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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Cystinosis

, MD and , MD, PhD.

Author Information
, MD
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland
, MD, PhD
Clinical Director
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: January 30, 2014.

Summary

Disease characteristics. Nephropathic cystinosis in untreated children is characterized by renal tubular Fanconi syndrome, poor growth, hypophosphatemic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine crystals in almost all cells, leading to cellular destruction and tissue dysfunction. The typical untreated child has short stature, light complexion, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these therapies, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life.

Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years.

The non-nephropathic (ocular) form of cystinosis is characterized only by photophobia resulting from corneal cystine crystal accumulation.

Diagnosis/testing. The diagnosis of cystinosis is established by documenting:

  • Renal tubular Fanconi syndrome: increased urinary losses of essential nutrients including electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, carnitine, and water;
  • Typical cystine crystals in the cornea on slit lamp examination;
  • Increased cystine content of leukocytes.

Identification of two mutations in CTNS, the only gene in which mutation is currently known to be cause cystinosis, is confirmatory.

Management. Treatment of manifestations: Renal tubular Fanconi syndrome is treated by replacement of renal losses; phosphate and vitamin D supplements prevent and treat severe hypophosphatemic rickets; skeletal deformities or metabolic bone disease should be addressed early with the help of orthopedic specialists. Nutrition must be adequate to minimize failure to thrive in infants. Cysteamine hydrochloride eyedrops dissolve corneal crystals within months and relieve photophobia within weeks. Required hormone replacement therapies may include: L-thyroxine, insulin, growth hormone, and/or testosterone. Physical and speech therapy is helpful for the muscle deterioration and swallowing difficulties of older individuals.

Prevention of primary manifestations: Therapy with cystine-depleting agents begun as soon as the diagnosis is made or (if possible) shortly after birth may attenuate the renal tubular Fanconi syndrome and significantly slow the progression of glomerular damage; however, renal damage present at the time of diagnosis is irreversible. With optimal symptomatic and cystine-depleting therapy affected individuals grow at a normal rate but generally do not recover lost height unless human growth hormone is administered.

Prevention of secondary complications: Those who have undergone renal transplantation should be monitored for signs of immunodeficiency and infection; carnitine supplementation may improve muscle strength; treatment with proton pump inhibitors helps relieve cysteamine-induced gastric acid hypersecretion.

Surveillance: Evaluation by a nephrologist every 3-6 months depending on the severity of renal impairment; ophthalmologic evaluation every 1-2 years; assessment of bone mineralization throughout the disease course; fasting blood glucose concentration and testosterone concentration every 2-3 years (in males, starting before puberty); routine monitoring for late-onset complications by a multidisciplinary medical team.

Agents/circumstances to avoid: Dehydration; sun exposure if photophobia is present.

Evaluation of relatives at risk: Biochemical and/or molecular genetic testing (if the mutation status of the proband is known) allows for early diagnosis and treatment.

Genetic counseling. Cystinosis is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing mutations have been identified in the family. For pregnancies at increased risk for nephropathic cystinosis, prenatal diagnosis is also possible biochemically, based on elevated cystine concentration in both chorionic villi and amniocytes.

GeneReview Scope

Cystinosis: Included Disorders
  • Nephropathic cystinosis
  • Intermediate cystinosis
  • Non-nephropathic cystinosis

For synonyms and outdated names see Nomenclature.

Diagnosis

Cystinosis Standards of Care [Nesterova & Gahl 2012], developed and approved by world experts on cystinosis, is available online.

Clinical Diagnosis

Nephropathic cystinosis (classic/infantile/early onset). The diagnosis of classic nephropathic cystinosis depends on the findings of renal tubular Fanconi syndrome in the untreated child in the first year of life, failure to thrive with growth retardation after approximately age six months, and progressive deterioration of renal glomerular function to end-stage renal disease (ESRD) over the first ten years of life [Gahl et al 2001, Gahl et al 2002].

Renal tubular Fanconi syndrome is established in the untreated child by documenting increased urinary losses of essential nutrients [Gahl et al 2001, Gahl et al 2002]. These include electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, tubular protein including β2-microglobulin, and water. These renal losses result in symptoms such as hypophosphatemic rickets, evident both clinically and radiographically. In cases of severe hypophosphatemia efficient ATP production can be impaired contributing to tissue dysfunction. Hypercalciuria and hyperphosphaturia can lead to medullary nephrocalcinosis detected by renal ultrasound examination.

Growth retardation is usually apparent in the untreated child from age six months and is characterized by a growth rate that is 50%-60% of normal.

Corneal cystine crystals cause photophobia and often blepharospasm and corneal erosions. A slit lamp examination of the cornea showing typical cystine crystals is diagnostic for cystinosis (Figure 1b). Corneal crystals may be present before age one year and are always present after age 16 months [Gahl et al 2000].

Figure 1

Figure

Figure 1. Findings on slit lamp examination of the cornea in cystinosis

a. Band keratopathy in a 33-year-old treated with cysteamine eye drops, which dissolved the cystine crystals, but not the calcified band
b. Corneal crystals (more...)

Intermediate nephropathic cystinosis (juvenile/late onset). This rare variant of cystinosis is characterized by the same renal and corneal events as those observed in untreated infantile nephropathic cystinosis, but with delayed onset and decreased severity. The tubular Fanconi syndrome can be so mild that it is not recognized, and rickets, growth retardation, electrolyte imbalance, and photophobia may be absent or clinically insignificant in childhood. In all cases, however, end-stage renal disease secondary to glomerular involvement occurs, usually between ages 15 and 25 years. Occasionally, such individuals are diagnosed with cystinosis only when renal failure occurs.

Ocular (non-nephropathic) cystinosis. Untreated individuals with this variant never have impairment of renal function or growth. Photophobia is the sole symptom, although cystine crystals are present in the bone marrow and conjunctiva as well as in the cornea. Diagnosis is usually made on routine eye examination with a slit lamp.

Testing

Leukocyte cystine measurement. The clinical diagnosis of cystinosis should be confirmed by measurement of cystine concentrations in polymorphonuclear leukocytes.

