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Background The purpose of this study is to evaluate the effectiveness and safety of switching from immediate-release (IR) to extended-release (ER) cysteamine in patients with nephropathic cystinosis (NC) in Spain. Methods We conducted an observational, retrospective, multicentre study in NC patients who received IR cysteamine for at least 12 months, switched to ER cysteamine, and received it for at least 6 months before inclusion. Results Data were collected from nine patients (four children, five adults) 36 months before and after the switch. Despite the highly selected population, an improvement in growth, particularly in children and a significant reduction in hospitalization days was observed. A decrease in halitosis, body odour and gastrointestinal effects was reported in most of the patients who suffered before the switch, and the use of proton pump inhibitors (PPIs) decreased in some patients. The estimated glomerular filtration rate (eGFR) remained stable in patients with preserved kidney function. No significant changes in white blood cell (WBC) cystine levels were observed after the switch. There was no significant difference in the cysteamine dose received. However, some patients were receiving <50% of the recommended dose of cysteamine before and after the switch and showed elevated levels of WBC cystine. Conclusions Switching from IR to ER cysteamine in clinical practice reduces hospital stays, improves nutritional status and growth in paediatric patients and could help to enhance treatment tolerability by reducing side effects. Furthermore, the dosing of ER cysteamine could promote therapeutic compliance and positively affect the quality of life of the NC population. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis (NC) is a rare lysosomal disease, leading to early kidney failure and extra-renal comorbidities. Its prognosis strongly relies on early diagnosis and treatment by cysteamine. Developing economies (DEing) face many challenges when treating patients for rare and chronic diseases. The aim here is to evaluate the access to investigations and treatment in DEing, and to assess for potential inequalities with Developed Economies (DEed). Methods: In this international cross-sectional study, a questionnaire on access, price and reimbursement of genetic, biological analyses, and treatment was sent to nephrology centers worldwide during 2022. Results: A total of 109 centers responded, coming from 49 countries and managing 741 patients: 43 centers from 30 DEing and Economies in transition (TrE), and 66 from 19 DEed. In 2022, genetics availability was 63% in DEing and 100% in DEed, whereas intra leukocytes cystine levels (IL-CL) were available for 30% of DEing patients, and 94% of DEed patients, both increasing over the last decade, as has access to immediate release cysteamine and to cysteamine eye drops in DEing. However, delayed released cysteamine can be delivered to only 7% vs. 74% of patients from DEing and DEed, respectively, and is still poorly reimbursed in DEing. Conclusions: Over the last decade, access to investigations (namely genetics and IL-CL) and to cysteamine have improved in DEing and TrE. However, discrepancies remain with DEed: access to delayed released cysteamine is limited, and reimbursement is still profoundly insufficient, therefore limiting their current use. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is a rare lysosomal storage disorder in which accumulation of cystine and formation of crystals particularly impair kidney function and gradually lead to multi-organ dysfunction. Lifelong therapy with the aminothiol cysteamine can delay the development of kidney failure and the need for transplant. The purpose of our long-term study was to explore the effects of transitioning from immediate release (IR) to extended release (ER) formulation in Norwegian patients in routine clinical care. Methods: We retrospectively analysed data on efficacy and safety in 10 paediatric and adult patients. Data were obtained from up to 6 years before and 6 years after transitioning from IR- to ER-cysteamine. Results: Mean white blood cell (WBC) cystine levels remained comparable between the different treatment periods (1.19 versus 1.38 nmol hemicystine/mg protein) although most patients under ER-cysteamine underwent dose reductions. For the non-transplanted patients, the mean estimated glomerular filtration rate (eGFR) change/year was more pronounced during ER-treatment (− 3.39 versus − 6.80 ml/min/1.73 m2/year) possibly influenced by individual events, such as tubulointerstitial nephritis and colitis. Growth measured by Z-height score tended to develop positively. Four of seven patients reported improvement of halitosis, one reported unchanged and two reported worsened symptoms. Most adverse drug reactions (ADRs) were of mild severity. One patient developed two serious ADRs and switched back to IR-formulation. Conclusions: The results from this long-term retrospective study indicate that switching from IR- to ER-cysteamine was feasible and well tolerated under routine clinical practice. ER-cysteamine allowed satisfactory disease control over the long period considered. [ABSTRACT FROM AUTHOR]

