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Clinical and genetic studies on patients with cystinuria
Linköping University, Department of Biomedicine and Surgery, Urology. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cystinuria is a genetic disorder with autosomal recessive inheritance. It is caused by a defective proximal tubular reabsorbtion of cystine and the dibasic amino acids. The low urinary solubility of cystine causes a life-long stone disease, contributing to about 1% of all urinary stones in adults. Treatment is based on high fluid intake and the use of sulfhydryl compounds such as tiopronin and D-penicillamine to decrease the urinary concentration of cystine, and alkalinization of the urine to increase the urinary solubility of cystine. Reduction of sodium intake is also a favoured regimen because of eo-transportation of sodium and cystine in the proximal tubules. Advancements in molecular genetics have led to the identification of two genes associated with cystinuria (SLC3A1 and SLC7A9). These genes cannot, however, explain all cases of cystinuria.

Investigation of SLC3A1 in 53 Swedish patients with cystinuria revealed 12 novel mutations, and the allelic frequency of the most common mutation (M467T) was shown to be 0.5% in a normal population. (Paper I). Studies of SLC7A9 revealed three novel and one previously known mutation. One patient had novel mutations in both alleles, one patient showed a novel mutation in one of the alleles and one patient showed a previously known mutation in SLC7A9 and two in SLC3A1, leaving 14 patients in whom cystinuria was not explained by genetic observations (Paper m. In order to relate these genetic findings to excretion of cystine in the urine, 33 patients treated with sulfhydryl compounds were studied (Paper III). Ten of these patients showed either mutation in one of the SLC3A1 alleles (8) or a complete lack of mutations in both genes (2). These 10 patients showed a significantly higher urinary excretion of total cystine compared to 23 patients in whom both SLC3A1 alleles were mutated (p < 0.01). The same was true for the 8 patients with only one SLC3A1 allele mutated (p < 0.05). These findings support the existence of yet unknown genes involved in the regulation of urinary cystine excretion, the basis of cystine stone formation. Treatment is primarily aimed at the prevention of such stones and should be guided by the urinary cystine concentration, trying to avoid supersaturation. In order to improve patient surveillance in terms of urinary supersaturation with cystine a procedure was introduced comprising one daytime and one night urine sample during the 24-hour period (Paper IV). Twenty-six patients were followed over a 3.5 year period using this strategy. It was found that 47% of cystine supersaturation episodes (> 1200 µmol/L) would have evaded detection by analysis carried out in 24-hour urine collections. Furthermore, a significant decrease in the frequency of renal stone episodes (p < 0.05) and active stone removals (p < 0.01) was found when compared to a previous, equivalent period during which 24-hour urine collections were used. The period guided by divided urine samples was also characterized by a significant decrease in free cystine concentrations (p < 0.01) and a significant increase in urinary volumes (p < 0.05). In the tiopronin-treated patients, there was a significant increase in the tiopronin dose and a subsequent decrease in urinary cystine excretion (p < 0.05). The use of cystine analysis in divided urine samples thus made a higher degree of individual treatment possible. The effects of sodium bicarbonate and potassium citrate were compared in 14 cystinuric patients (Paper V). Potassium citrate has been the favoured agent, as it does not contain sodium, but there have been no reports in which potassium citrate has been compared to sodium bicarbonate in the treatment of patients with cystinuria. Sodium bicarbonate was effective in alkalizing the urine, but caused a significantly increased urinary sodium excretion (p < 0.01). A significant correlation was found between urinary sodium and cystine excretion in tiopronin treated patients (p < 0.001). Potassium citrate was shown to produce a significant increase in urinary pH. Potassium citrate was associated with a significant increase in plasma potassium (p < 0.05), but no case of severe hyperkalemia was found. Potassium citrate could thus be recommended for urinary alkalinization in cystinuric patients without severe renal impairment.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2003. , 74 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 817
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25643Local ID: 10018ISBN: 91-7373-507-8 (print)OAI: oai:DiVA.org:liu-25643DiVA: diva2:246191
Public defence
2003-11-05, Viktoriasalen, Hälsouniversitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-10-17Bibliographically approved
List of papers
1. Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients
Open this publication in new window or tab >>Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients
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2001 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 18, no 6, 516-525 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
cystinuria, CSNU, CNSU1, CNSU3, SLC3A1, SLC7A9, transporter, amino acid
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12855 (URN)10.1002/humu.1228 (DOI)
Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2017-12-14Bibliographically approved
2. Mutation analysis of SLC7A9 in cystinuria patients in Sweden
Open this publication in new window or tab >>Mutation analysis of SLC7A9 in cystinuria patients in Sweden
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2003 (English)In: Genetic Testing, ISSN 1090-6576, E-ISSN 1557-7473, Vol. 7, no 1, 13-20 p.Article in journal (Refereed) Published
Abstract [en]