  • Measurement is best performed using mass spectrometry or the cystine binding protein assay, a competitive radioassay that detects nanomole quantities of cystine [Gahl et al 2001, Gahl et al 2002].
    • Individuals with nephropathic cystinosis generally have values of 3.0-23.0 nmol half-cystine/mg protein.
    • Individuals with non-nephropathic cystinosis have values of 1.0-3.0 nmol half-cystine/mg protein.
    • Heterozygotes have ≤1.0 nmol half-cystine/mg protein.
    • Normal values are ≤0.2 nmol half-cystine/mg protein.
  • Measurement by amino acid analysis (i.e., anion exchange chromatography) is less sensitive and can give spurious results if small amounts of leukocyte protein are available.

Note: In preparing leukocytes for assay, care must be taken to avoid (1) a significant number of lymphocytes, which store only fivefold normal amounts of cystine compared with 50-fold normal amounts in polymorphonuclear leukocytes; and (2) contamination with red blood cells, which contribute protein but not cystine to the calculated cystine value. Both interfering substances produce artifactually low leukocyte cystine levels.

Other cystine measurements. Cystinosis can also be diagnosed by the demonstration of increased cystine content in cultured fibroblasts or in the placenta at the time of birth [Gahl et al 2001].

Crystals. On tissue biopsy of bone marrow, conjunctiva, kidney, liver, intestine, and other tissues, cystine crystals appear hexagonal or rectangular in shape and are birefringent under polarizing light [Gahl et al 2001, Gahl et al 2002].

Note: (1) The tissue should be fixed in 100% alcohol, as aqueous solutions can dissolve the crystals. (2) A skin biopsy does not contain crystals; neither do cultured cells of any type.

Molecular Genetic Testing

Gene. CTNS is currently the only gene in which mutations are known to cause cystinosis.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Cystinosis

Gene 1Test MethodMutations Detected 2% of Northern Europeans w/Nephropathic Cystinosis% of Non-Northern Europeans w/CystinosisMutation Detection Frequency by Test Method 3
CTNSTargeted mutation analysis57-kb deletion 440%0%~100%
Mutation panel optimized for the French-Canadian population 565%Unknown~100%
Sequence analysis 6Sequence variantsUnknownUnknownUnknown
Deletion/ duplication analysis 7Detects 57-kb deletion and other partial and whole-gene deletions/duplicationsUnknownUnknownUnknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. In the United States and northern European populations, approximately 50% of individuals with nephropathic cystinosis are homozygous for a 57-kb deletion that encompasses the first nine exons and introns of CTNS and interrupts exon 10 [Shotelersuk et al 1998, Town et al 1998, Touchman et al 2000]. In individuals with intermediate and non-nephropathic cystinosis, the 57-kb deletion can be present in the compound heterozygous state, along with a more "benign" mutation, but not in the homozygous state [Anikster et al 1999a, Forestier et al 1999].

5. 57-kb deletion, p.Trp138Ter, p.Thr7PhefsTer7, p.Gln128Ter, p.Trp182Arg, p.Leu158Pro, p.Gly308Arg, p.Asp205del, p.Ile133Pro; total of 55 pathogenic variants known [Kalatzis & Antignac 2003]. Testing for a panel of mutations optimized for the French-Canadian population is possible.

6. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of cystinosis is established by documenting the following:

  • Renal tubular Fanconi syndrome. Increased urinary losses of essential nutrients including electrolytes (sodium, potassium, and bicarbonate), minerals (calcium, phosphate, and magnesium), glucose, amino acids, carnitine, and water
  • Typical cystine crystals in the cornea on slit lamp examination
  • Increased cystine content of leukocytes
  • Two mutations in CTNS

Note: Although the finding of typical hexagonal or rectangular cystine crystals in any of a variety of tissues can establish the diagnosis of cystinosis, tissue biopsy is no longer indicated for diagnosis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The three types of cystinosis, i.e., nephropathic (classic renal and systemic disease), intermediate (a late-onset variant of nephropathic cystinosis), and non-nephropathic (ocular), are allelic disorders caused by CTNS mutations [Thoene et al 1999, Anikster et al 2000].

Nephropathic cystinosis. The clinical characteristics of untreated nephropathic cystinosis include those associated with failure to thrive, poor growth, renal tubular Fanconi syndrome, renal glomerular failure, and non-renal involvement of a variety of tissues and organ systems. With effective cystine-depleting therapy, cystinosis was transformed from a progressive, fatal renal disease to a treatable chronic multisystemic disease, with life span increasing from about ten years to 50 years or more [Nesterova & Gahl 2008].

  • Growth. Infants with untreated nephropathic cystinosis are normal at birth. In untreated individuals, initially failure to thrive and later failure to grow are generally noticed between ages six and nine months. A high frequency of vomiting, poor appetite, and feeding difficulties, combined with renal losses of nutrients, causes poor nutrition and severe failure to thrive. Typically, infants are at the third percentile for height and weight at age one year [Gahl et al 2001, Gahl et al 2002]. Later, growth occurs at 60% of the normal rate. Bone age is usually delayed one to three years. Head circumference is normal for age.
  • With early and optimal symptomatic and cystine-depleting therapy, individuals grow at a normal rate. In the past, height often remained below the third centile and weight remained slightly above the third centile; however, recently, many affected infants and toddlers have height profiles following the 10th-25th percentiles for age and falling in the range of mid-parental constitutional growth. Growth hormone administration improves height velocity in prepubertal children.
  • Renal tubular Fanconi syndrome. Infants with untreated nephropathic cystinosis show signs of renal tubular Fanconi syndrome, i.e. generalized proximal tubular dysfunction, as early as age six months. The Fanconi syndrome involves failure of the renal tubules to reabsorb water, electrolytes, bicarbonate, phosphate, calcium, glucose, carnitine, amino acids, and tubular proteins. Individuals with untreated cystinosis have severe polyuria (2-6 L/day), polydipsia, dehydration, and hypochloremic metabolic acidosis, sometimes requiring hospitalization as a result of life-threatening hypovolemia, particularly during a gastrointestinal illness.

