Cystinosis
Galina Nesterova, MD and William A Gahl, MD, PhD.
Author Information and AffiliationsInitial Posting: March 22, 2001; Last Revision: December 7, 2017.
Estimated reading time: 31 minutes
Summary
Clinical characteristics.
Cystinosis comprises three allelic phenotypes:
Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, 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 interventions, 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 clinically only by photophobia resulting from corneal cystine crystal accumulation.
Diagnosis/testing.
The diagnosis of cystinosis is established in a proband by one of the following:
Identification of cystine crystals in the cornea on slit lamp examination
Identification of elevated cystine concentration in polymorphonuclear leukocytes
Demonstration of increased cystine content in cultured fibroblasts or in the placenta at the time of birth
Management.
Treatment of manifestations: Renal Fanconi syndrome is treated by replacement of tubular losses of electrolytes, bicarbonate, minerals, and other small molecular weight nutrients; children should have free access to water and bathroom privileges and supplementation with citrate to alkalinize the blood; phosphate replacement and vitamin D supplements are also used to prevent and treat rickets; skeletal deformities should be addressed early with the help of orthopedic specialists. Fluid and nutrient replacement is required during episodes of dehydration. For renal glomerular disease, oral cysteamine reduces cellular cystine; renal transplantation provides the ultimate treatment. Cysteamine eye drops relieve photophobia. Nutrition must be adequate to minimize failure to thrive in infants. Growth hormone replacement, L-thyroxine for hypothyroidism, insulin for diabetes mellitus, and testosterone for hypogonadism in males are all beneficial. 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 will significantly slow the progression of glomerular damage; 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 administered pre-transplant may improve muscle strength; treatment with proton pump inhibitors helps relieve cysteamine-induced gastric acid hypersecretion.
Surveillance: Evaluation by a nephrologist every three to six months depending on the severity of renal impairment; ophthalmologic evaluation every one to two years; assessment of bone mineralization throughout the disease course; fasting blood glucose concentration and testosterone concentration every two to three years (in males, starting before puberty); 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 genetic 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 pathogenic variants have been identified in the family. For pregnancies at increased risk for nephropathic cystinosis, prenatal diagnosis is also possible biochemically, based on elevated cystine concentrations in both chorionic villi and amniocytes.
Diagnosis
Cystinosis Standards of Care [Nesterova & Gahl 2012], developed and approved by international experts on cystinosis, is available online.
Suggestive Findings
Nephropathic cystinosis should be suspected in infants and young children with the following clinical, laboratory, and radiographic features.
Clinical
Failure to thrive and growth retardation from age six months
Vomiting; feeding difficulties
Severe polyuria, polydipsia, and dehydration
Progressive rachitic skeletal changes; failure to walk at a normal age
Tetany
Laboratory
Hypochloremic metabolic acidosis
Renal Fanconi syndrome: increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, tubular protein including β2-microglobulin
Elevated serum alkaline phosphatase, hypocalcemia, hypophosphatemia, hypokalemia
Radiographic
Radiographic features of rickets including: bowing of the long bones in the lower extremities; metaphyses may be widened and epiphyses frayed or cupped; generalized osteopenia
Renal ultrasound examination showing medullary nephrocalcinosis and/or increased echogenicity
Intermediate nephropathic cystinosis (juvenile/late onset)
should be suspected in individuals exhibiting renal tubular Fanconi syndrome combined with progressive chronic glomerular insufficiency leading to end-stage renal disease (ESRD).
Ocular (non-nephropathic) cystinosis should be suspected in adults with photophobia and/or cystine crystals in the cornea on slit lamp examination (see ).
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
Establishing the Diagnosis
The diagnosis of cystinosis is established in a proband by ONE of the following:
Identification of cystine crystals in the cornea on slit lamp examination visible after age 12 months, and always present after age of 16 months (See .)
Identification of elevated cystine concentration in polymorphonuclear leukocytes
Demonstration of increased cystine content in cultured fibroblasts or in the placenta at the time of birth
Elevated cystine concentration in polymorphonuclear leukocytes is best identified using mass spectrometry [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.
