhood, although
    cysteamine and renal replacement therapy have improved survival.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "within the first 12 years of life if untreated"
    explanation: GeneReviews describes childhood progression to end-stage kidney disease without treatment.
  - reference: PMID:29260317
    reference_title: Effects of long-term cysteamine treatment in patients with cystinosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "develop end-stage renal disease (ESRD) by 10-12 years of age."
    explanation: Treatment review confirms the natural-history timing of untreated kidney failure.
  downstream:
  - target: Renal insufficiency
    description: Progressive glomerular impairment manifests as renal insufficiency and end-stage kidney disease.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000083 | Renal insufficiency | Frequent (79-30%)
      explanation: This evidence supports Renal insufficiency as a cystinosis consequence represented by the Progressive kidney failure edge.
  - target: Nephropathy
    description: Chronic tubular and glomerular injury produce nephropathic disease.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000112 | Nephropathy | Very frequent (99-80%)
      explanation: This evidence supports Nephropathy as a cystinosis consequence represented by the Progressive kidney failure edge.
- name: Corneal cystine crystal deposition
  description: >
    Cystine crystal deposition in the cornea is a hallmark ocular manifestation
    and causes photophobia; ocular cystinosis can present with photophobia from
    corneal cystine accumulation even without nephropathic disease.
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  chemical_entities:
  - preferred_term: cystine
    term:
      id: CHEBI:17376
      label: cystine
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting from corneal cystine crystal accumulation."
    explanation: GeneReviews directly links ocular symptoms to corneal cystine crystal accumulation.
  - reference: PMID:29260317
    reference_title: Effects of long-term cysteamine treatment in patients with cystinosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early corneal cystine crystal deposition is a hallmark of the disease."
    explanation: Review evidence supports corneal crystal deposition as a hallmark feature.
  downstream:
  - target: Photophobia
    description: Corneal cystine crystal deposition causes photophobia.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000613 | Photophobia | Very frequent (99-80%)
      explanation: This evidence supports Photophobia as a cystinosis consequence represented by the Corneal cystine crystal deposition edge.
  - target: Corneal opacity
    description: Corneal crystal disease contributes to corneal opacity.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0007957 | Corneal opacity | Very frequent (99-80%)
      explanation: This evidence supports Corneal opacity as a cystinosis consequence represented by the Corneal cystine crystal deposition edge.
  - target: Band keratopathy
    description: Chronic corneal involvement can present as band keratopathy.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000585 | Band keratopathy | Frequent (79-30%)
      explanation: This evidence supports Band keratopathy as a cystinosis consequence represented by the Corneal cystine crystal deposition edge.
  - target: Visual impairment
    description: Ocular cystine crystal disease can impair vision.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000505 | Visual impairment | Occasional (29-5%)
      explanation: This evidence supports Visual impairment as a cystinosis consequence; the edge is indirect because known clinical intermediates connect it to Corneal cystine crystal deposition.
- name: Extrarenal tissue cystine accumulation
  description: >
    Continued cystine storage affects multiple organs over time, including the
    eye, thyroid, gonads, pancreas, muscle, bone marrow, liver, nervous system,
    lungs, and bones, explaining the broad extrarenal phenotype burden.
  chemical_entities:
  - preferred_term: cystine
    term:
      id: CHEBI:17376
      label: cystine
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accumulation of cystine in almost all cells, leading to cellular dysfunction"
    explanation: GeneReviews connects widespread cystine accumulation to cellular and organ dysfunction.
  - reference: PMID:29260317
    reference_title: Effects of long-term cysteamine treatment in patients with cystinosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "may affect several other organs over time, including the eye, thyroid gland, gonads, pancreas, muscles"
    explanation: Treatment review enumerates the multi-organ complications of cystinosis.
  downstream:
  - target: Retinopathy
    description: Eye involvement beyond the cornea can include retinopathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000488 | Retinopathy | Frequent (79-30%)
      explanation: This evidence supports Retinopathy as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Hypothyroidism
    description: Thyroid involvement causes hypothyroidism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000821 | Hypothyroidism | Very frequent (99-80%)
      explanation: This evidence supports Hypothyroidism as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Hypogonadism
    description: Gonadal involvement contributes to hypogonadism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000135 | Hypogonadism | Frequent (79-30%)
      explanation: This evidence supports Hypogonadism as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Delayed puberty
    description: Gonadal endocrine dysfunction can delay puberty.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000823 | Delayed puberty | Very frequent (99-80%)
      explanation: This evidence supports Delayed puberty as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Azoospermia
    description: Male gonadal involvement can result in azoospermia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000027 | Azoospermia | Occasional (29-5%)
      explanation: This evidence supports Azoospermia as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Glucose intolerance
    description: Pancreatic involvement can impair glucose handling.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001952 | Glucose intolerance | Occasional (29-5%)
      explanation: This evidence supports Glucose intolerance as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Abnormality of endocrine pancreas physiology
    description: Pancreatic involvement can alter endocrine pancreas function.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0012093 | Abnormality of endocrine pancreas physiology | Occasional (29-5%)
      explanation: This evidence supports Abnormality of endocrine pancreas physiology as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Type I diabetes mellitus
    description: Pancreatic endocrine dysfunction can manifest as diabetes mellitus.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0100651 | Type I diabetes mellitus | Very frequent (99-80%)
      explanation: This evidence supports Type I diabetes mellitus as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Myopathy
    description: Muscle involvement contributes to cystinotic myopathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0003198 | Myopathy | Very frequent (99-80%)
      explanation: This evidence supports Myopathy as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Muscle weakness
    description: Myopathic involvement causes progressive muscle weakness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001324 | Muscle weakness | Very frequent (99-80%)
      explanation: This evidence supports Muscle weakness as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: EMG myopathic abnormalities
    description: Muscle involvement can produce myopathic abnormalities on electromyography.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'HP:0003458 | EMG: myopathic abnormalities | Frequent (79-30%)'
      explanation: This evidence supports EMG myopathic abnormalities as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Hypotonia
    description: Neuromuscular involvement can manifest as hypotonia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001252 | Hypotonia | Occasional (29-5%)
      explanation: This evidence supports Hypotonia as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Gait disturbance
    description: Neuromuscular involvement can impair gait.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001288 | Gait disturbance | Occasional (29-5%)
      explanation: This evidence supports Gait disturbance as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Dysphagia
    description: Gastrointestinal and muscle involvement can produce swallowing difficulty.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1007/s00467-023-06211-6
      reference_title: 'Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: vomiting, hyperacidity, dysphagia, dysmotility, and diarrhea, are nearly universal among patients with nephropathic cystinosis.
      explanation: This evidence supports Dysphagia as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Feeding difficulties
    description: Gastrointestinal involvement contributes to feeding difficulties.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0011968 | Feeding difficulties | Frequent (79-30%)
      explanation: This evidence supports Feeding difficulties as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Vomiting
    description: Gastrointestinal involvement contributes to vomiting.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002013 | Vomiting | Very frequent (99-80%)
      explanation: This evidence supports Vomiting as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Constipation
    description: Gastrointestinal dysmotility can contribute to constipation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002019 | Constipation | Occasional (29-5%)
      explanation: This evidence supports Constipation as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Malabsorption
    description: Gastrointestinal and pancreatic involvement can contribute to malabsorption.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002024 | Malabsorption | Occasional (29-5%)
      explanation: This evidence supports Malabsorption as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Exocrine pancreatic insufficiency
    description: Pancreatic involvement can impair exocrine pancreatic function.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001738 | Exocrine pancreatic insufficiency | Occasional (29-5%)
      explanation: This evidence supports Exocrine pancreatic insufficiency as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Hepatomegaly
    description: Liver involvement can manifest as hepatomegaly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002240 | Hepatomegaly | Frequent (79-30%)
      explanation: This evidence supports Hepatomegaly as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Splenomegaly
    description: Hepatic and portal-system involvement can manifest as splenomegaly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001744 | Splenomegaly | Frequent (79-30%)
      explanation: This evidence supports Splenomegaly as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Portal hypertension
    description: Hepatobiliary involvement can contribute to portal hypertension.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001409 | Portal hypertension | Occasional (29-5%)
      explanation: This evidence supports Portal hypertension as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Mild intellectual disability
    description: Nervous-system involvement can affect neurocognitive development.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001256 | Intellectual disability, mild | Occasional (29-5%)
      explanation: This evidence supports Mild intellectual disability as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Aphasia
    description: Nervous-system involvement can contribute to language impairment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0002381 | Aphasia | Occasional (29-5%)
      explanation: This evidence supports Aphasia as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Cranial nerve paralysis
    description: Nervous-system involvement can manifest as cranial nerve dysfunction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0006824 | Cranial nerve paralysis | Occasional (29-5%)
      explanation: This evidence supports Cranial nerve paralysis as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Fatigue
    description: Multisystem cystinosis burden can contribute to fatigue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0012378 | Fatigue | Very frequent (99-80%)
      explanation: This evidence supports Fatigue as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
  - target: Fever
    description: Multisystem cystinosis can include fever, with the specific storage-to-fever intermediate unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001945 | Fever | Occasional (29-5%)
      explanation: This evidence supports Fever as a cystinosis manifestation; the edge remains indirect because the specific intermediates from Extrarenal tissue cystine accumulation to this target are not fully resolved.
phenotypes:
- name: Azoospermia
  category: Reproductive
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000027 | Azoospermia | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists azoospermia as occasional in cystinosis.
- name: Renal insufficiency
  category: Renal
  frequency: FREQUENT
  subtypes:
  - Nephropathic infantile cystinosis
  - Nephropathic juvenile cystinosis
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000083 | Renal insufficiency | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists renal insufficiency as frequent in cystinosis.
- name: Proteinuria
  category: Renal
  frequency: VERY_FREQUENT
  subtypes:
  - Nephropathic infantile cystinosis
  - Nephropathic juvenile cystinosis
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000093 | Proteinuria | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists proteinuria as very frequent in cystinosis.
- name: Nephropathy
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nephropathy
    term:
      id: HP:0000112
      label: Nephropathy
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000112 | Nephropathy | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists nephropathy as very frequent in cystinosis.
- name: Nephrocalcinosis
  category: Renal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000121 | Nephrocalcinosis | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists nephrocalcinosis as frequent in cystinosis.
- name: Renal tubular dysfunction
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Renal tubular dysfunction
    term:
      id: HP:0000124
      label: Renal tubular dysfunction
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000124 | Renal tubular dysfunction | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists renal tubular dysfunction as very frequent in cystinosis.
- name: Hypogonadism
  category: Reproductive
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000135 | Hypogonadism | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists hypogonadism as frequent in cystinosis.
- name: Retinopathy
  category: Ocular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Retinopathy
    term:
      id: HP:0000488
      label: Retinopathy
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000488 | Retinopathy | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists retinopathy as frequent in cystinosis.
- name: Visual impairment
  category: Ocular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000505 | Visual impairment | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists visual impairment as occasional in cystinosis.
- name: Band keratopathy
  category: Ocular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Band keratopathy
    term:
      id: HP:0000585
      label: Band keratopathy
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000585 | Band keratopathy | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists band keratopathy as frequent in cystinosis.
- name: Photophobia
  category: Ocular
  frequency: VERY_FREQUENT
  subtypes:
  - Nephropathic infantile cystinosis
  - Nephropathic juvenile cystinosis
  - Non-nephropathic ocular cystinosis
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000613 | Photophobia | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists photophobia as very frequent in cystinosis.
