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PubMed1997

Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1.

Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes (I, II, and III) have been described. An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. Mutational and linkage analysis demonstrated the presence of genetic heterogeneity in which the SLC3A1 gene is responsible for type I cystinuria but not for type II or type III. In this study, we report the identification of the cystinuria type III locus on the long arm of chromosome 19 (19q13.1), obtained after a genomewide search. Pairwise linkage analysis in a series of type III or type II families previously excluded from linkage to the cystinuria type I locus (SLC3A1 gene) revealed a significant maximum LOD score (zeta max) of 13.11 at a maximum recombination fraction (theta max) of .00, with marker D19S225. Multipoint linkage analysis performed with the use of additional markers from the region placed the cystinuria type III locus between D19S414 and D19S220. Preliminary data on type II families also seem to place the disease locus for this rare type of cystinuria at 19q13.1 (significant zeta max = 3.11 at theta max of .00, with marker D19S225).

Chromosome Mapping↗
PubMed2001

Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients.

Cystinuria is an autosomal recessive disorder that affects luminal transport of cystine and dibasic amino acids in the kidneys and the small intestine. Three subtypes of cystinuria can be defined biochemically, and the classical form (type I) has been associated with mutations in the amino acid transporter gene SLC3A1. The mutations detected in SLC3A1 tend to be population specific and have not been previously investigated in Sweden. We have screened the entire coding sequence and the intron/exon boundaries of the SLC3A1 gene in 53 cystinuria patients by means of single strand conformation polymorphism (SSCP) and DNA sequencing. We identified 12 novel mutations (a 2 bp deletion, one splice site mutation, and 10 missense mutations) and detected another three mutations that were previously reported. Five polymorphisms were also identified, four of which were formerly described. The most frequent mutation in this study was the previously reported M467T and it was also detected in the normal population with an allelic frequency of 0.5%. Thirty-seven patients were homozygous for mutations in the SLC3A1 gene and another seven were heterozygous which implies that other genes may be involved in cystinuria. Future investigation of the non-type I cystinuria gene SLC7A9 may complement our results but recent studies also suggest the presence of other potential disease genes.

Adolescent↗
PubMed2000

Dating the origin of the V170M mutation causing non-type I cystinuria in Libyan Jews by linkage disequilibrium and physical mapping of the SLC7A9 gene.

Cystinuria is an autosomal recessive disorder of the transepithelial transport of amino acids, clinically manifested by the development of kidney stones. Mutations in the gene encoding rBAT (SLC3A1, on chromosome 2p16.3) are linked to type I cystinuria, while the SLC7A9 locus (19q13.1), expressing b0,+ AT protein, is involved in non-type I cystinuria, which is very common among Libyan Jews. Applying two methods for linkage disequilibrium analysis to haplotype data spanning six 19q12-q13.1 polymorphic markers, and relying on the physical distances between the markers and the recently mapped SLC7A9 (CSNU3) locus, the age of the founder missense V170M mutation causing non-type I cystinuria in Jews of Libyan ancestry is calculated to be approximately 14 to 15 generations (g) (95% confidence interval: 9-20 g) or slightly more. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes back to the time (or some decades before) Jewish families settled in Libya following their expulsion from the Iberian Peninsula. This finding makes the molecular population genetics of cystinuria understandable in the context of the Libyan Jews' history.

Amino Acid Substitution↗
PubMed2005

Search for mutations in SLC1A5 (19q13) in cystinuria patients.

To elucidate whether SLC1A5 is involved in the aetiology of cystinuria, we screened two non-type I cystinuria families without detectable mutations inSLC7A9 (and SLC3A1) but compatible with linkage to 19q13 for genomic variants in SLC1A5. Despite evidence for an involvement of SLC1A5 in the aetiology of cystinuria, we could not identify any mutation in this gene in the two families. With SLC1A5, a further candidate gene for cystinuria can be excluded as being involved in the pathogenesis of this disease in these two families. Of course, there remains the possibility that other genes are involved in cystinuria; further molecular studies will clarify the complex nature of this disorder.

Adolescent↗
PubMed2001

[Sensitivity, specificity and predictive value of the genetic analysis of SLC3A1 gene variants used for the diagnosis of cystinuria among the spanish population].

