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PubMed1981

Cystinuria in children.

7 children, 20 months to 11 years old, with cystinuria and renal calculi were studied. Surgical treatment and alpha-mercaptopropionylglycine (MPG) gave satisfactory results in 5 children. The causes of the recurrences in the other 2 children are discussed. MPG therapy is effective but can cause a nephrotic syndrome at a dose of more than 50 mg/kg/day. A cystinuria of less than 200 mg/day cannot always be considered safe in children. The alkalinization and dilution of urine remain extremely important in the treatment of cystinuria.

Amino Acids, Sulfur↗
PubMed2006

Efficient screening of the cystinuria-related C663T Slc3a1 nonsense mutation in Newfoundland dogs by denaturing high-performance liquid chromatography.

Cystinuria in Newfoundland dogs is a metabolic disease associated with a nonsense mutation in the exon 2 of the Slc3a1 gene. Similar to type I human cystinuria, heterozygote carriers are not affected by the disease and do not reveal differences in urinary concentration of dibasic amino acids when compared with normal dogs. However, through a recessive mode of inheritance, these dogs are able to transmit the disease to their offspring. Early detection of mutation carriers through cost-effective reliable methods is therefore essential for the implementation of breeding methods aimed at the eradication of the disease. Denaturing high-performance liquid chromatography (DHPLC) is a recently developed technique for rapid and efficient screening of nucleotide polymorphisms in polymerase chain reaction-amplified products. This technique was used for the identification of the C663T Slc3a1 mutation in Portuguese Newfoundland dogs. Polymerase chain reaction products amplified from a region containing the C663T locus were subjected to DHPLC analysis, and results were double checked by DNA sequencing. Results showed the presence of the mutation in 6 of the 22 dogs tested. Urine biochemical parameters correlated well with the number of mutated Slc3a1 copies, and homozygotes for the C663T mutation were the only dogs diagnosed with cystinuria. Sequence analysis confirmed the DHPLC results, demonstrating that the technique could be a reliable alternative to sequencing for the rapid and cost-effective identification of mutations in canine breeds.

Amino Acid Transport Systems↗
PubMed2001

[Nephrotic syndrome and anasarca status, secondary to treatment with tiopronin in a case of cystinuria].

OBJECTIVE: To describe a case of cystinuria treated with tiopronin that produced the nephrotic syndrome. METHODS/RESULTS: A case of nephrotic syndrome with ascites and heart failure in a patient who had received tiopronin for the treatment of cystinuria is presented. Cystinuria as a rare cause of kidney stones is analyzed. The clinical features, diagnosis and the side effects of treatment with tiopronin are discussed. The patient recovered after withdrawal of the drug. CONCLUSIONS: It must be emphasized that patients treated with tiopronin should be screened for proteinuria.

Adult↗
PubMed2001

[Molecular biology of cystinuria].

Cystine stones belong to the kidney stones diseases which are difficult to manage due to the high rate of recidivation and the necessary surgical procedures. Cystinuria is an autosomal recessive defect of the transport of cystine and the dibasic amino acids in the proximal kidney tube. Recently, two subunits of a renal cystine transporter have been identified. Mutations in these genes have been shown to lead to the cystinuria phenotype. Genetic and functional analyses have helped to modify the classification of cystinuria which had previously been exclusively based on biochemical data. Furthermore, first steps towards a molecular genetic testing have been carried out replacing the so far diagnostic procedure which are stressing for the patients. The results of these testings make an individual therapy possible.

Cystinuria↗
PubMed2003

Clinical manifestations in Israeli cystinuria patients and molecular assessment of carrier rates in Libyan Jewish controls.