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "photophobia resulting from corneal cystine crystal accumulation."
    explanation: GeneReviews links photophobia directly to corneal cystine crystal accumulation.
- name: Nephrolithiasis
  category: Renal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000787 | Nephrolithiasis | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists nephrolithiasis as frequent in cystinosis.
- name: Hypothyroidism
  category: Endocrine
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000821 | Hypothyroidism | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists hypothyroidism as very frequent in cystinosis.
- name: Delayed puberty
  category: Reproductive
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000823 | Delayed puberty | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists delayed puberty as very frequent in cystinosis.
- name: Hypotonia
  category: Neuromuscular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists hypotonia as occasional in cystinosis.
- name: Mild intellectual disability
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001256 | Intellectual disability, mild | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists mild intellectual disability as occasional in cystinosis.
- name: Gait disturbance
  category: Neuromuscular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001288 | Gait disturbance | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists gait disturbance as occasional in cystinosis.
- name: Muscle weakness
  category: Neuromuscular
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001324 | Muscle weakness | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists muscle weakness as very frequent in cystinosis.
- name: Portal hypertension
  category: Hepatobiliary
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001409 | Portal hypertension | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists portal hypertension as occasional in cystinosis.
- name: Failure to thrive
  category: Growth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001508 | Failure to thrive | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists failure to thrive as very frequent in cystinosis.
- name: Growth delay
  category: Growth
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001510 | Growth delay | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists growth delay as frequent in cystinosis.
- name: Exocrine pancreatic insufficiency
  category: Gastrointestinal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Exocrine pancreatic insufficiency
    term:
      id: HP:0001738
      label: Exocrine pancreatic insufficiency
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001738 | Exocrine pancreatic insufficiency | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists exocrine pancreatic insufficiency as occasional in cystinosis.
- name: Splenomegaly
  category: Hepatobiliary
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001744 | Splenomegaly | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists splenomegaly as frequent in cystinosis.
- name: Metabolic acidosis
  category: Metabolic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001942 | Metabolic acidosis | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists metabolic acidosis as occasional in cystinosis.
- name: Dehydration
  category: Systemic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001944 | Dehydration | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists dehydration as very frequent in cystinosis.
- name: Fever
  category: Systemic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001945 | Fever | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists fever as occasional in cystinosis.
- name: Glucose intolerance
  category: Endocrine
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Glucose intolerance
    term:
      id: HP:0001952
      label: Glucose intolerance
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001952 | Glucose intolerance | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists glucose intolerance as occasional in cystinosis.
- name: Polydipsia
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Polydipsia
    term:
      id: HP:0001959
      label: Polydipsia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001959 | Polydipsia | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists polydipsia as very frequent in cystinosis.
- name: Renal Fanconi syndrome
  category: Renal
  frequency: VERY_FREQUENT
  subtypes:
  - Nephropathic infantile cystinosis
  - Nephropathic juvenile cystinosis
  phenotype_term:
    preferred_term: Renal Fanconi syndrome
    term:
      id: HP:0001994
      label: Renal Fanconi syndrome
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001994 | Renal Fanconi syndrome | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists renal Fanconi syndrome as very frequent in cystinosis.
  - reference: PMID:29260317
    reference_title: Effects of long-term cysteamine treatment in patients with cystinosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "present with renal Fanconi syndrome by 6-12 months of age"
    explanation: Review evidence supports early renal Fanconi syndrome in nephropathic cystinosis.
- name: Vomiting
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002013 | Vomiting | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists vomiting as very frequent in cystinosis.
- name: Dysphagia
  category: Gastrointestinal
  frequency: FREQUENT
  subtypes:
  - Nephropathic infantile cystinosis
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: DOI:10.1007/s00467-023-06211-6
    reference_title: "Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "vomiting, hyperacidity, dysphagia, dysmotility, and diarrhea, are nearly universal among patients with nephropathic cystinosis."
    explanation: Gastrointestinal review evidence supports dysphagia as a common sequela of nephropathic cystinosis.
- name: Constipation
  category: Gastrointestinal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002019 | Constipation | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists constipation as occasional in cystinosis.
- name: Malabsorption
  category: Gastrointestinal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002024 | Malabsorption | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists malabsorption as occasional in cystinosis.
- name: Hypophosphatemia
  category: Metabolic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002148 | Hypophosphatemia | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists hypophosphatemia as very frequent in cystinosis.
- name: Hepatomegaly
  category: Hepatobiliary
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002240 | Hepatomegaly | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists hepatomegaly as frequent in cystinosis.
- name: Aphasia
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Aphasia
    term:
      id: HP:0002381
      label: Aphasia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002381 | Aphasia | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists aphasia as occasional in cystinosis.
- name: Rickets
  category: Skeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002748 | Rickets | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists rickets as frequent in cystinosis.
- name: Osteomalacia
  category: Skeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Osteomalacia
    term:
      id: HP:0002749
      label: Osteomalacia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002749 | Osteomalacia | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists osteomalacia as frequent in cystinosis.
- name: Hypokalemia
  category: Metabolic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002900 | Hypokalemia | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists hypokalemia as very frequent in cystinosis.
- name: Hypocalcemia
  category: Metabolic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002901 | Hypocalcemia | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists hypocalcemia as frequent in cystinosis.
- name: Hyponatremia
  category: Metabolic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002902 | Hyponatremia | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists hyponatremia as occasional in cystinosis.
- name: Glycosuria
  category: Renal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Glycosuria
    term:
      id: HP:0003076
      label: Glycosuria
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003076 | Glycosuria | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists glycosuria as frequent in cystinosis.
- name: Hyperphosphaturia
  category: Renal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperphosphaturia
    term:
      id: HP:0003109
      label: Hyperphosphaturia
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003109 | Hyperphosphaturia | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists hyperphosphaturia as frequent in cystinosis.
- name: Elevated circulating alkaline phosphatase concentration
  category: Metabolic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003155 | Elevated circulating alkaline phosphatase concentration | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists elevated circulating alkaline phosphatase as frequent in cystinosis.
- name: Myopathy
  category: Neuromuscular
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003198 | Myopathy | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists myopathy as very frequent in cystinosis.
- name: Decreased circulating carnitine concentration
  category: Metabolic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Decreased circulating carnitine concentration
    term:
      id: HP:0003234
      label: Decreased circulating carnitine concentration
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003234 | Decreased circulating carnitine concentration | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists decreased circulating carnitine as occasional in cystinosis.
- name: Aminoaciduria
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Aminoaciduria
    term:
      id: HP:0003355
      label: Aminoaciduria
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003355 | Aminoaciduria | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists aminoaciduria as very frequent in cystinosis.
- name: EMG myopathic abnormalities
  category: Neuromuscular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: "EMG: myopathic abnormalities"
    term:
      id: HP:0003458
      label: "EMG: myopathic abnormalities"
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003458 | EMG: myopathic abnormalities | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists EMG myopathic abnormalities as frequent in cystinosis.
- name: Short stature
  category: Growth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004322 | Short stature | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists short stature as very frequent in cystinosis.
- name: Cranial nerve paralysis
  category: Neurologic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cranial nerve paralysis
    term:
      id: HP:0006824
      label: Cranial nerve paralysis
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006824 | Cranial nerve paralysis | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists cranial nerve paralysis as occasional in cystinosis.
- name: Corneal opacity
  category: Ocular
  frequency: VERY_FREQUENT
  subtypes:
  - Nephropathic infantile cystinosis
  - Nephropathic juvenile cystinosis
  - Non-nephropathic ocular cystinosis
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007957 | Corneal opacity | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists corneal opacity as very frequent in cystinosis.
- name: Nephrogenic diabetes insipidus
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Nephrogenic diabetes insipidus
    term:
      id: HP:0009806
      label: Nephrogenic diabetes insipidus
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009806 | Nephrogenic diabetes insipidus | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists nephrogenic diabetes insipidus as very frequent in cystinosis.
- name: Feeding difficulties
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011968 | Feeding difficulties | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists feeding difficulties as frequent in cystinosis.
- name: Aciduria
  category: Metabolic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Aciduria
    term:
      id: HP:0012072
      label: Aciduria
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012072 | Aciduria | Frequent (79-30%)"
    explanation: Orphanet phenotype table lists aciduria as frequent in cystinosis.
- name: Abnormality of endocrine pancreas physiology
  category: Endocrine
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormality of endocrine pancreas physiology
    term:
      id: HP:0012093
      label: Abnormality of endocrine pancreas physiology
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012093 | Abnormality of endocrine pancreas physiology | Occasional (29-5%)"
    explanation: Orphanet phenotype table lists abnormal endocrine pancreas physiology as occasional in cystinosis.
- name: Fatigue
  category: Systemic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012378 | Fatigue | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists fatigue as very frequent in cystinosis.
- name: Type I diabetes mellitus
  category: Endocrine
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Type I diabetes mellitus
    term:
      id: HP:0100651
      label: Type I diabetes mellitus
  evidence:
  - reference: ORPHA:213
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100651 | Type I diabetes mellitus | Very frequent (99-80%)"
    explanation: Orphanet phenotype table lists type I diabetes mellitus as very frequent in cystinosis.
biochemical:
- name: Elevated leukocyte cystine
  presence: Elevated
  context: >
    Elevated cystine concentration in polymorphonuclear leukocytes is a
    diagnostic biochemical finding and reflects the lysosomal cystine storage
    mechanism.
  readouts:
  - target: Intralysosomal cystine accumulation and lysosomal dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Elevated cystine in polymorphonuclear leukocytes reports the systemic
      lysosomal cystine storage mechanism caused by CTNS/cystinosin deficiency.
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated cystine concentration in polymorphonuclear leukocytes"
    explanation: GeneReviews lists elevated leukocyte cystine as a diagnostic criterion.
- name: Renal tubular solute wasting
  presence: Present
  context: >
    Fanconi syndrome causes urinary wasting of electrolytes, bicarbonate,
    minerals, glucose, amino acids, and low-molecular-weight proteins.
  readouts:
  - target: Proximal tubule cell dysfunction and renal Fanconi syndrome
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased urinary losses of electrolytes, minerals, glucose, amino acids,
      and low-molecular-weight solutes report the proximal-tubule Fanconi
      syndrome mechanism.
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals"
    explanation: GeneReviews describes the characteristic renal tubular losses.
diagnosis:
- name: Slit-lamp corneal crystal examination
  description: >
    Slit-lamp examination for corneal cystine crystals is part of diagnostic
    evaluation and is especially central for ocular disease recognition.
  results: Identification of cystine crystals in the cornea.
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cystine crystals in the cornea identified on slit lamp examination"
    explanation: GeneReviews lists slit-lamp identification of corneal crystals as diagnostic evidence.
- name: Leukocyte or fibroblast cystine measurement
  description: >
    Elevated cystine concentration in polymorphonuclear leukocytes, cultured
    fibroblasts, or placenta supports biochemical diagnosis of cystinosis.
  markers: polymorphonuclear leukocyte cystine; cultured fibroblast cystine; placental cystine
  results: Elevated cystine concentration.
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated cystine concentration in polymorphonuclear leukocytes"
    explanation: GeneReviews identifies elevated leukocyte cystine as a diagnostic criterion.
- name: CTNS molecular genetic testing
  description: >
    Molecular confirmation is established by identifying biallelic pathogenic
    or likely pathogenic CTNS variants in a proband with supportive clinical
    and laboratory findings.
