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PubMedDate not supplied

Evaluation of the reproductive and developmental safety of cysteamine in the rat: effects on female reproduction and early embryonic development.

Cystinosis is an autosomal recessive metabolic disease in which the amino acid cystine accumulates in lysosomes due to a defect in lysosomal cystine transport. Cystinosis in infancy is associated with poor growth, muscle wastage, and death at about age 10 due to kidney failure. Treatment with cysteamine and kidney transplantation enables cystinotic girls to reach reproductive age and to be healthy enough to permit pregnancy. It is not known whether exposure to cysteamine will have adverse effects on reproduction in the human. It is also possible that some of the complications seen in cystinotic children could be avoided if a pregnant woman carrying a cystinotic fetus were given cysteamine. However, this treatment is not likely to occur until therapeutic exposures to cysteamine are judged to present no increased risk to the human fetus. As part of a larger investigation assessing the reproductive and developmental safety of cysteamine (as phosphocysteamine) using the rat, the two studies reported herein were performed. The first, a dose-finding study, led to the selection of 150 mg/kg/day as the highest dose of cysteamine used for the second and primary focus of this report. The second study involved the exposure of female rats to cysteamine from premating through day 6.5 postconception and assessment of female fertility and early embryonic development. Cysteamine was administered orally in doses of 0, 37.5, 75, 100, or 150 mg/kg/day. There were no clinical signs of maternal toxicity during the exposures of 2 to 5 weeks before successful mating. Animals in the 150 mg/kg/day group experienced a nonsignificant decrease in body weight gain during pregnancy to day 6.5 postconception, a significant increase in liver and spleen weights, and a significant increase in days to coitus--suggesting that a low level of toxicity was manifested. However, there were no adverse effects on reproductive performance with respect to conception and early embryonic development.

Animals↗
PubMed1976

[Morphological and biochemical investigations of hairs in inborn errors of amino acid metabolism (author's transl)].

The influence of inborn errors of metabolism on the amino acid content, the structure and growth of human hair has been studied in patients suffering from Phenylketonuria, Cystinosis, Homocystinuria and Tyrosinosis. Examiniation of hairs under the scanning electron microscope reveals defects and abnormalities such as a plicated pattern of the cuticula in patients with Phenylketonuria and Cystinosis. The amino acid content of the hydrolized hair keratin of all patients was within normal range and did not reveal significant changes of phenylalanine, cystine, homocystine, methionine or tyrosine. Disturbance in hair growth was determined by evaluation of standardized hair root samples. The results indicate an increase in hair root atrophy with increasing severity of the disorder of amino acid metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed1987

Ocular changes in some progressive hereditary nephropathies.

Ocular involvement is a common feature of three hereditary nephropathies: cystinosis, nephronophthisis and Alport's syndrome. The follow-up of 25 cases of infantile cystinosis over a period of 26 years demonstrated that the corneal and retinal epithelium were affected in the same way as the kidney epithelium. Corneal involvement induced photophobia and discomfort, but actual blindness was mainly due to retinal involvement, and therefore no corneal graft was performed. The use of topical cysteamine appears to be promising, but its production raises many questions so no definitive conclusions may be made. Since 1965, 51 patients with nephronophthisis have had ocular examinations; all patients had characteristic clinical symptoms and histological findings. The first group, which consisted of 18 children, all under 10 years of age, was found to have obvious chorioretinal degeneration. The second group, which consisted of 11 children, had a normal ocular examination and normal electroretinogram (ERG). The third group, consisting of 22 children, had a normal clinical examination but ERG tracings with variable alterations. In 28 instances of Alport's syndrome, two types of ocular abnormalities have been observed. In six cases, an anterior lenticonus was noted, which caused a major decline in visual acuity. Retinopathy, which did not affect vision, was observed in 13 cases.

Adolescent↗
PubMed2006

Inefficient cleavage of palmitoyl-protein thioesterase (PPT) substrates by aminothiols: implications for treatment of infantile neuronal ceroid lipofuscinosis.