    Hypophosphatemic rickets, characterized by high excretion of phosphate, elevated serum alkaline phosphatase, and bone deformities, make walking painful enough to delay ambulation. Nutritional deficiencies of vitamin D and calcium may accompany rickets, leading to seizures and tetany.

    Severe hypokalemia can threaten cardiac conduction. Occasionally, hyponatremia and hypomagnesemia also occur.

    Diligent treatment with replacement of renal losses is required for resolution of rickets, tetany, acidosis, and laboratory abnormalities. Cystine-depleting therapy begun just after birth when tubular damage is not complete can attenuate the renal tubular Fanconi syndrome [Kleta et al 2004a]. However, renal tubular damage present at the usual time of diagnosis (i.e., age ~1 year) is irreversible.
  • Renal glomerular failure. In the natural history of untreated nephropathic cystinosis, glomerular function gradually deteriorates, resulting in renal failure at approximately age ten years [Gahl et al 2001, Gahl et al 2002].The serum creatinine concentration may not exceed 1.0 mg/dL until age five years, but once it rises, it increases exponentially. Many affected individuals have significant proteinuria, sometimes in nephrotic ranges, along with granular casts and microhematuria.
  • Early treatment with cystine-depleting therapy (i.e., oral cysteamine) slows or stops the progression of glomerular damage and can delay or eliminate the need for renal transplantation [Kleta et al 2004a].
  • Non-renal involvement. Without optimal therapy, cystine accumulation occurs in virtually all organs and tissues, including bone marrow, liver, intestine, muscle, brain, spleen, eye, thyroid, pancreas, and testes. Without therapy, several complications of cystinosis occur prior to renal transplantation:
    • Infants and children can have poor appetite and vomit regularly (usually in the morning), and can develop malnutrition
    • Children with cystinosis have mildly altered craniofacial morphology, reduced airway dimensions, delayed dental development, and delayed eruption of permanent teeth [Bassim et al 2010].
    • Photophobia develops when the cornea becomes packed with crystals, generally at the end of the first decade of life.
    • Affected individuals typically develop hypothyroidism at the end of the first decade of life.
    • Sweating is impaired and affected individuals can suffer heat prostration [Gahl et al 2001, Gahl et al 2002].
    • Intelligence is normal in cystinosis, although neurobehavioral abnormalities, including visual memory defects, have been reported [Gahl et al 2001, Gahl et al 2002].
    • Benign intracranial hypertension presents with headaches and papilledema [Dogulu et al 2004].
    • Puberty is generally delayed one to two years. Untreated males exhibit primary hypogonadism [Chik et al 1993].
    • No male with untreated cystinosis has fathered a child; a few females with untreated cystinosis have delivered healthy children [Haase et al 2006].
    • It is currently not known whether diligent cysteamine treatment can prevent primary hypogonadism in males.
  • Late-onset abnormalities. Well after renal transplantation (i.e., at age ~20-40 years), another set of complications can occur from the longstanding accumulation of cystine crystals in non-renal organs in individuals not treated with cysteamine [Servais et al 2008].
    • Increased cystine content in the muscles causes vacuolar myopathy in 60% of individuals [Gahl et al 2007]. Generalized myopathy leads to progressive muscle wasting and weakness (Figures 2a, 2c, 2d) [Ishak et al 1994]. Oral motor dysfunction causes swallowing and feeding difficulties [Trauner et al 2001, Sonies et al 2005]. Electromyography demonstrates a myopathic pattern.
    • Extrinsic chest muscle impairment causes extraparenchymal restriction of ventilation leading to pulmonary insufficiency with decreased values of FVC and FEV1 on routine pulmonary function tests [Anikster et al 2001].
    • Gastrointestinal findings can include reflux, dysmotility, esophagitis, gastric/duodenal ulcers, hepatomegaly with nodular regenerating hyperplasia of the liver with portal hypertension, exocrine pancreatic insufficiency [DiDomenico et al 2004, O’Brien et al 2006], inflammatory bowel disease, bowel perforation, and peritonitis [Gahl et al 2007].
    • Cardiovascular manifestations can include arteriopathy caused by the combination of vascular calcifications and obstructive atherosclerosis with hypercholesterolemia (Figure 2e) [Ueda et al 2006]; ESRD and renin-dependent hypertension; dilated cardiomyopathy; and aortic aneurysms. All of these factors contribute to cardiovascular morbidity and increase the risk for myocardial infarction and neurovascular incidents.
    • Metabolic bone disease develops as a result of direct deposition of cystine crystals in bone, mineral imbalance, and renal osteodystrophy prior to renal transplantation [Zimakas et al 2003].
    • Hypercoagulopathy and hypocoagulopathy occur as a result of renal failure and platelet aggregation dysfunction [Nesterova & Gahl 2008].
    • CNS calcifications (Figure 2f), benign intracranial hypertension with non-absorptive hydrocephalus, and parenchymal deterioration of the central nervous system with cerebral atrophy lead to various degrees of encephalopathy [Gahl et al 2001, Gahl et al 2002]. Occasionally, cerebrovascular incidents with paresis or pseudobulbar palsy occur [Gahl et al 2007].
  • Intellectual abilities are low-normal; affected children have mainly average school performance. They have impaired visual and spatial cognition with preserved language and intellectual function [Spilkin et al 2007]. Their distinctive behavioral and psychosocial difficulties stem from the chronic disease: ESRD, renal dialysis, prolonged hospitalizations, and treatment with multiple therapeutic agents, including steroids [Ballantyne & Trauner 2000, Delgado et al 2005].
  • Late ocular complications. Crystal deposition in the anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve manifests as [Tsilou et al 2007]:
    • Anterior segment problems. Crystals in the anterior lens surface, band keratopathy (Figure 1a), peripheral corneal neovascularization, and posterior synechiae
    • Posterior segment problems. Pigmentary retinopathy with degeneration of the photoreceptors that contributes to the impaired visual function in the late stage of the disease [Tsilou et al 2002]. Electroretinogram (ERG) is used to confirm the retinopathy.
Figure 2

Figure

Figure 2. A 37-year-old man with nephropathic cystinosis

a. Thin habitus
b. Gastrostomy tube
c. Clawed hand with wasting of thenar and hypothenar eminences and interosseous muscles
d. Muscle wasting in upper (more...)

