Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 190681003, 62332007; ICD10CM: E72.04; ORPHA: 213, 411629; DO: 1064;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.2 | Cystinosis, nephropathic | 219800 | Autosomal recessive | 3 | CTNS | 606272 |
| 17p13.2 | Cystinosis, atypical nephropathic | 219800 | Autosomal recessive | 3 | CTNS | 606272 |
A number sign (#) is used with this entry because nephropathic cystinosis has been found to be caused by mutation in the gene encoding cystinosin (CTNS; 606272). There is an adolescent (219900) as well as an infantile type of nephropathic cystinosis.
Cystinosis has been classified as a lysosomal storage disorder on the basis of cytologic and other evidence pointing to the intralysosomal localization of stored cystine. Cystinosis differs from the other lysosomal diseases inasmuch as acid hydrolysis, the principal enzyme function of lysosomes, is not known to play a role in the metabolic disposition of cystine. The fact that plasma levels are well below saturation indicates that the defect is a cellular one. Within the cell, cystine is compartmentalized with acid phosphatase and is membrane-bound as demonstrated by electron microscopy. Ferritin accumulates in the same organelle which appears to be the lysosome.
An abnormality in heterozygotes was demonstrated by Schneider et al. (1967) who found the concentration of free cystine to be about 6 times normal in the leukocytes of parents of patients. The features resulting from accumulation of cystine in the kidney are those of the Fanconi syndrome (134600).
Teree et al. (1970) studied physiologically and anatomically 2 male sibs with cystinosis. Microdissection of the kidney tubules suggested that the morphologic abnormality of the proximal tubule is 'acquired' and progressive. Mahoney et al. (1970) found that renal transplants in 4 children with cystinosis did not develop glomerular and tubular epithelial cellular changes of cystinosis.
Sensenbrenner et al. (1974), Hurley and Liu (1977), and Lucky et al. (1977) reported hypothyroidism due to extensive deposits in the thyroid as an important factor in the growth retardation of cystinosis.
Jonas et al. (1987) described a patient with onset at about age 1 year and with end-stage renal failure from age 7 years. At the age of 24, her height was 123 cm. She had marked photophobia, corneas and conjunctiva laden with refractile material, and a patchy retinopathy. There were signs of ovarian failure, intermittent confusion, short-term memory loss, and cerebral atrophy on computerized axial tomography. Autopsy examination at age 25 showed cystine storage in multiple tissues including pancreatic islet cells, the aorta, the atrophic ovaries, and brain. Gahl et al. (1988) reported myopathy with generalized muscle weakness and wasting due to accumulation of cystine in and around muscle fibers in a 22-year-old man. Renal allograft had been performed at age 10 years. Schnaper et al. (1992) described a patient who required renal transplantation at age 30 months. Exhaustive evaluation did not identify a cause of progressive renal failure other than cystinosis. Furthermore, the patient's genetic lesion was allelic with those of other patients with cystinosis; fusion of her fibroblasts with those from another patient with infantile nephropathic cystinosis failed to demonstrate complementation.
The long-term ill effects of cystinosis, observed particularly in patients with long survival as a result of renal transplant, include pancreatic endocrine and exocrine insufficiency (Fivush et al. (1987, 1988)) and, as mentioned earlier, recurrent corneal erosions, central nervous system involvement, and severe myopathy. Sonies et al. (1990) studied oral motor function in 43 patients with cystinosis, aged 3 to 31 years, 24 of whom had received a renal transplant. Approximately half of the patients were slow eaters. Oral motor dysfunction increased with age. Speech and tongue and lip strength were affected. Seven of 9 patients, aged 21 to 31 years, had abnormalities in all 3 phases of swallowing. In studies of intelligence in 14 families of children with infantile nephropathic cystinosis, Williams et al. (1994) found that the IQs of 15 children with cystinosis were significantly lower on the average than those of their sibs and parents. Even though the mean IQ of the children with cystinosis (94.4 +/- 10) was within the average range, there was evidence that they had a mild global intellectual deficit relative to their expected IQ based upon the IQs of their relatives.
