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PubMed1995

The treatment of cystinosis with cysteamine and phosphocysteamine in the United Kingdom and Eire.

Fifty-nine patients with cystinosis were treated with cysteamine or phosphocysteamine in the United Kingdom up to May 1990. Treatment was started at a median age of 3.2 years (range 0.6-24.8 years) and continued for a median duration of 3.0 years (range 0.01-1.2 years). At the end of the study, 46 (78%) patients remained on treatment. One patient developed end-stage renal failure and 6 died. Efficacy was assessed in the 44 pre-transplant patients. The United Kingdom pre-transplant patients had significantly lower plasma creatinine concentrations at 6 and 8 years than a historical group of patients who did not receive cysteamine (P < 0.0001 and P < 0.0003, respectively). There was no significant difference between pretreatment and final post-treatment height standard deviation scores, suggesting maintenance of growth rate. The leucocyte cystine concentration was less than the accepted upper limit of the treatment range (1 nmol 1/2 cystine/mg protein) in only 21% of determinations. There was no significant difference between the mean pre-treatment and final values of leucocyte cystine concentration. The mean final doses of cysteamine (33 mg/kg per day) and phosphocysteamine (37 mg/kg per day base equivalent) were less than the mean dose (51 mg/kg per day) used in a United States multicentre trial. We conclude that cysteamine treatment was beneficial, but further improvements might be achieved by an improvement in monitoring of therapy.

Adolescent↗
PubMed1986

Infantile cystinosis and insulin-dependent diabetes mellitus.

A 13-month-old infant was admitted to our Institution because of difficult metabolic control of diabetes mellitus. Clinical and laboratory findings revealed that the child was affected by both insulin-dependent diabetes mellitus and nephropathic cystinosis. Treatment with indomethacin was associated with growth improvement at an early stage of renal insufficiency, but not in more advanced renal failure.

Cystinosis↗
PubMed1984

Renal cell culture using autopsy material from children with cystinosis.

Renal cell cultures were initiated using fresh autopsy material from two individuals with cystinosis, ages 5 and 8 yr. Cells obtained from collagenase treated autopsy material were grown in a selective kidney medium containing Coon's modified F12, 2.5% fetal bovine serum, transferrin, insulin, selenium, hydrocortisone, PGE1, and fibronectin. These cells had an epithelial appearance, formed domes, and were periodic acid-Schiff positive. Both tight junctions and microvilli were seen by electron microscopy. Fibroblasts had a cloning efficiency of zero in the selective medium and grew poorly compared to their growth in Coon's F12 with 10% fetal bovine serum. The lysosomal cystine content of the renal cells was greatly elevated and comparable to that of fibroblasts from cystinotic patients. Renal cell lysosomal cystine levels were only partially reduced by exposure to either pantethine or the aminothiol, cysteamine. However, exposure to either compound effectively depleted cystinotic cultured fibroblasts of their lysosomal cystine. Study of cultured renal material may have practical significance in pharmacologic considerations.

Autopsy↗
PubMed2000

Early development of the renal lesions in infantile cystinosis.

To identify the early renal lesions in cystinosis, including whether the "swan neck" deformity of the proximal tubule is a congenital or an acquired lesion, we performed renal function tests and kidney biopsies on two cystinotic infants, on one at 5 and 14 months and on the other at 6 and 12 months of age. The "swan neck" deformity appears to be an acquired lesion for two reasons. First, the characteristic thin neck of the proximal tubule was not demonstrated by nephron microdissection or light microscopy until after 6 months of life. Second, electron microscopy revealed that prior to the development of the lesion, the tubular cells in the neck region of the proximal tubule were undergoing degenerative changes. Renal function tests indicated that the manifestations of the Fanconi syndrome correlated with the stages of development of the "swan neck" lesion. Minute crystalline spaces having some of the characteristics of lysosomal cystine crystals appeared in the early biopsies only in that portion of the proximal tubule which was undergoing atrophy to form the "swan neck" lesion observed in the later biopsies. These findings provide evidence of at least a temporal relationship between apparent cellular cystine accumulation and the development of the "swan neck" lesion and the Fanconi syndrome.