Infantile neuronal ceroid lipofuscinosis (INCL, also known as infantile Batten disease) is a devastating neurodegenerative disorder caused by deficiency in the lysosomal enzyme palmitoyl-protein thioesterase (PPT, or CLN1), which functions to remove long-chain fatty acids from cysteine residues in proteins. A previous study suggested that the drug cysteamine, a simple aminothiol used in the treatment of cystinosis, may have utility in the treatment of INCL. In the current study, we compared the catalytic rate constants for the conversion of palmitoyl-CoA (a PPT substrate) and cystine (which accumulates in cystinosis) by cysteamine. We found that while cysteamine can react with palmitoyl-CoA, the rate constant is 10(3)-fold less than the reaction with cystine. Structure-activity studies suggested that it is the thiolate ion that is reactive in the cleavage reaction and that the amino group probably facilitates lysosomal entry. A modest effect of cysteamine (and two related aminothiols, WR 1065 and dimethylaminoethanethiol, DMAET) on PPT substrate accumulation in INCL lymphoblasts was observed. However, at optimum concentration a paradoxical increase in saposin immunoreactivity was seen, indicating possible lysosomal dysfunction. Improvements are needed in the design of small molecules for the treatment of INCL disease.

Cells, Cultured↗
PubMed1988

Measurement of total plasma cysteamine using high-performance liquid chromatography with electrochemical detection.

Cysteamine is currently used to treat children with the inherited disorder nephropathic cystinosis. A method for the quantitative determination of this aminothiol in human plasma is presented. Whole plasma was reduced with sodium borohydride to convert disulfides to thiols. Cysteamine was then separated by high-performance liquid chromatography and detected electrochemically. The recovery of standard cysteamine added to plasma was 96.6 +/- 1.9%. In a patient with cystinosis, an oral dose of cysteamine was absorbed rapidly, with plasma cysteamine reaching a maximum of 56 microM 1 h after the dose. By 1.8 h the plasma cysteamine concentration had decreased to one-half the maximum value.

Borohydrides↗
PubMed1999

A study of the relative bioavailability of cysteamine hydrochloride, cysteamine bitartrate and phosphocysteamine in healthy adult male volunteers.

AIMS: Cysteamine, the only drug available for the treatment of cystinosis in paediatric patients, is available as the hydrochloride, the bitartrate and as sodium phosphocysteamine salts. It has been suggested that cysteamine bitartrate and phosphocysteamine are better tolerated and may have a better bioavailability than cysteamine hydrochloride. This has, however, never been demonstrated. METHODS: We compared the pharmacokinetics and tolerance of these three formulations of cysteamine in 18 healthy adult male volunteers in a double-blind, latin-square, three-period, single oral dose cross-over relative bioavailability study. RESULTS: No statistical difference was found between relative bioavailabilities, AUC (0, infinity) (geometric mean and s.d. in micromol l(-1) h: 169+/-51, 158+/-46, 173+/-49 with cysteamine hydrochloride, phosphocysteamine and cysteamine bitartrate respectively), Cmax (geometric mean and s.d. in micromol l(-1); 66+/-25.5, 59+/-12, 63+/-20) and tmax (median and range in h: 0.88 (0.25-2), 1.25 (0.25-2), 0.88 (0.25-2)) with each of the three forms of cysteamine tested. Bioequivalence statistics (90% confidence intervals) showed non equivalence of Cmax of cysteamine base as the only non equivalence of pharmacokinetics between the three formulations: 90% CI for Cmax relative ratios to cysteamine hydrochloride were [75.6-105.81 for phosphocysteamine and [74.2-124.2] for cysteamine bitartrate. The only significant adverse event was vomiting whose frequency was inversely correlated with body weight (Spearman's r=-0.76, P<0.001). The nature of the salt tested did not influence vomiting. CONCLUSIONS: While none of the three forms of cysteamine tested has a clear advantage over the others in terms of pharmacokinetics and tolerance profile, this should now however be addressed in patients treated for cystinosis during repeat administrations.

Adult↗
PubMed2001

Results of simultaneous and sequential pediatric liver and kidney transplantation.

