Improving the prognosis of nephropathic cystinosis.
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ABSTRACT:
SUBMITTER: Besouw MT
PROVIDER: S-EPMC4109637 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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Project description:Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.
| S-EPMC4158338 | biostudies-literature
Project description:The molecular and cellular mechanisms underlying nephropathic cystinosis, which exhibits generalized proximal tubular dysfunction and progressive renal failure, remain largely unknown. Renal biopsies from patients with this disorder can reveal abnormally large mitochondria, but the relevance of this and other ultrastructural abnormalities is unclear. We studied the ultrastructure of fibroblasts and renal proximal tubular epithelial cells from patients with three clinical variants of cystinosis: Nephropathic, intermediate, and ocular. Electron microscopy revealed the presence of morphologically abnormal mitochondria and abnormal patterns of mitochondrial autophagy (mitophagy) with a high number of autophagic vacuoles and fewer mitochondria (P < 0.02) in nephropathic cystinosis. In addition, we observed increased apoptosis in renal proximal tubular epithelial cells, greater expression of LC3-II/LC3-I (microtubule-associated protein 1 light chain 3), and significantly more autophagosomes in the nephropathic variant. The autophagy inhibitor 3-methyl adenine rescued cell death in cystinotic cells. Cystinotic cells had increased levels of beclin-1 and aberrant mitochondrial function with a significant decrease in ATP generation and an increase in reactive oxygen species. This study provides ultrastructural and functional evidence of abnormal mitophagy in nephropathic cystinosis, which may contribute to the renal Fanconi syndrome and progressive renal injury.
| S-EPMC2834547 | biostudies-literature
Project description:Study questionDo males with the rare lysosomal storage disease infantile nephropathic cystinosis (INC) have a chance of biological fatherhood?Summary answerCryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval from the centre of the testes providing additional opportunities for fatherhood.What is known alreadyBiallelic mutations in the cystinosin (CTNS) gene in INC cause dysfunction in cystine transport across lysosomal membranes and cystine accumulation throughout the body. Spontaneous paternity in cystinosis has not been described, despite the availability of cysteamine treatment. Azoospermia has been diagnosed in small case series of males with INC. ART using ICSI requires few spermatozoa, either from semen or extracted surgically from the testes of azoospermic men. However, there is limited evidence to suggest this could be successful in INC.Study design, size, durationIn this prospective cohort study performed between 2018 and 2019, we performed a cross-sectional investigation of 18 male patients with INC to delineate endocrine and spermatogenic testicular function.Participants/materials, setting, methodsSerum hormone levels, semen samples (according to World Health Organization 2010 standards), and testicular ultrasound images were analysed in 18 male patients aged 15.4-40.5 years. Surgical sperm extraction was performed in two, and their testicular biopsies were investigated by light and electron microscopy. Past adherence to cysteamine treatment was assessed from medical record information, using a composite scoring system.Main results and the role of chanceAdherence to cysteamine treatment was high in most patients. Testicular volumes and testosterone levels were in the normal ranges, with the exception of two and three older patients, respectively. Serum LH levels were above the normal range in all subjects aged ≥20 years. FSH levels were elevated in all but four males: three with spermatozoa in semen and one adolescent. Inhibin B levels were shown to be lower in older men. Testicular ultrasound revealed signs of obstruction in 67% of patients. Reduced fructose and zinc seminal markers were found in 33%, including two patients with azoospermia who underwent successful surgical sperm retrieval. Histology identified fully preserved spermatogenesis in the centre of their testes, but also tubular atrophy and lysosomal overload in Sertoli and Leydig cells of the testicular periphery.Limitations, reasons for cautionLimitations of this study are the small number of assessed patients and the heterogeneity of their dysfunction in cystine transport across lysosomal membranes.Wider implications of the findingsThis study suggests that testicular degeneration in cystinosis results from the lysosomal overload of Sertoli and Leydig cells of the testicular periphery, and that this can possibly be delayed, but not prevented, by good adherence to cysteamine treatment. Endocrine testicular function in INC may remain compensated until the fourth decade of life; however, azoospermia may occur during adolescence. Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval providing additional opportunities for biological fatherhood.Study funding/competing interest(s)This work was supported by the Cystinosis Foundation Germany. The authors have no competing interests to declare.Trial registration numbern/a.
| S-EPMC8058591 | biostudies-literature
Project description:Nephropathic cystinosis is a rare autosomal recessive disorder characterized by amino acid cystine accumulation and caused by biallelic mutations in the CTNS gene. The analysis methods are as follows: tandem mass spectrometry to determine the cystine concentration in polymorphonuclear blood leukocytes, Sanger sequencing for the entire coding sequence and flanking intron regions of the CTNS gene, multiplex PCR to detect a common mutation-a 57 kb deletion, and multiplex ligation-dependent probe amplification to analyze the number of exon copies in the CTNS gene. Haplotype analysis of chromosomes with major mutations was carried out using microsatellite markers D17S831, D17S1798, D17S829, D17S1828, and D17S1876. In this study, we provide clinical, biochemical, and molecular genetic characteristics of 40 Russian patients with mutations in the CTNS gene, among whom 30 patients were selected from a high-risk group of 85 people as a result of selective screening, which was carried out through cystine concentration measurement in polymorphonuclear blood leukocytes. The most common pathogenic variant, as in most described studies to date, was the 57 kb deletion, which represented 25% of all affected alleles. Previously non-described variants represented 22.5% of alleles. The founder effect in the Karachay and Chechen ethnic groups was shown for the following major variants: c.1015G > A and c.518A > G.
