"Cystinuria"

The genetics of cystinuria - an update and critical reevaluation. We aimed to critically evaluate how the establishment of genotype-based treatment for cystinuria has been hampered due to the large number of variants of unknown significance (VUS) within the disease causing genes as well as challenges in accessing a large enough sample size for systematic analysis of endpoint parameters that truly reflect disease severity. This review further discusses how to overcome these hurdles with the establishment of a cystinuria-specific refinement of the current American College of Medical Genetics and Genomics (ACMG)-criteria of variant interpretation. Novel tools such as AlphaMissense combined with the establishment of a refined ACMG criterion will play a significant role in classifying VUS

Cystinuria Complicated by Anuria from Bilateral Obstructing Stones Requiring Bilateral Mini Percutaneous Nephrolithotomy in a 22-Month-Old. Pediatric nephrolithiasis is increasing in incidence and presents differently compared to adults. We report a case of nephrolithiasis in a pediatric patient, presenting with complaints of emesis, anuria, hematuria, and abdominal distension, leading

Unraveling the natural history of presymptomatic cystinuria. Servais et al. recently published clinical practice recommendations for the care of cystinuria patients. However, these guidelines were largely based on retrospective data from adults and children presenting with stones. Significant questions remain about the natural history of cystinuria in presymptomatic children. We review the natural history of cystinuria in presymptomatic children followed from birth. In total, 130 pediatric patients were assigned putative genotypes based on parental urinary phenotype: type A/A (N = 23), B/B (N = 6), and B/N (N = 101). Stones were identified in 12/130 (4% of A/A, 17% of B/B, and 1% of B/N patients). Type B/B patients had lower cystine excretion than type A/A patients. Although urine cystine

Declaration: Novel SLC3A1 mutation in a cystinuria patient with xanthine stones: a case report. Cystinuria and xanthinuria are both rare genetic diseases involving urinary calculi. However, cases combining these two disorders have not yet been reported. In this study, we report a case of cystinuria with xanthine stones and hyperuricemia. The 23-year-old male patient was diagnosed with kidney sequencing revealed that the patient's parents carried this heterozygous mutation, which is a pathogenic variant that can cause cystinuria. The 24-h urine metabolism analysis showed that the cystine content was 644 mg (<320 mg/24 h), indicating that the patient had cystinuria, consistent with the genetic test results. This case shows that cystinuria and xanthine stones can occur simultaneously

Gene therapy for kidney disease: targeting cystinuria. The aim of this study was to summarize recent findings in kidney gene therapy while proposing cystinuria as a model kidney disease target for genome engineering therapeutics. Despite the advances of gene therapy for treating diseases of other organs, the kidney lags behind. Kidney-targeted gene delivery remains an obstacle to gene therapy of kidney disease. Nanoparticle and adeno-associated viral vector technologies offer emerging hope for kidney gene therapy. Cystinuria represents a model potential target for kidney gene therapy due to its known genetic and molecular basis, targetability, and capacity for phenotypic rescue. Although gene therapy for kidney disease remains a major challenge, new and evolving technologies may actualize

Pharmacological Dilutional Therapy Using the Vasopressin Antagonist Tolvaptan for Young Patients With Cystinuria: A Pilot Investigation. To perform a pilot study of short-term safety, tolerability, and impact on urinary stone risk parameters of the vasopressin V2-receptor antagonist tolvaptan (which increases urinary excretion of free water) among adolescents and young adults with cystinuria. We enrolled cystinuria patients age 12-25 years. Subjects were treated for 4 days at low-dose tolvaptan (0.3 mg/kg/day, maximum 30 mg) and 4 days at high dose (0.6 mg/kg/day, maximum 60 mg). Twenty-four-hour urine collections were done at baseline, day 3-4 of the dosing period, day 7-8 of the dosing period, and 3-6 days after washout. Primary outcome was cystine capacity (mg/L, target capacity > 0

