The genetics of cystinuria - an update and critical reevaluation.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: Novel tools such as AlphaMissense combined with the establishment of a refined ACMG criterion will play a significant role in classifying VUS within the responsible disease genes SLC3A1 (rBAT) and SLC7A9 (BAT1). This will also be essential in elucidating the role of promising candidate genes, such as SLC7A13 (AGT1), which have been derived from murine model systems and still need further research to determine if they are involved in human cystinuria. SUMMARY: Cystinuria was one of the first disorders to receive a gene-based classification, nonetheless, the clinically actionable implications of genetic diagnostics is still minor. This is due to poorly characterized genotype-phenotype correlations which results in a lack of individualized (genotype-) based management and metaphylaxis.

Postnatal outcome of children with antenatal colonic hyperechogenicity.

OBJECTIVE: To evaluate the postnatal outcome of children with antenatal colonic hyperechogenicity, currently considered as a sign of lysinuria-cystinuria, but which may also be a sign of other disorders with a more severe prognosis. METHOD: We carried out a French multi-centric retrospective study via 15 Multidisciplinary Center for Prenatal Diagnosis from January 2011 to January 2021. We included pregnancies for which fetal colonic hyperechogenicity had been demonstrated. We collected the investigations performed during pregnancy and at birth as well as the main clinical features of the mother and the child. We then established the prevalence of pathologies such as lysinuria-cystinuria (LC), hypotonia-cystinuria syndrome (HC), or lysinuric protein intolerance (LPI). RESULTS: Among the 33 cases of colonic hyperechogenicity collected, and after exclusion of those lost to follow-up, we identified 63% of children with lysinuria-cystinuria, 8% with lysinuric rotein intolerance, and 4% with hypotonia-cystinuria syndrome. CONCLUSION: Management of prenatal hyperechoic colon should include a specialized consultation with a clinical geneticist to discuss further investigations, which could include invasive amniotic fluid sampling for molecular diagnosis. A better understanding of diagnoses and prognosis should improve medical counseling and guide parental decision making.

Novel compound heterozygous pathogenic variants in the SLC3A1 gene in a Chinese family with cystinuria.

BACKGROUND: Cystinuria is an autosomal recessive disorder characterized by a cystine transport deficiency in the renal tubules due to mutations in two genes: SLC3A1 and SLC7A9. Cystinuria can be classified into three forms based on the genotype: type A, due to mutations in the SLC3A1 gene; type B, due to mutations in the SLC7A9 gene; and type AB, due to mutations in both genes. METHODS: We report a 12-year-old boy from central China with cystine stones. He was from a non-consanguineous family that had no known history of genetic disease. A physical examination showed normal development and neurological behaviors. Whole-exome and Sanger sequencing were used to identify and verify the suspected pathogenic variants. RESULTS: The compound heterozygous variants c.898_905del (p.Arg301AlafsTer6) is located in exon5 and c.1898_1899insAT (p.Asp634LeufsTer46) is located in exon10 of SLC3A1 (NM_000341.4) were deemed responsible for type A cystinuria family. The variant c.898_905del was reported in a Japanese patient in 2000, and the variant c.1898_1899insAT is novel. CONCLUSION: A novel pathogenic heterozygous variant pair of the SLC3A1 gene was identified in a Chinese boy with type A cystinuria, enriching the mutational spectrum of the SLC3A1 gene. We attempted to find a pattern for the association between the genotype of SLC3A1 variants and the manifestations of cystinuria in patients with different onset ages. Our findings have important implications for genetic counseling and the early clinical diagnosis of cystinuria.

Unraveling the natural history of presymptomatic cystinuria.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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/creatinine fell with age, urine cystine/l rose progressively in parallel with the risk of nephrolithiasis. Each new stone was preceded by 6-12 months of urine specific gravity of more than 1.020. However, average urine specific gravity and pH were not different in stone formers vs. nonstone formers, suggesting that intrinsic stone inhibitors or other unknown factors may be the strongest determinants of individual risk. SUMMARY: The current study reviews the clinical evolution of cystinuria in a cohort of children identified by newborn screening, who were categorized by urinary phenotype and followed from birth.

Cystinuria, an Atypical Presentation and Challenges of Establishing its Diagnosis in a Poor Resource Set Up.

