First cardiac manifestation of hypotonia-cystinuria syndrome.

Hypotonia-cystinuria syndrome is a very rare autosomal recessive contiguous gene deletion syndrome of PREPL and SLC3A1 at 2p21 with neuromuscular and neuroendocrinologic presentation. We report a two-year-six-month-old affected female infant and her five-month-old affected brother with a novel homozygous deletion in SLC3A1 and PREPL gene. Both of siblings had mild facial dysmorphism, hypotonia, feeding problems, failure to thrive, developmental delay. She also had dilated cardiomyopathy which differ from other reported patients. Therefore cardiomyopathy may also be considered one of the features of hypotonia-cystinuria syndrome. With this case report, we present cardiac manifestation of hypotonia-cystinuria syndrome for the first time. Because of two siblings had hyperechogenic bowel in prenatal sonography, it might be a prenatal marker for HCS.

Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b0,+AT (Slc7a9) in mice.

Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 (rBAT) and SLC7A9 (b(0,+)AT). Gene targeting of the catalytic subunit (Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b(0,+). No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b(0,+)AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.

Cystinuria: mechanisms and management.

Cystinuria is a relatively uncommon cause of pediatric stone disease, but has significant morbidity if not properly controlled because of its significant stone recurrence rate. Cystinuria is caused by the inability of the renal tubules to reabsorb filtered cystine, which is poorly soluble at a typical urine pH <7. Although many advances have been made in the understanding of the genetic and physiological basis of cystinuria, the cornerstones of treatment still involve stone prevention with dietary measures and pharmacological therapy, coupled with surgical interventions for stone removal. Pharmacological treatments can carry significant side effects that must be monitored and can limit therapy as well as impede compliance. Most patients will require surgical intervention for stone removal, although compliance with prevention strategies reduces the need for intervention.

Hypotonia-cystinuria 2p21 deletion syndrome: Intrafamilial variability of clinical expression.

Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thrive. Later in childhood, the brother developed cystinuria and nephrolithiasis whereas the older sister suffered from cystinuria and chronic neurobehavioral disturbances. Biopsied muscle studies demonstrated deficient cytochrome c oxidase activities consistent with a mitochondrial disease. Whole exome sequencing (WES), however, revealed a homozygous 2p21 deletion involving two contiquous genes, SLC3A1 (deletion of exons 2-10) and PREPL (deletion of exons 2-14). The molecular findings were consistent with the hypotonia-cystinuria 2p21 deletion syndrome, presenting similarly in infancy with mitochondrial dysfunction but diverging later in childhood and displaying intrafamilial phenotypic variability.

Multi-system disorder syndromes associated with cystinuria type I.

Cystinuria type I is an autosomal recessive disorder with an exclusively renal phenotype caused by inactivating mutations in SLC3A1. Recently 3 similar but distinct syndromes associated with cystinuria type I have been described: 2p21 deletion syndrome, Hypotonia-Cystinuria Syndrome (HCS) and atypical HCS. Genetic analysis indicated that these are recessive contiguous gene deletion syndromes which differ in the number of genes affected. Patients with HCS are missing both alleles of SLC3A1 and PREPL. In atypical HCS an additional gene (C2orf34) is deleted, and finally, in the 2p21 deletion syndrome the open reading frame of PPM1B is also disrupted. With the exception of SLC3A1, the gene products have not been fully characterized. The severity of the different syndromes reflects the number of genes which are deleted. HCS, a relatively mild syndrome, is characterised by cystinuria type I, generalised hypotonia at birth, growth retardation and minor facial dysmorphic features. On the other end of the spectrum is the 2p21 deletion syndrome, a severe syndrome with a number of additional features including a moderate to severe psychomotor retardation and a decrease in activity of the respiratory chain complexes I, III, IV and V. Finally, atypical HCS displays an intermediate phenotype comparable with classical HCS but associated with mild to moderate mental retardation and a decrease in activity of only the respiratory chain complex IV. This review will focus on the phenotypic similarities and differences observed in these syndromes. Furthermore, we speculate on the function of the gene products, based on the available data.