Intermediate cystinosis. All the early manifestations of untreated nephropathic cystinosis, including the renal tubular Fanconi syndrome, growth delay, photophobia, and glomerular failure, occur in individuals with untreated intermediate cystinosis, but at a later age, mostly during adolescence.

Non-nephropathic cystinosis. Individuals with untreated ocular cystinosis experience only photophobia.

Histopathology. Electron microscopy of the glomeruli reveals fusion of foot processes, thickening of Bowman’s membrane, and localization of cystine crystals in interstitial cells. Cystinotic glomeruli show focal glomerulosclerosis [Mahoney & Striker 2000].

Pathophysiology. The pathophysiology of renal tubular Fanconi syndrome is under investigation. Several mechanisms have been suggested:

  • Inhibition of the Na-phosphate cotransporter resulting from cystine accumulation in the proximal tubular cells with depletion of intracellular ATP [Baum 1998, Kleta & Gahl 2002, Park et al 2002]
  • Degeneration of the proximal tubules, which is well documented in nephropathic cystinosis [Mahoney & Striker 2000]
  • Inappropriately increased apoptosis, leading to progressive cell death in proximal tubules resulting in atubular glomeruli and renal failure [Larsen et al 2010]

Genotype-Phenotype Correlations

Some genotype-phenotype correlations can be made:

  • Within the group of individuals with nephropathic cystinosis, truncating CTNS mutations, as well as the 57-kb deletion, result in severe, classic (early-onset or infantile type) disease [Shotelersuk et al 1998, Attard et al 1999].
  • Individuals with apparent residual activity (i.e., lower levels of cystine accumulation in leukocytes) often have missense mutations in CTNS [Attard et al 1999]. Individuals with intermediate cystinosis (i.e., nephropathic but late onset) or non-nephropathic cystinosis (i.e., corneal and bone marrow crystals but no renal involvement) have one severe CTNS mutation, typical for nephropathic cystinosis, and one mild mutation. The mild mutations include p.Gly197Arg and c.853-3C>G [Anikster et al 1999b]. The organ specificity in benign cystinosis may result from tissue-specific splicing factors.
  • Deletions of CTNS and its flanking genes may lead to contiguous gene deletion syndromes with more complex phenotypes than those of classic cystinosis [Kalatzis & Antignac 2003]. For example, the 57-kb deletion on chromosome 17p13 extends into TRPV1 causing dysregulation of TRPV1 transcription in peripheral blood mononuclear cells [Freed et al 2011].
  • Heterozygotes have 50% of transport capacity in their lysosomes [Thoene 1995, Gahl et al 2002].
  • Loss of cystinosin may result in the unregulated activation of other transporters and pathways, including redox-based signaling or protein cysteinylation [Bellomo et al 2010]. Other lysosomal functions may also be impaired in cystinosis [Wilmer et al 2010]. Recent studies of whole-genome expression profiles in peripheral blood samples from people with cystinosis identified modifier genes and pathways associated with nephropathic cystinosis; further investigation is needed to confirm the role of these genes in modulating the cystinosis phenotype [Sansanwal et al 2010].

Nomenclature

Nephropathic cystinosis is also referred to as infantile nephropathic type cystinosis.

Intermediate cystinosis is also referred to as adolescent nephropathic type cystinosis.

The terms "adult cystinosis" and "benign cystinosis" should be replaced by "ocular cystinosis" and "non-nephropathic cystinosis."

Prevalence

Cystinosis occurs with a frequency of approximately one in 100,000 to 200,000 and has been found worldwide in all ethnic groups. The frequency of cystinosis in Brittany has been given as one in 26,000 [Gahl et al 2001, Gahl et al 2002].

Cystinosis accounts for 5% of childhood renal failure [Middleton et al 2003].

Differential Diagnosis

Untreated nephropathic cystinosis is the most common identifiable cause of the renal tubular Fanconi syndrome in childhood. Other causes:

  • Wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances or a combination of these, from age three to over 50. Diagnosis depends in part on the detection of low serum copper and ceruloplasmin concentrations, Kayser-Fleischer rings in the cornea, and/or increased urinary copper excretion. Mutation of ATP7B are causative. Inheritance is autosomal recessive.
  • Oculocerebrorenal syndrome of Lowe is found in males and involves the eyes (cataracts, glaucoma, decreased visual acuity), central nervous system (hypotonia, intellectual disability), and kidneys (Fanconi syndrome). Slowly progressive glomerulosclerosis and renal failure are often noted after age ten years. It is diagnosed by demonstrating reduced (<10% of normal) activity of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in cultured skin fibroblasts. Pathogenic allelic variants in the responsible gene, OCRL1, are detectable in most males and carrier females. (Mutation of OCRL1 can also cause Dent disease, which can present with findings typical for renal Fanconi syndrome.) Inheritance is X-linked.
  • Galactosemia is a disorder of galactose metabolism that can result in feeding problems, failure to thrive, hepatocellular damage, bleeding, and sepsis in untreated infants. It is most often caused by deficient activity of the enzyme galactose-phosphate uridyltransferase (GALT), and can be diagnosed by measurement of erythrocyte GALT enzyme activity and by isoelectric focusing of GALT. Molecular genetic testing of GALT is possible for individuals with biochemically confirmed galactosemia.
  • Glycogen storage disease type I presents mainly with hepatomegaly and hypoglycemia.
  • Tyrosinemia type I presents with severe liver disease in infancy and shows abnormal tyrosine metabolites on organic acid analyses.
  • Glucosuria associated with renal tubular Fanconi syndrome can result in misdiagnosis as diabetes mellitus.
  • Polyuria often leads to a misdiagnosis of diabetes insipidus (see Nephrogenic Diabetes Inspidus).
  • Electrolyte abnormalities can suggest Bartter syndrome.
  • The rickets of cystinosis can falsely suggest vitamin D-deficient rickets.
  • Multiple myeloma can cause photophobia and corneal crystals similar to those in ocular cystinosis [Kleta et al 2004b].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Clinical practice guidelines for the treatment of individuals with cystinosis, developed and approved by international experts on cystinosis, have been published. See Cystinosis Standards of Care [Nesterova & Gahl 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with cystinosis, the following evaluations are recommended.