Note: (1) In preparing leukocytes for assay, care must be taken to avoid: (a) a significant number of lymphocytes, which store only fivefold normal amounts of cystine compared with 50-fold normal amounts in polymorphonuclear leukocytes; and (b) 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. (2) 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.
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].
Molecular genetic testing
Targeted analysis for the
CTNS
57-kb deletion in individuals of northern European ancestry may be performed first. Targeted analysis of
CTNS pathogenic variants, optimized for the French-Canadian population, may be performed first.
A multigene panel that includes
CTNS and other genes of interest (see
Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
More comprehensive genomic testing (when available) including
exome sequencing and
genome sequencing may be considered if single-
gene testing (and/or use of a
multigene panel that includes
CTNS) fails to confirm a diagnosis in an individual with features of cystinosis. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive
genomic testing click
here. More detailed information for clinicians ordering genomic testing can be found
here.
Table 1.
Molecular Genetic Testing Used in Cystinosis
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Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
---|
CTNS
| Sequence analysis 3 | 56% 4 |
Gene-targeted deletion/duplication analysis 5 | 44% 4 |
- 1.
- 2.
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
The three types of cystinosis ‒ nephropathic (classic renal and systemic disease), intermediate (a late-onset variant of nephropathic cystinosis), and non-nephropathic (ocular) ‒ are allelic disorders caused by pathogenic variants in CTNS.
Non-Nephropathic Cystinosis
Individuals with untreated ocular cystinosis experience only photophobia.
Genotype-Phenotype Correlations
Some genotype-phenotype correlations can be made:
Individuals with apparent residual activity (i.e., lower levels of cystine accumulation in leukocytes) often have
missense variants 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 pathogenic variant, typical for nephropathic cystinosis, and one mild pathogenic variant. The mild variants include
p.Gly197Arg and
c.853-3C>G [
Anikster et al 1999]. The organ specificity in benign cystinosis may result from tissue-specific
splicing factors.
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]. 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 (or juvenile) nephropathic type cystinosis.
The terms "adult cystinosis" and "benign cystinosis" should be replaced by "ocular cystinosis," "non-nephropathic cystinosis," or "ocular 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
Renal tubular Fanconi syndrome. Untreated nephropathic cystinosis is the most common identifiable cause of renal tubular Fanconi syndrome in childhood. Other causes include:
Wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances or a combination of these; onset ranges from age three to older than 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. Pathogenic variants in
ATP7B are causative. Inheritance is
autosomal recessive.
Lowe syndrome (oculocerebrorenal syndrome) 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. A
pathogenic variant in
OCRL is 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.
Classic 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-1-phosphate uridyltransferase (GALT). The diagnosis of classic galactosemia is established by detection of elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte GALT enzyme activity, and/or
biallelic pathogenic variants in
GALT. Inheritance is
autosomal recessive.
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.
Electrolyte abnormalities can suggest Bartter syndrome.
The rickets of cystinosis can falsely suggest vitamin D-deficient rickets.
Ocular (non-nephropathic) cystinosis. Multiple myeloma can cause photophobia and corneal crystals similar to those in ocular cystinosis [Kleta et al 2004b].
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. Quantitative 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
Consultation with a clinical geneticist and/or genetic counselor
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 dual-energy x-ray absorptiometry (DXA) scan
Consultation with a clinical geneticist and/or genetic counselor
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 Fanconi syndrome
Replacement of tubular losses of electrolytes, bicarbonate, minerals, and other small molecular weight nutrients
For children, free access to water and bathroom privileges and supplementation with citrate to alkalinize the blood
Phosphate replacement to prevent and treat rickets; vitamin D supplementation to assist the gastrointestinal absorption of phosphate and calcium
Early treatment of skeletal deformities with the help of orthopedic specialists
Careful attention to fluid and nutrient replacement is required during episodes of dehydration. (Obligatory urinary losses amount to 2-6 L electrolyte-rich water per day.)