Several have commented that patients with cystinosis have skin and hair pigmentation noticeably lighter than that of their unaffected sibs. It has been speculated that pigment formation may be impaired in the melanosomes, which are the melanocyte counterparts of lysosomes (Gahl, 1997). Most children with nephropathic cystinosis display an inability to produce the normal volume of sweat, although sweat electrolyte concentrations are normal (Gahl et al., 1984). This deficiency results in heat intolerance and avoidance, flushing, hyperthermia, and vomiting in small children.
Gahl et al. (2000) employed a scoring system, based on a library of slit-lamp photographs of corneas with increasing crystal densities, to assess the degree of crystal accumulation in 170 patients with nephropathic cystinosis. None of the patients had received topical cystine-depleting therapy at the time of the evaluation. In this natural history study, infants in the first year of life had absent or minimal corneal crystals, i.e., a corneal cystine crystal score (CCCS) of 0.0 to 0.25. However, the CCCS increased linearly with age, such that every patient had visible crystals by 16 months of age, and plateaued at approximately 3.00 by early adolescence. Longitudinal studies in representative patients supported the cross-sectional results. Individuals homozygous for the common 57-kb deletion involving the CTNS gene displayed the same course of corneal crystal accumulation as did individuals not bearing the large deletion. Patients with ocular or nonnephropathic cystinosis (219750) had CCCSs that were, in general, half those expected for patients with nephropathic cystinosis of the same age. Administration of 0.55% cysteamine eyedrops, given 6 to 12 times per day, dissolved corneal cystine crystals in 10 representative patients with nephropathic cystinosis aged 1 to 32 years within 8 to 41 months.
Tsilou et al. (2006) studied the posterior segment manifestations associated with infantile nephropathic cystinosis and determined retrospectively the effect of chronic oral cysteamine therapy on the frequency of these abnormalities. Pigmentary changes with retinal pigment epithelial mottling, seen as early as infancy, were the most common posterior segment manifestations. Moderate to severe constriction of the visual fields, as well as moderate to severe reduction of rod- and cone-mediated electroretinographic responses, was seen in older patients. The frequency of retinopathy correlated directly with time not receiving oral cysteamine therapy and inversely with time receiving oral cysteamine therapy. Thus, early initiation oral cysteamine therapy could reduce the frequency of posterior segment complications and significant visual handicap in cystinosis patients.
Reiss et al. (1988) described successful pregnancy in a 20-year-old woman in whom the diagnosis of cystinosis had been made at the age of 6 on the basis of corneal crystals and renal tubular Fanconi syndrome. At the age of 8 years, renal failure required dialysis, and 1 year later she underwent renal allograft from her father. Because of cephalopelvic disproportion, mild preeclampsia, and possible streptococcal amnionitis, a cesarean section was performed. The maternal portion of the placenta showed striking accumulation of cystine crystals. The baby developed normally.
In a comprehensive review of cystinosis, Gahl et al. (2002) tabulated the age-related clinical characteristics of untreated nephropathic cystinosis, giving age of onset and prevalence in affected patients: renal Fanconi syndrome, 6 to 12 months, 95%; hypothyroidism, 5 to 10 years, 50%; photophobia, 8 to 12 years, 50%; chronic renal failure, 8 to 12 years, 95%; myopathy, difficulty swallowing, 12 to 40 years, 20%; retinal blindness, 13 to 40 years, 10-15%; diabetes mellitus, 18 to 40 years, 5%; male hypogonadism, 18 to 40 years, 70%; pulmonary dysfunction, 21 to 40 years, 100%; CNS calcifications, 21 to 40 years, 15%; and CNS symptomatic deterioration, 21 to 40 years, 2%.
Trauner et al. (2007) found that 25 children with cystinosis aged 3 to 8 years performed significantly worse on tests of visual spatial and visual motor function compared to controls. Visual perceptive abilities were equal in the 2 groups. Trauner et al. (2007) noted that these same specific cognitive deficits had been observed in older patients with the disorder; however, the 25 children in this study had been treated from an early age, suggesting an influence of the CTNS gene on brain development rather than an adverse effect of prolonged cysteine accumulation in the brain.