Cystinuria.

Cystinuria is an inherited disorder characterized by the impaired reabsorption of cystine in the proximal tubule of the nephron and the gastrointestinal epithelium. The only clinically significant manifestation is recurrent nephrolithiasis secondary to the poor solubility of cystine in urine. Although cystinuria is a relatively common disorder, it accounts for no more than 1% of all urinary tract stones. Thus far, mutations in 2 genes, SLC3A1 and SLC7A9, have been identified as being responsible for most cases of cystinuria by encoding defective subunits of the cystine transporter. With the discovery of mutated genes, the classification of patients with cystinuria has been changed from one based on phenotypes (I, II, III) to one based on the affected genes (I and non-type I; or A and B). Most often this classification can be used without gene sequencing by determining whether the affected individual's parents have abnormal urinary cystine excretion. Clinically, insoluble cystine precipitates into hexagonal crystals that can coalesce into larger, recurrent calculi. Prevention of stone formation is the primary goal of management and includes hydration, dietary restriction of salt and animal protein, urinary alkalinization, and cystine-binding thiol drugs.

The impact of surgical intervention on renal function in cystinuria.

INTRODUCTION: Cystinuria is an autosomal recessive disorder due to intestinal and renal transport defects in cystine and dibasic amino acids, which result in recurrent urolithiasis and surgical interventions. This study aimed to assess the impact of surgical interventions on renal function by analyzing estimated glomerular filtration rates. METHODS: Thirteen pediatric patients with cystinuria, who were followed-up in a single tertiary institution between 2004 and 2016, were included in the study. Medical records were reviewed to collect data on clinical presentation of patients, urine parameters, stone formation, medical treatment, surgical intervention, stone recurrence after surgical procedure, stone analysis, ultrasonography, 99m-technetium dimercaptosuccinic acid (99mTc-DMSA) radionuclide imaging results, and follow-up time. Creatinine clearances estimated by modified Schwartz (eGFR) formula before and after surgery were used to assess renal function and compared statistically. RESULTS: Nine patients (69.2%) had renal scarring which were detected with 99mTc-DMSA radionuclide imaging. In ten patients (76.9%), open surgical intervention for stones were needed during follow-up. Significant difference was not detected between eGFR before and after surgical intervention (mean 92 versus 106, p = 0.36). Nine of the patients (69.2%) were stone free in the last ultrasonographic examination. Relapses of stone after surgery were seen in 66.6% of patients who underwent surgical intervention. CONCLUSIONS: Surgical interventions for urinary stones are commonly required in patients with cystinuria. Renal scarring is a prevalent finding in cystinuric patients. Surgical interventions have no negative impact on eGFR in patients with cystinuria according to the present study.

Clinical Outcomes for Cystinuria Patients with Unilateral Versus Bilateral Cystine Stone Disease.

INTRODUCTION: Cystinuria is a genetic disorder marked by elevated urinary cystine excretion and recurrent cystine nephrolithiasis. Interestingly, despite seemingly similar contralateral renal anatomy, a subset of cystinuric patients consistently form stones in only one kidney. The aim of this study is to evaluate clinical outcomes in unilateral vs bilateral cystine stone formers. PATIENTS AND METHODS: We performed a retrospective case-control study of cystinuric patients evaluated and treated at the University of California, San Francisco between 1994 and 2015 and categorized patients as either unilateral or bilateral stone formers. Clinical presentation, baseline patient demographics, stone procedures, medical therapy regimens, and long-term renal function were compared between the two groups. RESULTS: A total of 42 cystine stone patients (22 female, 20 male) were included in the analysis. The median age at first presentation was 18.5 years and median age at study conclusion was 45.5 years. Two-thirds of patients (n = 28) had a history of bilateral stones, whereas one-third (n = 14) had unilateral stones. Medical therapy regimens were similar between groups. Despite an increased average number of lifetime surgeries (7.5 sessions for bilateral vs 3.7 sessions for unilateral, p < 0.05), there was no significant difference in medians of the most recent glomerular filtration rate when compared with unilateral stone formers (81.5 vs 95 mL/min, respectively; p = 0.28). CONCLUSIONS: The majority of cystinuric patients within our cohort form stones bilaterally during their lifetime, and require more surgical interventions than unilateral stone formers. Despite this, overall renal function is well preserved in unilateral and bilateral cystinuric stone formers treated with minimally invasive stone extraction procedures.