BACKGROUND: Cystinuria is an autosomal recessive disease that is manifested by the development of kidney stones. Mutations in SLC3A1 cause type I disease, while mutations in SLC7A9 are associated with non-type I disease. In Israel, cystinuria is especially common among Libyan Jews who suffer from non-type I disease. OBJECTIVES: To compare clinical manifestations of patients with mutations in SLC3A1 to those with mutations in SLC7A9, and to assess the carrier rate among unaffected Libyan Jewish controls. METHODS: Clinical manifestations were evaluated in patients with mutations in SLC3A1 and in patients with mutations in SLC7A9. Carrier rates for two SLC7A9 mutations were assessed in 287 unaffected Libyan Jewish controls. RESULTS: Twelve patients with mutations in SLC3A1 were compared to 15 patients with mutations in SLC7A9. No differences were detected between the patients with mutations in SLC3A1 and those with mutations in SLC7A9 in relation to the age of disease onset, the estimated number of stones, the number of invasive procedures, the number of patients receiving drug therapy, or the patients' urinary pH. Eleven of the unaffected Libyan Jewish controls were found to be heterozygotes for the V170M mutation, establishing a carrier rate of 1:25. The 1584 + 3 del AAGT mutation was not found in any of the Libyan Jewish controls. CONCLUSION: Mutations in SLC3A1 and SLC7A9 cystinuria patients result in indistinguishable disease manifestations. The high carrier rate among Libyan Jews is a result of a single missense mutation, V170M.

Age of Onset↗
PubMed1992

Balanced translocation (14;20) in a mentally handicapped child with cystinuria.

A mentally handicapped 3 year old child with cystinuria is presented. Routine chromosomal analysis showed an apparently balanced de novo translocation in the child with breakpoints 14q22 and 20p13. Family studies suggested that the child is a type I/type II compound heterozygote for cystinuria. This translocation may indicate a possible locus for the gene for cystinuria.

Child, Preschool↗
PubMed1991

[Cystinuria with symptoms of cerebellar atrophy--a case report].

We report cystinuria and symptoms of cerebellar atrophy in a 45-year-old man. His parents were first cousins, and many members of his family had stones of urinary tract or gait impairment. Neurological examination disclosed cerebellar signs resembling those of spinocerebellar degeneration. Urinalysis disclosed high cystine, lysine, ornitine and arginine output. Cystine was 1153.8 micro mol/day (normal range, 22-170); lysine, 3443.9 (normal range, 44-1000); ornitine, 283.8 (normal range, 7-40); and arginine, 154.0 (normal range, 9-50). Neurological complications reported to be associated with cystinuria include mental retardation, muscular dystrophy, hypotonia and dwarfism, mongolism, paroxysmal dyskinesia, myopathy, migraine, spastic paraplegia, multiple sclerosis, subacute combined degeneration and cranial polyneuropathy. Cerebellar signs have been reported in only two cases, and to our knowledge, this is the first case of cystinuria with cerebellar atrophy ever reported. Some common metabolic errors may have caused both disorders, although they also may have developed independently.

Atrophy↗
PubMed1990

Cystinuria.

Cystinuria is an hereditary disorder of renal and intestinal transport characterized by the excessive urinary excretion of cystine, arginine, lysine, and ornithine. It is inherited as a common recessive gene with allelic mutations. Complementary studies of the plasma response to oral cystine loading, intestinal mucosal transport patterns, and urine cystine excretion allow separation of homozygous cystinuric subjects into three groups. In type I, the most common form, there is no active transport of cystine or dibasic amino acids across the mucosal gradient, and heterozygous subjects show normal urine cystine values. Type II is characterized by markedly reduced or absent intestinal transport of cystine. Heterozygotes for type II show significantly elevated urine cystine but less than is seen in homozygotes. In type III there is diminished, although demonstrable, intestinal absorption of cystine and dibasic amino acids. Urine cystine in heterozygotes is intermediate between types I and II. Urolithiasis with its attendant complications is the sole clinical manifestation of cystinuria and is due to the relative insolubility of cystine in the urine. The urolithiasis may become clinically manifest at any time from infancy through the ninth decade, although the mean age is the second to third decade. Clinical presentation is similar to that of other types of urolithiasis. Although cystinuria accounts for only 1% to 2% of all urolithiasis and 6% to 8% of urolithiasis in pediatric populations, repeated stone formation in affected patients often causes considerable morbidity. Cystine crystals in the urine are diagnostic but show up in only 19% to 26% of homozygous cystinuric patients. Sodium cyanide nitroprusside is a suitable screening test that should identify homozygous stone formers but will not detect all heterozygotes. A positive screening test should be followed by quantitation of urinary amino acids. A homozygous patient can be functionally defined as one who excretes 250 mg or more of cystine/g of creatinine in a 24-hour urine collection. Other causes of excess urinary cystine must be excluded. Medical therapy will be directed toward dissolution of existing calculi and prevention of new stone formation. Increasing urine volume by generous oral fluid intake is beneficial. Dietary sodium restriction has a favorable effect on urinary cystine excretion. Cystine solubility can be improved by urinary alkalinization and where necessary by the administration of thiol chelators, particularly D-penicillamine or mercaptopropionylglycine. Because these chelators have significant adverse effects, they should be reserved for patients who do not respond to a more conservative program. Patients with infected, symptomatic, or obstructing stones require surgical intervention.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Transport↗
PubMed1987