Renal glomerular disease
Ophthalmologic problems are treated symptomatically and with cystine-depleting agents:
Growth for children with cystinosis requires good nutrition, adequate phosphate supplementation, and robust intracellular cystine depletion (see Prevention of Primary Manifestations):
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 ()
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 worldwide treatment of choice for cystinosis. 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].
Prevention of Secondary Complications
Affected individuals who have undergone a renal transplantation should be monitored for the signs of immunodeficiency and infection.
Carnitine supplementation may improve muscle strength in pre-transplant individuals.
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, endocrine, 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 DXA 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
EKG
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
It is appropriate to evaluate relatives at risk (e.g., newborn sibs of a proband) in order to identify as early as possible those who would benefit from early treatment to prevent life-threatening complications of cystinosis.
Evaluations can include:
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 increased 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.
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 detects homozygosity for the CTNS 57-kb deletion, and molecular genetic testing for the most common CTNS pathogenic variants [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, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members
Parents of a proband
Sibs of a proband
Offspring of a proband
The offspring of an individual with cystinosis are obligate heterozygotes (carriers) for a
CTNS pathogenic variant.
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 pathogenic variant.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CTNS pathogenic variant.
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 pathogenic variants in the family are known.
Prenatal Testing and Preimplantation Genetic Testing
Biochemical testing. For pregnancies at risk for nephropathic cystinosis, prenatal diagnosis is possible biochemically, based on elevated cystine concentrations in either chorionic villi or amniocytes obtained by amniocentesis [Gahl et al 2001].
Molecular genetic testing. Once the CTNS pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for cystinosis are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
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 Ireland
Ireland
Email: mail@cystinosis.ie
Cystinosis Research Foundation
Cystinosis Research Network
Phone: 847-735-0471
Email: info@cystinosis.org
Metabolic Support UK
United Kingdom
Phone: 0845 241 2173
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
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure.
CTNS is 26 kb in length and has 12 exons with a coding region of 1,104 bp [Town et al 1998]. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. At least 128 different pathogenic variants including promoter variants 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]. Pathogenic variant types include missense, nonsense, and splice site variants, deletions, and insertions leading to downstream stop codons or abolition of splice sites [Kiehntopf et al 2002]. The missense variants are usually present within transmembrane regions [Anikster et al 1999]. There are no mutational hot spots.
By far the most common pathogenic variant (50% of affected individuals) is the 57-kb deletion involving exons 1-9 and part of exon 10; this variant apparently represents a founder effect [Shotelersuk et al 1998]. Another relatively common pathogenic variant is p.Trp138Ter. A higher incidence of infantile cystinosis (1:26,000) was reported in the French province of Brittany. The splice site variant 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
View in own window
DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
g.36,254_93,510del (57-kb del) 1 | -- |
AF168787
|
c.18_21del4 | p.Thr7PhefsTer7 |
NM_004937.2
NP_004928.2
|
c.198_218del (198del21bp or 537del21) 2 | p.Ile67_Pro73del |
c.382C>T | p.Gln128Ter |
c.397A>T | p.Ile133Pro |
c.414G>A | p.Trp138Ter |
c.416C>T | p.Ser139Phe |
c.473T>C | p.Leu158Pro |
c.544T>C | p.Trp182Arg |
c.589G>A | p.Gly197Arg |
c.611_613del3 | p.Asp205del |
c.853-3C>G | -- 3 |
c.898_900+24del27 | -- |
c.922G>A | p.Gly308Arg |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
- 2.
Variant designation that does not conform to current naming conventions
- 3.
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 mutated alleles of CTNS are predicted to produce truncated cystinosin in the case of severely affected individuals and to produce cystinosin that retains some residual function in the case of mildly affected individuals.
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 individuals 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
6 October 2016 (sw) Comprehensive update posted live
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 live
January 2001 (wg) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Cystinosis" is in the public domain in the United States of America.
References
Published Guidelines / Consensus Statements
Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van't Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Available
online. 2014. Accessed 3-23-22. [
PMC free article: PMC4158338] [
PubMed: 25165189]
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 3-23-22.
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