Cystinosis is an autosomal recessive lysosomal storage disease, caused by mutations in the CTNS gene, resulting in multi-organ cystine accumulation. Three forms of cystinosis are distinguished: infantile and juvenile nephropathic cystinosis affecting kidneys and other organs such as the eyes, endocrine system, muscles, and brain, and adult ocular cystinosis affecting only the eyes. Currently, elevated white blood cell (WBC) cystine content is the gold standard for the diagnosis of cystinosis. We present a patient with proteinuria at adolescent age and corneal cystine crystals, but only slightly elevated WBC cystine levels (1.31 ½ cystine/mg protein), precluding the diagnosis of nephropathic cystinosis. We demonstrate increased levels of cystine in skin fibroblasts and urine-derived kidney cells (proximal tubular epithelial cells and podocytes), that were higher than the values observed in the WBC and healthy control. CTNS gene analysis shows the presence of a homozygous missense mutation (c.590 A > G; p.Asn177Ser), previously described in the Arab population. Our observation underlines that low WBC cystine levels can be observed in patients with juvenile cystinosis, which may delay the diagnosis and timely administration of cysteamine. In such patients, the diagnosis can be confirmed by cystine measurement in slow-dividing cells and by molecular analysis of the CTNS gene. [ABSTRACT FROM AUTHOR]

The widespread use of whole exome sequencing (WES) resulted in the discovery of multilocus pathogenic variations (MPV), defined as two or more distinct or overlapping Mendelian disorders occurring in a patient, leading to a blended phenotype. In this study, we report on a child with autosomal recessive primary microcephaly-5 (MCPH5) and nephropathic cystinosis. The proband is the first child of consanguineous parents, presenting a complex phenotype including neurodevelopmental delay, microcephaly, growth restriction, significant delay of bone maturation, lissencephaly, and abnormality of neuronal migration, photophobia, and renal tubular acidosis. WES revealed two pathogenic and homozygous variants: a c.4174C>T variant in the ASPM gene and a c.382C>T variant in the CTNS gene, explaining the complex phenotype. The literature review showed that most of the patients harboring two variants in recessive disease genes are born to consanguineous parents. To the best of our knowledge, the patient herein described is the first one harboring pathogenic variants in both the ASPM and CTNS genes. These findings highlight the importance of searching for MPV in patients with complex phenotypes investigated by genome-wide testing methods, especially for those patients born to consanguineous parents. [ABSTRACT FROM AUTHOR]

The aim of this letter to the editor is to summarize the results from three clinical trial programs evaluating delayed-release cysteamine bitartrate (DR-CYS), which demonstrated the long-term clinical benefits in patients with nephropathic cystinosis when dosed every 12 h. The authors of "A comparison of immediate release and delayed release cysteamine in 17 patients with nephropathic cystinosis" presented recommendations altering the dosage and dosing scheme from what has been previously approved by the FDA for DR-CYS. In this letter to the editor, we critique the authors' aforementioned article as it is a retrospective analysis of a small number of patients and does not follow the dosing recommendation by the FDA for equivalent dosing of DR-CYS to immediate-release cysteamine bitartrate (IR-CYS). In addition, the article does not include study data to properly support the authors' suggestion of increased dosing effects and benefits. We present a summary of the results from the DR-CYS clinical trial program and evidence of the rigor from which the clinical data for DR-CYS were generated and recommendation for usage as prescribed. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Nephropathic cystinosis is a lysosomal storage disorder with known myopathic features, including dysphagia. Evaluation of oropharyngeal swallowing physiology can be standardized using the Modified Barium Swallow Impairment Profile (MBSImP), a validated assessment tool used to analyze and rate swallowing across 17 distinct physiologic domains. Our objective was to better characterize swallowing impairments in nephropathic cystinosis using MBSImP analysis. Methods: We retrospectively evaluated 40 video fluoroscopic swallowing studies performed at two time points over 1 y in patients with nephropathic cystinosis with various levels of oral and pharyngeal stage dysphagia. Patients completed two self‐administered dysphagia outcome measures (the M. D. Anderson Dysphagia Inventory [MDADI] and the 10‐item Eating Assessment Tool [EAT‐10]). Results: We demonstrated oral stage and pharyngeal stage dysphagia across domains that impacted bolus control, transit, and clearance through both the oral cavity and pharyngeal lumen. Also captured were deficits related to onset and completeness of laryngeal closure that impact airway protection during swallow. There were significant correlations between pharyngeal total score and EAT‐10 (r = 0.5, p < 0.001) and between oral total score and EAT‐10 (r = 0.7, p < 0.001), MDADI‐e (r = −0.6, p < 0.001), MDADI‐p (r = −0.5, p < 0.001) and MDADI‐c (r = −0.6, p < 0.001). There were no differences in oral or pharyngeal total scores across the 1‐y time span. Discussion: This study identifies oral and pharyngeal stage dysphagia as crucial to patients with nephropathic cystinosis and paves the path for future studies of treatment targets. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by kidney and extra-renal complications due to the accumulation of cystine crystals in various tissues and organs. Herein, we describe the early neuromuscular complications in a cohort of pediatric nephropathic cystinosis patients. Methods: We prospectively evaluated the clinical, biochemical, and neurophysiological data of 15 cystinosis patients. Neurophysiological evaluation was performed to confirm or exclude presence of neuropathy and/or myopathy. Results: Patients' age ranged between 20 and 216 months at time of examination. Nine patients were males. Three patients had early abnormal neurophysiological features consistent with neuromuscular involvement (clinically asymptomatic proximal myopathy with a patchy distribution in one patient and isolated asymptomatic sensory nerve conduction changes in two patients). A fourth patient had mixed abnormal motor and sensory axonal neuropathic changes associated with overt clinical features (predominantly motor symptoms). Patients with abnormal neuromuscular features were significantly older in age than the unaffected group (P = 0.005) and had a diagnosis of cystinosis with subsequent cysteamine therapy at a significantly older age than the unaffected group (P = 0.027 and 0.001, respectively). Conclusions: We expanded the recognized phenotypes of cystinosis neuromuscular complications with early proximal skeletal myopathy and symptomatic motor and sensory axonal neuropathy. Early asymptomatic neuromuscular complications could develop in pediatric patients and would require neurophysiological studies for early detection prior to development of overt clinical manifestations. Prompt diagnosis and timely initiation of cysteamine therapy with recommended dose can delay the development of neuromuscular complications. A higher resolution version of the Graphical abstract is available as Supplementary information [ABSTRACT FROM AUTHOR]