Cystine Stone Formers Have Impaired Health-Related Quality of Life Compared with Noncystine Stone Formers: A Case-Referent Study Piloting the Wisconsin Stone Quality of Life Questionnaire Among Patients with Cystine Stones.

INTRODUCTION: Cystinuria is a rare cause of urolithiasis. Affected patients have an earlier onset and more aggressive disease than patients with other stone etiologies. We assessed the health-related quality of life (HRQOL) of cystine stone-forming patients using the disease-specific Wisconsin Stone Quality of Life questionnaire (WISQOL). METHODS: Cystine patients treated in our stone clinics (n = 12) completed the WISQOL; information about medical and stone histories was gathered. Patients were matched with noncystine stone formers (n = 12) for gender, age, and comorbidities. In addition, a second control group (n = 90), also from our institution and consisting of mixed calcium stone formers, was included. WISQOL responses were compared between groups. RESULTS: Cystine patients had significantly lower total WISQOL scores than noncystine patients. Compared with noncystine stone formers, cystine stone formers also had lower HRQOL scores for subscales (domains) related to social impact, emotional impact, disease impact, and vitality (p ≤ 0.04 for all). On specific items, cystine patients reported significantly more sleep problems (p = 0.02), more bother with nocturia (p = 0.03), and feeling tired or fatigued (p = 0.02). Among those with current stones, cystine patients scored lower than noncystine patients for total score and in two of four domains. CONCLUSIONS: Using a stone-specific questionnaire, patients with cystine stones have lower HRQOL compared with noncystine stone formers. Identifying and addressing specific areas of decrement in patients with cystine stones may improve disease management and patients' HRQOL.

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,+).

Urolithiasis in adolescent children.

Idiopathic urolithiasis in children has become more frequent in the past few decades as a result of increasing affluence and rapid change in our society's dietary habits. In Western societies, calcium stones in the kidney and ureter predominate. Pediatric urolithiases, unlike the adult form, require a comprehensive metabolic evaluation, because metabolic and enzymatic derangements play an important role in their pathogenesis. The recent advancements in endoscopic procedures, interventional radiology, and lithotripsy have allowed children to be managed effectively without open surgery. Pediatric urolithiasis requires a close working relationship between the urologist for acute surgical management of urolithiasis and the nephrologists for prevention of stone formation. In many children and adolescents with urolithiasis, a nonpharmacologic approach involving the adoption of healthy nutrition habits may suffice.

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).

Cystine calculi. Diagnosis and management.

The genetics, pathophysiology, diagnosis, and treatment of cystinuria are discussed in this article. Newer chemotherapeutic and surgical options that are used to treat this disease process also are reviewed. The authors suggest a multimodal approach in the treatment of cystinuria and cystine calculi.

The molecular basis of cystinuria.

Cystinuria is an inherited form of nephrolithiasis due to failure of reabsorptive transport in the proximal tubule. Patients with classical recessive cystinuria have inherited two mutations of the SLC3A1 gene, encoding a subunit of the transport mechanism. Patients with the dominant form of cystinuria have inherited two mutations of the SLC7A9 gene, encoding the transport channel itself. A smaller subset of patients have mixed-type cystinuria, combining recessive and dominant mutant alleles. Children at risk for nephrolithiasis can be identified by the level of urinary cystine only after tubular transport has matured (age 2 years). Conservative therapy with high urine volume and urinary alkalinization is sufficient for some, but recurrent stone formation may cause renal damage and warrants prophylaxis with agents that form mixed disulfides with cystine.

