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PubMed1998

Usefulness of cyanide-nitroprusside test in detecting incomplete recessive heterozygotes for cystinuria: a standardized dilution procedure.

We present the results of a cyanide-nitroprusside test (CNT) after a standardized dilution procedure of urine samples and report the efficiency of this method in detecting heterozygotes for cystinuria when applied on an open pediatric population. In the preliminary study we assayed by quantitative determination of amino acids 162 urine samples from a hospital population identifying 24 type III heterozygotes and 2 type II heterozygotes for cystinuria. The classic CNT gave 38 false positive results and 5 false negative results showing a sensitivity and specificity of 0.808 and 0.721, respectively. When progressively diluted, all samples of heterozygotes remained CNT positive up to a creatinine concentration of 90 mg/dl. At this level of dilution 31 out of 38 false positive turned to negative, thus obtaining a specificity of 0.922 without a lowering of the sensitivity in detecting heterozygotes. The standardized dilution at 90 mg/dl of creatinine concentration was applied to 74.7% of a population of 1024 schoolchildren. In this way 163 out of 210 positive results were eliminated and thus the specificity of CNT rose from 0.789 to 0.953. On the basis of these results, the method proposed can be regarded as reliable and useful for a screening program in detecting heterozygotes for cystinuria.

Adolescent↗
PubMed1996

Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism.

A cystinuria disease gene (rBAT) has recently been identified, but evidence strongly suggests that only Type-I cystinuria is due to mutations in this gene. Sixteen point mutations and a large deletion causing the disease have so far been described in the rBAT gene sequence. To identify new mutated alleles, genomic DNA was analyzed, after the determination of the entire genomic structure of the rBAT gene, by RNA-single strand conformation polymorphism analysis, an accurate and sensitive method able to detect nucleotide changes. Four new point mutations, a large deletion, and a common intragenic polymorphism were detected. These new mutations increase to 22 the number of mutated alleles so far characterized in rBAT. In addition, the frequency of 21 mutations was assessed in a sample of accurately defined Type-I cystinuria chromosomes. They account for about 58% of all Type-I chromosomes, mutation M467T being the most common (0.26).

Alleles↗
PubMed2004

Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up.

Cystinuria, an autosomal-recessive disorder of a renal tubular amino acid transporter, is the cause of about 10% of all kidney stones observed in children. Different genetic characteristics are not represented by different phenotypes. The stones are formed of cystine, which is relatively insoluble at the physiological pH of urine. Without any preventive measures, the patients will suffer from recurrent stone formation throughout their life. Even with medical management, long-term outcome is poor due to insufficient efficacy and low patient compliance. Many patients suffer from renal insufficiency as a result of recurrent stone formation and repeated interventions. However, regular follow-up and optimal pharmacotherapy significantly increase stone-free intervals. Medical management is mainly based on hyperhydration and urine alkalinization. Sulfhydryl agents such as tiopronin can be added. Recurrent stone formation necessitates repeated urological interventions. These mostly minimally invasive procedures carry the risk of impairment of renal function. In adults, extracorporeal shockwave lithotripsy (SWL) as well as intracorporeal lithotripsy is often unsuccessful. However, in children SWL shows excellent results for cystine stones. In cases with large stone burden, percutaneous nephrolithotripsy (PNL) or even open surgical nephrolithotomy are preferred. This review discusses the underlying pathogenetic mechanisms and provides guidance for the diagnosis, therapy, and management of cystinuria following the recommendations of the International Cystinuria Consortium and the European Association of Urology.

Adolescent↗
PubMed1986

Frequency of cystinuria among stone-forming patients in region of Brazil.