Early diagnosis and effective therapy are essential for improving the overall prognosis and quality of life of patients with nephropathic cystinosis. The severity of kidney dysfunction and the multi-organ involvement as a consequence of the increased intracellular concentration of cystine highlight the necessity of accurate monitoring of intracellular cystine to guarantee effective treatment of the disease. Cystine depletion is the only available treatment, which should begin immediately after diagnosis, and not discontinued, to significantly slow progression of renal and extra-renal organ damage. This review aims to discuss the importance of the close monitoring of intracellular cystine concentration to optimize cystine depletion therapy. In addition, the role of new biomarkers in the management of the disease, from timely diagnosis to implementing treatment during follow-up, is overviewed. [ABSTRACT FROM AUTHOR]

The article presents questions and answers related to medicine, namely, the findings that are inconsistent with a diagnosis of Bartter syndrome, and the tests that should be conducted for the differential diagnosis.

Gastrointestinal (GI) sequelae, such as vomiting, hyperacidity, dysphagia, dysmotility, and diarrhea, are nearly universal among patients with nephropathic cystinosis. These complications result from disease processes (e.g., kidney disease, cystine crystal accumulation in the GI tract) and side effects of treatments (e.g., cysteamine, immunosuppressive therapy). GI involvement can negatively impact patient well-being and jeopardize disease outcomes by compromising drug absorption and patient adherence to the strict treatment regimen required to manage cystinosis. Given improved life expectancy due to advances in kidney transplantation and the transformative impact of cystine-depleting therapy, nephrologists are increasingly focused on addressing extra-renal complications and quality of life in patients with cystinosis. However, there is a lack of clinical data and guidance to inform GI-related monitoring, interventions, and referrals by nephrologists. Various publications have examined the prevalence and pathophysiology of selected GI complications in cystinosis, but none have summarized the full picture or provided guidance based on the literature and expert experience. We aim to comprehensively review GI sequelae associated with cystinosis and its treatments and to discuss approaches for monitoring and managing these complications, including the involvement of gastroenterology and other disciplines. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is a rare and severe metabolic disease leading to an accumulation of cystine in lysosomes which especially harms kidney function. A lifelong therapy with the aminothiol cysteamine can delay the development of end-stage renal disease and the necessity of kidney transplantation. The purpose of our study was to compare the effectiveness of immediate-release and delayed-release cysteamine on cystine and cysteamine levels as well as assessing the onset of adverse effects.Methods: We retrospectively analysed cystine and cysteamine levels of 17 patients after a single dose of immediate-release cysteamine (Cystagon®, Mylan Pharmaceuticals, Canonsburg, PA and Recordati Pharma GmbH) as well as a single dose of delayed-release cysteamine (Procysbi®; Horizon Pharma USA and Chiesi Farmaceutici S.p.A., Parma, Italy) respectively. Data were collected during a period of three years in the context of optimizing the individual treatment regimens. The dose of DR-cysteamine was reduced to 70% of the equivalent dose of IR-cysteamine. The efficacy of both formulas in depleting white blood cells' cystine levels and their side effects were compared.Results: Immediate (IR)- and delayed-release (DR) cysteamine effectively decreased intracellular cystine levels under the target value of 0.5 nmol cystine/mg protein, while fewer side effects occurred under DR-cysteamine. Mean maximum levels of cysteamine were reached after 60 min with IR-cysteamine and after 180 min with DR-cysteamine.Conclusion: A therapy with DR-cysteamine is as effective as IR-cysteamine while less side effects were reported. Our data show that DR-cysteamine should be dosed higher than 70% of the equivalent dose of IR-cysteamine in order to decrease cystine levels over an extended period of time. Moreover, our data suggest increasing the dosing scheme of Procysbi® to three times daily, to prevent a rapid decrease and achieve a steadier decline in cystine levels. Due to the more convenient dosing scheme, DR-cysteamine might ameliorate therapy adherence and improve patients' quality of life. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis (NC) is a rare autosomal recessive disease, which causes cysteine-crystals accumulation with progression to end-stage renal disease (ESRD). Von willebrand disease (VWD) type III is a rare subtype of von willebrand factor (VWF) abnormality, which is characterized by severe reduction of VWF and factor VIII activity. A 16-year-old patient with NC and VWD type III presented with uremic symptoms due to ESRD. Dialysis access was inserted and followed by hemodialysis (HD) for 4 months with a proper infusion of blood products. While renal transplant remains the treatment of choice of NC and superior to chronic HD, bleeding complications were a major concern in this case with coexisting VWD type III. However, with the meticulous implementation of the Hematology team's daily recommendations, renal transplantation was successfully performed. This is the first case that mentions a new association between two inherited rare disorders, NC and VWD type III, and this entity has not been reported before. Moreover, successful kidney transplantation in our patient supports the possibility of these procedures in hereditary clotting disorders. [ABSTRACT FROM AUTHOR]