OBJECTIVE: To test the clinical usefulness of the analysis of point mutations R452W, M467T, 114C > A, 231T > A, 1136 + 3delT and 1332 + 7T > C in the gene SLC3A1 as well as their possible haplotypes used for the diagnosis of cystinuria in the mediterranean spanish population. MATERIAL AND METHODS: A total of 48 patients with cystinuria, 44 relatives without cystinuria, and 81 healthy controls were studied. A genetic analysis was conducted in order to identify variants in the gene SLC3A1. The sensitivity, specificity, and predictive value for each genetic variant and for the possible haplotypes were calculated. RESULTS: The specificity of mutations M467T, R452W, and 231T > A used for the diagnosis of cystinuria in the general population or for the different subtypes of cystinuria in involved families, was higher than 90%; nevertheless, none of the analysed variants reached a sensitivity higher than 80%. In the study of haplotypes, the highest sensitivity was obtained with the haplotype CTTT (83.8%); however, its specificity and predictive value were low (20.6% and 53.4%, respectively). CONCLUSIONS: The studied genetic variants did not show enough clinical usefulness.

Amino Acid Transport Systems, Basic↗
PubMed2003

Durability of the medical management of cystinuria.

PURPOSE: Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney that leads to an abundance of cystine in the urine. This molecule is poorly soluble in urine and it is prone to crystallization and stone formation at concentrations above 300 mg./l. Medical treatment in these patients has incorporated increasing urine volumes, alkalinization and thiol medications that decrease the availability of free cystine in urine. Despite a reasonable prognosis for reduced stone formation we and others have noted difficulties in patients complying with medical management recommendations. Therefore, we evaluated the durability of treatment success in our patients with cystinuria. MATERIALS AND METHODS: A retrospective chart review was performed in all patients with cystinuria referred to the comprehensive kidney stone center at our institution for an 8-year period. Medical therapy, stone recurrence rates, compliance with medications and scheduled followup, and the results of metabolic evaluations via 24-hour urine collections were reviewed. The average concentrations of urinary cystine in initial and followup 24-hour samples were compared in patients compliant and noncompliant with medical treatment. In addition, each patient was mailed a 1-page questionnaire to assess the self-perception of medical compliance. RESULTS: We identified 26 patients with a mean age of 32 years at referral (range 13 to 67) who were followed an average of 38.2 months (range 6 to 83). Females represented 58% of those with cystinuria. Overall compliance with medical recommendations was poor with a short duration of success. Of the 26 patients followed at our stone center only 4 (15%) achieved and maintained therapeutic success, as defined by urine cystine less than 300 mg./l. An additional 11 patients (42%) achieved therapeutic success but subsequently had failure at an average of 16 months (range 6 to 27). Of these patients 7 (64%) regained therapeutic success at an average of 9.4 months (range 4 to 20). Five patients (19%) never achieved therapeutic success, while an additional 6 (23%) failed to present to followup appointments or provide subsequent 24-hour urine studies despite referral to a tertiary care center. Patient self-assessment of medical compliance was uniformly high regardless of physician perceptions or treatment results. CONCLUSIONS The durability of medically treating patients with cystinuria is limited with only a small percent able to achieve and maintain the goal of decreasing cystine below the saturation concentration. Greater physician vigilance in these complicated stone formers is required to achieve successful prophylactic management. Furthermore, these patients require better insight into the own disease to improve compliance.

Adolescent↗
PubMed1999

Pilot screening programme for cystinuria in the Valencian community.

Cystinuria is an autosomal recessive disorder of the kidneys and small intestine, affecting a luminal transport mechanism shared by cystine, ornithine, arginine and lysine. When cystine exceeds its solubility at low pH, the risk of stone formation increases. The data reported in the literature show a variation for the incidence of cystinuria, from 1 in 600 to 1 in 17,000, depending on the definition of cystinuria and the method used for screening the population. We set up a pilot screening programme to determine the incidence of cystinuria in the population of the Valencian Community. Urine filter paper samples submitted for the neonatal screening programme from 33,995 newborns (5-10 days old) were used for the study. Thin layer chromatography (TLC) was performed to screen cystinuric patients. To confirm positive filter paper samples, liquid samples were requested and TLC as well as the cyanide-nitroprusside test (CNT) were performed. Final diagnosis was achieved by quantifying cystine, lysine, ornithine and arginine using high-performance liquid chromatography (HPLC) in children's urine samples which remained positive for TLC and CNT for more than 1 year. We conclude that the incidence of subjects at risk for cystine stones in the Valencian Community is 1:1887. TLC is shown as a reliable method to perform newborn screening in large population to detect cystinuric subjects. Additional studies, including characterization of appropriate haplotypes, should be carried out for a more precise identification of the frequency of the different types of cystinuria in our population.