Occasional urine samples from 200 stone-forming individuals were screened by the successive application of the cyanide-nitroprusside test, qualitative-semiquantitative thin-layer amino acid chromatography, and quantitative ion-exchange amino acid analysis to determine the frequency of cystinuria in this region of Brazil. Only 1 homozygous cystinuria patient was detected, a lower frequency than 1 to 6 per cent reported in other countries. The patient's family showed a I/I genotype. Since 6 heterozygotes for cystinuria +/II or +/III were also detected, the relative rarity of homozygotes in this sample supports the view of the relatively greater contribution of etiologic factors other than gene frequency to stone formation. The importance of diagnosis based on quantitative amino acid analysis is emphasized because of the different therapeutic and prognostic implications of the homozygote and heterozygote forms of the disease.

Amino Acids↗
PubMed1999

Reference values of urinary excretion of cystine and dibasic aminoacids: classification of patients with cystinuria in the Valencian Community, Spain.

OBJECTIVE: Cystinuria is an autosomal-recessive disorder of the kidneys and small intestine affecting a luminal transport mechanism shared by cystine, ornithine, arginine, and lysine. Three different types of cystinuria can be distinguished according to the excretion of these amino acids in urine samples. We propose cutoff values from our population as references and we present a classification of cystinuric patients using quantitative amino acid chromatography in first morning urine samples. DESIGN AND METHODS: A random sample of forty healthy subjects belonging to general population of the Valencian Community were selected as control subjects. Cystine, lysine, arginine, and ornithine were quantified by reverse-phase HPLC. Seventy-two subjects, diagnosed previously as cystinuric by the cyanide-nitroprusside test were classified. Probands excreting more than 113.12 micromol cystine per mmol of creatinine (i.e., 1,000 micromol cystine per gram of creatinine) were classified as homozygotes. Parents of homozygotes in whom excretion of amino acids were normal were classified as heterozygotes type I. Those probands showing the excretion of at least one amino acid and the sum of urinary cystine plus the basic amino acids higher than the corresponding references ranges in our population were classified as heterozygotes type II or type III (heterozygotes non-type 1). RESULTS: We identified 24 homozygotes, 39 non-type I heterozygotes and 3 type I heterozygotes. The remaining 6 probands could not be classified. Means for cystine, lysine, arginine ornithine and their sum in homozygotes and heterozygotes non-type I were significantly (p < 0.001) in excess of the respective reference ranges. Moreover, means values in homozygotes were statistically different (p < 0.001) from heterozygotes non-type I. CONCLUSION: Urinary excretion of cystine per mmol creatinine allow us to distinguish heterozygotes from homozygotes. However, the best discriminator to distinguish non-type I heterozygotes from normal population might be the excretion of lysine per mmol creatinine. Additional studies including characterization of appropriate haplotypes should be carried out for a more precise identification of types of cystinuria.

Adolescent↗
PubMed1996

Medical treatment of cystinuria: results of contemporary clinical practice.

PURPOSE: We determined the efficacy of a contemporary medical regimen for treatment of cystinuria. MATERIALS AND METHODS: A total of 16 patients with cystinuria was followed for 7 to 141 months (mean 78.1). Standard therapy included hydration and alkalization. D-penicillamine or alpha-mercaptoproprionylglycine was added for failure of hydration and alkalization to prevent new stones or stone growth, or to cause dissolution. Captopril was added for failure of or intolerance to D-penicillamine or alpha-mercaptopropionylglycine. Radiography was performed every 6 to 12 months, at which time stone events were documented. RESULTS: During hydration and alkalization 46 stone events occurred in 8 of 9 patients (1.6 events per patient-year). With addition of thiol derivatives 7 of 9 patients experienced 24 stone events, all 6 treated with hydration, alkalization and captopril experienced 10 events, and 4 of 5 treated with alkalization, thiols and captopril experienced 8 events (0.52, 0.71 and 0.54 events per patient-year, respectively). During a total treatment time of 104.1 patient-years 88 stone events occurred in 14 of 16 patients (0.84 events per patient-year). CONCLUSIONS: D-penicillamine and alpha-mercaptopropionylglycine are effective in decreasing the rate of stone formation in patients in whom hydration and alkalization failed. While captopril may also be beneficial in this setting, it does not appear to be as effective as D-penicillamine or alpha-mercaptopropionylglycine, and it does not clearly add clinical benefit to those thiols. Our study demonstrates that patients with cystinuria are at high risk for recurrence when treated with any contemporary medical program. This natural history must be considered when evaluating the long-term efficacy of newer or alternative modes of medical and urological treatment.