Tolvaptan treatment of cystine urolithiasis in a mouse model of cystinuria. Cystinuria is an inherited disease characterized by increased urinary cystine excretion and recurrent cystine stones. Current treatment regimens have limited effectiveness in preventing stone recurrence and are often poorly tolerated. The aim of this study was to evaluate the effect of tolvaptan, a vasopressin receptor 2 (V2) antagonist, on cystine stone volume in mice with cystinuria. Tolvaptan (0.4 mg per mouse) or placebo was delivered by gavage daily for 30 days. Urinary amino acids and cystine stones were analyzed to assess drug efficacy in preventing L-cystine stone growth using several analytical methods. Data were entered into SPSS and analyzed by paired sample T test. p value < 0.05 was considered

Metabolic consequences of cystinuria. Cystinuria is an inherited disorder of renal amino acid transport that causes recurrent nephrolithiasis and significant morbidity in humans. It has an incidence of 1 in 7000 worldwide making it one of the most common genetic disorders in man. We phenotypically characterized a mouse model of cystinuria type A resultant from knockout of Slc3a1. Knockout disease in an animal model of cystinuria, which may have important implications for patients with this disease. Additionally, reduced glutathione may predispose those with cystinuria to injury caused by oxidative stress. Word count: 327.

Adverse Effects of Currently Used Medical Treatments for Cystinuria and Treatment Goals: Results from a French Series of 442 Patients. To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria. Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects

Effect of increasing doses of cystine-binding thiol drugs on cystine capacity in patients with cystinuria. Appropriate dosing of cystine-binding thiol drugs in the management of cystinuria has been based on clinical stone activity. When new stones form, the dose is increased. Currently, there is no method of measuring urinary drug levels to guide the titration of therapy. Increasing cystine capacity, a measure of cystine solubility, has been promoted as a method of judging the effects of therapy. In this study, we gave increasing doses of tiopronin or D-penicillamine, depending on the patients' own prescriptions, to ten patients with cystinuria and measured cystine excretion and cystine capacity. The doses were 0, 1, 2, 3 g per day, given in two divided doses, and administered in a random

No evidence for point mutations in the novel renal cystine transporter AGT1/SLC7A13 contributing to the etiology of cystinuria. Cystinuria is caused by the defective renal reabsorption of cystine and dibasic amino acids, and results in cystine stone formation. So far, mutations in two genes have been identified as causative. The SLC3A1/rBAT gene encodes the heavy subunit of the heterodimeric rBAT-bAT transporter, whereas the light chain is encoded by the SLC7A9/ bAT gene. In nearly 85% of patients mutations in both genes are detectable, but a significant number of patients currently remains without a molecular diagnosis. Thus, the existence of a further cystinuria gene had been suggested, and the recently identified AGT1/SLC7A13 represents the long-postulated partner of rBAT and third

Spectrum of mutations in cystinuria patients presenting with prenatal hyperechoic colon. Cystinuria is a heterogeneous, rare but important cause of inherited kidney stone disease due to mutations in 2 genes: SLC3A1 and SLC7A9. Antenatal hyperechoic colon (HEC) has been reported in some patients as a non-pathological consequence of the intestinal transport defect. We report 83 patients affected by cystinuria: 44 presented prenatally with a HEC (HEC group) and 39 with a classical postnatal form (CC group). SLC3A1 and SLC7A9 were sequenced. All patients were fully genotyped, and the relationship between the genotype and clinical features was analyzed. We identified mutations in SLC3A1 in 80% of the HEC group and in only 49% of the CC group. The SLC3A1 p.Thr216Met mutation was found in 21

Delineation of cystinuria in Saudi Arabia: A case series. Cystinuria is an inherited metabolic disease that is caused by defects in two genes, SLC3A1 and SLC7A9, which result in a renal reabsorptive defect of cystine and other dibasic amino acids, including ornithine, arginine, and lysine. Patients usually present with recurrent renal calculi and may develop renal impairment. Medical management includes high fluid intake and chelating agents. To the best of our knowledge, this is the first study describing cystinuria in Saudi Arabia. A retrospective chart review for cystinuria patients from the genetic and nephrology divisions between 2010 to 2015. All patients were investigated, diagnosed and treated at King Abdulaziz Medical City in Saudi Arabia. Eight patients were identified from five