Introduction: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems. Methods: Patients with confirmed NC, aged > 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included. Adherence to treatment was primarily assessed as the percentage of days with a good adherence score, adherence score rating from 0 (poor) to 2 (good). A descriptive analysis was performed after 1-year follow-up. Results: Seventeen patients (10 girls, median age: 13.9 (5.4–33.0) years) were included. Median age at diagnosis was 17.0 (3.0–76.9) months and age at start of cysteamine was 21.0 (15.5–116.3) months. Median daily dose of cysteamine was 1.05 (0.55–1.63) g/m2/day. Over the year, the median percentage of days with a good adherence score was 80 (1–99)% decreasing to 68 (1–99)% in patients > 11 years old. The median of average number of hours covered by treatment in a day was 22.5 (6.1–23.9) versus 14.9 (9.2–20.5) hours for delayed release versus short acting cysteamine. Conclusion: Our data are the first describing a rather good adherence to cysteamine, decreasing in adolescents and adults. We described a potential interest of the delayed release formulation. Our data highlight the need for a multidisciplinary approach including therapeutic education and individualized approaches in NC patients transitioning to adulthood. Graphical abstract [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is a lysosomal storage disorder with late‐onset systemic complications, such as myopathy and dysphagia. Currently employed outcome measures lack sensitivity and responsiveness for dysphagia and myopathy, a limitation to clinical trial readiness. Methods: We evaluated 20 patients with nephropathic cystinosis in two visits over the course of a year to identify outcomes sensitive to detect changes over time. Patients also underwent an expiratory muscle strength training program to assess any effects on aspiration and dysphagia. Results: There were significant differences in the Timed Up and Go Test (TUG) and Timed 25‐Foot Walk (25‐FW) between baseline and 1‐y follow‐up (P <.05). Maximum expiratory pressure (MEP) and peak cough flow (PCF) significantly improved following respiratory training (P <.05). Conclusions: Improved respiratory outcomes may enhance patients ability to expel aspirated material from the airway, stave off pulmonary sequelae associated with chronic aspiration, and yield an overall improvement in physical health and well‐being. See Editorial on pages 652–652 in this issue. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is a lysosomal storage disorder. Patient survival years after renal transplantation has revealed systemic complications including distal myopathy and dysphagia.Methods: We evaluated 20 adult patients with nephropathic cystinosis using patient-reported and clinical outcome measures. Standard motor measures, video fluoroscopy swallow studies, and tests of respiratory function were performed. We also used Rasch analysis of an initial survey to design a 16-item survey focused on upper and lower extremity function, which was completed by 31 additional patients.Results: Distal myopathy and dysphagia were common in patients with nephropathic cystinosis. Muscle weakness ranges from mild involvement of intrinsic hand muscles to prominent distal greater than proximal weakness and contractures.Conclusions: In addition to further characterization of underlying dysphagia and muscle weakness, we propose a new psychometrically devised, disease specific, functional outcome measures for distal myopathy in patients with nephropathic cystinosis. [ABSTRACT FROM AUTHOR]