Adolescent↗
PubMed1979

Heterozygous cystinuria and calcium oxalate urolithiasis.

Many variables are known to be associated with the formation of calcium oxalate urolithiasis but none is essential for the initiation or growth of stones. It is likely that the predisposition to stone formation is related to multiple factors. We herein describe still another metabolic state that seems to predispose to calcium oxalate stone disease, namely heterozygosity for cystinuria. Cystine screening tests were done on 24-hour urine specimens obtained from 126 patients in whom recurrent calcium oxalate stones form and 84 controls and quantitative amino acid determinations were done on all positive specimens. Of those studied 17 of 126 stone patients and 1 of 84 controls were heterozygous cystinurics. A test of the differences between the relative frequencies of cystinuria heterozygotes in the 2 groups with Fisher's exact test revealed them to be highly significant (p less than 0.001). Our study indicates that carrier status for 1 of the cystinuria genes predisposes to calcium oxalate stone formation but, like other factors related to urolithiasis, it is not a necessary cause of stone disease.

Adolescent↗
PubMed2002

Cystinuria and other noncalcareous calculi.

Urinary stone disease is the only clinical presentation in patients with cystinuria. Two genes have been associated with type I (SLC3A1) and non-type I (SLC7A9) cystinuria and multiple mutations of these genes have been identified. The type I form is completely recessive while the non-type I form is incompletely recessive. Clinically, heterozygotes with type I mutations are silent while heterozygotes with non-type I (types II and III) present with a wide range of urinary cystine levels and some even have symptomatic urolithiasis. Although the exact molecular basis for these differences needs additional investigations, the future of medical management of cystinuria is based on molecular and gene therapy. Minimally invasive surgery using percutaneous and ureteroscopic techniques is the cornerstone of surgical management. Both cystine and struvite calculi can form staghorn configuration with propensity for rapid growth and frequent recurrences after surgical treatment. While urinary alkalinization for cystine calculi is an integral part of medical management, the effect of oral alkalinizing agents is limited because of the high pKa (8.3) of cystine. Chelating agents, therefore, are frequently used to decrease cystine solubility and stone recurrences. Similarly, urinary acidification for struvite calculi may dissolve existing stones and prevent recurrences. However, no effective oral agent is available today. A future challenge will be to introduce reliable oral agents for urinary acidification.

Amino Acid Transport Systems, Basic↗
PubMed1996

Molecular genetics of cystinuria in French Canadians: identification of four novel mutations in type I patients.

Cystinuria, a hereditary disorder of cystine and dibasic amino acid reabsorption, has been classified into three subtypes on the basis of urinary excretion in obligate heterozygous parents. Thirteen cystinuric patients, identified primarily through the Quebec newborn urinary screening program, were investigated by phenotypic classification and by mutational analysis of the D2H (rBAT) gene. Mutations were identified on 7 of 25 alleles; all of these 7 mutant alleles were associated with Type I cystinuria. Four of the mutations (a large deletion, a 5'splice site mutation, a 2 bp deletion, and a nonsense mutation) have not been previously reported. These findings suggest that abnormalities in the D2H gene may account for only one subtype (Type I) of cystinuria, and that this subtype can be caused by a wide variety of population-specific mutations.

Amino Acid Transport Systems, Basic↗
PubMed2004

Cystinuria-specific rBAT(R365W) mutation reveals two translocation pathways in the amino acid transporter rBAT-b0,+AT.