BACKGROUND: The indications for simultaneous and sequential pediatric liver (LTx) and kidney (KTx) transplantation have not been well defined. We herein report the results of our experience with these procedures in children with end-stage liver disease and/or subsequent end-stage renal disease. PATIENTS AND METHODS: Between 1984 and 1995, 12 LTx recipients received 15 kidney allografts. Eight simultaneous and seven sequential LTx/KTx were performed. There were six males and six females, with a mean age of 10.9 years (1.5-23.7). One of the eight simultaneous LTx/KTx was part of a multivisceral allograft. Five KTx were performed at varied intervals after successful LTx, one KTx was performed after a previous simultaneous LTx/KTx, and one KTx was performed after previous sequential LTx/KTx. Immunosuppression was with tacrolimus or cyclosporine and steroids. Indications for LTx were oxalosis (four), congenital hepatic fibrosis (two), cystinosis (one), polycystic liver disease (one), A-1-A deficiency (one), Total Parenteral Nutrition (TPN)-related (one), cryptogenic cirrhosis (one), and hepatoblastoma (one). Indications for KTx were oxalosis (four), drug-induced (four), polycystic kidney disease (three), cystinosis (one), and glomerulonephritis (1). RESULTS: With a mean follow-up of 58 months (0.9-130), the overall patient survival rate was 58% (7/12). One-year and 5-year actuarial patient survival rates were 66% and 58%, respectively. Patient survival rates at 1 year after KTx according to United Network of Organ Sharing (liver) status were 100% for status 3, 50% for status 2, and 0% for status 1. The overall renal allograft survival rate was 47%. Actuarial renal allograft survival rates were 53% at 1 and 5 years. The overall hepatic allograft survival rate was equivalent to the overall patient survival rate (58%). Six of seven surviving patients have normal renal allograft function, and one patient has moderate chronic allograft nephropathy. All surviving patients have normal hepatic allograft function. Six (86%) of seven sequentially transplanted kidneys developed acute cellular rejection compared with only two (25%) of eight simultaneously transplanted kidneys (P<0.04). CONCLUSIONS: Simultaneously transplanted kidneys were less likely to develop rejection than sequentially transplanted kidneys in this series. This did not have any bearing on patient or graft survival rates. Mortality correlated directly with the severity of United Network of Organ Sharing status at the time of kidney transplantation. Candidates for simultaneous or sequential LTx/KTx should be prioritized based on medical stability to optimize distribution of scarce renal allografts.

Adolescent↗
PubMed2005

ERS1 encodes a functional homologue of the human lysosomal cystine transporter.

Cystinosis is a lysosomal storage disease caused by an accumulation of insoluble cystine in the lumen of the lysosome. CTNS encodes the lysosomal cystine transporter, mutations in which manifest as a range of disorders and are the most common cause of inherited renal Fanconi syndrome. Cystinosin, the CTNS product, is highly conserved among mammals. Here we show that the yeast Ers1 protein and cystinosin are functional orthologues, despite sharing only limited sequence homology. Ers1 is a vacuolar protein whose loss of function results in growth sensitivity to hygromycin B. This phenotype can be complemented by the human CTNS gene but not by mutant ctns alleles that were previously identified in cystinosis patients. A genetic screen for multicopy suppressors of an ers1Delta yeast strain identified a novel gene, MEH1, which is implicated in regulating Ers1 function. Meh1 localizes to the vacuolar membrane and loss of MEH1 results in a defect in vacuolar acidification, suggesting that the vacuolar environment is critical for normal ERS1 function. This genetic system has also led us to identify Gtr1 as an Meh1 interacting protein. Like Meh1 and Ers1, Gtr1 associates with vacuolar membranes in an Meh1-dependent manner. These results demonstrate the utility of yeast as a model system for the study of CTNS and vacuolar function.

Amino Acid Sequence↗
PubMed1999

Long-term outcome of paediatric patients with hereditary tubular disorders.

BACKGROUND: An increasing number of children with hereditary tubular disorders (HTD) reach adult life due to diagnostic and therapeutic advances which results in growing need to manage these patients by adult centres. Data on the prevalence and the late clinical problems of these patients are limited. METHODS: We observed 177 paediatric patients with isolated or complex HTD between 1969 and 1994. The median age at the time of diagnosis was 3 (range 0-18) years and the median observation period 10 (range 1-43) years. The long-term outcomes with respect to renal function, bone disease, and body growth were analyzed. RESULTS: The prevalence of HTD was 3.2% of all patients observed in our renal unit and 14% of those patients with chronic renal failure and/ or end-stage renal disease. The three most frequent disorders observed were nephropathic cystinosis (n = 34), X-linked hypophosphataemic rickets (n = 26), and idiopathic hypercalciuria (n = 17). At the last observation, 12% of the patients with isolated HTD and 30% of those with complex HTD had developed preterminal chronic renal failure; end-stage renal disease was observed in 5 and 25%, respectively (p < 0.001). Progressive disease occurred mainly in patients having cystinosis, primary hyperoxaluria, the syndrome of hypomagnesaemia/hypercalciuria, primary Fanconi syndrome, Fanconi-Bickel syndrome, and methylmalonic aciduria. Nephrocalcinosis was found in 42%, urolithiasis in 14%, bone deformities and/or fractures in 28%, and other extrarenal alterations in 29% of all patients. The median body height at last observation was 2.0 SD below the normal mean (range from -10.4 to +2. 6), and the adult height was subnormal in 48% of 67 grown-up patients. Growth retardation was more severe in complex than in isolated HTD. The mortality decreased from 17% in 1969-1981 to 12% in 1982-1994. CONCLUSION: Although HTD are rare nephropathies, their frequently progressive course associated with extrarenal complications requires the attention of nephrologists beyond the paediatric age.