Introduction: Infantile nephropathic cystinosis (INC) is an autosomal recessive lysosomal disorder in which patients develop deposits of cystine crystals in their kidneys and corneas from a young age.Methods: We conducted a retrospective analysis of children with INC seen by ophthalmologists at the Manchester Royal Eye Hospital between 2002 and 2018, to evaluate clinical findings, symptoms and treatment.Results: Twenty-two children diagnosed with INC from age 0 (prenatally) to 11 years were assessed. All evaluable patients had corneal cystine crystal deposits, and 15 had mild to moderate photophobia. Ten patients had other ocular conditions including blepharitis/chalzion (n = 6), swollen optic nerve (n = 3), punctate epitheliopathy (n = 3), corneal scarring (n = 1),and elevated intraocular pressure (n = 2). Confocal imaging identified nerve abnormalities in two patients (enlarged corneal nerve + abnormal-looking tortuous nerves in one patient and beaded nerves in the sub-basal plexus in the other), both of whom had significant crystal deposition in the anterior stroma. Visual acuity was relatively unaffected. All 22 patients were receiving oral cysteamine, and 21 were applying cysteamine eye drops (galenic preparation of 0.55% concentration, compounded by a hospital pharmacy). Recommended application frequency was at least eight times per day in all patients with dosing information available.Conclusions: This case series of patients with INC highlights the consistent pattern of corneal cystine crystal deposition, which is universally present from a young age in this condition, and the high incidence of photophobia even in young children. Corneal manifestations of INC persisted despite frequent administration of the hospital pharmacy-made eye drop preparation. Reasons for this lack of efficacy may include the lag period between diagnosis and first prescription of cysteamine eye drops and the difficulty in maintaining rigorous compliance with this treatment. In addition, the challenge for patients of maintaining optimal storage conditions may adversely affect the stability and efficacy of cysteamine within this preparation.Funding: Editorial assistance was funded by Orphan Europe Ltd. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We report a Russian patient with atypical onset of infantile nephropathic cystinosis. The disease debuted with vomiting and loss of weight and motor skills. Nephropathic changes appeared 6 months after onset of disease. Exome sequencing can be useful for diagnosing cystinosis in patients with neurological abnormalities before onset of nephropathic symptoms. [ABSTRACT FROM AUTHOR]

Background Bone impairment is a poorly described complication of nephropathic cystinosis (NC). The objectives of this study were to evaluate in vitro effects of cystinosin (CTNS) mutations on bone resorption and of cysteamine treatment on bone cells [namely human osteoclasts (OCs) and murine osteoblasts]. Methods Human OCs were differentiated from peripheral blood mononuclear cells (PBMCs) of patients and healthy donors (HDs). Cells were treated with increasing doses of cysteamine in PBMCs or on mature OCs to evaluate its impact on differentiation and resorption, respectively. Similarly, cysteamine-treated osteoblasts derived from murine mesenchymal stem cells were assessed for differentiation and activity with toxicity and proliferation assays. Results CTNS was expressed in human OCs derived from HDs; its expression was regulated during monocyte colony-stimulating factor- and receptor activator of nuclear factor-κB-dependent osteoclastogenesis and required for efficient bone resorption. Cysteamine had no impact on osteoclastogenesis but inhibited in vitro HD osteoclastic resorption; however, NC OC-mediated bone resorption was impaired only at high doses. Only low concentrations of cysteamine (50 μM) stimulated osteoblastic differentiation and maturation, while this effect was no longer observed at higher concentrations (200 µM). Conclusion CTNS is required for proper osteoclastic activity. In vitro low doses of cysteamine have beneficial antiresorptive effects on healthy human-derived OCs and may partly correct the CTNS-induced osteoclastic dysfunction in patients with NC. Moreover, in vitro low doses of cysteamine also stimulate osteoblastic differentiation and mineralization, with an inhibitory effect at higher doses, likely explaining, at least partly, the bone toxicity observed in patients receiving high doses of cysteamine. [ABSTRACT FROM AUTHOR]

Background: Bone impairment appears to be a novel complication of nephropathic cystinosis despite cysteamine therapy. Its exact underlying pathophysiology is nevertheless unclear. The objective of this study was to evaluate bone status among patients included in the French Crystobs study.Methods: In addition to clinical data, bone status was evaluated using biomarkers (ALP, PTH, 25-D, 1-25D, FGF23), DXA (spine and total body), and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the tibia and radius. Results were compared to age- and gender-matched healthy controls (1:2 basis) from the local reference cohorts.Results: At a median age of 22.5 (10.2-34.6) years, 10 patients with nephropathic cystinosis were included (2 receiving conservative therapies, 2 undergoing hemodialysis, 6 with a past of renal transplantation); 7 out of 10 patients complained of a bone symptom (past of fracture, bone deformations, and/or bone pain). Biochemicals and spine DXA did not show any significant abnormalities. Using HR-pQCT, significant decreases in cortical parameters (e.g., cortical thickness 850 (520-1100) versus 1225 (480-1680) μm; p < 0.05) and total volumetric bone mineral density (290 (233-360) versus 323 (232-406) mg/cm3; p < 0.05) were observed in cystinotic patients in comparison to controls at the tibia. There were no differences for trabecular parameters. Similar results were observed at the radius.Conclusions: In this pilot study, bone impairment (rather cortical than trabecular) is a significant clinical problem in nephropathic cystinosis; 70% of patients displayed significant bone symptoms, during teenage or young adulthood. This new complication should be known by physicians because of its potential dramatic impact on quality of life. [ABSTRACT FROM AUTHOR]