| S-EPMC9096100 | biostudies-literature
Project description: Not available
| S-EPMC9263244 | biostudies-literature
Project description:Nephropathic cystinosis, characterized by accumulation of cystine in the lysosomes, is caused by mutations in CTNS. The molecular and cellular mechanisms underlying proximal tubular dysfunction and progressive renal failure in nephropathic cystinosis are largely unclear, and increasing evidence supports the notion that cystine accumulation alone is not responsible for the end organ injury in cystinosis. We previously identified clusterin as potentially involved in nephropathic cystinosis. Here, we studied the expression of clusterin in renal proximal tubular epithelial cells obtained from patients with nephropathic cystinosis. The cytoprotective secretory form of clusterin, as evaluated by Western blot analysis, was low or absent in cystinosis cells compared with normal primary cells. Confocal microscopy revealed elevated levels of intracellular clusterin in cystinosis cells. Clusterin in cystinosis cells localized to the nucleus and cytoplasm and showed a filamentous and punctate aggresome-like pattern compared with diffuse cytoplasmic staining in normal cells. In kidney biopsy samples from patients with nephropathic cystinosis, clusterin protein expression was mainly limited to the proximal tubular cells. Furthermore, expression of clusterin overlapped with the expression of apoptotic proteins (apoptosis-inducing factor and cleaved caspase-3) and autophagy proteins (LC3 II and p62). Silencing of the clusterin gene resulted in a significant increase in cell viability and attenuation of apoptosis in cystinosis cells. Results of this study identify clusterin as a pivotal factor in the cell injury mechanism of nephropathic cystinosis and provide evidence linking cellular stress and injury to Fanconi syndrome and progressive renal injury in nephropathic cystinosis.
| S-EPMC4341467 | biostudies-literature
Project description: Not available
| S-EPMC6224624 | biostudies-literature
Project description:A 7-month-old male infant was referred to us for evaluation of hypercalcemia and failure to thrive. He was the second-born child to third-degree consanguineous parents with a birth weight of 3.5 kg. The index child was severely underweight. Initial laboratory investigations showed hypercalcemia (13.6 mg/dL), hypophosphatemia, hyponatremia, hypokalemia and hypochloremia. The initial serum bicarbonate level was 20.9 mEq/L. The urine calcium: creatinine ratio (0.05) was normal. He was noted to have polyuria (6 mL/kg/hr) and required intravenous fluids to maintain intravascular volume and manage hypercalcemia, along with potassium chloride supplements. The serum calcium decreased to 9.7 mg/dL after hydration for 48 h. At this juncture, the child was noted to exhibit metabolic acidosis (serum bicarbonate 16 mEq/L) for the first time. Thereafter, fractional excretion of bicarbonate was estimated to be 16.5% while the tubular threshold maximum for phosphorus per glomerular filtration rate was 1.2 mg/dL; indicating bicarbonaturia and phosphaturia, respectively. Glycosuria with aminoaciduria were also noted. Clinical exome sequencing revealed a NM_004937.3:c.809_811del in exon 10 of the CTNS gene that resulted in in-frame deletion of amino acids [NP_004928.2:p.Ser270del] at the protein level. The child is now growing well on oral potassium citrate, neutral phosphate and sodium bicarbonate supplements. This case was notable for absence of metabolic acidosis at admission. Instead, severe hypercalcemia was a striking presenting manifestation, that has not been reported previously in literature. Cystinosis has been earlier described in association with metabolic acidosis, hypocalcemia and hypomagnesemia. However, typical features like metabolic acidosis were masked in early stages of the disease in our case posing a diagnostic challenge. This atypical initial presentation adds to the constellation of clinical features in this condition.
| S-EPMC9343515 | biostudies-literature
Project description:Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in CTNS gene leading to Fanconi syndrome. Independent studies reported defective clearance of damaged mitochondria and mitochondrial fragmentation in cystinosis. Proteins involved in the mitochondrial dynamics and the mitochondrial ultrastructure were analyzed in CTNS-/- cells treated with cysteamine, the only drug currently used in the therapy for cystinosis but ineffective to treat Fanconi syndrome. CTNS-/- cells showed an overexpression of parkin associated with deregulation of ubiquitination of mitofusin 2 and fission 1 proteins, an altered proteolytic processing of optic atrophy 1 (OPA1), and a decreased OPA1 oligomerization. According to molecular findings, the analysis of electron microscopy images showed a decrease of mitochondrial cristae number and an increase of cristae lumen and cristae junction width. Cysteamine treatment restored the fission 1 ubiquitination, the mitochondrial size, number and lumen of cristae, but had no effect on cristae junction width, making CTNS-/- tubular cells more susceptible to apoptotic stimuli.
| S-EPMC6982165 | biostudies-literature
Project description:BackgroundNephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis.MethodsWe conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1β, IL-6, IL-18, and chitotriosidase enzyme activity.ResultsA multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications.ConclusionsChitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis.
| S-EPMC7217422 | biostudies-literature