Steinherz et al. (1982) found that heterozygotes could be reliably identified by clearance of 35S-cystine dimethyl ester from leukocytes. The mean half-time was intermediate between the normal and cystinotics. The 60-minute cysteine/cystine ratio was also significantly reduced and intermediate between that of the 2 homozygotes. Gahl et al. (1984) found that heterozygotes exhibit about half normal rates of cystine countertransport into isolated leukocyte lysosomes. This gene-dosage effect strongly supports previous conclusions that the basic defect in cystinosis is impaired cystine transport across the lysosomal membrane. Smolin et al. (1987) found that when the cystine content of mixed-leukocyte preparations was examined in obligate heterozygotes, overlap with the normal range was encountered. However, when pure polymorphonuclear leukocyte preparations were tested, no heterozygote values were within the normal range.
Jonas et al. (1982) demonstrated that efflux of cystine from lysosomes is dependent upon the functioning of a proton-pump ATPase. This ATPase-dependent cystine efflux appeared to be aberrant in cystinotic cell lysosomes. Lysosomal cystine efflux was greatly enhanced by exogenous ATP in cell lines from normal individuals but was unresponsive to ATP in lysosomes from individuals with cystinosis. Efflux of cystine from normal cell lysosomes was inhibited by both an ATP analog and a proton translocator. It had earlier been observed that cystine loss could not be demonstrated from isolated lysosomes from either normal or cystinotic cells.
Pisoni et al. (1992) found that loading of cystinosis cells with cystine dimethyl ester (CDME) was lethal, whereas most normal fibroblasts survived. They proposed, furthermore, that transfection of cystinotic fibroblasts with normal human genomic DNA or cDNA results in survival of the loaded cells. Thus this selection method should be useful in the identification of the gene coding for the lysosomal cystine transport protein.
Malekzadeh et al. (1977) found that extrarenal features such as photophobia and hypothyroidism were not relieved by renal transplant. Cystine deposits appeared in the mesangium and interstitial tissue but not in the tubular cells of the grafts; the relation between amount of cystine deposited in the graft and rejection suggested to the authors that recipient cells infiltrating the graft were the source of cystine deposition.
Kaiser-Kupfer et al. (1987) treated 2 affected children with cysteamine eyedrops. In each, one eye was treated and the other eye used as a control. There was a striking decrease in the number of corneal crystals in the treated eyes within 4 to 5 months of entering the study. Both children were begun on treatment before 2 years of age. Gahl et al. (1987) treated 98 children with oral cysteamine for periods as long as 73 months. The mean cystine depletion from leukocytes was 82%. A historical control group of children received either ascorbic acid or placebo. Lower levels of serum creatinine, higher levels of creatinine clearance, and improved growth were observed in the treated group.
Markello et al. (1993) reported on experience in the treatment of 76 children with cystinosis at the National Institutes of Health between 1960 and 1992. Treatment with cysteamine was considered to be adequate in 17 children, since they had depletion of cystine from leukocytes and began therapy before the age of 2 years; treatment lasted a mean of 7.1 years. Treatment was considered to have been partial in 32 children who had poor compliance or began treatment after the age of 2; treatment lasted a mean of 4.5 years. No cysteamine therapy was received by 27 children who were followed in the era before the introduction of this mode of treatment. Markello et al. (1993) concluded that children with cystinosis treated early and adequately with cysteamine have renal function that increases during the first 5 years of life and then declines at a normal rate. Patients with poorer compliance and those who are treated at an older age do less well.
Gahl et al. (2002) stated that many patients with cystinosis have survived into the third decade of life without the need for renal transplantation. If the diagnosis is established and cysteamine therapy is started before symptoms develop, the prognosis for glomerular function is especially good, but tubular dysfunction still develops at an early age. Cysteamine therapy has been shown to obviate the need for levothyroxine replacement in patients with cystinosis (Kimonis et al., 1995), indicating that it has a beneficial effect on at least 1 nonrenal organ, the thyroid. This suggests that cysteamine should be useful in preventing posttransplantation complications in patients with cystinosis. The mechanism of lysosomal cystine depletion involves entry of cysteamine into the lysosomal compartment through a specific transporter, reaction with cystine to form the mixed disulfide of cysteamine and cysteine, exit of that compound from the lysosomes through an intact lysine transporter, and reduction to cysteamine and cysteine by glutathione in the cytoplasm. This process permits the cycling of cysteamine between lysosomes and cytoplasm, with each cycle removing 1 mole of half-cystine per mole of cysteamine.
Liu et al. (2012) identified PQLC2 (SLC66A1; 614760) as the lysosomal lysine/arginine transporter that transports the mixed disulfide of cysteine-cysteamine out of the lysosomes in cystinosis.