Objectives: To summarize available clinical evidence for cysteamine bitartrate preparations in the treatment of nephropathic cystinosis as identified through a systematic literature review (SLR).Methods: We searched MEDLINE, MEDLINE In-Process and Embase using Ovid with a predefined search strategy through 19 January 2016. All publicly available clinical reports on the use of delayed-release (DR) cysteamine bitartrate (Procysbi 1 ) or immediate-release (IR) cysteamine bitartrate (Cystagon 2 ) in patients with cystinosis were included.Results: We identified a total of 103 publications and 10 trial records. Of these, 9 studies describe DR cysteamine bitartrate (n = 267 patients), 42 describe IR cysteamine bitartrate (n = 1,427 patients) and in 53 studies the exact preparation was not specified (n = 906 patients). The vast majority of the studies used a non-randomized study design, with randomized clinical trials (RCTs) being scarce (1 study comparing DR and IR formulation) and case reports (n = 49) being the most common study design representing 47% of the total.Conclusion: A substantial evidence base for cysteamine bitartrate in the treatment of nephropathic cystinosis was identified. However, the majority of the evidence was of relatively low quality, with evidence levels of 3 or 4. [ABSTRACT FROM AUTHOR]

Cystinosis is a rare autosomal recessive metabolic disorder characterized by the accumulation of cystine in lysosomes, which results from defects in the carrier-mediated transport protein encoded by the CTNS gene. Infantile nephropathic cystinosis (INC) is one of the major complications of cystinosis. It is characterized by findings of Fanconi's syndrome within the first year of life. Here we report two patients with INC presenting with signs of Fanconi's syndrome and describe a novel CTNS mutation. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is a rare lysosomal storage disease which is characterized by the accumulation of free cystine in lysosomes and subsequent intracellular crystal formation of cystine throughout the body. If not treated with cysteamine, a cystine-depleting agent, end-stage renal disease will develop early, followed by multiple organ failure as the disease progresses. The established cysteamine formulation requires a strict dosing regimen at 6-h intervals. An extended release (ER) twice-daily formulation has recently been developed. The aim of our study was to evaluate the implementation and outcomes of this option in routine care. Methods: All pediatric cystinosis patients' records in Hannover Medical School were screened, and data on cysteamine therapy, tolerability, dosing, estimated glomerular filtration rates (eGFR), white blood cell cystine levels, and proton pump inhibitor (PPI) use were extracted for the period January 2014 to January 2016. Results: The median age of the 12 patients enrolled in the study was 12.5 (range 1-18) years. At the end of the study period ten of these patients received ER-cysteamine. There were no additional side effects. Halitosis/bad breath was often subjectively judged as improved or eliminated, and PPI use could be stopped in one of three patients. The main reasons for switching to the ER formulation were difficult night-time administration and uncontrolled disease. Mean eGFR values remained stable with a median of 67 ml/min/1.73 m before and after the transition. White blood cell (WBC) cystine values remained low after the switch (1 nmol/mg protein before and after transition; p = 0.64). Conclusions: In this single-center cohort, the switch from IR- to ER-cysteamine was safe and effective over the short term and provided advantages in terms of frequency of administration and less halitosis/bad breath. The long-term benefit of this option needs to be evaluated in future studies. [ABSTRACT FROM AUTHOR]

To overcome the major disadvantages of cysteamine, the only registered treatment for the rare genetic disease cystinosis, nine prodrugs of γ-glutamyl-cysteamine ( 4 ) were synthesized for evaluation. Esterification of the thiol conferred oxidative stability, while sufficient lipophilicity for oral bioavailability was achieved by acylation of the α-carboxyl group of γ-glutamyl-cysteamine ( 4 ). Low cytotoxicity was observed in cultured HaCaT keratinocytes using the MTT assay, with EC 50 values higher than or similar to that of cysteamine. Successful uptake of the esterified prodrugs and the subsequent release of cysteamine into cultured human proximal tubule epithelial cells were demonstrated using CMQT derivatisation and HPLC with UV detection. These prodrugs show potential as novel delivery vehicles of cysteamine to improve the treatment of the genetic disorder nephropathic cystinosis. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis is a rare disorder causing the accumulation of intracellular cystine crystals in tissues. The damage to the proximal tubules of the kidneys results in Fanconi syndrome, and patients with cystinosis experience the progression of chronic kidney disease, resulting in the need for kidney transplantation. Treatment of cystinosis with cysteamine has proven to be effective; however, it has many gastrointestinal side effects that are concerning for transplant specialists during the immediate post-transplant period. Transplant specialists routinely discontinue cysteamine therapy for up to six weeks to ensure proper immunosuppressant absorption. This practice is worrisome because it communicates the acceptability of lapses of cysteamine treatment to patients. It may be better to re-initiate cysteamine therapy shortly after transplantation while the patient is followed more closely by the transplant team. This report presents two pediatric patients with nephropathic cystinosis who successfully restarted cysteamine therapy in the immediate post-transplant period without issue in regard to immunosuppression absorption or gastrointestinal side effects. These cases challenge current practice of discontinuing cysteamine therapy during kidney transplantation, and immediate re-initiation of cysteamine therapy in cystinosis patients post-transplant should be considered. [ABSTRACT FROM AUTHOR]

