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.

The impact of surgical intervention on renal function in cystinuria / O impacto da intervenção cirúrgica sobre a função renal na cistinúria

ABSTRACT 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.

RESUMO Introdução: A cistinúria é um distúrbio autossômico recessivo causado por defeitos de transporte intestinal e renal da cistina e aminoácidos dibásicos que resultam em urolitíase recorrente e necessidade de intervenção cirúrgica. O presente estudo teve por objetivo avaliar o impacto das intervenções cirúrgicas sobre a função renal por meio da análise da taxa de filtração glomerular estimada. Métodos: Treze pacientes pediátricos com cistinúria acompanhados em uma instituição terciária entre 2004 e 2016 foram incluídos no estudo. Os prontuários médicos foram analisados e utilizados como fonte de dados sobre a apresentação clínica dos pacientes, parâmetros urinários, formação de cálculos, tratamento clínico, intervenção cirúrgica, recidiva de cálculos após procedimento cirúrgico, análise de cálculos, ultrassonografia, resultados de imagens com ácido dimercaptossuccínico marcado com tecnécio metaestável (99mTc-DMSA) e tempo de seguimento. A depuração de creatinina estimada pela fórmula modificada de Schwartz (TFGe) antes e após a cirurgia foi utilizada para avaliar e comparar estatisticamente os níveis de função renal. Resultados: Nove pacientes (69,2%) apresentaram cicatrizes renais detectadas por exame de imagem com 99mTc-DMSA. Dez pacientes (76,9%) necessitaram intervenção cirúrgica aberta por cálculo renal durante o seguimento. Não foram detectadas diferenças significativas entre os valores de TFGe anteriores e posteriores à intervenção cirúrgica (média de 92 vs. 106, p = 0,36). Nove pacientes (69,2%) não apresentaram cálculos no último exame ultrassonográfico. Recidivas de cálculos renais após cirurgia foram observadas em 66,6% dos pacientes submetidos a cirurgia. Conclusões: Intervenções cirúrgicas relativas a cálculos renais são frequentemente necessárias em pacientes com cistinúria. Cicatrizes renais são um achado prevalente em pacientes com cistinúria. De acordo com o presente estudo, cirurgia não afeta negativamente a TFGe de pacientes com cistinúria.

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.

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.

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.

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.

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: an inborn cause of urolithiasis.

Cystinuria (OMIM 220100) is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b(0,+) transporter while SLC7A9 (chromosome 19q12) encodes its interacting light subunit b(0,+)AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21. By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids. In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies.

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.

PREPL, a prolyl endopeptidase-like enzyme by name only?--Lessons from patients.

Deletion of the Prolyl Endopeptidase-like (PREPL) gene has been described in three contiguous gene deletion syndromes at the 2p21 locus and current developments in high resolution microarrays and whole genome sequencing will no doubt soon result in the identification of isolated PREPL deficiency. But by comparing the differences in phenotypes with the number of genes deleted, the contribution of PREPL deficiency can already be deduced. Homozygous or compound heterozygous loss of PREPL is predicted to cause neonatal hypotonia and severe feeding problems. Failure to thrive usually persists for several years, followed by a period of hyperphagia and excessive weight gain. Growth retardation is usually observed, which responds well to growth hormone therapy. In addition, minor facial dysmorphism, nasal speech, viscous saliva, hypergonadotropic hypogonadism and learning problems are frequently observed. How PREPL deficiency causes these clinical manifestations remains unknown. PREPL is highly expressed in brain and based on gene coexpression network architecture it has been placed in a group enriched with markers of neurons and synaptic proteins. PREPL is predicted to be a serine oligopeptidase based on its homology with prolyl endopeptidase (PREP) and the presence of an active catalytic triad. However, until now no substrates have been found. Recent observations that PREP has non-catalytic functions in the cytoplasm through interactions with its amino- terminal propeller domain, suggests that of PREPL may also have biological functions independent of its predicted peptidase activity. This raises the possibility that PREP and PREPL are homologous, not just by name but also by nature.

Pathophysiology and treatment of cystinuria.