Apical reabsorption of dibasic amino acids and cystine in kidney is mediated by the heteromeric amino acid antiporter rBAT/b(0,+)AT (system b(0,+)). Mutations in rBAT cause cystinuria type A, whereas mutations in b(0,+)AT cause cystinuria type B. b(0,+)AT is the catalytic subunit, whereas it is believed that rBAT helps the routing of the rBAT/b(0,+)AT heterodimeric complex to the plasma membrane. In the present study, we have functionally characterized the cystinuria-specific R365W (Arg(365)-->Trp) mutation of human rBAT, which in addition to a trafficking defect, alters functional properties of the b(0,+) transporter. In oocytes, where human rBAT interacts with the endogenous b(0,+)AT subunit to form an active transporter, the rBAT(R365W) mutation caused a defect of arginine efflux without altering arginine influx or apparent affinities for intracellular or extracellular arginine. Transport of lysine or leucine remained unaffected. In HeLa cells, functional expression of rBAT(R365W)/b(0,+)AT was observed only at the permissive temperature of 33 degrees C. Under these conditions, the mutated transporter showed 50% reduction of arginine influx and a similar decreased accumulation of dibasic amino acids. Efflux of arginine through the rBAT(R365W)/b(0,+)AT holotransporter was completely abolished. This supports a two-translocation-pathway model for antiporter b(0,+), in which the efflux pathway in the rBAT(R365W)/b(0,+)AT holotransporter is defective for arginine translocation or dissociation. This is the first direct evidence that mutations in rBAT may modify transport properties of system b(0,+).

Amino Acid Substitution↗
PubMed1976

Cystinuria: a new genetic variant.

1. A family is reported with an unusual type of cystinuria. 2. The propositus presented with a cystine renal stone; the renal tubular reabsorption of cystine was grossly abnormal but the tubular reabsorption of ornithine, lysine and arginine was only slightly less than normal. 3. One of the children of the propositus escreted cystine and lysine in increased amounts typical of type II heterozygotes for cystinuria. 4. The renal transport defect in this family may represent one end of the spectrum of cystinuria or it may be a form akin to isolated hypercystinuria.

Amino Acids↗
PubMed1998

Molecular genetics of cystinuria: mutation analysis of SLC3A1 and evidence for another gene in type I (silent) phenotype.

BACKGROUND: Cystinuria is a hereditary disorder that affects luminal transport of cystine and dibasic amino acids in kidney and small intestine. Three subtypes have been defined on the basis of urinary excretion of cystine in obligate heterozygotes. Mutations in the SLC3A1 gene have been associated with the Type I phenotype. METHODS: We investigated 20 cystinuria patients from Quebec (8 Type I/I, 9 Type I/III and 3 Type II/N) for mutations in SLC3A1. DNA was studied by Southern blotting and by the single strand conformation polymorphism (SSCP) protocol to identify mutations. Expression of mutations in Xenopus oocytes was performed to confirm the effect of missense mutations on cystine uptake. RESULTS: Six novel mutations (2 large deletions, a 2 bp deletion and 3 single bp substitutions) were identified on the Type I allele. Four missense mutations (T216M, S217R, R270L and I618M) were expressed in vitro; the first three changes significantly decreased uptake. CONCLUSIONS: Combined with our previous work, we have identified 15/16 mutations in SLC3A1 on Type I alleles in the eight Type I/I patients, but only one SLC3A1 mutation on the nine Type I alleles of the Type I/III patients. Therefore, we propose that the Type I phenotype could be caused by mutations in other, as yet unidentified cystinuria genes.

Amino Acid Transport Systems, Basic↗
PubMed2003

Significant contribution of genomic rearrangements in SLC3A1 and SLC7A9 to the etiology of cystinuria.