Cystinuria caused by a SLC7A9 missense mutation in Siamese-crossbred littermates in Germany Cystinuria is caused by defective proximal renal tubular reabsorption of the amino acids cystine, ornithine, lysine, and arginine (COLA). The low solubility of cystine in mildly acidic urine may lead to the formation of urinary cystine crystals and uroliths. Much progress has been made recently in the diagnosis and understanding of cystinuria in companion animals. In cats, cystinuria affects equally both genders independent of neutering status and, despite being rare, already more cystinuria-causing mutations have been detected in cats compared to dogs. In this study a litter of Siamese-crossbred cats in Germany was assessed clinically for cystinuria and screened for mutations known to cause cystinuria

Clinical and molecular characterization of cystinuria in a French cohort: relevance of assessing large‐scale rearrangements and splicing variants Cystinuria is an autosomal recessive disorder of dibasic amino acid transport in the kidney and the intestine leading to increased urinary cystine excretion and nephrolithiasis. Two genes, and , coding respectively for rBAT and b0,+AT, account for the genetic basis of cystinuria. This study reports the clinical and molecular characterization of a French cohort including 112 cystinuria patients and 25 relatives from 99 families. Molecular screening was performed using sequencing and Quantitative Multiplex PCR of Short Fluorescent Fragments analyses. Functional minigene-based assays have been used to characterize splicing variants. Eighty-eight

Report of SLC3A1/rBAT gene mutations in Iranian cystinuria patients: A direct sequencing study Considering a few studies on the genetic basis of the cystinuria in the Middle East and the population-specific distribution of mutations in the , we tried to find genetic variants in three exons (1, 3, and 8) of . In this study, exons 1, 3, and 8 of gene of 25 unrelated cystinuria patients searched for genetic variations by polymerase chain reaction and sequencing. There were five different variations in our studied population. We found one mutation in the gene including missense variant M467K and identified three polymorphisms: nonsynonymous variant G38G, c. 610 + 169C>T and c. 610 + 147C>G within the gene, and one new variant. Our results confirm that cystinuria is a heterogeneous disorder

α-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria Cystinuria is an incompletely dominant disorder characterized by defective urinary cystine reabsorption that results in the formation of cystine-based urinary stones. Current treatment options are limited in their effectiveness at preventing stone recurrence and are often poorly tolerated. We report that the nutritional supplement α-lipoic acid inhibits cystine stone formation in the Slc3a1 mouse model of cystinuria by increasing the solubility of urinary cystine. These findings identify a novel therapeutic strategy for the clinical treatment of cystinuria.

Case Report: Cystinuria and Polycystic Kidney Disease. Cystinuria and polycystic kidney disease are 2 genetic disorders that affect the genitourinary tract but rarely together. This case report presents 2 pediatric patients diagnosed with polycystic kidney disease and cystinuria requiring surgical treatment. Both subjects presented acutely with stone disease. Imaging studies and stone analysis established the diagnoses. Although coexistence of these 2 conditions is rare, cystinuria should be considered in the differential diagnosis when evaluating patients with cystic disease who develop renal calculi.

Cystinuria Associated with Different SLC7A9 Gene Variants in the Cat Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA) reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 , respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats.

L-Cystine Diamides as L-Cystine Crystallization Inhibitors for Cystinuria l-Cystine bismorpholide (1a) and l-cystine bis(N'-methylpiperazide) (1b) were seven and twenty-four times more effective than l-cystine dimethyl ester (CDME) in increasing the metastable supersaturation range of l-cystine, respectively, effectively inhibiting l-cystine crystallization. This behavior can be attributed to inhibition of crystal growth at microscopic length scale, as revealed by atomic force microscopy. Both 1a and 1b are more stable than CDME, and 1b was effective in vivo in a knockout mouse model of cystinuria.