Cystinuria is a primary inherited aminoaciduria caused by mutations in the genes that encode the two subunits (neutral and basic amino acid transport protein rBAT and b(0,+)-type amino acid transporter 1) of the amino acid transport system b(0,+). This autosomal recessive disorder (in which few cases show dominant inheritance) causes a failure in the reabsorption of filtered cystine and dibasic amino acids in the proximal tubule. The clinical symptoms of this disease are caused by the loss of poorly soluble cystine, which precipitates to form stones. Although rare, the prevalence of cystinuria is sufficiently high that the disease results in a substantial contribution to pediatric renal lithiasis. A thorough understanding of cystine transport processes over the past 15 years and the genetic abnormalities responsible for the disease has led to a new classification of cystinuria and recognition that some cases result from an autosomal dominant etiology with incomplete penetrance. This Review examines the molecular and mechanistic effects of some of the mutations that cause cystinuria based on our current understanding of the structural and cellular biology of system b(0,+). This Review also describes the current treatments to prevent recurrent cystine lithiasis.

Cistinuria / Cystinuria

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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.

Reduced renal function and benefits of treatment in cystinuria vs other forms of nephrolithiasis.

UNLABELLED: A significant study from the USA compares cystine stone formers and routine stone formers; the former group had a higher requirement for therapeutic procedures, but this was less if they took chelating agents, although remaining higher than in the latter group. Other interesting findings are also presented. OBJECTIVE: First, to compare two types of stone formers (SF), those with cystinuria and those without, for effects of treatments for stones, as cystinuria leads to recurrent stones that are difficult to fragment with shock-wave lithotripsy, and there is disagreement about the efficacy of current treatments. Second, to compare these two groups with respect to blood pressure (BP) and renal function, as cystine stones may be associated with more morbidity than are routine stones. PATIENTS AND METHODS: Fifty-two cystinuric patients (cystine SF) entering our programme since 1970 were compared with 3215 SF without cystinuria (routine SF), of whom 114 had a single functioning kidney (routine SF + nephrectomy). All patients had three 24-h urine and blood samples taken to determine the risk of stones before their first clinic visit; these studies were repeated after therapy was initiated, and at regular intervals to monitor therapy. Cystine was measured in the urine samples of the cystine SF. All stone-related procedures were recorded, and BP measured at clinic visits. Creatinine clearances (CCr) were calculated from each set of serum and urine values. Cystine supersaturation (SS) was directly measured in 16 urine samples collected before treatment and 13 afterward. RESULTS: Patients were treated with increased fluid intake, potassium alkali and chelating agents such as alpha-mercapto-propionyl-glycine, as needed. The mean (sd) CCr, corrected for age and gender, was significantly lower at entry in cystine SF than in routine SF, at 91 (6) vs 160 (1) L/day, respectively (P < 0.001), and remained so at the last CCr. Neither systolic nor diastolic BP, similarly corrected, differed between the groups, but cystine SF had significantly more procedures, corrected for time at risk, before treatment than did routine SF, at 4.0 (0.4) vs 1.86 (0.06), respectively (P < 0.001); time-adjusted procedures decreased significantly in both groups during treatment, but remained higher in cystine SF, at 0.88 (0.14) vs 0.23 (0.02), respectively, (P < 0.001). Urine volume and pH were significantly higher in cystine SF than in routine SF, both before and during treatment. Cystine SS decreased during treatment, consistent with the increase in urine volume and decline in procedure rates during treatment. CONCLUSION: Cystine SF have significantly higher procedure rates than routine SF, but procedure rates decline during therapy, although they remain higher than in routine SF. The lower CCr in cystinurics suggests that treatment to prevent stone recurrence and the need for procedures is particularly important, and emphasizes the need for a close follow-up. Use of cystine SS measurements may allow closer monitoring of the effect of treatment on the risk of stone recurrence.

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.

The genetics of heteromeric amino acid transporters.

Heteromeric amino acid transporters (HATs) are composed of a heavy (SLC3 family) and a light (SLC7 family) subunit. Mutations in system b(0,+) (rBAT-b(0,+)AT) and in system y(+)L (4F2hc-y(+)LAT1) cause the primary inherited aminoacidurias (PIAs) cystinuria and lysinuric protein intolerance, respectively. Recent developments [including the identification of the first Hartnup disorder gene (B0AT1; SLC6A19)] and knockout mouse models have begun to reveal the basis of renal and intestinal reabsorption of amino acids in mammals.

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.