Cystinuria is an autosomal recessive defect in re-absorptive transport of amino acids: cysteine, ornithine, arginine and lysine from renal proximal convoluted tubules leading to urinary excretion of these amino acids. The phenotypic manifestations are recurrent urolithiasis, hematuria, flank pain and frequent urinary tract infection. An eighteen years old boy, diagnosed case of cystinuria at the age of two years is presented in this case report highlighting the atypical presentation of recurrent infections with multiple organ involvement. The challenges in establishing the diagnosis and the role of simple biochemical tests in confirming the diagnosis in a poor resource setup is highlighted. Performance of simple biochemical tests in the urine sample of this patient was done for the utility of these tests for future diagnostic purpose in any suspected cases of cystinuria in our set up. Keywords: Case report; cystinuria; Nepal.

Phenotypic characterization of a pediatric cohort with cystinuria and usefulness of newborn screening.

BACKGROUND: Cystinuria is an inherited metabolic disease involving the defective transport of cystine and the dibasic amino acids in the renal proximal tubules that causes the formation of stones in the urinary system. In our regional child health program, cystinuria is included in newborn metabolic screening. Our objectives are the phenotypic characterization of our cystinuric pediatric cohort and to present our experience in neonatal cystinuria screening. METHODS: The study of clinical cases of pediatric patients diagnosed with cystinuria over a period of 32 years. All patients were studied at demographic, clinical, laboratory, radiological, and therapeutic levels. RESULTS: We diagnosed 86 pediatric patients with cystinuria; 36% of them had the homozygous biochemical phenotype. 95.3% of the patients were detected by neonatal metabolic screening. We performed urine biochemical analyses of parents with additional diagnoses of 63 adult patients. The mean follow-up time was 16.8 ± 8.5 years. 11.6% of patients developed one or more episodes of urinary tract infection during that period. Chronic kidney disease, proteinuria, and hypertension were uncommon (1.2%). 10.5% developed kidney stones at the mean age of presentation of 7.78 ± 7.6 years; 33% were recurrent. The risk of developing lithiasis was higher for homozygous biochemical-phenotype patients. Hypercalciuria was a significant risk factor in the development of lithiasis. CONCLUSIONS: Our clinical data suggest that diagnosing cystinuria through neonatal screening could be a useful strategy for the detection of presymptomatic cases, in order to establish preventive measures, as well as for the detection of relatives at risk. A higher resolution version of the Graphical abstract is available as Supplementary information.

Cistinuria como causa de litiasis urinaria / Cystinuria as a cause of urolithiasis

La cistinuria es una enfermedad genética que provoca un defecto de reabsorción de cistina, causando como manifestación principal litiasis urinarias que pueden llegar a ser de gran tamaño. Es importante tratarla desde temprana edad porque puede comportar importantes comorbilidades. (AU)

Cystinuria is a genetic disease that causes impaired cystine reabsorption. Its main manifestation is urolithiasis, in some cases producing very large stones. It is important to treat it from an early age because it can lead to important comorbidities. (AU)

A case of early onset cystinuria in a 4-month-old girl.

Cystinuria is an autosomal recessive disorder characterized by a decrease in the reabsorption of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the renal proximal tubule. It presents with recurrent urolithiasis. Cystinuria accounts for 6-8% of all pediatric urolithiasis. The age of onset is typically 10-30 years. Here, we report a case of early-onset cystinuria. A 4-month-old girl presented with hematuria. We noticed multiple renal calculi in ultrasonography and abdominal computerized tomography scans. The diagnosis was cystinuria with urinary calculus analysis and urinary amino acid analysis. The patient was treated with urine alkalinization and cystine chelating drugs. Gene analysis showed a P482L heterozygous mutation from her mother, and an A70V heterozygous mutation from her father, in the SLC7A9 gene. This gene encodes a putative subunit of the neutral and basic amino acid transport protein, BAT1. Although cystinuria is an autosomal recessive disease, there have been previous reports of P482L heterozygous mutations greatly suppressing cystine reabsorption and causing cystinuria symptoms. Therefore, the highly influential P482L mutation of the SLC7A9 gene may have contributed to the onset of this autosomal recessive disease at an extremely young age.