BACKGROUND: Cystinuria is an inherited disorder of defective renal reabsorption of cystine and the dibasic amino acids. Recently, SLC3A1 and SLC7A9 have been identified as responsible genes. While point mutations in the two genes are well known to cause cystinuria, only a few studies are aimed on the identification of gross genomic alterations. Here, we report our results of a systematic screening for deletions and duplications in SLC3A1 and SLC7A9 by quantitative real-time polymerase chain reaction (PCR). METHODS: We screened a cohort of 49 cystinurics for copy number deviations in the genes SLC3A1 and SLC7A9 by quantitative real-time PCR assays using fluorogenic 5' nuclease chemistry. The detected duplication in SLC3A1 was analyzed in detail by further real-time assays, reverse transcription (RT)-PCR and direct sequencing. RESULTS: In seven patients, we could identify a large duplication in SLC3A1 spanning from intron 4 to intron 9. This tandem duplication was accompanied by a small inversion of 25 bp and a 2 bp deletion in intron 9. As a formation mechanism, we presume that the inversion in intron 9 and several Alu sequences neighbored to the affected region provoke a chromatin structure that stimulates the duplication event. In addition to the SLC3A1 duplication, we observed deletions in SLC7A9 in three patients. CONCLUSION: The frequency of genomic rearrangements in our patient population illustrates the significant contribution of large genomic alterations to the mutation spectrum in cystinuria. As we could show, quantitative real-time PCR is a reliable and effective tool for the identification of unbalanced genomic rearrangements.

Amino Acid Transport Systems, Basic↗
PubMed2005

Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome.

In 11 patients with a recessive congenital disorder, which we refer to as "the hypotonia-cystinuria syndrome," microdeletion of part of the SLC3A1 and PREPL genes on chromosome 2p21 was found. Patients present with generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor facial dysmorphism, and failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. Since loss-of-function mutations in SLC3A1 are known to cause isolated cystinuria type I, and since the expression of the flanking genes, C2orf34 and PPM1B, was normal, the extended phenotype can be attributed to the deletion of PREPL. PREPL is localized in the cytosol and shows homology with prolyl endopeptidase and oligopeptidase B. Substitution of the predicted catalytic residues (Ser470, Asp556, and His601) by alanines resulted in loss of reactivity with a serine hydrolase-specific probe. In sharp contrast to prolyl oligopeptidase and oligopeptidase B, which require both aminoterminal and carboxyterminal sequences for activity, PREPL activity appears to depend only on the carboxyterminal domain. Taken together, these results suggest that PREPL is a novel oligopeptidase, with unique structural and functional characteristics, involved in hypotonia-cystinuria syndrome.

Amino Acid Sequence↗
PubMed2005

Identification of novel cystinuria mutations and polymorphisms in SLC3A1 and SLC7A9 genes: absence of SLC7A10 gene mutations in cystinuric patients.

Cystinuria represents 3% of nephrolithiasis in humans with an overall prevalence of 1 in 7,000 neonates. Two genes have been reported to account for the genetic basis of cystinuria, the SLC3A1 and the SLC7A9. Recently, the possible involvement of the SLC7A10 gene in the genetic basis of the disorder was also reported. In the present study, we found a total of 15 mutations in 20 Greek cystinuric patients. Eight mutations are novel, 4 in the SLC3A1: F266S, T351I, R456C, and N516D, and 4 in the SLC7A9: 479-1G>C, Y232C, D233E, and 1399+1G>T. Furthermore, 2 polymorphisms were identified in the SLC3A1 gene and 16 polymorphic variants were also found in the SLC7A9 gene of which the 235+18C>A, 604+10G>A, and 604+24T>C are novel. Finally, no mutation was found in the SLC7A10 gene in all patients. Only, the novel 634+8C>G and the previously reported 913-11C+T polymorphisms were identified in the SLC7A10 gene. In conclusion, a spectrum of SLC3A1 and SLC7A9 mutations are responsible for the genetic basis of cystinuria in Greek patients.