Contemporary management of cystinuria.

Cystinuria is an autosomal recessive disorder characterized by a defect in intestinal and renal tubular transport of dibasic amino acids which results in excessive urinary excretion of cystine. Because of the relative insolubility of cystine in urine, patients with this condition are prone to recurrent stone formation. Medical therapy aims both to decrease the urinary concentration of cystine and to increase its solubility. Standard prevention and treatment regimens include hydration, moderate salt and protein restriction, oral alkalinization, and thiol derivatives. Despite aggressive medical management, however, cystinuric patients are likely to suffer frequent recurrent episodes of stones necessitating urologic intervention. Fortunately, the application of safe and efficacious minimally invasive modalities, including advancements in shockwave lithotripsy, ureteroscopic lithotripsy, and percutaneous nephrolithotomy, have obviated open operative intervention in nearly all cases.

[Cystinuria - Cystine Stones: Recommendations for Diagnosis, Therapy and Follow-up]. / Zystinurie - Zystinsteinleiden: Aktuelle Empfehlungen zur Diagnostik, Therapie und Nachsorge.

Cystinuria, an autosomal-recessive disorder, is the cause of 1 - 2 % of all kidney stones observed in adults and about 10 % of those observed in infants. Despite increasing understanding of underlying pathomechanisms, patients still form recurrent stones and have to undergo repeated interventions with increasing risk of renal insufficiency. Dietary and medical metaphylaxis may lower the frequency of recurrent stones but are often not practiced. Regular follow-up examinations and optimal therapy significantly enlarge stone-free intervals. This review offers an overview of the underlying pathogenetic mechanisms as well as guidance for diagnosis, monitoring, metaphylaxis and therapy of cystinuria following the recommendations of the Deutsche Gesellschaft für Urologie (DGU) and the European Association of Urology (EAU).

[Medical treatment of cystinuria: evaluation of long-term results in 30 patients]. / Traitement médical de la cystinurie: évaluation des résultats à long terme chez 30 patients.

OBJECTIVE: Because urinary hyper-excretion of cystine is permanent in homozygous cystinuric patients, stone recurrence is frequent and may alter renal function. Identification of factors predictive of success of medical treatment (no further urological procedure required) is therefore needed to improve patient management. PATIENTS AND METHODS: Thirty adult patients with homozygous cystinuria and urolithiasis were referred to the nephrology department of the Necker Hospital from 1963 to 1999, with a mean follow-up of medical therapy of 10.5 +/- 8.4 years. The basal treatment schedule was hyperdiuresis and alkalinization with thiol derivative (D-penicillamine or tiopronine) added when needed. RESULTS: Overall incidence of urological procedures decreased from 0.33/pt-year in the pretherapeutic period to 0.15 on treatment (p < 0.01), a 55% reduction. Sixteen patients (53%) did not require any urological procedure during follow-up. The only significant difference between those patients and the other 14 in whom medical therapy failed was the daily urine volume (3.2 l/day in the former compared with 2.4 l/day in the latter, p < 0.001). CONCLUSION: Regular medical therapy was able to stop stone disease activity in the long term in more than half of the patients. Sustained hyperdiuresis, with a daily urine volume > 3 liters, appears as a major factor of therapeutic success, even in patients treated with thiols.

[Pathophysiology, diagnosis and conservative therapy of non-calcium kidney calculi]. / Pathophysiologie, Diagnostik und konservative Therapie bei nicht-kalziumhaltigen Nierensteinen.