In individuals who are initially diagnosed at any age:

  • Height and weight, plotted on age-appropriate growth charts
  • Renal tubular and glomerular function, especially serum concentrations of creatinine, phosphate, bicarbonate, and potassium; and urine concentrations of creatinine, phosphate, bicarbonate, potassium, glucose, and protein. Quantative measurement of urine amino acid loss helps to identify the severity of renal Fanconi syndrome [Charnas et al 1991].
  • Glomerular filtration rate (GFR) or creatinine clearance test
  • Thyroid function studies
  • Lipid panel
  • Renal ultrasound examination for evaluation of nephrocalcinosis
  • Ophthalmologic evaluation, including slit lamp examination of the cornea to assess corneal involvement, ERG to assess retinal involvement, and fundoscopic examination for possible intracranial hypertension
  • Medical genetics consultation, including family counseling.

In individuals who are initially diagnosed at an older age:

  • In pre- and postpubertal males, measurement of serum concentration of testosterone, FSH, and LH
  • Glucose tolerance test to assess for diabetes mellitus if symptoms are present
  • Baseline ophthalmology evaluation, including a fundoscopic examination
  • Evaluation of the extent of metabolic bone disease causing skeletal deformities by performing skeletal radiographs and DEXA scan

Treatment of Manifestations

It is recommended that a multidisciplinary team that includes nephrologists, metabolic disease specialists, ophthalmologists, neurologists, gastroenterologists, nutritionists, and psychologists manage individuals with cystinosis.

Renal tubular Fanconi syndrome is treated by replacement of renal losses:

  • For children, free access to water and bathroom privileges and supplementation with citrate to alkalinize the blood
  • Phosphate replacement to prevent and heal hypophosphatemic rickets; vitamin D supplementation to assist the gastrointestinal absorption of phosphate and calcium
  • Early treatment of skeletal deformities resulting from severe rickets or metabolic bone disease. Deformities should be corrected with the help of orthopedic specialists.
  • Potassium, calcium, magnesium, or carnitine supplementation as needed
  • Careful attention to fluid and electrolyte replacement during gastrointestinal illnesses (Obligatory urinary losses amount to 2-6 L electrolyte-rich water per day.)
  • Reduction of cellular cystine concentration through treatment with the cystine-depleting agent cysteamine (see Prevention of Primary Manifestations)
  • ACE inhibitors could be used to slow the progression of renal insufficiency attributed to proteinuria [Levtchenko et al 2004].
  • Renal transplantation. Renal replacement is usually indicated when the creatinine clearance falls below 20 mL/min/1.73 m2 and azotemia and hypertension rapidly progress. The time frame for appropriate renal replacement is the point at which the reciprocal serum creatinine value plotted against age reaches approximately 0.1. Symptoms often determine the exact time of transplantation.

Ophthalmologic problems are treated symptomatically and with cystine-depleting agents:

  • The photophobia, resulting from corneal crystal accumulation, can be ameliorated by sun avoidance, dark glasses, and lubrication with over-the-counter eye drops (see Prevention of Primary Manifestations).
  • Corneal transplantation is very rarely required for intractable pain resulting from recurrent corneal ulcerations.
  • Retinal involvement is irreversible.

Growth for children with cystinosis requires good nutrition, adequate phosphate supplementation, and robust intracellular cystine depletion (see Prevention of Primary Manifestations):

  • Nutrition must be adequate for growth.
  • Growth hormone therapy has proven beneficial for children with cystinosis in providing catch-up growth and bringing them into the normal percentiles for height [Gahl et al 2001, Wühl et al 2001, Gahl et al 2002].
  • Early and diligent treatment with supplements and oral cysteamine can obviate the need for growth hormone [Kleta et al 2004a].

Other

  • Oral L-thyroxine replacement for hypothyroidism
  • Insulin for diabetes mellitus
  • Testosterone to induce secondary sexual characteristics in males with primary hypogonadism
  • Specific exercises for the muscle deterioration and swallowing difficulties of older individuals with cystinosis; hand tendon transfer has been partially successful in improving strength.
  • Speech therapy and physical therapy
  • Standard treatment for benign intracranial hypertension; other central nervous system complications are irreversible.
  • Feeding via gastrostomy for those with dysphagia, poor nutrition, and risk of aspiration (Figure 2b)

Prevention of Primary Manifestations

Cystine depletion therapy with cysteamine bitartrate (Cystagon®) has revolutionized the management and prognosis of people with nephropathic cystinosis. Cysteamine is now the treatment of choice for cystinosis throughout the world. This free thiol can deplete cystinotic cells of more than 90% of their cystine content [Kleta & Gahl 2004]. Wilmer et al [2011] found that cysteamine also increased intracellular glutathione levels and restored the glutathione redox status of cystinotic cells.

Cysteamine therapy should be considered for all affected individuals, regardless of age and transplantation status [Gahl et al 2007]. With early, diligent treatment many individuals with cystinosis have survived into their twenties without the need for renal transplantation [Gahl et al 2002].