  markers: biallelic CTNS pathogenic or likely pathogenic variants
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic pathogenic variants in CTNS identified by molecular"
    explanation: GeneReviews includes biallelic CTNS pathogenic variants in diagnostic testing.
genetic:
- name: CTNS variants
  gene_term:
    preferred_term: CTNS
    term:
      id: hgnc:2518
      label: CTNS
  association: Causative
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: ORPHA:213
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Autosomal recessive"
      explanation: Orphanet reports autosomal recessive inheritance.
    - reference: PMID:20301574
      reference_title: "Cystinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cystinosis is inherited in an autosomal recessive manner."
      explanation: GeneReviews confirms autosomal recessive inheritance.
  variants:
  - name: Biallelic pathogenic CTNS variants
    description: >
      Biallelic pathogenic CTNS variants establish the molecular diagnosis and
      produce the cystinosin transporter defect.
    evidence:
    - reference: PMID:20301574
      reference_title: "Cystinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "biallelic pathogenic variants in CTNS identified by molecular"
      explanation: GeneReviews includes biallelic CTNS pathogenic variants in diagnostic testing.
  - name: Common 57-kb CTNS deletion
    description: >
      A recurrent 57-kb deletion affecting CTNS is the most common pathogenic
      variant in individuals from northern Europe and North America and is
      treated as an important founder variant in molecular diagnosis.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1400/
      reference_title: Cystinosis - GeneReviews - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This deletion accounts for 50%-70% of pathogenic variants identified in individuals from these regions"
      explanation: GeneReviews summarizes the regional frequency of the recurrent 57-kb CTNS deletion.
  features: >
    CTNS encodes cystinosin, a lysosomal cystine transporter. Biallelic
    pathogenic variants cause cystinosis by impairing lysosomal cystine export.
    Variant spectrum includes truncating, missense, splice, small insertion or
    deletion, and larger deletion alleles; the recurrent 57-kb deletion is a
    major founder allele in northern Europe and North America.
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "caused by pathogenic variants in CTNS."
    explanation: GeneReviews identifies CTNS pathogenic variants as causative.
  - reference: PMID:29260317
    reference_title: Effects of long-term cysteamine treatment in patients with cystinosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by mutations in the CTNS gene that encodes"
    explanation: Review evidence confirms CTNS encodes cystinosin and causes cystinosis.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1400/
    reference_title: Cystinosis - GeneReviews - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Founder variants have been identified in several populations"
    explanation: GeneReviews supports founder-variant considerations for CTNS molecular testing.
  - reference: CGGV:assertion_51c40c8e-b9e5-4f2e-a587-f75b029397af-2022-03-02T170000.000Z
    reference_title: "CTNS / cystinosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CTNS | HGNC:2518 | cystinosis | MONDO:0016239 | AR | Definitive"
    explanation: ClinGen classifies the CTNS-cystinosis gene-disease relationship as definitive with autosomal recessive inheritance.
environmental: []
treatments:
- name: Oral cysteamine bitartrate therapy
  description: >
    Oral cysteamine bitartrate is disease-directed cystine-depleting therapy.
    Early and lifelong treatment lowers lysosomal cystine burden, delays
    glomerular damage and ESRD, improves growth, and reduces extrarenal
    complications, although it does not fully correct the Fanconi syndrome.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cysteamine
      term:
        id: CHEBI:17141
        label: cysteamine
  target_mechanisms:
  - target: Intralysosomal cystine accumulation and lysosomal dysfunction
    treatment_effect: INHIBITS
    description: Cysteamine facilitates cystine depletion from lysosomes.
    evidence:
    - reference: PMID:27990015
      reference_title: "The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "cysteamine, facilitates lysosomal cystine clearance"
      explanation: Review evidence directly supports lysosomal cystine clearance as the treatment mechanism.
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cystine depletion therapy (cysteamine bitartrate) significantly delays progression of glomerular damage."
    explanation: GeneReviews supports cysteamine bitartrate as disease-directed therapy that delays kidney damage.
  - reference: PMID:29260317
    reference_title: Effects of long-term cysteamine treatment in patients with cystinosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long-term cysteamine treatment delays progression to ESRD"
    explanation: Treatment review supports long-term clinical benefit of cysteamine.
- name: Cysteamine ophthalmic drops
  description: >
    Cysteamine eye drops are used for corneal disease involvement and can
    relieve photophobia caused by corneal cystine crystals.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cysteamine
      term:
        id: CHEBI:17141
        label: cysteamine
  target_mechanisms:
  - target: Corneal cystine crystal deposition
    treatment_effect: INHIBITS
    description: Topical cysteamine treats corneal cystine crystal disease.
    evidence:
    - reference: PMID:20301574
      reference_title: "Cystinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cysteamine ophthalmic drops can relieve photophobia."
      explanation: GeneReviews supports topical cysteamine for symptoms caused by corneal cystine crystal disease.
  target_phenotypes:
  - preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  - preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cysteamine ophthalmic drops can relieve photophobia."
    explanation: GeneReviews supports ophthalmic cysteamine for photophobia.
  - reference: PMID:29260317
    reference_title: Effects of long-term cysteamine treatment in patients with cystinosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "needs to be combined with cysteamine eye drops for"
    explanation: Treatment review supports combining oral cysteamine with eye drops for corneal involvement.
- name: Fanconi syndrome replacement therapy
  description: >
    Replacement of renal tubular losses includes electrolytes, bicarbonate,
    minerals, and other small-molecular-weight nutrients, with free access to
    water and additional fluid/nutrient replacement during dehydration.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Proximal tubule cell dysfunction and renal Fanconi syndrome
    treatment_effect: MODULATES
    description: Replacement therapy mitigates consequences of renal tubular wasting.
    evidence:
    - reference: PMID:20301574
      reference_title: "Cystinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Renal Fanconi syndrome is treated by replacement of tubular losses of electrolytes"
      explanation: GeneReviews supports replacement therapy as management for renal tubular wasting downstream of Fanconi syndrome.
  target_phenotypes:
  - preferred_term: Renal Fanconi syndrome
    term:
      id: HP:0001994
      label: Renal Fanconi syndrome
  - preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
  - preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  - preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal Fanconi syndrome is treated by replacement of tubular losses of electrolytes"
    explanation: GeneReviews supports replacement of tubular losses as Fanconi syndrome management.
- name: Growth hormone therapy
  description: >
    Growth hormone therapy is supportive endocrine management used as needed
    for impaired growth in cystinosis.
  treatment_term:
    preferred_term: human growth hormone replacement therapy
    term:
      id: MAXO:0000780
      label: human growth hormone replacement therapy
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  target_mechanisms:
  - target: Electrolyte wasting, rickets, and growth failure
    treatment_effect: MODULATES
    description: Growth hormone is supportive management for impaired growth downstream of the Fanconi-syndrome growth-failure mechanism.
    evidence:
    - reference: PMID:20301574
      reference_title: "Cystinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "growth hormone therapy as needed"
      explanation: GeneReviews lists growth hormone therapy for growth problems in cystinosis.
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth hormone therapy as needed"
    explanation: GeneReviews lists growth hormone therapy as supportive management when needed for growth problems.
- name: L-thyroxine therapy
  description: L-thyroxine is used as needed for cystinosis-associated hypothyroidism.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  target_mechanisms:
  - target: Extrarenal tissue cystine accumulation
    treatment_effect: MODULATES
    description: L-thyroxine is supportive endocrine management for hypothyroidism downstream of extrarenal thyroid involvement.
    evidence:
    - reference: PMID:20301574
      reference_title: "Cystinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "L-thyroxine as needed for hypothyroidism"
      explanation: GeneReviews lists thyroid hormone replacement for cystinosis-associated hypothyroidism.
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "L-thyroxine as needed for hypothyroidism"
    explanation: GeneReviews lists L-thyroxine as supportive treatment for hypothyroidism.
- name: Renal dialysis
  description: >
    Dialysis is used as renal replacement therapy when renal glomerular disease
    progresses despite medical treatment.
  treatment_term:
    preferred_term: renal dialysis
    term:
      id: MAXO:0000601
      label: renal dialysis
  target_mechanisms:
  - target: Progressive kidney failure
    treatment_effect: MODULATES
    description: Dialysis manages kidney failure rather than correcting cystinosin deficiency.
    evidence:
    - reference: PMID:20301574
      reference_title: "Cystinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "additional treatment of renal glomerular disease include dialysis and kidney transplant"
      explanation: GeneReviews lists dialysis as renal replacement management once cystinosis progresses to glomerular kidney disease.
  target_phenotypes:
  - preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "additional treatment of renal glomerular disease include dialysis and kidney transplant"
    explanation: GeneReviews lists dialysis as additional treatment for renal glomerular disease.
- name: Kidney transplantation
  description: >
    Kidney transplantation is indicated when medical treatment is no longer
    effective for progressive kidney failure in cystinosis.
  treatment_term:
    preferred_term: whole kidney transplantation
    term:
      id: MAXO:0010043
      label: whole kidney transplantation
  target_mechanisms:
  - target: Progressive kidney failure
    treatment_effect: MODULATES
    description: Transplantation replaces failed kidney function without reversing systemic cystine storage.
    evidence:
    - reference: PMID:20301574
      reference_title: "Cystinosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Kidney transplantation is indicated when other medical treatments are no longer effective."
      explanation: GeneReviews supports kidney transplantation as management for progressive renal disease not controlled by medical therapy.
  target_phenotypes:
  - preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:20301574
    reference_title: "Cystinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney transplantation is indicated when other medical treatments are no longer effective."
    explanation: GeneReviews supports kidney transplantation for refractory renal disease.
clinical_trials:
- name: NCT03897361
  phase: PHASE_I
  status: COMPLETED
  description: >
    Phase 1/2 study of autologous human CD34+ hematopoietic stem cells from
    cystinosis patients modified ex vivo with CTNS lentiviral vector, evaluating
    safety and efficacy of gene-corrected hematopoietic stem cells.
  evidence:
  - reference: clinicaltrials:NCT03897361
    reference_title: A Phase 1/2 Study to Determine Safety and Efficacy of Transplantation With Autologous Human CD34+ Hematopoietic Stem Cells (HSC) From Mobilized Peripheral Blood Stem Cells (PBSC) of Patients With Cystinosis Modified by Ex Vivo Transduction Using pCCL-CTNS or pCDY.EFS.CTNS.T260I Lentiviral Vector and Will Include Transduction Enhancer When Required During Manufacturing
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study is a Phase 1/2 clinical trial that will assess the safety and efficacy of enriched gene-corrected hematopoietic stem cells isolated from patients affected with cystinosis."
    explanation: ClinicalTrials.gov documents the cystinosis CTNS lentiviral HSC gene-therapy trial.
  notes: >
    Trial title indicates a Phase 1/2 design; mapped to PHASE_I because the
    schema has no combined Phase 1/2 enum value.
references:
- reference: ORPHA:213
  title: Cystinosis
  findings: []
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1400/
  title: Cystinosis - GeneReviews - NCBI Bookshelf
  findings: []
- reference: PMID:20301574
  title: Cystinosis.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:11689434
  title: "Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter."
  findings: []
- reference: PMID:27990015
  title: "The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives."
  findings: []
- reference: PMID:29260317
  title: Effects of long-term cysteamine treatment in patients with cystinosis.
  findings: []
- reference: DOI:10.1007/s00467-023-06179-3
  title: "Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective"
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1007/s00467-023-06211-6
  title: "Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives"
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1007/s00467-024-06345-1
  title: Addressing the psychosocial aspects of transition to adult care in patients with cystinosis
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1007/s44162-024-00041-2
  title: "Cystinosis - a review of disease pathogenesis, management, and future treatment options"
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1007/s44162-024-00046-x
  title: Unveiling cystinosis in India
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.jtos.2023.06.002
  title: The gene therapy for corneal pathology with novel nonsense cystinosis mouse lines created by CRISPR Gene Editing
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: PMID:37355021
  title: The gene therapy for corneal pathology with novel nonsense cystinosis mouse lines created by CRISPR Gene Editing.
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1038/s41598-023-47085-w
  title: Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: PMID:38016974
  title: Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis.
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1051/medsci/2023025
  title: Cystinose
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3390/ph17050649
  title: A New and Rapid LC-MS/MS Method for the Determination of Cysteamine Plasma Levels in Cystinosis Patients
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3390/pharmacy12040123
  title: "Adherence to Cysteamine Therapy Among Patients Diagnosed with Cystinosis in Saudi Arabia: A Prospective Cohort Study"
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
- reference: clinicaltrials:NCT03897361
  title: A Phase 1/2 Study to Determine Safety and Efficacy of Transplantation With Autologous Human CD34+ Hematopoietic Stem Cells (HSC) From Mobilized Peripheral Blood Stem Cells (PBSC) of Patients With Cystinosis Modified by Ex Vivo Transduction Using pCCL-CTNS or pCDY.EFS.CTNS.T260I Lentiviral Vector and Will Include Transduction Enhancer When Required During Manufacturing
  found_in:
  - Cystinosis-deep-research-falcon.md
  findings: []
notes: >-
  Curation emphasizes the direct ORPHA:213/MONDO disease mapping and the compact
  mechanistic chain from CTNS/cystinosin loss of lysosomal cystine export to
  lysosomal cystine accumulation, proximal tubular Fanconi syndrome, progressive
  kidney failure, corneal crystal disease, and multisystem extrarenal storage
  complications.
📚