Chromatography, Thin Layer↗
PubMed1997

Genomic organization of a human cystine transporter gene (SLC3A1) and identification of novel mutations causing cystinuria.

Cystinuria is a common inherited aminoaciduria that leads to recurrent cystine nephrolithiasis. Mutations in a gene encoding a renal amino acid transporter (SLC3A1) have been identified in patients with cystinuria establishing one molecular cause for the disease. To facilitate systematic screening of this gene for mutations, we have delineated the complete genomic organization of the SLC3A1 coding region using polymerase chain reaction strategies. The complete coding region of the gene is contained within a single yeast artificial chromosome clone and consists of 10 exons and 9 introns. Oligonucleotide primers capable of amplifying selected exons have been made and used in mutational analysis of DNA from 24 cystinuria probands. We illustrate the usefulness of this approach by identifying two novel SLC3A1 mutations. One novel mutation causes replacement of a highly conserved arginine residue (arginine-452) with tryptophan in the cytoplasmic loop between the putative third and fourth membrane spanning segments. A second previously unreported mutation results in replacement of a highly conserved tyrosine (tyrosine-461) residue with histidine in the same region of the protein. In addition, we detected three previously reported SLC3A1 mutations, R270X, 1500 +1/G to T, and M467T, the latter being present in approximately 20% of cystinuria chromosomes examined. Our findings provide a foundation for the development of more accessible diagnostic screening assays for detecting SLC3A1 mutations using patient genomic DNA, and also contribute to the emerging spectrum of cystinuria genotypes.

Amino Acid Sequence↗
PubMed2001

Cystinuria type I: identification of eight new mutations in SLC3A1.

BACKGROUND: Cystinuria is a heritable disorder of amino acid transport characterized by the defective transport of cystine and the dibasic amino acids through the brush border epithelial cells of the renal tubule and intestine tract. Three types of cystinuria (I, II, and III) have been described based on the urinary excretion of cystine and dibasic amino acids in obligate heterozygotes. The SLC3A1 gene coding for an amino acid transporter named rBAT is responsible for type I cystinuria, whereas the SLC7A9 gene coding for a subunit (b0,+AT) of rBAT is involved in determining non-type I (types II and III) cystinuria. METHODS: The SLC3A1 gene sequence was investigated in a sample of seven type I/type I, three type I/non-type I, six type I/untyped, and four untyped unrelated cystinuric patients by RNA single-strand conformation polymorphism (RNA-SSCP). RESULTS: Eight new point mutations (S168X, 765+1G>T, 766-2A>G, R452Q, Y461X, S547W, L564F, and C673W) and seven previously reported mutations were detected. These new mutations increase the number of mutated alleles so far characterized in SLC3A1 to 62. CONCLUSIONS: We have found SLC3A1 mutations in 0.739 of the type I chromosomes studied. The relatively high proportion of uncharacterized type I chromosomes suggests either that there may be mutations not yet found in SLC3A1 or that many of the assigned type I chromosomes in mixed type I/non-type I patients may have mutations in SLC7A9. If the hypothesis is excluded in the future, we believe that a third gene may be involved in cystinuria.

Adolescent↗
PubMed2001

Human cystinuria-related transporter: localization and functional characterization.

BACKGROUND: Cystinuria has been proposed to be an inherited defect of apical membrane transport systems for cystine and basic amino acids in renal proximal tubules. Although the mutations of the recently identified transporter BAT1/b(0,+)AT have been related to nontype I cystinuria, the function and localization of human BAT1 (hBAT1)/b(0,+)AT have not been well characterized. METHODS: The cDNA encoding hBAT1 was isolated from human kidney. Fluorescence in situ hybridization was performed to map the hBAT1 gene on human chromosomes. Tissue distribution and localization of expression were examined by Northern blot and immunohistochemical analyses. hBAT1 cDNA was transfected to COS-7 cells with rBAT cDNA, and the uptake and efflux of 14C-labeled amino acids were measured to determine the functional properties. The roles of protein kinase-dependent phosphorylation were investigated using inhibitors or activators of protein kinases. RESULTS: The hBAT1 gene was mapped to 19q12-13.1 on the human chromosome, which is the locus of nontype I cystinuria. hBAT1 message was expressed predominantly in kidney. hBAT1 protein was localized in the apical membrane of proximal tubules in human kidney. When expressed in COS-7 cells with a type II membrane glycoprotein rBAT (related to b(0,+)-amino acid transporter), hBAT1 exhibited the transport activity with the properties of amino acid transport system b(0,+), which transported cystine as well as basic and neutral amino acids presumably via a substrate exchange mechanism. BAT1-mediated transport was reduced by the protein kinase A activator and enhanced by the tyrosine kinase inhibitor. CONCLUSIONS: hBAT1 exhibited the properties expected for a transporter subserving the high-affinity cystine transport system in renal proximal tubules. The hBAT1 gene was mapped to the locus of nontype I cystinuria, confirming the involvement of hBAT1 in cystinuria.