The incidence of cystinosis is estimated to be between 1 in 100,000 and 1 in 200,000. In France, the estimated incidence is much higher in Brittany (1 in 26,000) than in the rest of the country (1 in 320,000) (Bois et al., 1976).
In a survey of Canadian pediatric nephrology centers, Gahl et al. (1988) found that 32 of 51 patients with infantile cystinosis were from Quebec and, of these, the significant majority were French Canadians. The high gene frequency (1 in 39) reported by De Braekeleer (1991) in French Canadians was consistent with a founder effect for the cystinosis gene, due to a small number of carrier individuals who were present in the founding population of Quebec, as had been described for other diseases in this same population. Through linkage studies in a French Canadian cystinosis cohort, McGowan-Jordan et al. (1999) identified a founding haplotype present in approximately half (21 of 40) of the chromosomes studied. Mutation analysis, in addition to identifying 2 novel mutations, unexpectedly revealed a mutation (trp138 to ter; 606272.0003) that had previously been found in Irish (but not French) cystinotic families on these 21 French Canadian chromosomes. Haplotype analysis of 2 Irish families with this mutation supported the hypothesis that Celtic chromosomes represent an extensive portion of cystinosis chromosomes in French Canada. The analysis underlined the genetic heterogeneity of that population, reflecting a frequently unrecognized contribution from non-Gallic sources including the Irish.
Gahl et al. (2002) stated that the most common CTNS mutation in cystinosis is the 57,257-bp deletion (606272.0005), which is found in homozygous state in approximately 50% of patients of northern European descent. The deletion is an ancient founder mutation.
Mason et al. (2003) analyzed the CTNS gene in 42 Italian patients with nephropathic cystinosis and found that the mutation spectrum in this population differed from that previously reported for the northern European population: the 57-kb deletion was present in a lower percentage (17%) and splicing mutations represented 30% of the mutations detected.
Prenatal Diagnosis
Schneider et al. (1974) showed that cystinosis can be diagnosed in the 18-week-old fetus on the basis of an increased content of nonprotein cystine in cultured amniotic fluid cells. Smith et al. (1987) reported diagnosis of cystinosis in a 9-week-old fetus by study of chorionic villi for direct cystine measurement. Patrick et al. (1987) succeeded in first-trimester diagnosis of cystinosis by studies of uptake and retention of (35S)-labeled cystine by intact biopsy specimens of chorionic villi.
Two groups who contributed equally to the work and referred to themselves as the Cystinosis Collaborative Research Group (McDowell et al., 1995) mapped the cystinosis gene to the short arm of chromosome 17 by linkage to microsatellite markers. Twenty-three cystinosis families of northern European, Pakistani, and Indian origin were studied. The families contained 29 affected males and 14 affected females. In 6 families, the parents were consanguineous. The phenotype was that of juvenile cystinosis (219900) in 2 affected sibs, with significant renal function maintained through adolescence. To define further the cystinosis region of 17p, the affected offspring in 4 cousin marriages were examined for homozygosity by descent. All these patients were homozygous for D17S1583 and D17S1584, the latter being closer to the centromere. An additional family with the juvenile form of cystinosis was also consistent with linkage to markers on 17p (McDowell, 1995). The specific location of the CTNS gene was thought to be 7p13. No families with adult cystinosis had been examined.
Jean et al. (1996) performed linkage analysis in 18 families with infantile nephropathic cystinosis. Since 17 of these were simplex families, they included the phenotypes of the heterozygous carriers as previously determined by their leukocyte cystine content in the linkage analysis. They were able to confirm the localization of the cystinosis gene to 17p. Crucial recombination events allowed them to find the interval of the cystinosis gene to a genetic distance of 1 cM. No evidence of genetic heterogeneity was found.
To refine further the genetic interval for the cystinosis gene, Town et al. (1998) typed DNA from a collection of cystinotic families with novel microsatellites mapping to the area of interest on 17p. No amplification product for D17S829 was detected in 23 of 70 unrelated patients. In addition, 14 patients, initially thought to be homozygous for this marker, were found to be missing 1 parental allele, suggesting that they carried heterozygous deletions of this locus. Haplotype analysis in 5 recombinant families confirmed the Genethon map position for D17S829 as being centromeric to D17S1798 and telomeric to D17S1828. The genetic distance between these 2 microsatellites was 3.1 cM and included the cystinosis region previously defined by linkage analysis.