References & Deep Research

References

19
ORPHA:213
Cystinosis
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/books/NBK1400/
Cystinosis - GeneReviews - NCBI Bookshelf
No top-level findings curated for this source.
PMID:20301574
Cystinosis.
No top-level findings curated for this source.
PMID:11689434
Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter.
No top-level findings curated for this source.
PMID:27990015
The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives.
No top-level findings curated for this source.
PMID:29260317
Effects of long-term cysteamine treatment in patients with cystinosis.
No top-level findings curated for this source.
DOI:10.1007/s00467-023-06179-3
Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective
No top-level findings curated for this source.
DOI:10.1007/s00467-023-06211-6
Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives
No top-level findings curated for this source.
DOI:10.1007/s00467-024-06345-1
Addressing the psychosocial aspects of transition to adult care in patients with cystinosis
No top-level findings curated for this source.
DOI:10.1007/s44162-024-00041-2
Cystinosis - a review of disease pathogenesis, management, and future treatment options
No top-level findings curated for this source.
DOI:10.1007/s44162-024-00046-x
Unveiling cystinosis in India
No top-level findings curated for this source.
DOI:10.1016/j.jtos.2023.06.002
The gene therapy for corneal pathology with novel nonsense cystinosis mouse lines created by CRISPR Gene Editing
No top-level findings curated for this source.
PMID:37355021
The gene therapy for corneal pathology with novel nonsense cystinosis mouse lines created by CRISPR Gene Editing.
No top-level findings curated for this source.
DOI:10.1038/s41598-023-47085-w
Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis
No top-level findings curated for this source.
PMID:38016974
Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis.
No top-level findings curated for this source.
No top-level findings curated for this source.
DOI:10.3390/ph17050649
A New and Rapid LC-MS/MS Method for the Determination of Cysteamine Plasma Levels in Cystinosis Patients
No top-level findings curated for this source.
DOI:10.3390/pharmacy12040123
Adherence to Cysteamine Therapy Among Patients Diagnosed with Cystinosis in Saudi Arabia: A Prospective Cohort Study
No top-level findings curated for this source.
clinicaltrials:NCT03897361
A Phase 1/2 Study to Determine Safety and Efficacy of Transplantation With Autologous Human CD34+ Hematopoietic Stem Cells (HSC) From Mobilized Peripheral Blood Stem Cells (PBSC) of Patients With Cystinosis Modified by Ex Vivo Transduction Using pCCL-CTNS or pCDY.EFS.CTNS.T260I Lentiviral Vector and Will Include Transduction Enhancer When Required During Manufacturing
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 29 citations 2026-05-03T07:09:20.921029

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Cystinosis
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Cystinosis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Cystinosis (Mendelian lysosomal storage disorder): Comprehensive disease characteristics report (evidence-focused)

Executive summary

Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic CTNS pathogenic variants leading to deficient lysosomal cystine export (cystinosin dysfunction) and intracellular/lysosomal cystine accumulation with crystal formation, producing early renal Fanconi syndrome and progressive multi‑organ disease (notably eye, endocrine organs, muscle, GI system). (devitt2024cystinosis—a pages 1-2, bondue2024novelmolecularmechanisms pages 20-23, cherqui2023[cystinosisfromthe pages 1-3)

A rapid-reference table of the highest-yield facts extracted from the evidence is provided here:

Topic Key details (with numbers) Source (paper/trial) Year URL/DOI Evidence citation ID
Definition / cause Rare autosomal recessive lysosomal storage disorder caused by biallelic CTNS variants encoding cystinosin, leading to lysosomal cystine accumulation and crystal formation Devitt review; Bondue review 2024 https://doi.org/10.1007/s44162-024-00041-2 (devitt2024cystinosis—a pages 1-2, bondue2024novelmolecularmechanisms pages 20-23)
Key identifiers MONDO_0016239 (cystinosis); related subtype MONDO terms include nephropathic infantile cystinosis and ocular cystinosis. Explicit MeSH term: D003554 Cystinosis Open Targets; ClinicalTrials.gov MeSH browse 2024 / 2010 https://platform.opentargets.org/ ; https://clinicaltrials.gov/study/NCT01197378 (NCT01197378 chunk 2)
Incidence / prevalence Incidence commonly reported as 0.5–1 per 100,000 live births; other reports cite 1:100,000–1:200,000. Regional founder-effect frequencies reported at 1:62,500 in Quebec and 1:26,000 in Brittany Devitt review; Simeoli study; Cherqui review 2024 / 2023 https://doi.org/10.1007/s44162-024-00041-2 ; https://doi.org/10.3390/ph17050649 ; https://doi.org/10.1051/medsci/2023025 (devitt2024cystinosis—a pages 1-2, simeoli2024anewand pages 1-2, cherqui2023[cystinosisfromthe pages 1-3)
Clinical forms / onset Three major forms: infantile/nephropathic (>95%, severe), juvenile/intermediate (<5%), ocular/non-nephropathic (<1%). Infantile disease typically presents at 6–12 months with renal Fanconi syndrome; juvenile around 12–15 years; ocular form causes mainly corneal disease/photophobia without major renal disease Bondue review; Cherqui review; Dong mouse paper 2024 / 2023 N/A ; https://doi.org/10.1051/medsci/2023025 ; PMID:37355021 / https://doi.org/10.1016/j.jtos.2023.06.002 (bondue2024novelmolecularmechanisms pages 20-23, cherqui2023[cystinosisfromthe pages 1-3, dong2023thegenetherapy pages 1-3)
Natural history / prognosis Untreated nephropathic disease progresses to kidney failure/ESKD in the first decade; with modern therapy, reports note 90% progress to kidney failure within the first 20 years. Kidney transplantation is required for ESKD Devitt review; Dong mouse paper 2024 / 2023 https://doi.org/10.1007/s44162-024-00041-2 ; PMID:37355021 / https://doi.org/10.1016/j.jtos.2023.06.002 (devitt2024cystinosis—a pages 1-2, dong2023thegenetherapy pages 1-3)
Key phenotypes Renal Fanconi syndrome with polyuria, phosphaturia, glycosuria, aminoaciduria, acidosis, growth retardation/rickets; extra-renal involvement includes corneal crystals/photophobia, hypothyroidism, diabetes, hypogonadism, myopathy, swallowing/respiratory complications Dong mouse paper; Devitt review; Cherqui review 2023 / 2024 PMID:37355021 / https://doi.org/10.1016/j.jtos.2023.06.002 ; https://doi.org/10.1007/s44162-024-00041-2 ; https://doi.org/10.1051/medsci/2023025 (dong2023thegenetherapy pages 1-3, devitt2024cystinosis—a pages 1-2, cherqui2023[cystinosisfromthe pages 1-3)
Diagnostic biomarker: leukocyte cystine PMN/WBC cystine thresholds reported as <0.20 healthy, <1.00 heterozygote, >3.00 nephropathic cystinosis. Preferred monitoring specimen is purified granulocytes/peripheral leukocytes Bondue review; Simeoli study 2024 https://doi.org/10.3390/ph17050649 (bondue2024novelmolecularmechanisms pages 20-23, simeoli2024anewand pages 1-2)
Diagnostic ophthalmology Slit-lamp examination for corneal cystine crystals is primary/pathognomonic; crystals may be evident by about 16 months. IVCM is described as gold standard in ocular assessment; AS-OCT can detect hyperreflective deposits Ocular review; India case series 2024 N/A ; https://doi.org/10.1007/s44162-024-00046-x (devitt2024ocularcystinosis–areview pages 1-2, heroor2024unveilingcystinosisin pages 9-11)
Diagnostic genetics >140–160 pathogenic CTNS variants reported; common 57-kb deletion accounts for about 50–70% of cases in North America/Northern Europe and up to ~75% of alleles in Northern Europe in one review. NGS-based CTNS testing is standard/feasible, including reflex use in newborn screening pilots Devitt review; Bondue review; Ocular review 2024 https://doi.org/10.1007/s44162-024-00041-2 (devitt2024cystinosis—a pages 1-2, bondue2024novelmolecularmechanisms pages 20-23, devitt2024ocularcystinosis–areview pages 1-2)
Standard treatment: oral cysteamine Disease-specific standard is cysteamine bitartrate. IR dosing generally every 6 h / four times daily; DR dosing every 12 h / twice daily. Cysteamine reduces cystine but is not curative and does not fully restore kidney function Simeoli study; Algasem cohort; Cherqui review 2024 / 2023 https://doi.org/10.3390/ph17050649 ; https://doi.org/10.3390/pharmacy12040123 ; https://doi.org/10.1051/medsci/2023025 (simeoli2024anewand pages 1-2, algasem2024adherencetocysteamine pages 1-2, cherqui2023[cystinosisfromthe pages 1-3)
Standard treatment: ocular cysteamine Oral cysteamine does not adequately treat avascular cornea. Topical cysteamine options include CYSTARAN (often hourly while awake) and more viscous gel formulations such as Cystadrops with less frequent dosing; older topical regimens may require 6–12 times/day Algasem cohort; Ocular review; India case series 2024 https://doi.org/10.3390/pharmacy12040123 ; https://doi.org/10.1007/s44162-024-00046-x (algasem2024adherencetocysteamine pages 1-2, devitt2024ocularcystinosis–areview pages 1-2, heroor2024unveilingcystinosisin pages 9-11)
Transplant / supportive care Kidney transplantation is standard for ESKD; cystinosis does not recur in the graft, but systemic cysteamine should be continued for extra-renal disease. Multidisciplinary supportive care is required for electrolytes, nutrition, endocrine, bone, eye, GI, and psychosocial complications Devitt review; India case series; Stabouli expert paper 2024 https://doi.org/10.1007/s44162-024-00041-2 ; https://doi.org/10.1007/s44162-024-00046-x ; https://doi.org/10.1007/s00467-024-06345-1 (devitt2024cystinosis—a pages 1-2, heroor2024unveilingcystinosisin pages 9-11)
Real-world adherence / QoL Saudi cohort: 25 patients, mean age 19.04 y, 64% female. MMAS-8: 26.7% high adherence, 46.7% medium, 26.7% low (n=15 respondents). Oral cysteamine MPR 96–100% in only 26.1% (6/23). Eye-drop adherence 76–95% in 38.4% (5/13). Most affected SF-36 domains: social functioning and energy/fatigue Algasem et al. prospective cohort 2024 https://doi.org/10.3390/pharmacy12040123 (algasem2024adherencetocysteamine pages 1-2, algasem2024adherencetocysteamine pages 4-6, algasem2024adherencetocysteamine pages 6-7)
Global access disparities International survey: 109 centers, 49 countries, 741 patients. Genetics availability 63% in developing/transition economies vs 100% in developed; intra-leukocyte cystine testing 30% vs 94–95%; delayed-release cysteamine access 7% vs 74%; cysteamine eye drops 63% vs 95% Regnier et al. survey 2024 https://doi.org/10.1007/s00467-023-06179-3 (regnier2024worldwidedisparitiesin pages 1-2, regnier2024worldwidedisparitiesin pages 7-8, regnier2024worldwidedisparitiesin pages 2-3, regnier2024worldwidedisparitiesin media 96f6e599)
Emerging therapy: HSPC gene therapy NCT03897361 Phase 1/2 autologous CD34+ lentiviral CTNS gene therapy; 6 participants planned/enrolled; busulfan conditioning; primary outcomes are safety, with leukocyte/granulocyte cystine, eGFR, thyroid measures, and vector copy number followed to 24 months plus long-term follow-up ClinicalTrials.gov stem cell gene therapy trial 2019 https://clinicaltrials.gov/study/NCT03897361 (NCT03897361 chunk 1, NCT03897361 chunk 2, NCT03897361 chunk 3)
Emerging therapy: ocular AAV gene therapy In CRISPR nonsense cystinosis mouse lines, scAAV-CTNS reduced corneal crystal pathology, supporting local ocular gene therapy development Dong et al. 2023 PMID:37355021 / https://doi.org/10.1016/j.jtos.2023.06.002 (dong2023thegenetherapy pages 1-3)
Emerging therapy: CTNS mRNA Synthetic CTNS mRNA restored lysosomal cystinosin in cell models and in ctns-/- zebrafish, reduced cystine for up to 14 days in vitro, improved proximal tubular reabsorption, reduced proteinuria, and restored megalin expression Bondue et al. 2023 PMID:38016974 / https://doi.org/10.1038/s41598-023-47085-w (bondue2023evaluationoftheefficacy pages 1-2)
Emerging strategy: newborn screening NCT06027385 completed German pilot using dried blood spots at 36–72 h; actual enrollment 300,000 newborns; first-tier multiplex PCR for 3 CTNS mutations with reflex NGS (~96.5% predicted detection). NCT05843851 recruiting pilot targets 200,000 newborns for cystinosis + primary hyperoxaluria using PCR plus reflex NGS ClinicalTrials.gov GENESIS studies 2018 / 2022 https://clinicaltrials.gov/study/NCT06027385 ; https://clinicaltrials.gov/study/NCT05843851 (NCT06027385 chunk 2, NCT06027385 chunk 1, NCT05843851 chunk 2, NCT05843851 chunk 1)

Table: This table condenses the most actionable cystinosis facts from the gathered evidence, including identifiers, epidemiology, phenotypes, diagnostics, standard care, real-world access/adherence data, and emerging therapies. It is useful as a rapid reference for populating a disease knowledge base entry.

A key visual summary of global disparities in access to testing and cysteamine therapy is available in the extracted table image. (regnier2024worldwidedisparitiesin media 96f6e599)

1. Disease information

1.1 Definition/overview (current understanding)

  • Cystinosis is described as a rare autosomal recessive lysosomal storage disorder characterized by lysosomal cystine accumulation due to CTNS/cystinosin dysfunction, causing cellular dysfunction and multi-organ damage. (devitt2024cystinosis—a pages 1-2, bondue2024novelmolecularmechanisms pages 20-23)
  • A recent review states: “Cystinosis is a rare autosomal recessive disease characterised by an accumulation of cystine in the lysosomes… caused by pathogenic variants of the cystinosin gene (CTNS).” (devitt2024cystinosis—a pages 1-2)

1.2 Key identifiers (as available from tool-retrieved evidence)

  • MONDO: MONDO_0016239 (“cystinosis”) appears as the disease identifier in Open Targets disease-target association data. (Open Targets tool output; MONDO ID itself is not reprinted in an evidence snippet, so it is not additionally citable beyond that tool-derived context.)
  • MeSH: ClinicalTrials.gov lists Cystinosis MeSH ID: D003554. (NCT01197378 chunk 2)

Not available in retrieved evidence excerpts: OMIM, Orphanet, ICD‑10/ICD‑11 codes were not explicitly provided in the texts successfully retrieved and evidence-scanned here; these will require direct lookup in OMIM/Orphanet/ICD resources outside the current evidence set.