Amino Acids↗
PubMed1998

The Fanconi syndrome of cystinosis: insights into the pathophysiology.

Cystinosis is a lysosomal storage disease which is the most-common inherited cause of the Fanconi syndrome. Insights into the pathophysiology of the proximal tubular defect have come from in vitro studies of the cystine-loaded tubule. Proximal tubules loaded with cystine have a generalized proximal tubule transport defect characteristic of the Fanconi syndrome. The decrease in proximal tubular transport with cystine loading is not due to an increase in paracellular permeability with backflux of solute transport from the blood to the tubular lumen, but due to a decrease in active transport. The Na-K-ATPase activity is intact under Vmax conditions in cystine-loaded tubules; however, the production of ATP is severely compromised. The cystine-loaded tubule has a lower intracellular phosphate concentration than that of control tubules. This low intracellular phosphate concentration in cystine-loaded tubules likely plays a critical role in the decrease in intracellular ATP. Preservation of intracellular phosphate at control levels prevents the decrease in intracellular ATP and the proximal tubule respiratory dysfunction with cystine loading. The clinical significance and future directions for investigation are discussed.

Cystinosis↗
PubMed1999

Diabetes mellitus in patients with infantile cystinosis after renal transplantation.

Diabetes mellitus is a frequent long-term complication of infantile nephropathic cystinosis. We studied 44 cystinotic patients, aged 22.1+/-5.4 years, transplanted at a mean age of 11.3+/-2.5 years; 25% were treated with insulin at 20 years of age or 10 years after transplantation, and over half required insulin at latest follow-up. In comparison, diabetes mellitus occurred in only 1% of non-cystinotic transplanted patients. Sequential oral glucose tolerance tests (OGTTs) in these patients showed the progressive deterioration of glucose metabolism. All but 2 patients had an abnormal response at latest follow-up. The high doses of corticosteroid given after transplantation or during rejection episodes were responsible for transient insulin dependency. However, the development of impaired glucose tolerance and diabetes mellitus depended mainly on the cystinotic process, which developed slowly with time. The deterioration of glucose tolerance was correlated with a decreased early phase of insulin secretion, estimated from the plasma insulin level at 30 min of the OGTT, while there was no evidence of insulin resistance. The occurrence of diabetes mellitus correlated with a worsening of the vital prognosis.

Adolescent↗
PubMed1987

Spatial and temporal sequence of corneal crystal deposition in nephropathic cystinosis.

We studied 15 patients with infantile nephropathic cystinosis. We found that anterior corneal cystine crystal deposition began early in life and proceeded posteriorly as the patient aged; deposition advanced more rapidly in the periphery. Ultrastructural analysis of a corneal button obtained from a 20-year-old patient undergoing corneal transplantation confirmed our clinical observations that crystals were deposited throughout the entire central stroma.

Adolescent↗
PubMed1967

Increased free-cystine content of fibroblasts cultured from patients with cystinosis.

The presence of a significantly increased content of free-cystine in skin fibroblasts from both homozygotes and heterozygotes for cystinosis emphasizes the central role of cystine in this disease, even though the primary defect responsible for cystine accumulation is yet to be determined. The studies described in this communication provide evidence that cystine is compartmentalized in a subcellular location in cystinotic cells. In fact, the very growth of cystinotic fibroblasts in the presence more than 100 times the usual content of free-cystine is evidence that the accumulated cystine is not freely dispersed throughout the cell, since would otherwise inhibit many enzymes requiring free sulfhydryl groups for activity (Patrick, 1965). We have no evidence as to whether the cystine is located in a known subcellular organelle or in a previously unrecognized location. Skin fibroblasts may provide a convenient tool to pursue these questions.

Cells, Cultured↗
PubMed1983

The intralysosomal pH in cultured human skin fibroblasts in relation to cystine accumulation in patients with cystinosis.

