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

[Analysis and clinical course of residual lithiasis after shock wave renal treatment].

OBJECTIVE: Although residual lithiasis after the application of shock waves is a situation that coexists with the procedure, in some cases it can be considered to be a failure of ESWL. The natural history and outcome of 244 cases of residual renal stone followed over a 5-year period are analyzed, and the approach based on a pre-established classification is discussed. METHODS: Of 1,407 patients treated by ESWL for renal lithiasis during 1995, 244 cases with a renal calculus larger than 3 mm were followed for a period of 5 years after treatment and evaluated by clinical, radiological, ultrasound and analytical methods. RESULTS: At 3 months post-ESWL, 1,013 cases (72%) were completely stone-free and 394 (28%) showed residual stone; of these, 244 (62%) had residual stone fragments greater than 3 mm. At 5 years, 190 (78%) remained stable and the remaining 54 (22%) showed stone regrowth that warranted additional treatments: 52 ESWL, 1 PNL and 1 partial nephrectomy. Despite the retreatments, only 42% became completely stone-free. CONCLUSIONS: A classification of residual renal stone can be established based on the data obtained to orient the approach in each case, although the frequency of residual stone can be reduced by the appropriate indication of ESWL. Once a renal stone has formed retreatments with ESWL cannot ensure complete elimination of the stone.

Humans↗

PubMed2001

[Cystinuria and cystine kidney lithiasis. Diagnosis and therapeutic approach].

OBJECTIVE: Cystine renal stone is the only clinical consequence of cystinuria, an autosomal recessive hereditary disease that affects an average of 1 out of 7,000 newborns, and whose geographical distribution varies significantly. The diagnosis and treatment of this condition is reviewed in the light of the advances in genetics and molecular biology. METHODS: The evolution of current knowledge about this disease is reviewed. RESULTS/CONCLUSIONS: The advances over the last 8 years have led to the characterization, at the present time, of two genes responsible for this disease, which demonstrates its polygenic origin. By phenotype, cystinuria can be classified into two types: type 1 and non-type 1. Both types show genetic and biochemical, but not clinical differences. From the therapeutic viewpoint, the main objective is to eliminate existing calculi and, above all, prevent recurrence by acting on the pathophysiologic mechanisms of renal cystine. Experience shows that despite the correct use of our current therapeutic armamentarium and the application of the general guidelines discussed in this paper, some cystinuric patients still maintain an important stone-forming activity. Patient clinical evaluation and a genetic study of both patient and family will be decisive for phenotyping.

Cystine↗

PubMed1999

[Isotopic study with double phase 99mTc-sestamibi in the localization of parathyroid gland lesions].

BACKGROUND: The use of preoperative imaging in patients with hyperparathyroidism remains controversial. The aim of this study is to assess the usefulness of the double-phase 99mTc-sestamibi scintigraphy in the diagnosis of abnormal parathyroid glands in patients with primary hyperparathyroidism. PATIENTS AND METHODS: We studied 60 patients presenting with primary hyperparathyroidism who were referred to surgery; four of them had been unsuccessfully operated. 99mTc-sestamibi scintigraphy were performed in all patients previously to surgery. Scintigraphic technique: planar imaging of the neck and thorax was done in the anterior view at 15 and 150 min postinjection of 740 MBq (20 mCi) of 99mTc-sestamibi. RESULTS: Surgery found 57 adenomas (2.59 [SD, 5.84] g; range 0.160-40), 6 hyperplastic glands (0.34 [SD, 0.26] g) and one carcinoma 8.2 g. The 99mTc-sestamibi was able to localize correctly 60 out of 64 lesions (55/57 adenomas, 4/6 hyperplastic glands and 1/1 carcinoma) (global sensitivity of 94%, adenomas sensitivity of 96%, positive predictive value of 97% and specificity of 98%). Isotopic imaging detected the abnormal tissue in all patients who had undergone unsuccessful previous surgery. PTH (4 [SD, 1.51] pmol/l) and calcium postoperative serum levels (2.13 [SD, 0.22] mmol/l) showed curation of all patients. CONCLUSION: Double phase parathyroid scintigraphy with 99mTc-sestamibi is the method of choice to localize abnormal parathyroid glands.

Adolescent↗

PubMed1999

Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.

Amino Acid Sequence↗

PubMed1995

Genetic heterogeneity in cystinuria: the SLC3A1 gene is linked to type I but not to type III cystinuria.

Cystinuria is an autosomal recessive amino-aciduria where three urinary phenotypes have been described (I, II, and III). An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. To assess whether mutations in SLC3A1 are involved in different cystinuria phenotypes, linkage with this gene and its nearest marker (D2S119) was analyzed in 22 families with type I and/or type III cystinuria. Linkage with heterogeneity was proved (alpha = 0.45; P < 0.008). Type I/I families showed homogeneous linkage to SLC3A1 (Zmax > 3.0 at theta = 0.00; alpha = 1), whereas types I/III and III/III were not linked. Our data suggest that type I cystinuria is due to mutations in the SLC3A1 gene, whereas another locus is responsible for type III. This result establishes genetic heterogeneity for cystinuria, classically considered as a multiallelic monogenic disease.

Adolescent↗

PubMed1995

Triglyceride-rich lipoprotein abnormalities in CAPD-treated patients.

In the present study intermediate-density lipoproteins (IDL) and very-low-density lipoproteins (VLDL) composition, structure, and mass were analysed in fasting uraemic patients on continuous ambulatory peritoneal dialysis (CAPD) (n = 12) and on haemodialysis (HD) (n = 15), and in 15 healthy volunteers. All the groups were matched for sex, age, and time on dialysis. Both groups of patients had elevated very-low-density lipoprotein levels, CAPD patients four and HD group three times that of control. We found a fourfold and a twofold increase in the concentration of IDL cholesterol in the CAPD and HD group respectively when they were compared with the control group. Both groups of patients present an increased VLDL mass. The CAPD group showed a four-fold increase in IDL mass compared with the control group, which indicated a preponderance of large size and suggested that defective IDL clearance was involved. The IDL composition of the CAPD patients was significantly different from that of the HD patients: a twofold increase in IDL mass was observed in the CAPD patients if compared with HD patients. We report new data concerning the metabolism of triglyceride-rich lipoproteins in CAPD treated patients, which confirm the adverse effect of CAPD on serum lipids.

Adult↗