Cystinuria is an autosomal recessive disorder characterized by increased urinary excretion of cystine and dibasic amino acids, which cause recurrent stone formation in affected individuals. Three subtypes of cystinuria have been described (type I, II, and III): type I is caused by mutations in the SLC3A1 gene, whereas non-type I (II and III) has been associated with SLC7A9 mutations. Of the 53 patients reported in our previous work, patients that showed SLC7A9 mutations in single-strand conformation polymorphism (SSCP) screening and/or either lacked or showed heterozygosity for SLC3A1 mutations were included in the present study. The entire coding region and the exon/intron boundaries of the SLC7A9 gene were analyzed by means of both SSCP and DNA sequencing in 16 patients, all but one of which were clinically diagnosed as homozygous cystinurics. Three novel SLC7A9 mutations were identified in the patient group: two missense mutations (P261L and V330M), and one single base-pair deletion (1009 delA). We also detected the previously reported A182T and nine novel polymorphisms in the patients. Mutations V330M and 1009delA occurred on different alleles in one individual, and we suggest that these mutations cause cystinuria in this patient. One patient that was homozygously mutated in the SLC3A1 gene carried the third novel mutation (P261L). We conclude that SLC3A1 is still the major disease gene among Swedish cystinuria patients, with only a minor contribution of SLC7A9 mutations as the genetic basis of cystinuria. The absence of SLC3A1 and SLC7A9 mutations in a substantial proportion of the patients implies that mutations in parts of the genes that were not analyzed may be present, as well as large deletions that escape detection by the methods used. However, our results raise the question of whether other, as yet unknown genes, may also be involved in cystinuria.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12856 (URN)10.1089/109065703321560886 (DOI)
Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2017-12-14Bibliographically approved
3. Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds
Open this publication in new window or tab >>Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds
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2003 (English)In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 31, no 6, 417-425 p.Article in journal (Refereed) Published
Abstract [en]

Advances in molecular genetics have brought a deeper understanding of cystinuria. This autosomal recessive disease, which is caused by a defective tubular reabsorption of cystine and the three dibasic amino acids arginine, lysine and ornithine, results in a lifelong risk of renal stone formation because of the low solubility of cystine in urine. Mutations detected within the two genes known to be associated with cystinuria, SLC3A1 (related to type I) and SLC7A9 (related to non-type I), cannot, however, in all cases explain the disease. Inasmuch as a high urinary concentration of cystine is the basis of stone formation in these patients, our aim was to measure urinary total cystine, arginine, lysine and ornithine, in patients currently lacking a full genetic explanation for their disease. Thirty-three patients with cystinuria who were on long-term treatment with tiopronin or D-penicillamine were divided into two groups. Group 1 comprised eight patients who carried mutation in one of the SLC3A1 alleles and two patients who completely lacked mutations both in the SLC3A1 and the SLC7A9 genes, that is genetic findings discordant with the increased urinary excretion of cystine and the dibasic amino acids in these patients. Group 2 comprised 23 patients homozygous for mutations within SLC3A1, that is genetic findings in accordance with the excretion pattern of classic type I cystinuria. When the two groups were compared, Group 1 had a significantly higher total urinary excretion of cystine (p<0.01) as well as of arginine, lysine and ornithine (p<0.05) than Group 2. Also, when the two patients without mutations were excluded from the calculations, there still was a significant difference in the urinary excretion of total cystine (p<0.05). This suggests that the two patients without any detected mutations in the two known cystine transport genes also contributed to the difference. These unexpected findings indicate that an additional gene or genes participate in the urinary cystine reabsorption in the cystinuric patients who currently are without a full genetic explanation for their disease.

Keyword
Cystinuria, Urinary cystine, Amino acid transport, SLC3A1, SLC7A9, Inherited disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-12857 (URN)10.1007/s00240-003-0366-6 (DOI)
Available from: 2008-02-13 Created: 2008-02-13 Last updated: 2017-12-14Bibliographically approved
4. Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria
Open this publication in new window or tab >>Cystine analyses of separate day and night urine as a basis for the management of patients with homozygous cystinuria
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2001 (English)In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 29, no 5, 303-310 p.Article in journal (Refereed) Published
Abstract [en]

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 µmol/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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24985 (URN)10.1007/s002400100201 (DOI)9400 (Local ID)9400 (Archive number)9400 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
5. A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria
Open this publication in new window or tab >>A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria
2001 (English)In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 29, no 5, 295-302 p.Article in journal (Refereed) Published
Abstract [en]

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 tiopronin-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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24984 (URN)10.1007/s002400100200 (DOI)9397 (Local ID)9397 (Archive number)9397 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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