Cystinuria: an update on pathophysiology, genetics, and clinical management.

Cystinuria is the most common genetic cause of nephrolithiasis in children. It is considered a heritable aminoaciduria as the genetic defect affects the reabsorption of cystine and three other amino acids (ornithine, lysine, and arginine) in the renal proximal tubule. Patients affected by this condition have elevated excretion of cystine in the urine, and because of this amino acid's low solubility at normal urine pH, patients tend to form cystine calculi. To date, two genes have been identified as disease-causative: SLC3A1 and SLC7A9, encoding for the two subunits of the heterodimeric transporter. The clinical features of this condition are solely related to nephrolithiasis. The diagnosis is usually made during infancy or adolescence, but cases of late diagnosis are common. The goal of therapy is to reduce excretion and increase the solubility of cystine, through both modifications of dietary habits and pharmacological treatment. However, therapeutic interventions are not always sufficient, and patients often have to undergo several surgical procedures during their lives to treat recurrent nephrolithiasis. The goal of this literature review is to synthesize the available evidence on diagnosis and management of patients affected by cystinuria in order to provide physicians with a practical tool that can be used in daily clinical practice. This review also aims to shed some light on new therapy directions with the aim of ameliorating kidney outcomes while improving adherence to treatment and quality of life of cystinuric patients.

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.

Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) detection as a rapid and convenient screening test for cystinuria.

BACKGROUND: Cystinuria is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. The Brand's test, used for diagnosis, requires dangerous substances, so has been replaced with high-performance liquid chromatography with fluorimetric detection (HPLC-FL). However, this technique requires the use of complex equipment. Infrared spectroscopy, universally used for stone analysis, recently was employed to detect insoluble cystine in urine. The aim of this study is to evaluate Infrared Spectroscopy combined with chemometric analysis as screening method to identify those patients requiring confirmation by HPLC-FL analysis. METHODS: We examined 24 h urine specimens from 57 patients. The quantitative analysis was performed by HPLC-FL. The infrared spectroscopic urine sediment analysis was performed with an ATR accessory (ATR-FTIR). Urine is centrifuged, the supernatant is discarded, and the sediment is dried on to the ATR prism surface. Statistical analysis was performed using a custom-made software developed in MATLAB environment. RESULTS: The HPLC-FL determination showed a normal excretion of cystine in 49 samples and an abnormal excretion in the remaining 8 samples. The ATR-FTIR analysis combined with a statistical approach gives a sensitivity of 1.0 and a specificity of 0.82 were obtained. CONCLUSIONS: The introduction of the ATR-FTIR technique in our clinical laboratory setting may reduce time and cost analysis for diagnosis of cystinuria.

[Cystinuria]. / Cystinurie.

Cystinuria is the most common monogenic nephrolithiasis disorder. Because of its poor solubility at a typical urine pH of less than 7, cystine excretion results in recurrent urinary cystine stone formation. A high prevalence of high blood pressure and of chronic kidney disease has been reported in these patients. Alkaline hyperdiuresis remains the cornerstone of the preventive medical treatment. To reach a urine pH between 7.5 and 8 and a urine specific gravity less than or equal to 1.005 should be the goal of medical treatment. D-penicillamine and tiopronin, two cysteine-binding thiol agents, should be considered as second line treatments with frequent adverse events that should be closely monitored.

An Update on Evaluation and Management in Cystinuria.

Cystinuria is the most common cause of inherited stone disease and is caused by the failure of absorption of filtered dibasic amino acids including cystine in the proximal tubules. It is associated with a very high recurrence rate in affected patients, with the potential for significant morbidity in such patients due to the need for repeated surgical interventions. A multimodal and multispecialty approach in a dedicated centre is the key to improving treatment outcomes and patient adherence to the treatment. This article reviews the latest knowledge on the clinical and diagnostic features and summarises key developments to aid clinicians in diagnosis and management options, together with future directions for the care of these patients.

Cystinuria: clinical practice recommendation.