  • Regular and diligent cysteamine therapy prevents or delays end-stage renal disease (ESRD) [Markello et al 1993] and hypothyroidism, enhances growth, and depletes muscle parenchyma of cystine [Gahl et al 2002].
  • It is critical to initiate cysteamine therapy immediately after diagnosis to allow for kidney growth and acquisition, rather than loss, of renal function [Kleta et al 2004a].
  • Cystagon® is taken orally every six hours at 60 to 90 mg of free base per kg per day (1.3 to 1.95 g/m2 per day). The recommended adult dose is 500 mg free base every six hours; however, for both children and adults, the dose is titrated to reduce, if possible, leukocyte cystine concentration (measured 5-6 hours after a dose) to below 1.0 nmol half-cystine/mg protein [Belldina et al 2003, Kleta & Gahl 2004, Kleta 2006].
  • Procysbi® (cysteamine bitartrate) is a delayed-release capsule intended for affected individuals age 6 years and older. Procysbi is taken every 12 hours. Blood testing showed Procysbi was non-inferior to Cystagon in controlling cystine levels [Langman et al 2012]. Procysbi has been available for only a short time, and thus its long-term safety and efficacy have not been demonstrated.
  • Side effects of cysteamine treatment include nausea and vomiting, in part because of its repulsive odor and taste [Schneider 2004]. Cysteamine increases gastrin synthesis and gastric acid production. Omeprazole may be of benefit for oral cysteamine treatment [Dohil et al 2003].
  • With long-term cystine-depleting therapy most late complications of cystinosis can be avoided.
  • Despite diligent oral cysteamine therapy, cysteamine hydrochloride eyedrops or CYSTARAN (cysteamine ophthalmic solution) 0.44% are required to achieve sufficient tissue concentration to dissolve corneal crystals [Gahl et al 2000]. Cysteamine eyedrops are given ten to 12 times per day as a 0.55% solution with benzalkonium chloride 0.01% as a preservative [Tsilou et al 2007]. With good compliance photophobia is relieved within weeks (Figures 1b, 1c) [Kaiser-Kupfer et al 1987, Gahl et al 2000]. Systemic cysteamine treatment ameliorates or postpones retinal deterioration [Tsilou et al 2006].

Prevention of Secondary Complications

Affected individuals who have undergone a renal transplantation should be monitored for the signs of immunodeficiency and infection.

Carnitine supplementation is used in some affected individuals to improve muscle strength.

Treatment with proton pump inhibitors, such as omeprazole, relieves cysteamine-induced gastric acid hypersecretion and improves gastrointestinal symptoms [Osefo et al 2009].

Surveillance

Clinical and laboratory examinations should be performed in individuals with nephropathic cystinosis according to disease severity and may include renal, endocrinologic, ophthalmologic, neurologic, and cardiac examinations [Kleta et al 2005]:

  • Evaluation by a nephrologist every three to six months depending on the severity of renal impairment
  • Renal function tests, electrolytes, and thyroid function tests at least every three to six months in those who are stable
  • Serum concentration of calcium, phosphate, alkaline phosphatase and intact parathyroid hormone. Plain bone radiographs as well as DEXA scans to detect osteopenia and bone fragility predisposing to fractures, starting as soon as diagnosis is made and continued throughout the course of the disease
  • Ophthalmologic evaluation with fundoscopic examination to screen for increased intracranial pressure every one to two years for those being treated appropriately
  • Fasting blood glucose concentration throughout the course of the disease and testosterone concentration (in males) every two to three years, starting before puberty
  • In advanced disease (i.e., poorly treated adults) and in late stages of disease, perform every two to three years:
    • Chest CT for detection of coronary and other vascular calcification
    • ECG
    • Brain CT or MRI for evaluation of cerebral atrophy or calcifications
    • Evaluation for the presence of progressive muscle weakness and swallowing difficulties using electromyography (EMG), oral sensorimotor examination, and modified barium swallowing studies with videofluoroscopy
    • Pulmonary function tests
    • Neurologic and neurocognitive evaluations including visual-motor integration, visual memory, planning, sustained attention, and motor speed beginning at age seven to eight years [Besouw et al 2010a]

Agents/Circumstances to Avoid

Avoid the following:

  • Dehydration, which compromises remaining renal function
  • Sun exposure, which can exacerbate photophobia

Evaluation of Relatives at Risk

Relatives at risk (e.g., newborn sibs of a proband) can undergo biochemical testing and/or molecular genetic testing (if the disease-causing mutations in the family are known). Early diagnosis allows for early treatment to prevent life-threatening complications of cystinosis.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancies in women with cystinosis are at a higher risk for premature delivery and must be monitored closely [Ramappa & Pyatt 2010]. For women who are post-transplantation, the abdominal renal allograft creates mechanical issues. For women who have not undergone transplantation, fluid and electrolyte status require careful management.

Therapies Under Investigation

Bone marrow-derived stem cell transplantation in mice improved chronic kidney disease [Yeagy et al 2011].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Development of a newborn screening test for cystinosis will potentially allow broader therapeutic success [Nesterova & Gahl 2008]. Two methods have been proposed: tandem mass spectrometry for the determination of derivative seven-carbon (C7) sugars in dried blood spots (DBS), which detect homozygosity for the CTNS 57-kb deletion and molecular genetic testing for the most common CTNS mutations [Wamelink et al 2011].

Therapies proven to be ineffective include dietary restriction of sulfur-containing amino acids, supplementation with ascorbic acid, and the use of dithiothreitol.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

All forms of cystinosis are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and thus carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of an individual with cystinosis are obligate heterozygotes (carriers) for a mutant allele causing cystinosis. Rarely, families with two-generation involvement (sometimes called “pseudodominance”) have been identified; two-generation involvement results from an affected individual having children with a partner who is heterozygous (i.e., a carrier) for a CTNS mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Biochemical testing. Carrier testing can be performed biochemically; it requires freshly prepared leukocytes and appropriate controls.

Molecular genetic testing. Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
  • Women with cystinosis have had successful pregnancies resulting in healthy newborns; however, the potential teratogenic effects of cysteamine on fetuses have not been studied in humans.
  • No data on fertility in males with cystinosis exist; however, spermatogenesis in testicular biopsies was sufficient. Cryopreservation of sperm could be considered in affected males [Besouw et al 2010b].

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Biochemical testing. For pregnancies at risk for nephropathic cystinosis, prenatal diagnosis is possible biochemically, based on elevated cystine concentrations in either chorionic villi, obtained at approximately ten to 12 weeks' gestation by chorionic villus sampling (CVS), or amniocytes, obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation [Gahl et al 2001].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular genetic testing. Molecular-based prenatal diagnosis is possible by analysis of DNA extracted from fetal cells obtained either by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or by chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing using molecular genetic testing methods can be performed.