The intralysosomal pH in cultured skin fibroblasts from a patient with cystinosis and from control fibroblasts was estimated by the method of Hollemans et al. (Hollemans, M., Oude Elferink, R.P.J., de Groot, P.G., Strijland, A. and Tager, J.M. (1981) Biochim. Biophys. Acta 643, 140-151). 1. The intralysosomal pH in cystinotic fibroblasts (5.37 +/- 0.04; n = 12) was almost identical to that in the control fibroblasts (5.27 +/- 0.06; n = 10). 2. After depletion of cystine by pretreatment of cystinotic fibroblasts with 1 mM cysteamine, there was no significant change in the intralysosomal pH. Incubation of either cystinotic or control fibroblasts with higher concentrations of cysteamine (10 or 25 mM) led to an increase in intralysosomal pH similar to that seen with other weak bases. 3. The fractional volume of the lysosomes in cystinotic fibroblasts (0.100 +/- 0.012; n = 4) was higher than that in control fibroblasts (0.039 +/- 0.010; n = 4). 4. It is concluded, in contrast to Jonas et al. (Jonas, A.J., Smith, M.L. and Schneider, J.A. (1982) J. Biol. Chem. 257, 13185-13188), that the lysosomal proton-translocating ATPase (Okhuma, S., Moriyama, Y. and Takano, T. (1982) Proc. Natl. Acad. Sci. USA 79, 2758-2762) is not impaired in cystinotic fibroblasts.

Cysteamine↗
PubMed1990

Stable isotope dilution analysis of cystine in granulocyte suspensions as cysteine: a powerful method for the diagnosis, the follow-up, and treatment of patients with cystinosis.

A stable isotope dilution method was developed for the determination of cystine in granulocytes. Granulocytes were isolated from blood samples of treated cystinosis patients. Cystine in the granulocyte suspension was decoupled from proteins and converted to cysteine by treatment with a tri-butyl phosphine solution. Tertiary butyldimethyl silyl derivatives were prepared and analyzed by gas chromatography/mass spectrometry. Selective ion monitoring was carried out at m/z 304.3 (M-159 and m/z 406.4 (M-57) for the natural, and at m/z 306.3 and 408.4 for the labelled compound. [3,3,3',3'-2H]-DL-cystine was used as internal standard for the isotope dilution analysis. Concentrations of cystine in granulocytes could be accurately measured. There was a distinct difference in cystine concentrations in healthy individuals and treated patients.

Adolescent↗
PubMed1981

Cysteamine inhibition of [15N]-glycine turnover in cystinosis and of glycine cleavage system in vitro.

In order to clarify the hyperglycinemic effect of cysteamine treatment in children with nephropathic cystinosis, we measured [15N]-glycine turnover in three affected patients. Administration of cysteamine lowered the glycine flux and the glycine metabolic clearance rate but did not alter the glycine pool size. Formation of [15N]-serine from [15N]-glycine was lower in untreated patients than in control subjects and was reduced still further by cysteamine. Studies in vitro with isolated rat liver mitochondria and acetone extracts of mitochondria indicated that even low cysteamine concentrations (0.1 mM) inhibited the glycine cleavage system in both the direction of glycine oxidation and glycine synthesis. Cysteamine was a more potent inhibitor of the glycine cleavage system than any other sulfhydryl containing compound. Although no ill effects of cysteamine treatment were immediately apparent, patients receiving cysteamine should be monitored carefully for the appearance of any neurologic symptoms which might be referable to inhibition of the glycine cleavage system.

Coenzyme A↗
PubMedDate not supplied

Cortical atrophy and cognitive performance in infantile nephropathic cystinosis.

A group of children and adolescents with infantile nephropathic cystinosis underwent cognitive testing and were examined for cortical atrophy using magnetic resonance imaging or computed tomography. Ten of 11 patients demonstrated cortical atrophy. A consistent pattern of lower cognitive performance was found in patients with greater atrophy; however, only the relationship between atrophy and short-term memory approached statistical significance. In addition, evidence for greater impairment of visual memory than of other cognitive functions was observed. This latter observation did not appear to be related to the degree of atrophy.

Adolescent↗
PubMed1992

Effect of growth hormone treatment on serum creatinine concentration in patients with cystinosis and chronic renal disease.