Captopril reduces urinary cystine excretion in cystinuria.

Cystinuria is characterized by cystine stone formation and loss of renal function. Conservative therapy is generally ineffective and penicillamine therapy can be complicated by serious side effects. To our knowledge, we report the first clinical use of captopril in the treatment of homozygous cystinuria in two siblings. In the first patient, a 70% reduction in cystine excretion was observed after 26 weeks of therapy with 150 mg/d of captopril. Discontinuation of use of the drug resulted in a return to baseline cystine excretion, further loss of renal function, and nephrotic range proteinuria. Repeated treatment with captopril stabilized renal function, reduced proteinuria, and returned cystine excretion to near normal levels. In the second patient, cystine excretion was reduced by 93% after nine weeks of therapy with 75 mg/d of captopril. No adverse side effects were observed in either patient. Formation of the captopril-cysteine disulfide accounts for part of the reduction in cystine excretion but other mechanisms probably contribute. Because captopril-cysteine disulfide is 200 times more soluble than cystine, long-term captopril therapy may be useful in the treatment of cystinuria.

Adult↗
PubMed1994

Cystinuria: pathogenesis and treatment.

Cystinuria is an inherited disorder of cystine and dibasic amino acids involving renal and intestinal transport mechanisms. Cystine stones are caused by the excessive renal excretion of cystine due to its low solubility in urine. The prevalence of homozygous cystinuria appears to vary in different parts of the world. Cystine stones frequently occur in the second or third decade of life, with an occasional occurrence in infancy and in old age. Urinary cystine excretion exceeding 250 mg/g creatinine is usually diagnostic of homozygous cystinuria. The goal of treatment is to reduce the urinary cystine concentration below its solubility limit (250 mg/l).

Adult↗
PubMed1996

Pathogenesis and medical management of cystinuria.

Cystinuria is an inheritable disorder of amino acid transport, transmitted as an autosomal recessive trait, Cystinuria is caused by defective transport of cystine and dibasic amino acids through the epithelial cells of the renal tubule and intestinal tract. Cystine stones are caused by the excessive renal excretion of cystine as a result of its low solubility in urine. Recently, a human kidney cDNA, named rBAT (also D2: the gene now designated SLC3A1), which elicits the transport for cystine and dibasic amino acids, has been reported. The 90-kd Type II glycoprotein stimulated cystine and dibasic and neutral amino acid uptake into oocytes with kinetics similar to the renal brush border transporter. The human gene for this protein resides on chromosome 2. The most frequent mutations found involved substitution of the threonine for methionine 467. Eight additional mutations in SLC3A1 have been found. Cystine stones frequently occur in the second or third decade of life, with an occasional occurrence in infancy and in old age. Urinary cystine excretion exceeding 250 mg/g creatinine is usually diagnostic of homozygous cystinuria. The goal of treatment is to reduce the urinary cystine concentration below its solubility limit (250 mg/L).

Chelating Agents↗
PubMed1997

Molecular analysis of cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping of a new locus on 19q.