1.3 Synonyms/alternative names (from retrieved sources)

  • Nephropathic cystinosis; infantile nephropathic cystinosis; juvenile/intermediate nephropathic cystinosis; ocular (non‑nephropathic) cystinosis. (bondue2024novelmolecularmechanisms pages 20-23, devitt2024ocularcystinosis–areview pages 1-2, dong2023thegenetherapy pages 1-3)

1.4 Evidence source types represented here

  • Aggregated disease-level resources: ClinicalTrials.gov metadata (MeSH mapping; trial protocol descriptions), and an international survey of treatment/testing access. (NCT01197378 chunk 2, regnier2024worldwidedisparitiesin pages 1-2)
  • Peer-reviewed reviews, clinical perspectives, cohort/case series, and preclinical model studies. (devitt2024cystinosis—a pages 1-2, joseph2024gastrointestinalchallengesin pages 1-2, algasem2024adherencetocysteamine pages 1-2, dong2023thegenetherapy pages 1-3)

2. Etiology

2.1 Disease causal factors

  • Genetic cause: Pathogenic variants in CTNS (cystinosin) disrupt lysosomal cystine export (cystine-H+ cotransporter), causing intralysosomal cystine accumulation and cystine crystal formation. (bondue2024novelmolecularmechanisms pages 20-23, devitt2024cystinosis—a pages 1-2, cherqui2023[cystinosisfromthe pages 1-3)
  • Variant spectrum: Reviews summarize >140–160 CTNS pathogenic variants and highlight a recurrent 57-kb deletion enriched in North America/Northern Europe (reported as 50–70% of cases in one ocular review and ~75% of alleles in Northern Europe in one review). (devitt2024ocularcystinosis–areview pages 1-2, bondue2024novelmolecularmechanisms pages 20-23, devitt2024cystinosis—a pages 1-2)

2.2 Risk factors

  • Primary risk is inheritance of biallelic CTNS pathogenic variants (autosomal recessive). (devitt2024cystinosis—a pages 1-2, cherqui2023[cystinosisfromthe pages 1-3)
  • Founder effects are implied by high regional frequencies (e.g., Quebec, Brittany) and recurrent variants/deletions reported in reviews. (devitt2024cystinosis—a pages 1-2)

2.3 Protective factors / gene–environment interactions

  • No protective genetic variants or specific gene–environment interactions were explicitly described in the retrieved evidence excerpts.

3. Phenotypes (clinical manifestations)

3.1 Core renal phenotype

  • Infantile/nephropathic cystinosis typically presents with renal Fanconi syndrome (proximal tubular dysfunction) starting in infancy (reported ~6–12 months), including polyuria, electrolyte losses, acidosis, phosphaturia, glycosuria, proteinuria, and growth retardation/rickets. (bondue2024novelmolecularmechanisms pages 20-23, dong2023thegenetherapy pages 1-3, cherqui2023[cystinosisfromthe pages 1-3)

Suggested HPO terms (examples): - Renal Fanconi syndrome (HP:0001994), Polydipsia (HP:0001959), Metabolic acidosis (HP:0001942), Hyperphosphaturia (HP:0003109), Glycosuria (HP:0003076), Aminoaciduria (HP:0003355), Rickets (HP:0002748), Growth delay (HP:0001510).

3.2 Ocular phenotype

  • Corneal cystine crystals are described as pathognomonic, with diagnosis “primarily made using slit lamp examination.” (devitt2024ocularcystinosis–areview pages 1-2)
  • A case series describes crystals as “needle‑shaped refractile opacities” and notes they can be evident by ~16 months, with photophobia. (heroor2024unveilingcystinosisin pages 9-11)

Suggested HPO terms: Photophobia (HP:0000613), Corneal opacity (HP:0007957).

3.3 Extra-renal phenotypes (endocrine, muscle, GI, neurologic)

  • Reviews and clinical perspectives summarize multi-organ disease including hypothyroidism, diabetes, hypogonadism, myopathy, and swallowing/respiratory complications. (devitt2024cystinosis—a pages 1-2, cherqui2023[cystinosisfromthe pages 1-3, joseph2024gastrointestinalchallengesin pages 7-9)
  • GI sequelae are described as “nearly universal” and occur “at virtually every disease stage,” with survey-based symptom frequencies including swallowing difficulties (54%), nausea (38%), loss of appetite (21%), diarrhea (19%), and vomiting (15%). (joseph2024gastrointestinalchallengesin pages 1-2)

Suggested HPO terms: Hypothyroidism (HP:0000821), Diabetes mellitus (HP:0000819), Hypogonadism (HP:0000135), Dysphagia (HP:0002015), Nausea (HP:0002018), Diarrhea (HP:0002014), Vomiting (HP:0002013).

3.4 Quality-of-life impact

  • A 2024 prospective cohort from Saudi Arabia found QoL deficits on SF‑36, with the lowest domain means in social functioning and energy/fatigue. (algasem2024adherencetocysteamine pages 1-2, algasem2024adherencetocysteamine pages 6-7)

4. Genetic / molecular information

4.1 Causal gene

  • CTNS encodes cystinosin, a lysosomal cystine–proton cotransporter; loss of function causes lysosomal cystine accumulation. (cherqui2023[cystinosisfromthe pages 1-3, bondue2024novelmolecularmechanisms pages 20-23)

4.2 Pathogenic variant types / notable alleles

  • Reviews cite numerous pathogenic variants (>140–160) and population-enriched large deletions (57 kb). (devitt2024cystinosis—a pages 1-2, bondue2024novelmolecularmechanisms pages 20-23, devitt2024ocularcystinosis–areview pages 1-2)

4.3 Modifier genes / epigenetic information

  • The retrieved evidence set does not provide a validated modifier-gene catalogue or epigenetic mechanisms specific to cystinosis.

5. Environmental information

Cystinosis is primarily genetic; the retrieved sources do not describe established environmental triggers or protective exposures.

6. Mechanism / pathophysiology

6.1 Primary molecular defect → cellular dysfunction → organ disease (causal chain)

  • Upstream: Biallelic CTNS loss-of-function → cystinosin deficiency in lysosomal membrane. (bondue2024novelmolecularmechanisms pages 20-23, cherqui2023[cystinosisfromthe pages 1-3)
  • Core biochemical consequence: failure of cystine export → intra-lysosomal cystine accumulation and crystal formation. (bondue2024novelmolecularmechanisms pages 20-23, cherqui2023[cystinosisfromthe pages 1-3)
  • Downstream (organ level): early proximal tubule dysfunction (Fanconi syndrome) → progression to chronic kidney disease/ESKD; systemic cystine/crystal effects in eye/endocrine/muscle/GI, etc. (bondue2024novelmolecularmechanisms pages 20-23, cherqui2023[cystinosisfromthe pages 1-3, joseph2024gastrointestinalchallengesin pages 1-2)

6.2 Key pathways and cellular processes (from retrieved sources)

  • Cysteamine is described mechanistically as reacting 1:1 with cystine to form products that can exit lysosomes; this reduces cystine but does not fully prevent later complications. (simeoli2024anewand pages 1-2)
  • Reviews also discuss downstream cellular dysfunction and note adjunct mechanistic approaches (e.g., TFEB activation; mTOR inhibition) as therapeutic concepts. (bondue2024novelmolecularmechanisms pages 20-23)

Suggested GO biological process terms (examples): lysosomal transport; cystine transport; autophagy; cellular response to oxidative stress. (GO IDs not provided in retrieved evidence; suggested conceptually.)

Suggested CL cell types (examples): kidney proximal tubule epithelial cell; podocyte; corneal epithelial cell; macrophage/monocyte (tissue crystals in macrophages are discussed in GI tissue studies). (joseph2024gastrointestinalchallengesin pages 1-2, joseph2024gastrointestinalchallengesin pages 4-6)

7. Anatomical structures affected

  • Primary organ/system: kidney (proximal tubule; Fanconi syndrome; ESKD). (bondue2024novelmolecularmechanisms pages 20-23, cherqui2023[cystinosisfromthe pages 1-3)
  • Common extra-renal: cornea/eye; endocrine organs (thyroid, pancreas/gonads); skeletal muscle; GI tract and hepatosplenic involvement. (devitt2024cystinosis—a pages 1-2, joseph2024gastrointestinalchallengesin pages 1-2, joseph2024gastrointestinalchallengesin pages 11-13)

Suggested UBERON terms (examples): kidney; proximal tubule; cornea; thyroid gland; pancreas; skeletal muscle; gastrointestinal tract; liver; spleen.

Suggested GO cellular component: lysosome.

8. Temporal development

  • Onset: infantile nephropathic cystinosis often starts in infancy (~6–12 months) with Fanconi syndrome. (bondue2024novelmolecularmechanisms pages 20-23, cherqui2023[cystinosisfromthe pages 1-3)
  • Progression: without treatment, progression to ESKD is described within the first decade; a review states “90%” progress to kidney failure within 20 years. (dong2023thegenetherapy pages 1-3, devitt2024cystinosis—a pages 1-2)

9. Inheritance and population

9.1 Inheritance

  • Autosomal recessive inheritance is consistently stated. (devitt2024cystinosis—a pages 1-2, cherqui2023[cystinosisfromthe pages 1-3)

9.2 Epidemiology statistics

  • Incidence estimates in recent sources include 0.5–1 per 100,000 live births and ~1:100,000–1:200,000 births, with higher regional frequencies reported in Quebec and Brittany. (devitt2024cystinosis—a pages 1-2, simeoli2024anewand pages 1-2, cherqui2023[cystinosisfromthe pages 1-3)

9.3 Health-system/real-world implementation disparities (2023 perspective; published 2024)

An international cross-sectional survey (109 centers/49 countries; 741 patients) quantified major inequities: - Genetic testing availability: 63% in developing/economies-in-transition vs 100% in developed economies. (regnier2024worldwidedisparitiesin pages 1-2, regnier2024worldwidedisparitiesin pages 2-3) - Intra-leukocyte cystine (IL‑CL) availability: 30% vs 94–95%. (regnier2024worldwidedisparitiesin pages 1-2, regnier2024worldwidedisparitiesin pages 2-3) - Delayed-release cysteamine availability: 7% vs 74%. (regnier2024worldwidedisparitiesin pages 1-2, regnier2024worldwidedisparitiesin pages 2-3) - Cysteamine eye drops availability: 63% vs 95%. (regnier2024worldwidedisparitiesin pages 2-3)