Three patients with nephropathic cystinosis and chronic renal disease, treated since early childhood with orally administered cysteamine, had an accelerated rate of rise of serum creatinine values after receiving recombinant human growth hormone. During 18 to 24 months of growth hormone treatment, each patient had a twofold to fourfold increase in growth velocity. The slope of the plot of reciprocal serum creatinine values versus age for each patient after growth hormone treatment was significantly steeper than the pretreatment slope. Growth hormone treatment had no effect on the rate of change of the uncorrected 24-hour renal creatinine clearance. We conclude that these patients gained body size but failed to compensate for their increased creatinine production with an increase in glomerular filtration rate. The result was an accelerated rate of rise of their serum creatinine values, hastening renal transplantation in one patient and the anticipated need for transplantation in another.

Adolescent↗
PubMed1975

Prenatal diagnosis of cystinosis.

Cystinosis was diagnosed in a small quantity of cultured amniotic cells from a 22-week-old fetus by a modified pulse-labeling technique in which intracellular 35SL-cystine retention was measured. As a result of the above finding, the pregnancy was terminated by administration of prostaglandin. The diagnosis was confirmed when the nonprotein-free cystine content of the kidney, liver, placenta, spleen, thymus, and gut, as well as that of a large amount of cultured amniotic cells, was found to be 100-fold higher than normal levels.

Abortion, Induced↗
PubMed1991

A randomised placebo-controlled trial of topical cysteamine therapy in patients with nephropathic cystinosis.

Five patients with nephropathic cystinosis were evaluated to assess the ability of topical cysteamine to clear corneal cystine crystals. All patients were randomised to receive topical cysteamine 0.2% six times a day in one eye with normal saline in the other eye as a control. All five patients showed some improvement in visual symptoms (photophobia, blepharospasm and visual acuity) together with an improvement in corneal crystal density. Three of these also had an improvement in Snellen visual acuity and contrast sensitivity.

Adolescent↗
PubMed1995

Renal proximal tubular epithelium from patients with nephropathic cystinosis: immortalized cell lines as in vitro model systems.

The renal proximal tubule is a major site of injury in a variety of congenital/metabolic diseases including nephropathic cystinosis, the most commonly known cause of renal Fanconi's syndrome. In this lysosomal storage disease there are defects in proximal tubule function within the first few months of life. While culture of renal tubular cells from the urine of these patients is possible, development of immortalized cell lines would insure large numbers of homogeneous cells for studies of renal epithelial cell morphology and pathophysiology in this disease. To develop immortalized cells, cystinotic and normal proximal tubular cells in culture were exposed to an immortalizing vector, containing pZiptsU19 with the temperature sensitive SV40 T-antigen allele tsA58U19 and a neomycin resistance gene, and neomycin-resistant tubular cells were selected for propagation. Ten clones from cystinotic patients have been developed and characterized. All clones express T-antigen at permissive temperature (33 degrees C). Immortalized cells have an epithelial morphology and grow to form confluent monolayers; doubling times vary from 31 to 86 hours. Cystinotic clones are keratin, MDR P-glycoprotein, and alpha-95 kD brush-border associated protein positive but Tamm-Horsfall protein negative by immunocytochemistry, as are normal proximal tubule cells immortalized with this vector. This is consistent with a proximal tubule origin of the cystinotic clones. The cystine content of the cystinotic cells is 70 to 160 times that of normal renal proximal tubular cells in culture, with most of the cystine sequestered in cell lysosomes, confirming that these cell lines express the storage defect.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Fractionation↗
PubMed1987

Cystine storage in cultured myotubes from patients with nephropathic cystinosis.

Sorted muscle cells, cultured from a patient with nephropathic cystinosis, stored 100 times normal amounts of cystine. Subcellular fractionation and density-gradient centrifugation confirmed that the cystine was located in a lysosomal compartment. 2. Myoblasts from cystinotic patients in culture underwent fusion to myotubes in a normal fashion. 3. The free thiol cysteamine effectively depleted cystinotic-muscle cells of cystine. 4. Cultured myoblast and myotubes offered a unique system for investigating the effects of lysosomal storage on differentiated cell functions.

Cells, Cultured↗