Amino Acid Transport System y+↗
PubMed1977

Cystinuria and mental deficiency.

Several studies have shown that the incidence of cystinuria in mentally retarded populations is higher than it is in the general population. The present study found that a group of cystinurics did not differ significantly in their intelligence from their normal siblings or intelligence test norms. Since cystinuria is a heterogeneous disease, the findings of the present study could be reconciled with previous findings by supposing that only certain genotypes for cystinuria lead to mental retardation.

Adolescent↗
PubMed2006

Reduced renal function and benefits of treatment in cystinuria vs other forms of nephrolithiasis.

UNLABELLED: A significant study from the USA compares cystine stone formers and routine stone formers; the former group had a higher requirement for therapeutic procedures, but this was less if they took chelating agents, although remaining higher than in the latter group. Other interesting findings are also presented. OBJECTIVE: First, to compare two types of stone formers (SF), those with cystinuria and those without, for effects of treatments for stones, as cystinuria leads to recurrent stones that are difficult to fragment with shock-wave lithotripsy, and there is disagreement about the efficacy of current treatments. Second, to compare these two groups with respect to blood pressure (BP) and renal function, as cystine stones may be associated with more morbidity than are routine stones. PATIENTS AND METHODS: Fifty-two cystinuric patients (cystine SF) entering our programme since 1970 were compared with 3215 SF without cystinuria (routine SF), of whom 114 had a single functioning kidney (routine SF + nephrectomy). All patients had three 24-h urine and blood samples taken to determine the risk of stones before their first clinic visit; these studies were repeated after therapy was initiated, and at regular intervals to monitor therapy. Cystine was measured in the urine samples of the cystine SF. All stone-related procedures were recorded, and BP measured at clinic visits. Creatinine clearances (CCr) were calculated from each set of serum and urine values. Cystine supersaturation (SS) was directly measured in 16 urine samples collected before treatment and 13 afterward. RESULTS: Patients were treated with increased fluid intake, potassium alkali and chelating agents such as alpha-mercapto-propionyl-glycine, as needed. The mean (sd) CCr, corrected for age and gender, was significantly lower at entry in cystine SF than in routine SF, at 91 (6) vs 160 (1) L/day, respectively (P < 0.001), and remained so at the last CCr. Neither systolic nor diastolic BP, similarly corrected, differed between the groups, but cystine SF had significantly more procedures, corrected for time at risk, before treatment than did routine SF, at 4.0 (0.4) vs 1.86 (0.06), respectively (P < 0.001); time-adjusted procedures decreased significantly in both groups during treatment, but remained higher in cystine SF, at 0.88 (0.14) vs 0.23 (0.02), respectively, (P < 0.001). Urine volume and pH were significantly higher in cystine SF than in routine SF, both before and during treatment. Cystine SS decreased during treatment, consistent with the increase in urine volume and decline in procedure rates during treatment. CONCLUSION: Cystine SF have significantly higher procedure rates than routine SF, but procedure rates decline during therapy, although they remain higher than in routine SF. The lower CCr in cystinurics suggests that treatment to prevent stone recurrence and the need for procedures is particularly important, and emphasizes the need for a close follow-up. Use of cystine SS measurements may allow closer monitoring of the effect of treatment on the risk of stone recurrence.

Adult↗
PubMed1991

Effects of variation in sodium intake on cystinuria.

This study was designed to characterize the effect of urinary sodium excretion on amino acid excretion in cystinuria. We studied three homozygous patients with cystinuria at various levels of sodium intake ranging between 50 and 230 mmol/day. A reduction in sodium intake produced a marked decrease in rates of urinary cysteine excretion. The low-sodium diet also reduced the excretion of lysine but had no significant effect on the excretion of ornithine or arginine. We conclude that a dietary restriction of sodium may reduce the urinary excretion of cystine and can provide a simple and safe long-term approach to the treatment of cystinuria.

Administration, Oral↗