Background and objectives: Nephropathic cystinosis is a lysosomal storage disorder characterized by renal tubular Fanconi syndrome in infancy and glomerular damage leading to renal failure at ∼10 years of age. Therapy with the cystine-depleting agent cysteamine postpones renal failure, but the degree of compliance with this treatment has not been correlated with preservation of kidney function. Methods: We assessed leucocyte cystine depletion by cysteamine and created the composite compliance score that incorporates the extent of leucocyte cystine depletion, as well as duration of cysteamine treatment, into a single integer. Age at renal failure was used to gauge preservation of renal function, and the Fanconi syndrome index (FSI), a measure of aminoaciduria, was used to assess renal tubular Fanconi syndrome. Results: Age at renal failure varied directly and linearly with the composite compliance score ( y = 0.3x +8.8; R = 0.61). The slope indicated that for every year of excellent cystine depletion, nearly 1 year of renal function was preserved. Age at renal failure correlated roughly with mean leucocyte cystine level, but not with mean cysteamine dosage. There was no correlation between the FSI and the composite compliance score. Conclusions: Greater compliance with oral cysteamine therapy yields greater preservation of renal glomerular, but not tubular, function. Oral cysteamine therapy should be given at the maximum tolerated dose, within the recommended limits. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is an inherited autosomal recessive lysosomal storage disorder characterized by the pathological accumulation and crystallization of cystine inside different cell types. WBC cystine determination forms the basis for the diagnosis and therapeutic monitoring with the cystine depleting drug (cysteamine). The chitotriosidase enzyme is a human chitinase, produced by activated macrophages. Its elevation is documented in several lysosomal storage disorders. Although, about 6% of Caucasians have enzyme deficiency due to homozygosity of 24-bp duplication mutation in the chitotriosidase gene, it is currently established as a screening marker and therapeutic monitor for Gaucher’s disease. Methods: Plasma chitotriosidase activity was measured in 45 cystinotic patients, and compared with 87 healthy controls and 54 renal disease patients with different degrees of renal failure (CKD1-5). Chitotriosidase levels were also correlated with WBC cystine in 32 treated patients. Furthermore, we incubated control human macrophages in-vitro with different concentrations of cystine crystals and monitored the response of tumor necrosis factor-alpha (TNF-α) and chitotriosidase activity. We also compared plasma chitotriosidase activity in cystinotic knocked-out (n = 10) versus wild-type mice (n = 10). Results: Plasma chitotriosidase activity in cystinotic patients (0–3880, median 163 nmol/ml/h) was significantly elevated compared to healthy controls (0–90, median 18 nmol/ml/h) and to CKD patients (0–321, median 52 nmol/ml/h), P < 0.001 for both groups. Controls with decreased renal function had mild to moderate chitotriosidase elevations; however, their levels were significantly lower than in cystinotic patients with comparable degree of renal insufficiency. Chitotriosidase activity positively correlated with WBC cystine content for patients on cysteamine therapy (r = 0.8), P < 0.001. In culture, human control macrophages engulfed cystine crystals and released TNF-α into culture supernatant in a crystal concentration dependent manner. Chitotriosidase activity was also significantly increased in macrophage supernatant and cell-lysate. Furthermore, chitotriosidase activity was significantly higher in cystinotic knocked-out than in the wild-type mice, P = 0.003. Conclusions: This study indicates that cystine crystals are potent activators of human macrophages and that chitotriosidase activity is a useful marker for this activation and a promising clinical biomarker and therapeutic monitor for nephropathic cystinosis. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis is a rare and severe disease caused by disruptions in the CTNS gene. Cystinosis is characterized by lysosomal cystine accumulation, vesicle trafficking impairment, oxidative stress, and apoptosis. Additionally, cystinotic patients exhibit weakening and leakage of the proximal tubular segment of the nephrons, leading to renal Fanconi syndrome and kidney failure early in life. Current in vitro cystinotic models cannot recapitulate all clinical features of the disease which limits their translational value. Therefore, the development of novel, complex in vitro models that better mimic the disease and exhibit characteristics not compatible with 2-dimensional cell culture is of crucial importance for novel therapies development. In this study, we developed a 3-dimensional bioengineered model of nephropathic cystinosis by culturing conditionally immortalized proximal tubule epithelial cells (ciPTECs) on hollow fiber membranes (HFM). Cystinotic kidney tubules showed lysosomal cystine accumulation, increased autophagy and vesicle trafficking deterioration, the impairment of several metabolic pathways, and the disruption of the epithelial monolayer tightness as compared to control kidney tubules. In particular, the loss of monolayer organization and leakage could be mimicked with the use of the cystinotic kidney tubules, which has not been possible before, using the standard 2-dimensional cell culture. Overall, bioengineered cystinotic kidney tubules recapitulate better the nephropathic phenotype at a molecular, structural, and functional proximal tubule level compared to 2-dimensional cell cultures. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is an autosomal recessive systemic severe disease characterized by intralysosomal cystine storage. Cysteamine is an essential component of treatment. There is solid evidence that cystine accumulation itself is not responsible for all abnormalities in cystinosis; there is also a deficiency of glutathione in the cytosol. Patients with cystinosis can be more susceptible to oxidative stress. Case-Diagnosis/Treatment: The patient cohort comprised 23 cystinosis patients (16 males) aged <18 years (mean age 8.0 ± 3.6 years) with chronic kidney disease class I-IV with good adherence to treatment, including cysteamine. Oxidative stress was evaluated based on the levels of serum thiobarbituric acid-reactive substances (TBARS), and renal function was evaluated based on serum creatinine and cystatin C levels and creatinine clearance (Schwartz formula). N-Acetylcysteine (NAC), an antioxidant drug was given to all patients for 3 months (T1) at 25 mg/kg/day divided in three doses per day. The measured values at just before the initiation of NAC treatment (T0) served as the control for each patient. Results: Median serum TBARS levels at T0 and T1 were 6.92 (range 3.3-29.0) and 1.7 (0.6-7.2) nmol/mL, respectively ( p < 0.0001). In terms of renal function at T0 and T1, serum creatinine levels (1.1 ± 0.5 vs. 0.9 ± 0.5 mg/dL, respectively; p < 0.0001), creatinine clearance (69.7 ± 32.2 vs. T1 = 78.5 ± 33.9 mL/min/1.73 m, respectively; p = 0.006), and cystatin c level (1.33 ± 0.53 vs. 1.15 ± 0.54 mg/l, respectively; p = 0.0057) were all significantly different at these two time points. Serum creatinine measurements at 6 (T −6) and 3 months (T −3) before NAC initiation and at 3 (T +3) and 6 months (T +6) after NAC had been withdrawn were also evaluated. Conclusion: During the 3-month period that our 23 cystinosis patients were treated with NAC, oxidative stress was reduced and renal function significantly improved. No side-effects were detected. Larger and controlled studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis (NC) is a rare autosomal recessive storage disease characterized by the lysosomal accumulation of cystine crystals throughout the body, particularly in blood cells, the cornea, skin, kidneys, the central nervous system, and the muscles. The skin and the cornea are the most accessible sites to explore, and in vivo reflectance confocal microscopy (IVCM) helps identify crystals in both but does not provide any information to help define their composition. Raman spectroscopy (RS) allows cystine to be easily recognized thanks to its characteristic signature with a band at 499 cm-1. Two dermatology confocal microscopes were used to visualize crystals in both the skin and the ocular surface of a cystinosis patient, and an ex vivo Raman examination of a skin biopsy and of the cornea was performed and removed during a corneal graft to confirm the cystine composition of the crystals. Recently, RS has been performed in vivo and coupled with IVCM. In the future, it is suggested that crystals in NC and other deposits in storage diseases could be identified with this noninvasive in vivo technique that combines IVCM to recognize the deposits and RS to confirm their chemical nature. [ABSTRACT FROM AUTHOR]