A table image extracted from the paper summarizes these access gaps by country grouping. (regnier2024worldwidedisparitiesin media 96f6e599)

10. Diagnostics

10.1 Core tests/biomarkers

  • Leukocyte (PMN/granulocyte) cystine is a key diagnostic/monitoring biomarker; one review reports thresholds: <0.20 (healthy), <1.00 (heterozygote), >3.00 (nephropathic cystinosis). (bondue2024novelmolecularmechanisms pages 20-23)
  • Ophthalmic slit-lamp examination for corneal crystals is a primary diagnostic approach for ocular involvement; corneal crystals are described as pathognomonic. (devitt2024ocularcystinosis–areview pages 1-2, heroor2024unveilingcystinosisin pages 9-11)
  • Genetic testing (CTNS) is part of diagnostic confirmation and is also the basis for newborn screening pilots using dried blood spots. (bondue2024novelmolecularmechanisms pages 20-23, NCT06027385 chunk 2)

10.2 Screening

  • Two German “GENESIS” molecular newborn screening pilots are documented on ClinicalTrials.gov:
  • NCT06027385 (GENESIS1): completed; dried blood spot at 36–72 h; first-tier multiplex PCR for 3 CTNS mutations with reflex NGS; actual enrollment 300,000. (NCT06027385 chunk 1, NCT06027385 chunk 2)
  • NCT05843851: recruiting; planned screening 200,000 newborns; PCR for common CTNS mutations with reflex amplicon-based NGS for pathogenic CTNS variants; start 2022‑03‑15. (NCT05843851 chunk 1, NCT05843851 chunk 2)

10.3 Differential diagnosis

A formal differential diagnosis list was not explicitly provided in the retrieved excerpts; clinically, early Fanconi syndrome prompts evaluation for other causes of proximal tubular dysfunction (not detailed in this evidence set).

11. Outcome / prognosis

  • Progression to kidney failure/ESKD remains a major outcome: one review reports “90% of cystinosis patients progress to kidney failure within the first 20 years of life” and notes kidney transplantation as the option at that stage. (devitt2024cystinosis—a pages 1-2)
  • GI and swallowing complications can contribute to morbidity and mortality: one clinical perspective reports that in a cohort, “5 of 33 deaths were attributed to a combination of respiratory and swallowing complications.” (joseph2024gastrointestinalchallengesin pages 7-9)

12. Treatment

12.1 Pharmacotherapy (standard of care)

  • Cysteamine bitartrate is the disease-specific cystine-depleting therapy; a 2024 methods paper states it is approved for children and adults and that it improved prognosis, but does not fully prevent progression/complications and has frequent side effects. (simeoli2024anewand pages 1-2)
  • Immediate-release (IR) vs delayed-release (DR) cysteamine: IR is commonly dosed q6h (four times/day) and DR q12h (twice/day); a cohort paper provides dosing examples and lists common adverse effects and adherence challenges. (algasem2024adherencetocysteamine pages 1-2)
  • Topical cysteamine is used for corneal crystals because oral therapy does not reach the avascular cornea; one cohort describes hourly dosing while awake for CYSTARAN®. (algasem2024adherencetocysteamine pages 1-2)

Suggested MAXO terms (examples): cystine-depleting therapy; oral pharmacotherapy; topical ophthalmic therapy; kidney transplantation; electrolyte supplementation; nutritional support.

12.2 Supportive and multidisciplinary management (real-world implementation)

  • A 2024 GI-focused clinical perspective emphasizes that GI sequelae are nearly universal and recommends proactive symptom monitoring, multidisciplinary management, and medication strategies to improve tolerability and adherence. (joseph2024gastrointestinalchallengesin pages 1-2, joseph2024gastrointestinalchallengesin pages 9-10)

12.3 Emerging/experimental therapies (pipeline)

  • Hematopoietic stem cell (HSPC) gene therapy: ClinicalTrials.gov trial NCT03897361 (Phase 1/2; status completed) evaluates autologous CD34+ cells transduced ex vivo with lentiviral vectors expressing CTNS, with primary outcomes focused on safety/tolerability and secondary measures including leukocyte/granulocyte cystine, eGFR, thyroid labs, and vector copy number through 24 months with long-term follow-up offered. (NCT03897361 chunk 1, NCT03897361 chunk 2, NCT03897361 chunk 3)
  • Ocular AAV gene therapy (preclinical): A 2023 mouse study reports experimental scAAV‑CTNS treatment reducing corneal crystal pathology in CRISPR-engineered nonsense cystinosis mouse lines. (dong2023thegenetherapy pages 1-3)

13. Prevention

  • Primary prevention: not applicable in the usual sense for an autosomal recessive monogenic disease.
  • Secondary prevention (earlier detection): molecular newborn screening pilots aim to enable earlier diagnosis and earlier initiation of cystine-depleting therapy to improve prognosis (ClinicalTrials.gov GENESIS programs). (NCT06027385 chunk 1, NCT05843851 chunk 1)

14. Other species / natural disease

The retrieved evidence set includes preclinical models but did not document naturally occurring cystinosis in companion animals or other species.

15. Model organisms

  • Mouse models: A 2023 ocular-surface study generated CRISPR-engineered nonsense cystinosis mouse lines and used them to evaluate ocular gene therapy (scAAV-CTNS) effects on corneal crystal phenotype. (PMID:37355021; dong2023thegenetherapy pages 1-3)

Recent developments (2023–2024 emphasis) and expert analysis

  1. Global implementation and access: A 2024 international survey provides quantitative evidence that disparities in access to genetic testing, leukocyte cystine monitoring, and delayed‑release cysteamine remain substantial between developing and developed economies, despite improvements over the last decade—important for real-world outcomes and equitable care. (regnier2024worldwidedisparitiesin pages 2-3, regnier2024worldwidedisparitiesin pages 1-2, regnier2024worldwidedisparitiesin media 96f6e599)
  2. Symptom burden beyond the kidney: A 2024 clinical perspective reframes GI morbidity as nearly universal and potentially modifiable with proactive multidisciplinary management; it also calls out evidence gaps and prioritizes future studies in GI care pathways. (joseph2024gastrointestinalchallengesin pages 1-2, joseph2024gastrointestinalchallengesin pages 13-14)
  3. Translation to disease-modifying therapies: Stem-cell gene therapy has progressed to a completed Phase 1/2 ClinicalTrials.gov study with long-term follow-up plans; ocular gene therapy has supportive preclinical evidence in mouse models. (NCT03897361 chunk 1, dong2023thegenetherapy pages 1-3)

Evidence gaps / limitations of this report

  • Many retrieved review/case-series excerpts did not include PMIDs in the available text; therefore, PMID-preferred citation could not be consistently provided from the tool-accessed evidence, even when the underlying articles likely have PubMed records. Key claims are nevertheless tied to the evidence snippets above.
  • OMIM/Orphanet/ICD codes were not explicitly stated in the retrieved evidence excerpts and should be added by direct database lookup.

URLs and publication dates (from evidence)

  • Devitt L. Cystinosis — a review… (Jun 2024). https://doi.org/10.1007/s44162-024-00041-2 (devitt2024cystinosis—a pages 1-2)
  • Regnier M et al. Worldwide disparities… (Nov 2024; survey conducted 2022; framed as “2023 perspective”). https://doi.org/10.1007/s00467-023-06179-3 (regnier2024worldwidedisparitiesin pages 1-2)
  • Joseph MW et al. Gastrointestinal challenges… (Feb 2024). https://doi.org/10.1007/s00467-023-06211-6 (joseph2024gastrointestinalchallengesin pages 1-2)
  • Simeoli R et al. LC‑MS/MS method for cysteamine plasma… (May 2024). https://doi.org/10.3390/ph17050649 (simeoli2024anewand pages 1-2)
  • Algasem R et al. Adherence to cysteamine therapy… (Aug 2024). https://doi.org/10.3390/pharmacy12040123 (algasem2024adherencetocysteamine pages 1-2)
  • Dong F et al. Gene therapy for corneal pathology... (Jul 2023). PMID:37355021; https://doi.org/10.1016/j.jtos.2023.06.002 (dong2023thegenetherapy pages 1-3)
  • Bondue T et al. Evaluation of CTNS mRNA delivery... (Dec 2023). PMID:38016974; https://doi.org/10.1038/s41598-023-47085-w (bondue2023evaluationoftheefficacy pages 1-2)
  • ClinicalTrials.gov: NCT03897361 (first posted 2019; primary completion 2024‑09‑18; last update 2026‑01‑14). https://clinicaltrials.gov/study/NCT03897361 (NCT03897361 chunk 1)
  • ClinicalTrials.gov: NCT06027385 (GENESIS1; start 2018‑01‑15; recruitment completed 2022‑09‑30). https://clinicaltrials.gov/study/NCT06027385 (NCT06027385 chunk 1)
  • ClinicalTrials.gov: NCT05843851 (start 2022‑03‑15; recruiting). https://clinicaltrials.gov/study/NCT05843851 (NCT05843851 chunk 1)

References

  1. (devitt2024cystinosis—a pages 1-2): Lauren Devitt. Cystinosis — a review of disease pathogenesis, management, and future treatment options. Journal of Rare Diseases, 3:1-12, Jun 2024. URL: https://doi.org/10.1007/s44162-024-00041-2, doi:10.1007/s44162-024-00041-2. This article has 6 citations.

  2. (bondue2024novelmolecularmechanisms pages 20-23): T Bondue, L van den Heuvel, R Gijsbers, and E Levtchenko. Novel molecular mechanisms and therapeutic options for renal fanconi syndrome: a focus on cystinosis. Unknown journal, 2024.

  3. (cherqui2023[cystinosisfromthe pages 1-3): Stéphanie Cherqui. [cystinosis: from the gene identification to the first gene therapy clinical trial]. Medecine sciences : M/S, 39 3:253-261, Mar 2023. URL: https://doi.org/10.1051/medsci/2023025, doi:10.1051/medsci/2023025. This article has 8 citations.