Cystinuria (OMIM 220100) is an autosomal recessive hereditary disorder in which high urinary cystine excretion leads to the formation of cystine stones because of the low solubility of cystine at normal urinary pH. We developed clinical practice recommendation for diagnosis, surgical and medical treatment, and follow-up of patients with cystinuria. Elaboration of these clinical practice recommendations spanned from June 2018 to December 2019 with a consensus conference in January 2019. Selected topic areas were chosen by the co-chairs of the conference. Working groups focusing on specific topics were formed. Group members performed systematic literature review using MEDLINE, drafted the statements, and discussed them. They included geneticists, medical biochemists, pediatric and adult nephrologists, pediatric and adult urologists experts in cystinuria, and the Metabolic Nephropathy Joint Working Group of the European Reference Network for Rare Kidney Diseases (ERKNet) and eUROGEN members. Overall 20 statements were produced to provide guidance on diagnosis, genetic analysis, imaging techniques, surgical treatment (indication and modalities), conservative treatment (hydration, dietetic, alkalinization, and cystine-binding drugs), follow-up, self-monitoring, complications (renal failure and hypertension), and impact on quality of life. Because of the rarity of the disease and the poor level of evidence in the literature, these statements could not be graded. This clinical practice recommendation provides guidance on all aspects of the management of both adults and children with cystinuria, including diagnosis, surgery, and medical treatment.

Clinical profile of a Polish cohort of children and young adults with cystinuria.

BACKGROUND: Cystinuria is an inherited disorder that results in increased excretion of cystine in the urine. It accounts for about 1-2% of pediatric kidney stones. In this study, we sought to identify the clinical characteristics of patients with cystinuria in a national cohort. METHODS: This was a retrospective study involving 30 patients from the Polish Registry of Inherited Tubulopathies. Initial data and that from a 6-month follow-up were analyzed. Mutational analysis was performed by targeted Sanger sequencing and, if applicable, MLPA analysis was used to detect large rearrangements. RESULTS: SLC7A9 mutations were detected in 15 children (50%; 10 males, 5 females), SLC3A1 mutations in 14 children (47%; 5 males, 9 females), and bigenic mutations in one male patient. The first clinical symptoms of the disease were detected at a median of 48 months of age (range 3-233 months). When individuals with different mutations were compared, there were no differences identified in gender, age of diagnosis, presence of UTI or urolithiasis, eGFR, calcium, or cystine excretion. The most common initial symptoms were urolithiasis in 26 patients (88%) and urinary tract infections in 4 patients (13%). Urological procedures were performed in 18 out of 30 (60%). CONCLUSIONS: The clinical course of cystinuria is similar among patients, regardless of the type of genetic mutation. Most patients require surgery before diagnosis or soon after it. Patients require combined urological and pharmacological treatment for prevention of stone recurrence and renal function preservation.

Metabolic and Clinical Characteristics of Children with Urolithiasis from Southern India.

OBJECTIVE: To study the etiological profile and patterns of clinical presentations of urolithiasis (UL) in children. METHODS: This observational study included patients <18 y with UL, who were referred to the pediatric nephrology clinic. Clinical features, family history, consanguinity and estimated glomerular filtration rate (eGFR) at presentation and follow-up were recorded. The children were evaluated using relevant blood and urine investigations. RESULTS: A total of 72 children with UL were evaluated for the study. The etiology of UL (n = 72) included hyperoxaluria (n = 25; 34.7%), idiopathic hypercalciuria (n = 21; 29.2%), idiopathic hyperuricosuria (n = 3; 4.2%), cystinuria (n = 3; 4.2%), urate transporter defect (n = 2; 2.8%) and mixed stones (predominant component calcium oxalate) (n = 9; 12.5%). No etiology was detected in 4 cases (5.5%). Common presenting complaints included flank pain (n = 41; 56.7%), hematuria (n = 29; 40.3%), urinary tract infection (UTI) (n = 29; 40.3%) and vomiting (n = 11; 15.3%). The median age of presentation was 60 (36, 96) mo. Family history and consanguinity were present in 30 cases (41.7%) and 28 cases (38.9%) respectively. Stone analysis was done in 20 cases, of which 9 cases were mixed stones (predominant calcium oxalate) and 6 were calcium oxalate stones. CONCLUSIONS: Among children with urolithiasis, hyperoxaluria, idiopathic hypercalciuria, idiopathic hyperuricosuria, and cystinuria were the predominant identifiable entities, together accounting for 72% of cases; and renal colic, hematuria and UTI were the commonest clinical complaints.