Adolescent↗
PubMedDate not supplied

A familial syndrome of growth retardation, severe Fanconi-type renal disease and glomerular changes--a new entity?

Two young siblings had a syndrome of growth retardation, severe rickets, anemia, renal insufficiency, and renal tubular dysfunction, the last including acidosis, aminoaciduria, and polyuria. There was moderate psychomotor developmental delay. Neither child had cystinosis. Renal biopsy in the older child revealed severe glomerular abnormalities, with capillary wall thickening reminiscent of the hemolytic-uremic syndrome. The proximal convoluted tubules were lined with short, cuboidal cells containing mildly abnormal mitochondria. There was also thinning of brush border microvilli and basolateral infoldings, perhaps as the result of regressive changes, and interstitial fibrous tissue was moderately increased. The etiology of the tubular and glomerular changes is uncertain. We believe these patients represent a previously unreported hereditary syndrome sharing certain clinical features with severe nephropathic cystinosis.

Child, Preschool↗
PubMed1975

Renal transplantation in congenital and metabolic diseases. A report from the ASC/NIH renal transplant registry.

The results of kidney transplantation in a variety of renal diseases have been analyzed. The diseases causing end-stage kidney failure in recipients were Alport syndrome, amyloidosis, cystinosis, diabetes mellitus, Fabry disease, familial nephritis, gout, medullary cystic disease, oxalosis, and systemic lupus erythematosus. The data indicate that renal transplantation is justifiable and parallels functional results for the more common causes of end-stage renal disease in all but Fabry disease and oxalosis. Although Fabry disease did not recur in any grafted kidney, only three patients have a functioning graft one year after transplantation. From a group of ten patients with oxalosis who received a total of 14 kidneys, only one survives. In no other metabolic disease, except one instance of primary amyloidosis, did the metabolic disease notably affect the transplant as it did in oxalosis.

Adolescent↗
PubMed1985

In vivo alteration of a mutant human protein using the free thiol cysteamine.

Inborn errors of metabolism in which there is a mutant protein due to a cysteine for arginine substitution may be amenable to treatment with the free thiol cysteamine. Evidence for this derives from patients with type III hyperlipoproteinemia, who are homozygous for apolipoprotein E2, which differs in charge and in vitro function based on a single such amino acid substitution. The plasma of a type III hyperlipoproteinemic patient, when made at least 50 microM with respect to cysteamine in vitro, demonstrated a charge shift of the apolipoprotein E isoelectric focusing pattern from the E2 to the normal E3 and E4 positions. Two children treated for cystinosis with cysteamine each exhibited some charge alteration of their apoE3 to a form migrating in the apoE4 position. The use of thiol reagents such as cysteamine to specifically alter selected mutant human proteins, such as antithrombin III Toyama, may be added to our therapeutic armamentarium in the treatment of life-threatening metabolic disorders.

Apolipoprotein E2↗
PubMed1993

Niemann-Pick C disease: cystine and lipids accumulate in the murine model of this lysosomal cholesterol lipidosis.

Cystine levels in tissues of the murine BALB/C mouse model of type C Niemann-Pick disease were shown to be greatly elevated. Subcellular fractionation of liver homogenates by differential centrifugation suggested preferential accumulation in a fraction corresponding to lysosomes. Developmentally, a sharp increase in the accumulation of cystine in the mutant mouse liver occurs subsequent to a similar change in the accumulation of cholesterol, sphingomyelin and glucocerebroside. The lysosomal accumulation of cystine in this mutant mouse provides the experimental opportunity to study some aspects of the deficiency of lysosomal cystine transport noted in cystinosis.

Animals↗
PubMed1991

Increased monocyte-dependent suppression of polyclonal activation of B lymphocytes from cystinotic children.