  4. (NCT01197378 chunk 2): Long-Term Safety Follow-up Study of Cysteamine Bitartrate Delayed-release Capsules (RP103). Amgen. 2010. ClinicalTrials.gov Identifier: NCT01197378

  5. (simeoli2024anewand pages 1-2): Raffaele Simeoli, Sara Cairoli, Marcella Greco, Francesco Bellomo, Alessandro Mancini, Chiara Rossi, Carlo Dionisi Vici, Francesco Emma, and Bianca Maria Goffredo. A new and rapid lc-ms/ms method for the determination of cysteamine plasma levels in cystinosis patients. Pharmaceuticals, 17:649, May 2024. URL: https://doi.org/10.3390/ph17050649, doi:10.3390/ph17050649. This article has 4 citations.

  6. (dong2023thegenetherapy pages 1-3): Fei Dong, Hassane Amlal, Jhuwala Venkatakrishnan, Jianhua Zhang, Matthew Fry, Yong Yuan, Yu Chia Cheng, Yueh-Chiang Hu, and Winston W-Y Kao. The gene therapy for corneal pathology with novel nonsense cystinosis mouse lines created by crispr gene editing. The Ocular Surface, 29:432-443, Jul 2023. PMID:37355021; URL: https://doi.org/10.1016/j.jtos.2023.06.002, doi:10.1016/j.jtos.2023.06.002. This article has 2 citations.

  7. (devitt2024ocularcystinosis–areview pages 1-2): L Devitt. Ocular cystinosis–a review of disease, diagnosis, and future treatment options. Unknown journal, 2024.

  8. (heroor2024unveilingcystinosisin pages 9-11): Aniruddh Heroor, Anshuman Verma, Divya Sree Achanta, Deepak Paul Edward, and Muralidhar Ramappa. Unveiling cystinosis in india. Journal of Rare Diseases, 3:1-12, Jun 2024. URL: https://doi.org/10.1007/s44162-024-00046-x, doi:10.1007/s44162-024-00046-x. This article has 0 citations.

  9. (algasem2024adherencetocysteamine pages 1-2): Reem Algasem, Nedaa Zainy, Essam Alsabban, Hamad Almojalli, Khalid Alhasan, Tariq Ali, Deiter Broering, and Hassan Aleid. Adherence to cysteamine therapy among patients diagnosed with cystinosis in saudi arabia: a prospective cohort study. Pharmacy, 12:123, Aug 2024. URL: https://doi.org/10.3390/pharmacy12040123, doi:10.3390/pharmacy12040123. This article has 0 citations.

  10. (algasem2024adherencetocysteamine pages 4-6): Reem Algasem, Nedaa Zainy, Essam Alsabban, Hamad Almojalli, Khalid Alhasan, Tariq Ali, Deiter Broering, and Hassan Aleid. Adherence to cysteamine therapy among patients diagnosed with cystinosis in saudi arabia: a prospective cohort study. Pharmacy, 12:123, Aug 2024. URL: https://doi.org/10.3390/pharmacy12040123, doi:10.3390/pharmacy12040123. This article has 0 citations.

  11. (algasem2024adherencetocysteamine pages 6-7): Reem Algasem, Nedaa Zainy, Essam Alsabban, Hamad Almojalli, Khalid Alhasan, Tariq Ali, Deiter Broering, and Hassan Aleid. Adherence to cysteamine therapy among patients diagnosed with cystinosis in saudi arabia: a prospective cohort study. Pharmacy, 12:123, Aug 2024. URL: https://doi.org/10.3390/pharmacy12040123, doi:10.3390/pharmacy12040123. This article has 0 citations.

  12. (regnier2024worldwidedisparitiesin pages 1-2): Maitena Regnier, Sacha Flammier, Mounia Boutaba, Aliou Abdoulaye Ndongo, Aude Servais, Franz Schaefer, Elena Levtchenko, Justine Bacchetta, and Aurélia Bertholet-Thomas. Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective. Pediatric Nephrology (Berlin, Germany), 39:1113-1123, Nov 2024. URL: https://doi.org/10.1007/s00467-023-06179-3, doi:10.1007/s00467-023-06179-3. This article has 10 citations.

  13. (regnier2024worldwidedisparitiesin pages 7-8): Maitena Regnier, Sacha Flammier, Mounia Boutaba, Aliou Abdoulaye Ndongo, Aude Servais, Franz Schaefer, Elena Levtchenko, Justine Bacchetta, and Aurélia Bertholet-Thomas. Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective. Pediatric Nephrology (Berlin, Germany), 39:1113-1123, Nov 2024. URL: https://doi.org/10.1007/s00467-023-06179-3, doi:10.1007/s00467-023-06179-3. This article has 10 citations.

  14. (regnier2024worldwidedisparitiesin pages 2-3): Maitena Regnier, Sacha Flammier, Mounia Boutaba, Aliou Abdoulaye Ndongo, Aude Servais, Franz Schaefer, Elena Levtchenko, Justine Bacchetta, and Aurélia Bertholet-Thomas. Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective. Pediatric Nephrology (Berlin, Germany), 39:1113-1123, Nov 2024. URL: https://doi.org/10.1007/s00467-023-06179-3, doi:10.1007/s00467-023-06179-3. This article has 10 citations.

  15. (regnier2024worldwidedisparitiesin media 96f6e599): Maitena Regnier, Sacha Flammier, Mounia Boutaba, Aliou Abdoulaye Ndongo, Aude Servais, Franz Schaefer, Elena Levtchenko, Justine Bacchetta, and Aurélia Bertholet-Thomas. Worldwide disparities in access to treatment and investigations for nephropathic cystinosis: a 2023 perspective. Pediatric Nephrology (Berlin, Germany), 39:1113-1123, Nov 2024. URL: https://doi.org/10.1007/s00467-023-06179-3, doi:10.1007/s00467-023-06179-3. This article has 10 citations.

  16. (NCT03897361 chunk 1): Stephanie Cherqui. Stem Cell Gene Therapy for Cystinosis. University of California, San Diego. 2019. ClinicalTrials.gov Identifier: NCT03897361

  17. (NCT03897361 chunk 2): Stephanie Cherqui. Stem Cell Gene Therapy for Cystinosis. University of California, San Diego. 2019. ClinicalTrials.gov Identifier: NCT03897361

  18. (NCT03897361 chunk 3): Stephanie Cherqui. Stem Cell Gene Therapy for Cystinosis. University of California, San Diego. 2019. ClinicalTrials.gov Identifier: NCT03897361

  19. (NCT06027385 chunk 2): Genetic Newborn Screening for Cystinosis and Spinal Muscular Atrophy. Cystinose Stiftung. 2018. ClinicalTrials.gov Identifier: NCT06027385

  20. (NCT06027385 chunk 1): Genetic Newborn Screening for Cystinosis and Spinal Muscular Atrophy. Cystinose Stiftung. 2018. ClinicalTrials.gov Identifier: NCT06027385

  21. (NCT05843851 chunk 2): Katharina Hohenfellner,MD. Genetic Newborn Screening for Cystinosis and Primary Hyperoxaluria. Cystinose Stiftung. 2022. ClinicalTrials.gov Identifier: NCT05843851

  22. (NCT05843851 chunk 1): Katharina Hohenfellner,MD. Genetic Newborn Screening for Cystinosis and Primary Hyperoxaluria. Cystinose Stiftung. 2022. ClinicalTrials.gov Identifier: NCT05843851

  23. (joseph2024gastrointestinalchallengesin pages 1-2): Mark W. Joseph, Deborah R. Stein, and Adam C. Stein. Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives. Pediatric Nephrology (Berlin, Germany), 39:2845-2860, Feb 2024. URL: https://doi.org/10.1007/s00467-023-06211-6, doi:10.1007/s00467-023-06211-6. This article has 6 citations.

  24. (joseph2024gastrointestinalchallengesin pages 7-9): Mark W. Joseph, Deborah R. Stein, and Adam C. Stein. Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives. Pediatric Nephrology (Berlin, Germany), 39:2845-2860, Feb 2024. URL: https://doi.org/10.1007/s00467-023-06211-6, doi:10.1007/s00467-023-06211-6. This article has 6 citations.

  25. (joseph2024gastrointestinalchallengesin pages 4-6): Mark W. Joseph, Deborah R. Stein, and Adam C. Stein. Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives. Pediatric Nephrology (Berlin, Germany), 39:2845-2860, Feb 2024. URL: https://doi.org/10.1007/s00467-023-06211-6, doi:10.1007/s00467-023-06211-6. This article has 6 citations.

  26. (joseph2024gastrointestinalchallengesin pages 11-13): Mark W. Joseph, Deborah R. Stein, and Adam C. Stein. Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives. Pediatric Nephrology (Berlin, Germany), 39:2845-2860, Feb 2024. URL: https://doi.org/10.1007/s00467-023-06211-6, doi:10.1007/s00467-023-06211-6. This article has 6 citations.

  27. (joseph2024gastrointestinalchallengesin pages 9-10): Mark W. Joseph, Deborah R. Stein, and Adam C. Stein. Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives. Pediatric Nephrology (Berlin, Germany), 39:2845-2860, Feb 2024. URL: https://doi.org/10.1007/s00467-023-06211-6, doi:10.1007/s00467-023-06211-6. This article has 6 citations.

  28. (joseph2024gastrointestinalchallengesin pages 13-14): Mark W. Joseph, Deborah R. Stein, and Adam C. Stein. Gastrointestinal challenges in nephropathic cystinosis: clinical perspectives. Pediatric Nephrology (Berlin, Germany), 39:2845-2860, Feb 2024. URL: https://doi.org/10.1007/s00467-023-06211-6, doi:10.1007/s00467-023-06211-6. This article has 6 citations.

  29. (bondue2023evaluationoftheefficacy pages 1-2): Tjessa Bondue, Sante Princiero Berlingerio, Florian Siegerist, Elena Sendino-Garvi, Maximilian Schindler, Hans Jacobus Baelde, Sara Cairoli, Bianca Maria Goffredo, Fanny Oliveira Arcolino, Jurgen Dieker, Manoe Jacoba Janssen, Nicole Endlich, Roland Brock, Rik Gijsbers, Lambertus van den Heuvel, and Elena Levtchenko. Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis. Scientific Reports, 13:21002, Dec 2023. PMID:38016974; URL: https://doi.org/10.1038/s41598-023-47085-w, doi:10.1038/s41598-023-47085-w.