ATP-Binding Cassette Transporters↗
PubMed2002

Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification.

Recent developments in the genetics and physiology of cystinuria do not support the traditional classification, which is based on the excretion of cystine and dibasic amino acids in obligate heterozygotes. Mutations of only two genes (SLC3A1 and SLC7A9), identified by the International Cystinuria Consortium (ICC), have been found to be responsible for all three types of the disease. The ICC set up a multinational database and collected genetic and clinical data from 224 patients affected by cystinuria, 125 with full genotype definition. Amino acid urinary excretion patterns of 189 heterozygotes with genetic definition and of 83 healthy controls were also included. All SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid urinary pattern (i.e., type I phenotype). The rest of the SLC7A9 carriers showed phenotype non-I (type III, 80.5%; type II, 5.5%). This makes the traditional classification imprecise. A new classification is needed: type A, due to two mutations of SLC3A1 (rBAT) on chromosome 2 (45.2% in our database); type B, due to two mutations of SLC7A9 on chromosome 19 (53.2% in this series); and a possible third type, AB (1.6%), with one mutation on each of the above-mentioned genes. Clinical data show that cystinuria is more severe in males than in females. The two types of cystinuria (A and B) had a similar outcome in this retrospective study, but the effect of the treatment could not be analyzed. Stone events do not correlate with amino acid urinary excretion. Renal function was clearly impaired in 17% of the patients.

Adolescent↗
PubMed1993

Decreased uptake of L-cystine by duodenal brush border membrane vesicles from patients with cystinuria.

BACKGROUND: The pathophysiology of cystinuria remains unclear. Decreased absorption of L-cystine across brush border membranes of small intestinal and renal proximal tubular epithelial cells is likely but has not been directly demonstrated. AIMS: To compare the rates of L-cystine transport by isolated duodenal brush border membranes of normal individuals and patients with cystinuria. METHODS: Distal duodenal biopsies were taken from normal individuals and patients with cystinuria. Brush border membrane vesicles (BBMV) were prepared using magnesium aggregation and differential centrifugation and the rates of L-cystine transport into the vesicles measured using a rapid filtration technique. RESULTS: Rates of L-cystine transport by BBMV from patients with cystinuria were reduced at 5 minute (p = 0.003) and 30 minute (p = 0.053). Time points, indicating that L-cystine absorption across brush border membranes is abnormal in cystinuria.

Adult↗
PubMed2004

The amino acid transporter asc-1 is not involved in cystinuria.

BACKGROUND: The human amino acid transporter asc-1 (SLC7A10) exhibits substrate selectivity for small neutral amino acids, including cysteine, is expressed in kidney, is located close to the cystinuria B gene and presents sequence variants (e.g., E112D) in some cystinuria patients. We have cloned human asc-1, assessed its transport characteristics, localized its expression in kidney, searched for mutations in cystinuria patients, and tested the transport function of variant E112D. METHODS: We used an EST-based homology cloning strategy. Transport characteristics of asc-1 were assessed by coexpression with 4F2hc in Xenopus oocytes and HeLa cells. Localization of asc-1 mRNA in kidney was assessed by in situ hybridization. Exons and intron-exon boundaries were polymerase chain reaction (PCR)-amplified from blood cell DNA and mutational screening was performed by single-stranded conformational polymorphism (SSCP). RESULTS: Asc-1 reaches the plasma membrane in HeLa cells, unlike in oocytes, most probably by interaction with endogenous 4F2hc and presents similar transport characteristics to those in oocytes coexpressing asc-1/4F2hc. Asc-1 mediates a substantial efflux of alanine in a facilitated diffusion mode of transport. Expression of asc-1 mRNA localized to Henle's loop, distal tubules, and collecting ducts. Finally, SLC7A10 polymorphisms were identified in cystinuria probands and the SLC7A10 sequence variant E112D showed full transport activity. CONCLUSION: The lack of expression of asc-1 in the proximal tubule indicates that it plays no role in the bulk of renal reabsorption of amino acids. No mutations causing cystinuria have been found in SLC7A10. The facilitated diffusion mode of transport and the expression in distal nephron suggest a role for asc-1 in osmotic adaptation.