Cystinuria is a hereditary disorder of amino acid transport and is manifested by the development of kidney stones. In some patients the disease is caused by mutations in the SLC3A1 gene, which is located on the short arm of chromosome 2 and encodes a renal/intestinal transporter for cystine and the dibasic amino acids. In Israel cystinuria is especially common among Jews of Libyan origin. After excluding SLC3A1 as the disease-causing gene in Libyan Jewish patients, we performed a genomewide search that shows that the Libyan Jewish cystinuria gene maps to the long arm of chromosome 19. Significant linkage was obtained for seven chromosome 19 markers. A maximal LOD score of 9.22 was obtained with the marker D19S882. Multipoint data and recombination analysis placed the gene in an 8-cM interval between the markers D19S409 and D19S208. Significant linkage disequilibrium was observed for alleles of four markers, and a specific haplotype comprising the markers D19S225, D19S208, D19S220, and D19S422 was found in 11 of 17 carrier chromosomes, versus 1 of 58 Libyan Jewish noncarrier chromosomes.

Amino Acid Transport Systems, Basic↗
PubMed1986

Measurement of urinary cystine and cysteinyl-penicillamine in patients with cystinuria.

A high-performance liquid chromatographic method with electrochemical detection (LC/EC) was developed to measure cystine and cysteinyl-penicillamine disulfide in the urine of patients screened or treated for cystinuria. Urine was acidified, centrifuged to remove urinary protein, diluted and injected. The disulfides were separated on a reversed-phase column, reduced at the upstream electrode of a dual electrochemical detector with gold-mercury amalgam (Au/Hg) electrodes and the resultant thiols measured at the downstream electrode. The sample preparation is simple, the analysis rapid, specimens can be easily batched and the specificity of the method is better than those of two other separative procedures with which it was compared. The coefficient of variation for cystine in cystinuric urine is 6.7%, 5.5% and 3.2% for levels of 0.09, 0.52 and 1.02 mmol/l respectively, and for cysteinyl-penicillamine disulfide 2.6% and 7.5% for levels of 0.45 and 0.98 mmol/l respectively. Urine for analysis of these disulfides should not be collected within 24 hours of administration of the radiopaque agent diatrizoate but no other interference to the assay has been noted. This method is suitable as a screen for cystinuria in patients with renal tract calculi, for ongoing monitoring of cystinuric patients and to check patient compliance with d-penicillamine therapy.

Amino Acids↗
PubMed1996

Genomic organization of SLC3A1, a transporter gene mutated in cystinuria.

The SLC3A1 gene encodes a transport protein for cystine and the dibasic amino acids. Recently mutations in this gene have been shown to cause cystinuria. We report the genomic structure and organization of SLC3A1, which is composed of 10 exons and spans nearly 45 kb. Until now screening for mutations in SLC3A1 has been based on RT-PCR amplification of illegitimate mRNA transcripts from white blood cells. In this report we provide primers for amplification of exons from genomic DNA, thus simplifying the process of screening for SLC3A1 mutations in cystinuria.

Amino Acid Transport Systems, Basic↗
PubMed2004

The population-specific distribution and frequencies of genomic variants in the SLC3A1 and SLC7A9 genes and their application in molecular genetic testing of cystinuria.

Cystinuria is a common inherited aminoaciduria resulting in nephrolithiasis. Mutations in two genes, SLC3A1 and SLC7A9, have been identified in cystinuric patients. Considering the population-specific distribution of genetic variants in the SLC3A1 gene, we focused our study on mutations in SLC3A1 and SLC7A9 described more than once in the literature. We evaluated the usefulness of this restricted analysis as a diagnostic approach. Furthermore, the data obtained were used to estimate the frequency of heterozygote carriers of SLC3A1 mutations in the general European population. A total of 22 unclassified cystinuric patients were screened for genetic variants in four exons of both SLC3A1 and SLC7A9 in which the most common mutations have been identified. For screening, we used single strand conformation polymorphism analysis (SSCP), restriction assays, real-time PCR and direct sequencing. In total, we identified mutations in 17 of our 22 patients, including a new mutation (R365Q) as well as a novel polymorphism (c.1035G/A) within the SLC3A1 gene. An ethnic influence on the distribution of mutations was confirmed: T216M in SLC3A1 is the major mutation in south-eastern Europe, whereas M467T in SLC3A1 is mainly found in western Europe. A complex duplication in SLC3A1 is restricted to German patients. Generally, we could show that a stepwise analysis directed to the most common mutations in the two cystinuria genes is sufficient to detect variants in more than 75% of patients of European origin. The test consists of nine different PCR-based approaches and therefore represents a low-cost, reliable and timesaving diagnostic tool.