Requests for prenatal testing for conditions which (like cystinosis) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Cystinosis Foundation
    Links to international cystinosis consumer groups can be found on The Cystinosis Foundation homepage.
    604 Vernon Street
    Oakland CA 94610
    Phone: 888-631-1588 (toll-free); 925-631-1588
    Email: Jean.Cystinosis@sbcglobal.net
  • Cystinosis Research Foundation (CRF)
    18802 Bardeen Avenue
    Irvine CA 92612
  • Cystinosis Research Network (CRN)
    302 Whytegate Court
    Lake Forest IL 60045
    Phone: 866-276-3669 (toll-free); 847-735-0471
    Fax: 847-235-2773
    Email: info@cystinosis.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Cystinosis: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CTNS17p13​.2CystinosinCTNS homepage - Mendelian genesCTNS

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Cystinosis (View All in OMIM)

219750CYSTINOSIS, ADULT NONNEPHROPATHIC
219800CYSTINOSIS, NEPHROPATHIC; CTNS
219900CYSTINOSIS, LATE-ONSET JUVENILE OR ADOLESCENT NEPHROPATHIC TYPE
606272CYSTINOSIN; CTNS

Gene structure. Normal CTNS is 26 kb in length and has 12 exons with a coding region of 1104 bp [Town et al 1998]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Several benign variants have been reported.

Pathogenic allelic variants. At least 112 different mutations including promotor mutations in CTNS have been reported in HGMD; they are found in different combinations in individuals with cystinosis [Shotelersuk et al 1998, Town et al 1998, Attard et al 1999, McGowan-Jordan et al 1999, Thoene et al 1999, Anikster et al 2000, Kleta et al 2001, Phornphutkul et al 2001, Kalatzis et al 2002, Kiehntopf et al 2002, Mason et al 2003]. The mutations include missense, nonsense, and splice site mutations, deletions, and insertions leading to downstream stop codons or abolition of splice sites [Kiehntopf et al 2002]. The missense mutations are usually present within transmembrane regions [Anikster et al 1999b]. There are no mutational hot spots.

By far the most common mutation (50% of affected individuals) is the 57-kb deletion involving exons 1-9 and part of exon 10; this mutation apparently represents a founder effect [Shotelersuk et al 1998]. Another relatively common mutation is p.Trp138Ter. A higher incidence of infantile cystinosis was reported in the French province of Brittany, with an incidence of 1:26000. The splice site mutation c.898_900+24del27 segregates in certain unrelated families [Kalatzis et al 2002]. (For more information, see Table A.)

Table 2. CTNS Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
g.36,254_93,510del
(57-kb del) 2
--AF168787
c.18_21del4p.Thr7PhefsTer7NM_004937​.2
NP_004928​.2
c.198_218del
(c.198del21bp or 537del21)
p.Ile67_Pro73del
c.382C>Tp.Gln128Ter
c.397A>Tp.Ile133Pro
c.414G>Ap.Trp138Ter
c.416C>Tp.Ser139Phe
c.473T>Cp.Leu158Pro
c.544T>Cp.Trp182Arg
c.589G>Ap.Gly197Arg
c.611_613del3p.Asp205del
c.853-3C>G-- 3
c.898_900+24del27--
c.922G>Ap.Gly308Arg

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Touchman et al [2000]

3. Anikster et al [2000]

Normal gene product. Cystinosin, the protein product of CTNS, is a 367-amino acid peptide with seven transmembrane and two lysosomal targeting motifs, a 128 amino-acid N-terminal region bearing seven potential N-glycosylation sites, and a ten amino-acid cytosolic C-terminal tail [Town et al 1998, Kalatzis & Antignac 2002, Kalatzis & Antignac 2003]. Cystinosin is expressed in the cells of virtually all tissues. Cystinosin transports the disulfide amino acid cystine out of the lysosome and into the cytoplasm [Gahl et al 2002, Kleta & Gahl 2002]. Cystinosin is highly conserved between man and mouse [Cherqui et al 2002].

Abnormal gene product. The 57-kb deletion allele produces no CTNS mRNA, while most other alleles produce some residual mRNA [Shotelersuk et al 1998]. The mutant alleles of CTNS are predicted to produce truncated cystinosin in the case of severely affected individuals and to produce cystinosis that retains some residual function in the case of mildly affected individuals.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. Nesterova G, Gahl WA. Infantile nephropathic cystinosis standards of care – a reference for people with infantile nephropathic cystinosis, their families,and medical team. Cystinosis Research Network. Available online. 2012. Accessed 1-21-14.