Amino Acid Transport System y+↗
PubMed2006

[SLC7A9 gene variation: impact of 13 frequent mutations in the etiology of cystinuria in a Spanish Mediterranean population].

BACKGROUND AND OBJECTIVE: The aim of this study was to investigate the presence of the most prevalent mutation in the SLC7A9 gene in families of the Mediterranean Spanish population and their association with clinical phenotypes. PATIENTS AND METHOD: Twenty cystinuria families were studied (6 type I, 12 non type I, and 2 unknown type), including 48 cystinuria patients and 44 relatives. DNA was isolated and molecular analysis of 13 variations (P52L, N58_G79del22, G63R, G105R, T123M, V170M, A182T, V188M, c.614dupA, G259R, L283F, A316V and R333W) in the SLC7A9 gene was undertaken. Association studies between these mutations and urinary aminoacid concentrations, stones, urinary infections, colics and other clinical traits were carried out. RESULTS: Of the 13 investigated mutations, the most prevalent mutation in cystinuria patients was c.614dupA (17.1%), which was found in 13 patients in heterozygous state (17.1%) and in 2 relatives, all of them belonging to 4 non type I families. Mutations G105R (9.2%), T123M (3.9%) and N58_G79del22 (2.6%) were detected only in non type I cystinuria patients. Meanwhile, a R333W carrier allele was found in a patient of a unknown family, and a G105R allele in a relative of a non type I family. No mutation was found in type I families and no patients with mutations in both SLC3A1 and SLC7A9 genes were found in any family. CONCLUSIONS: Although we have not carried out the whole screening of SLC7A9 gene, the detection rate of variations in SLC7A9 gene suggests a greater impact of this gene in the etiology of cystinuria in our population than variations in the previously screened SLC3A1 gene. The wide variation of phenotypical traits in subjects of families with the same mutations suggests that further investigation of other genetic and/or environmental factors should be carried out.

Adolescent↗
PubMed1998

The long-term outcome of cystinuria in Japan.

Recurrence of growth of urinary stone is frequently observed during the clinical course of cystinuria patients. The aim of the present study is to examine the long-term outcome of cystinuria in Japan and clarify the effects of medical treatment on urinary stone. Thirty-one patients with cystinuria who had been followed up longer than 6 months were included. The follow-up period was 6-264 months with a mean of 89.5 months. Stone event was defined as appearance of new stone or radiological evidence of stone growth. All patients were managed with forced hydration and urine alkalization. Twenty-eight patients were treated with administration of thiol such as D-penicillamine or alpha-mercaptopropionylglycine. Stone events per year ranged from 0 to 1.09 with a median of 0.09. Stone events per patient-year was 0.19 for all patients. The average urinary cystine concentration during treatment in the favorable outcome group (stone events per year < 0.3) was lower that that in the unfavorable outcome group (stone events per year >/=0.3); 221.2 +/- 75.2 vs. 303.3 +/- 93.5 mg/l, although the difference was not statistically significant. Prognosis of urinary stone in Japanese patients with cystinuria was relatively good with large variation. The medical treatment to reduce urinary cystine concentration would be useful for the management of cystinuria.

Adult↗
PubMed2002

Genomic and functional investigations of mutations of the SLC3A1 gene in cystinuria.

BACKGROUND: Cystinuria is the second most frequent autosomal recessively inherited disorder in Europe, and it is based on a disturbance of the transepithelial transport of cystine and amino acids in the proximal renal tubule as well as in the intestinum. From the point of view of the urologist, patients suffering from cystine stones represent an important population because they develop a great number of recurrences which necessitate frequent stone removal. METHODS/RESULTS: Advances in the field of molecular genetics have rendered it possible to correlate genotype and phenotype of these patients. In the candidate gene, the SLC3A1 gene, 25 mutations in patients suffering from cystinuria have been described so far. Investigations in our patients (n = 15) as well as results obtained by other study groups have revealed an average detection rate of approximately 50%. The low rate as well as in-depth physiological analyses of the individual mutations indicate that the SLC3A1 is a subunit of a heteromeric complex. This supposition is supported by the structure of the transporter as well as by biochemical analyses of the urine of cystinuric patients and their relatives. Investigations on other genomic segments and candidate genes localized there are being performed. However, it has already appeared that cystinuria is not based on alterations of one single gene, but that a variety of factors combine in the development of this disease. CONCLUSIONS: To be able to offer a molecular genetic diagnosis for patients suffering from cystinuria, the search for mutations of the SLC3A1 gene is being expanded and a screening for other candidate genes set up which are designed to early recognize the risk factors of cystinuria as well as to be able to initiate early therapy.