Amino Acid Transport Systems, Basic↗
PubMed2001

A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria.

For many years, urine alkalinization has been one of the cornerstones in the treatment of homozygous cystinuria. Because of the relationship found between the excretion of urinary sodium and cystine, potassium citrate has emerged as the preferred sodium-free alkalizing agent. To evaluate the usefulness of potassium citrate for urine alkalization in cystinuric patients, sodium bicarbonate and potassium citrate were compared in 14 patients (10 on tiopronin treatment and four without treatment with sulfhydryl compounds). The study started with 1 week without the use of any alkalizing agents (Period 0) followed by 2 weeks with sodium bicarbonate (Period 1) and 2 weeks with potassium citrate (Period 2). Urinary pH, volume, excretion of sodium, potassium, citrate and free cystine, as well as the plasma potassium concentration, were recorded. Potassium citrate was shown to be effective as an alkalizing agent and, in this respect, not significantly different from sodium bicarbonate. Even though a normal diet was used, a significant increase in urinary sodium excretion was observed with sodium bicarbonate (Period 1). Urinary potassium and citrate excretion increased with potassium citrate (Period 2). A significant correlation was found between urinary sodium and cystine in the tio-pronin-treated patients. No significant differences in cystine excretion were recorded in Periods 0, 1 and 2. Plasma potassium was significantly higher during Period 2, but only one patient developed a mild hyperkalemia (5.0 mmol/l). The use of potassium citrate for urine alkalization in homozygous cystinuria is effective and can be recommended in the absence of severe renal impairment.

Adult↗
PubMed2001

Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria.

Based on previous observations of the diurnal variation of urinary cystine excretion, the use of separate day and night urine collections was proposed. To improve the medical treatment of patients with cystinuria, this strategy was performed to guide the fluid intake and the administration of SH compounds (tiopronin, D-penicillamine, and MESNA).Twenty-six patients (19 treated with SH compounds and seven with alkalinization and hydration only) were followed during two 3.5-year periods. During Period 1, 24-h urine was collected and during Period 2, separate day and night urine was collected. There were 56 episodes of high urinary cystine supersaturation (> 1,200 micromol/l) during Period 2, 47% of which would have evaded detection with 24-h urine analysis. In comparison with Period 1, the urinary cystine concentration was lower (P < 0.05), and the urinary volume was higher (P < 0.05) during Period 2. Patients treated with tiopronin had reduced cystine excretion (P < 0.05) and at the end of Period 2, an increased dose of tiopronin, reflecting a more aggressive treatment. Furthermore, a reduced number of stone episodes and need of active stone removal (P < 0.05) was noted in the whole group of patients. Analyses of separate day and night urine samples can be used advantageously to reveal episodes of high supersaturation with cystine not detected in 24-h urine samples. Such a procedure might be useful for optimizing the treatment of patients with cystinuria.

Adult↗
PubMed1975

A study of the renal handling and intestinal absorption of dibasic amino acids in a patient with genotype +/11 heterozygous cystinuria and idiopathic hypercalcuria.

A case is reported of a patient with idiopathic hypercalcuria who was referred for investigation of renal calculi. Studies of urinary amino acid excretion in the patient and all living members of his family, as well as studies of endogenous renal clearances of dibasic amino acids and cystine in the patient and his daughter, indicated that the patient had genotype +/11 heterozygous cystinuria. Intestinal perfusion studies showed however that the patient was able to absorb L-lysine, L-arginine normally from the jejunum and ileum. This suggests that a difference exists between renal and intestinal handling of lysine and arginine in cystinuria.

Adult↗