From study of 5 families, Steinherz et al. (1981) concluded that linkage with HLA is unlikely; all lod scores were negative (-2.04 at theta 0.01). However, positive association was found with HLA-B7 and negative association with HLA-A9. The haplotypes A3B7 and A1B7 were significantly increased. HLA association of a mendelian disorder without linkage is a phenomenon not previously noted, according to Steinherz et al. (1981). They commented on the seemingly increased tendency for the disorder to occur in males.
Town et al. (1998) found that the marker locus D17S829 was homozygously deleted in 23 of 70 patients with nephropathic cystinosis, and they mapped a novel gene, CTNS (606272), to the deletion interval.
Shotelersuk et al. (1998) performed mutation analysis of 108 American-based nephropathic cystinosis patients and found that 48 (44%) were homozygous for the 'European' 65-kb deletion (606272.0005), 2 had a smaller major deletion, 11 were homozygous and 3 were heterozygous for 753G-A (W138X; 606272.0003), and 24 had 21 other mutations. In 20 patients (19%), no mutations were found. Of 82 alleles bearing the 65-kb deletion, 38 derived from Germany, 28 from the British Isles, and 4 from Iceland. The 18 new mutations identified in this study included the first reported missense mutation, 2 in-frame deletions, and mutations in patients of African American, Mexican, and Indian ancestry. CTNS mutations were spread throughout the leader sequence, transmembrane, and nontransmembrane regions. According to a cystinosis clinical severity score, homozygotes for the 65-kb deletion and for W138X had average disease, whereas mutations involving the first amino acids prior to transmembrane domains were associated with mild disease. By Northern blot analysis, CTNS was not expressed in patients homozygous for the 65-kb deletion but was expressed in all 15 other patients tested.
Structure predictions suggested that cystinosin is a novel integral lysosomal membrane protein. Attard et al. (1999) examined the predicted effects of mutations on this model of cystinosin. They screened patients with infantile nephropathic cystinosis, those with late-onset cystinosis, and patients whose phenotype did not fit the classic definitions. They identified 23 different mutations in the CTNS gene, 14 of which were novel. Of 25 patients with infantile nephropathic cystinosis, 12 had 2 severely truncating mutations, consistent with a loss of functional protein, and 13 had missense or in-frame deletions, which would result in disruption of transmembrane domains and loss of protein function. Mutations identified in 2 late-onset patients (see, e.g., 606272.0008) affected functionally unimportant regions of cystinosin, accounting for the patients' milder phenotype. For 3 patients, the age of onset of cystinosis was under 7 years, but the course of the disease was milder than the infantile nephropathic form. This suggested that the missense mutations identified in these individuals (see, e.g., 606272.0007) allowed production of a functional protein and may also indicate regions of cystinosin that are not functionally important.
Forestier et al. (1999) characterized 2 deletion breakpoints in the CTNS gene in affected individuals: one of approximately 65 kb, which was found in homozygous state in nearly one-third of cystinotic individuals, and a smaller one of 9.5 to 16 kb, which was carried by a single family. Forestier et al. (1999) demonstrated that although both deletions occur in regions of repetitive sequences, they are the result of nonhomologous recombination. This type of mechanism suggested that the deletion of approximately 65 kb is not a recurrent mutation, and the results confirmed that it is identical in all patients. Haplotype analysis showed that this large deletion is due to a founder effect that occurred in a white individual, and that it probably arose in the middle of the first millennium. Forestier et al. (1999) also described a rapid PCR-based assay that will accurately detect both homozygous and heterozygous deletions. They used this assay to show that the 65-kb deletion is present in either the homozygous or the heterozygous state in 76% of cystinotic patients of European origin.
Touchman et al. (2000) sequenced 200 kb surrounding the CTNS gene and found that the common cystinosis deletion (606272.0005) is approximately 57 rather than 65 kb.
In a patient who had atypical nephropathic cystinosis, presenting with Fanconi syndrome (134600) and end-stage renal disease, but surprisingly without extrarenal symptoms even late in life, Kalatzis et al. (2002) detected a missense mutation in the CTNS gene (G110V; 606272.0017).
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