In infantile cystinosis the amino acid cystine preferentially accumulates in phagocytic cells, polymorphonuclear leucocytes (PMN) and monocytes, rather than in lymphocytes. We previously described functional abnormalities in the oxidative metabolism and locomotion of cystinotic PMN and monocytes. The present study shows an abnormal lymphocyte polyclonal activation as evidenced by a decreased immunoglobulin (Ig) production and generation of Ig-containing cells (ICC) in cultures of peripheral blood mononuclear cells (PBMC) from cystinotic children upon stimulation with pokeweed mitogen and Staphylococcus aureus Cowan I. However, monocyte depletion from cystinotic PBMC fully reconstituted Ig production and ICC generation, indicating: (1) the presence of an increased monocyte-dependent suppression on lymphocyte polyclonal activation, and (2) that the intrinsic ability of cystinotic lymphocytes to respond to polyclonal stimulation was preserved. The increased cystinotic monocyte-dependent suppressive effect was not mediated by prostaglandin E2 (PGE2) since its production by cystinotic PBMC upon polyclonal activation was not different from that of controls. In addition, the sensitivity of cystinotic lymphocytes to the immunosuppressive effect of varying concentrations of exogenous PGE2 was similar to that of controls. Finally, indomethacin and 2-mercaptoethanol, two agents able to scavenge hydroxyl (.OH) radicals, restored Ig production by cystinotic PBMC, suggesting a role for reactive oxygen species in the increased cystinotic monocyte-dependent suppression.

Adolescent↗
PubMed1992

Description of a selection method highly cytotoxic for cystinotic fibroblasts but not normal human fibroblasts.

Nephropathic cystinosis is an inherited disorder characterized by a high intralysosomal accumulation of cystine due to a defect in lysosomal cystine transport. Cystine can be specifically loaded into the lysosomal compartment of intact cells by incubating cells with cystine dimethyl ester (CDME). We have applied this methyl ester loading technique to develop a selection method that is highly cytotoxic for cystinotic fibroblasts but not normal human fibroblasts and that is based on the inherent differences in lysosomal cystine transport activity of normal and cystinotic fibroblasts. Thus, only 0-0.03% of fetal cystinotic fibroblasts survive exposure to 2 mM CDME for 20 min whereas 70-80% of normal fetal fibroblasts survive these same conditions. Following transfection of cystinotic fibroblasts with normal human genomic DNA or cDNA, this CDME selection method can be used to select for those cells that have been transformed to the normal phenotype and thus aid in the identification of the gene coding for the lysosomal cystine transport protein.

Biological Transport↗
PubMed1986

Renal ultrasound in metabolic bone disease.

Fifty-one patients aged 1 year to 56 years with metabolic bone disease underwent renal ultrasound. Medullary nephrocalcinosis was found in nine of 24 patients with X-linked hypophosphatemic rickets and is considered to be iatrogenic, related to vitamin D therapy. Another three in this group of 24 with both medullary and cortical increased renal echogenicity had suffered from repeated episodes of vitamin D intoxication and had secondary hyperparathyroidism. Nephrocalcinosis was less frequent in patients with treated vitamin D-dependent rickets or hypophosphatemic bone disease where generally smaller doses of vitamin D are given. Patients with pseudohypoparathyroidism, on small doses of vitamin D, had a normal renal ultrasound. In cystinosis and Fanconi's syndrome, the kidneys are small, echodense (both the cortex and medulla) with a tendency to cyst formation.

Adolescent↗
PubMed1999

Cerebral vascular complication and hyperhomocysteinemia in a cystinotic uremic child.

We report a 13-year-old girl with nephropathic cystinosis on chronic peritoneal dialysis who presented with two episodes of stroke. Laboratory evaluation showed severe hyperhomocysteinemia (108 mumol/l). Further testing revealed that she was homozygous for the thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR) gene. Treatment with folic acid and vitamin B12 lowered plasma homocysteine to less than 20 mumol/l. No further episodes of stroke occurred over a follow-up of 12 months. Homocysteine levels should be measured in patients with chronic renal failure, since simple and safe treatment with folic acid and vitamin B12 is effective in lowering the plasma homocysteine level in patients with the thermolabile MTHFR allele.

Adolescent↗
PubMed1984

The effect of ions and ionophores on cystine egress from human leucocyte lysosome-rich granular fraction.

This paper describes the stimulation of exodus of cystine from lysosome-rich granular fractions by potassium. Potassium permeability into lysosomes is low, but in the presence of an ionophore or permeable anion, the movement of K+ into lysosomes caused a large stimulation of cystine exodus. Lysosomal preparations from leucocytes of cystinotic patients, which lack carrier-mediated cystine transport, also manifested stimulation of cystine egress by valinomycin and K+. This suggests that potassium-dependent cystine egress involves a carrier different from that defective in cystinosis, or occurs through a non-carrier-mediated mechanism.

Cations, Monovalent↗