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  53. Phornphutkul C, Anikster Y, Huizing M, Braun P, Brodie C, Chou JY, Gahl WA. The promoter of a lysosomal membrane transporter gene, CTNS, binds Sp-1, shares sequences with the promoter of an adjacent gene, CARKL, and causes cystinosis if mutated in a critical region. Am J Hum Genet. 2001;69:712–21. [PMC free article: PMC1226058] [PubMed: 11505338]
  54. Ramappa AJ, Pyatt JR. Pregnancy-associated cardiomyopathy occurring in a young patient with nephropathic cystinosis. Cardiol Young. 2010;20:220–2. [PubMed: 20199711]
  55. Sansanwal P, Li L, Hsieh SC, Sarwal MM. Insights into novel cellular injury mechanisms by gene expression profiling in nephropathic cystinosis. J Inherit Metab Dis. 2010;33:775–86. [PubMed: 20865335]
  56. Schneider JA. Treatment of cystinosis: simple in principle, difficult in practice. J Pediatr. 2004;145:436–8. [PubMed: 15480361]
  57. Servais A, Morinière V, Grünfeld JP, Noël LH, Goujon JM, Chadefaux-Vekemans B, Antignac C. Late-onset nephropathic cystinosis: clinical presentation, outcome, and genotyping. Clin J Am Soc Nephrol. 2008;3:27–35. [PMC free article: PMC2390982] [PubMed: 18178779]
  58. Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA. CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet. 1998;63:1352–62. [PMC free article: PMC1377545] [PubMed: 9792862]
  59. Sonies BC, Almajid P, Kleta R, Bernardini I, Gahl WA. Swallowing dysfunction in 101 patients with nephropathic cystinosis: benefit of long-term cysteamine therapy. Medicine (Baltimore). 2005;84:137–46. [PubMed: 15879904]
  60. Spilkin AM, Ballantyne AO, Babchuck LR, Trauner DA. Non-verbal deficits in young children with a genetic metabolic disorder: WPPSI-III performance in cystinosis. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:444–7. [PubMed: 17471495]
  61. Thoene J, Lemons R, Anikster Y, Mullet J, Paelicke K, Lucero C, Gahl W, Schneider J, Shu SG, Campbell HT. Mutations of CTNS causing intermediate cystinosis. Mol Genet Metab. 1999;67:283–93. [PubMed: 10444339]
  62. Thoene JG. Cystinosis. J Inherit Metab Dis. 1995;18:380–6. [PubMed: 7494397]
  63. Touchman JW, Anikster Y, Dietrich NL, Maduro VV, McDowell G, Shotelersuk V, Bouffard GG, Beckstrom-Sternberg SM, Gahl WA, Green ED. The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion. Genome Res. 2000;10:165–73. [PMC free article: PMC310836] [PubMed: 10673275]
  64. Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore SA, Callen DF, Gribouval O, Broyer M, Bates GP, van't Hoff W, Antignac C. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet. 1998;18:319–24. [PubMed: 9537412]
  65. Trauner DA, Fahmy RF, Mishler DA. Oral motor dysfunction and feeding difficulties in nephropathic cystinosis. Pediatr Neurol. 2001;24:365–8. [PubMed: 11516611]
  66. Tsilou ET, Rubin BI, Reed G, Caruso RC, Iwata F, Balog J, Gahl WA, Kaiser-Kupfer MI. Nephropathic cystinosis: posterior segment manifestations and effects of cysteamine therapy. Ophthalmology. 2006;113:1002–9. [PubMed: 16603246]
  67. Tsilou ET, Rubin BI, Reed GF, Iwata F, Gahl W, Kaiser-Kupfer MI. Age-related prevalence of anterior segment complications in patients with infantile nephropathic cystinosis. Cornea. 2002;21:173–6. [PubMed: 11862089]
  68. Tsilou ET, Zhou M, Gahl W, Sieving P, Chan CC. Ophthalmic manifestations and histopathology of infantile nephropathic cystinosis: report of a case and review of the literature. Surv Ophthalmol. 2007;52:97–105. [PMC free article: PMC1850966] [PubMed: 17212992]
  69. Ueda M, O’Brien K, Rosing D, Ling A, Kleta R, McAreavey D, Bernardini I, Gahl W. Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. Clin J Am Soc Nephrol. 2006;1:555–62. [PubMed: 17699259]
  70. Wamelink MM, Struys EA, Jansen EE, Blom HJ, Vilboux T, Gahl WA, Kömhoff M, Jakobs C, Levtchenko EN. Elevated concentrations of sedoheptulose in bloodspots of patients with cystinosis caused by the 57-kb deletion: implications for diagnostics and neonatal screening. Mol Genet Metab. 2011;102:339–42. [PubMed: 21195649]
  71. Wilmer MJ, Emma F, Levtchenko EN. The pathogenesis of cystinosis: mechanisms beyond cystine accumulation. Am J Physiol Renal Physiol. 2010;299:F905–16. [PubMed: 20826575]
  72. Wilmer MJ, Kluijtmans LA, van der Velden TJ, Willems PH, Scheffer PG, Masereeuw R, Monnens LA, van den Heuvel LP, Levtchenko EN. Cysteamine restores glutathione redox status in cultured cystinotic proximal tubular epithelial cells. Biochim Biophys Acta. 2011;1812:643–51. [PubMed: 21371554]
  73. Wühl E, Haffner D, Offner G, Broyer M, van't Hoff W, Mehls O. European Study Group on Growth Hormone Treatment in Children with Nephropathic Cystinosis; Long-term treatment with growth hormone in short children with nephropathic cystinosis. J Pediatr. 2001;138:880–7. [PubMed: 11391333]
  74. Yeagy BA, Harrison F, Gubler MC, Koziol JA, Salomon DR, Cherqui S. Kidney preservation by bone marrow cell transplantation in hereditary nephropathy. Kidney Int. 2011;79:1198–206. [PubMed: 21248718]
  75. Zimakas PJ, Sharma AK, Rodd CJ. Osteopenia and fractures in cystinotic children post renal transplantation. Pediatr Nephrol. 2003;18:384–90. [PubMed: 12700967]

Suggested Reading

  1. Gahl WA, Thoene JG, Schneider JA. Cystinosis: A disorder of lysosomal membrane transport. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 199. Available online. Accessed 1-21-14.
  2. Gangoiti JA, Fidler M, Cabrera BL, Schneider JA, Barshop BA, Dohil R. Pharmacokinetics of enteric-coated cysteamine bitartrate in healthy adults: a pilot study. Br J Clin Pharmacol. 2010;70:376–82. [PMC free article: PMC2949910] [PubMed: 20716238]

Chapter Notes

Author Notes

Dr. Gahl is a pediatrician, medical geneticist, and biochemical geneticist who performs clinical and basic research into rare diseases. He has seen approximately 300 patients with cystinosis and published more than 85 articles and reviews on the subject.

Author History

William A Gahl, MD, PhD (2001-present)
Robert Kleta, MD, PhD; National Human Genome Research Institute (2001-2009)
Galina Nesterova, MD (2009-present)

Revision History

  • 30 January 2014 (me) Comprehensive update posted live
  • 17 May 2012 (cd) Revision: to include deletion/duplication analysis for identification of deletions/duplications in addition to the common 57-kb deletion
  • 11 August 2011 (me) Comprehensive update posted live
  • 9 April 2009 (me) Comprehensive update posted live
  • 18 October 2005 (me) Comprehensive update posted live
  • 6 June 2003 (ca) Comprehensive update posted live
  • 22 March 2001 (me) Review posted to live Web site
  • January 2001 (wg) Original submission

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