Blotting, Southern↗
PubMed1983

Renal transport of lysine and arginine in cystinuria.

To study the defective transport mechanism of cystinuria, renal tubular reabsorption of lysine or arginine in normal and cystinuria subjects was investigated by increasing the filtered load employing intravenous amino acid infusion. In the normal group the amino acid reabsorption rose with increases of the filtered load and reached a maximum (Tm). In the cystinuria group the elevation of amino acid reabsorption was poor at low filtered loads and some of the reabsorption rates fell below zero, whereas the tubular transport proceeded at a normal rate with a great increase of the filtered load. This might be explained as follows: At low filtered loads the filtered amino acid in the tubular lumen in patients with cystinuria is not absorbed into the cell because of a transport defect of the luminal membrane of the tubular cell, causing a large amount of urinary amino acid excretion. At high filtered loads the accumulated intraluminal amino acid permeates the tubular cell by a passive diffusion and is transported to the capillary across the intact basolateral membrane, which in turn only brings about a small urinary loss of amino acid. The infusion of lysine or arginine depressed the percentage of tubular reabsorption of other dibasic amino acids in both groups. In the cystinuria group the percentage of the dibasic amino acid reabsorption dropped sharply with an initial load of the inhibitor, but no more depression of the percentage of reabsorption occurred with further loads of the inhibitor.

Absorption↗
PubMed1998

[Clinical study on cystinuria in children--the stone management and the prevention of calculi recurrence].

BACKGROUND: Cystinuria is an autosomal recessive disorder, and primary manifestation is the repeated formation of cystine calculi. Little information is available regarding clinical course of pediatric cystinuria having followed into adulthood. We report our experience with the management and the clinical course on cystinuria in children, who have been followed up for relatively long time. MATERIALS AND METHODS: We retrospectively reviewed the records of all pediatric patients with cystinuria in whom urolithiasis was treated from 1970 to 1996. RESULTS: A total of 15 pediatric patients with cystine calculi (9 boys, 6 girls) were treated in our hospital. Average age at diagnosis was 3 years 4 months old. Mean follow-up was 104 months. Stone location was upper urinary tract in 11 cases, bladder in 3 cases and both upper urinary tract and bladder in 1 case. Medical treatments including hydration, urine alkalization and dissolution therapy were performed in all patients. In three cases whose urinary cystine level ranged from 138 to 326 mg/gCr, cystine calculi were disappeared by medical therapy alone. In one of 3 cases vesicoureteral reflux was identified. Side effects were noticed in 30.0% of patients with tiopronin and in 85.7% of those with D-penicillamine, especially in 1 case with tiopronin nephrotic syndrome being noticed. Surgical procedures were performed in 13 patients (lithotomy: 17 calculi, endourology: 7 calculi and ESWL: 7 calculi). The stone free rate was 100% with lithotomy, 80 to 100% with endourology and 43% with ESWL at an average of 5.9 procedures. No complications were recognized after the surgical treatments. The stone events of 15 patients ranged from 0 to 1.5 (average 0.55). In all six patients followed up over the age of 20 years, stone recurrences were observed exclusively between 17 and 20 years of age. CONCLUSION: Dissolution therapy is more effective for cystinuric patients in whom urinary cystine excretion is less than 330 mg/gCr. For those cases with low urinary cystine level it is necessary to evaluate structural abnormalities of the urinary tract to avoid stone recurrence. ESWL and endourology should be tried for pediatric cystinuria except for neonates and infants, considering its safety. The patients and their parents must have adequate knowledge about the disease itself and its management. Prevention of cystine calculi recurrences depends on patient compliance to the therapeutic regimens necessitating close follow up according to the clinical conditions, especially for those in pubertic or postpubertic age.

Adolescent↗