While calcium oxalate and calcium phosphate make up at least 80% of all kidney stones, infection-induced and uric acid stones occur in 10% and 8%, respectively. Although any type of stone may become infected, the term "infection stones" means that stone formation exclusively depends on urease-producing bacteria. The splitting of urea leads to a rise in urinary pH which may induce crystallization of struvite (magnesium-ammonium-phosphate), the major constituent of infection stones, or carbonate apatite. Struvite stones account for the majority of staghorn calculi. They can grow quite large and may fill the entire collecting system. Patients with struvite stones may present with acute flank pain or remain completely asymptomatic. The cure of infection stones requires complete removal of the stone material. For uric acid crystallization and stone formation, low urine pH (below 5.5) is a more important risk factor than increased urinary uric acid excretion. Main causes of low urine pH are tubular disorders (including gout), chronic diarrheal states or severe dehydration. Accordingly, the treatment of uric acid stones consists not only of hydration (urine volume above 2000 ml per day), but mainly of urine alkalinization to pH values between 6.2 and 6.8. Urinary uric acid excretion can be reduced by a low-purine diet as well as--in case of recurrent uric acid stones and/or gout--by allopurinol. Cystinuria is a rare hereditary gene disorders with impaired tubular reabsorption of cystine. Stone formation occurs as a consequence of cystine's relatively low solubility at urine pH levels below 8. Only symptomatic diet and drug treatments are currently available, with urine dilution and urine alkalinization being the most efficient ones. Cystine stones respond poorly to shockwave lithotripsy, so that invasive procedures may regularly be necessary. 2,8-dihydroxy-adenine stones occur as a consequence of an enzyme deficiency that involves purine metabolism. These resulting stones are not visible by fluoroscopy and are therefore often misinterpreted as uric acid stones. Low-purine diet and allopurinol reduce the frequency of stone formation.

[Physiopathology, etiology and medical treatment of non-calcium lithiasis]. / Physiopathologie, étiologie et traitement médical des lithiases non calciques.

Under the term "non-calcium nephrolithiasis", three types of renal stone formation are considered. (1) Infected nephrolithiasis, which is due to bacteriological ureolysis. Its treatment includes lowering of oversaturation by antibiotics, urease inhibition and/or acidification of the urine; lowering of crystallization by eradicating concomitant infections caused by non-ureolytic organisms; prevention of crystal adherence by exogenous glycosaminoglycans, and prevention of bacterial adherence by glycolipids. (2) Uric acid lithiasis is defined on physico-chemical and physiopathological grounds. Medical treatment consists of increasing water intake, reducing puric acid intake, alkalinizing the urine inhibiting xanthine-oxidase. (3) Cystinuria is described as a nephrolithogenic proximal tubulopathy. Medical treatment includes reduction of urinary cystine concentration by a strong increase of water intake; reduction of urinary cystine excretion by diet and increase of cystine solubility by urinary alkalinization or administration of some thiol compounds.

An animal model of type A cystinuria due to spontaneous mutation in 129S2/SvPasCrl mice.

Cystinuria is an autosomal recessive disease caused by the mutation of either SLC3A1 gene encoding for rBAT (type A cystinuria) or SLC7A9 gene encoding for b0,+AT (type B cystinuria). Here, we evidenced in a commonly used congenic 129S2/SvPasCrl mouse substrain a dramatically high frequency of kidney stones that were similar to those of patients with cystinuria. Most of 129S2/SvPasCrl exhibited pathognomonic cystine crystals in urine and an aminoaciduria profile similar to that of patients with cystinuria. In addition, we observed a heterogeneous inflammatory infiltrate and cystine tubular casts in the kidney of cystinuric mice. As compared to another classical mouse strain, C57BL/6J mice, 129S2/SvPasCrl mice had an increased mortality associated with bilateral obstructive hydronephrosis. In 129S2/SvPasCrl mice, the heavy subunit rBAT of the tetrameric transporter of dibasic amino acids was absent in proximal tubules and we identified a single pathogenic mutation in a highly conserved region of the Slc3a1 gene. This novel mouse model mimicking human disease would allow us further pathophysiological studies and may be useful to analyse the crystal/tissue interactions in cystinuria.