Background: Nephropathic cystinosis is an autosomal recessively inherited metabolic disorder presenting with metabolic acidosis, Fanconi syndrome and renal failure. Case Presentation: We present a 6-year-old girl with severe growth failure, hyponatremia and hypokalemia. Her parents were 4th degree relatives. Two relatives were diagnosed as end stage renal failure. She also had persistant hypokalemic hypochloremic metabolic alkalosis. Her renal function was normal at presentation. She was thought to have Bartter syndrome with supporting findings of elevated levels of renin and aldosterone with normal blood pressure, and hyperplasia of juxtaglomerular apparatus. Her metabolic alkalosis did not resolve despite supportive treatment. At 6th month of follow-up proteinuria, glucosuria and deterioration of renal function developed. Diagnosis of cystinosis was made with slit lamp examination and leukocyte cystine levels. At 12th month of follow-up her metabolic alkalosis has converted to metabolic acidosis. Conclusion: In children presenting with persistant metabolic alkalosis, with family history of renal failure, and parental consanguinity, cystinosis should always be kept in mind as this disease is an important cause of end stage renal failure which may have features mimmicking Bartter syndrome. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis (NC) is a severe disease that is complicated by early-onset chronic renal failure (CRF) and other complications related to cystine deposition in tissue. Since the 1980s, the prognosis of NC has dramatically improved after the introduction of cysteamine treatment. Limited data are available documenting improvement in prognosis. We reviewed our long-term data (follow-up 6.3-27.8 years) on 23 patients followed in the past 26 years. Overall, stage III CRF was reached at 10 years of age in >90% of patients, whereas >80% reached end-stage renal disease before the age of 14 years. Three patients died during the follow-up. Our analysis shows a clear improvement in renal outcome ( p = 0.001) and linear growth ( p = 0.04) in patients treated more recently. Improvement in the evolution of renal function was significantly associated with early initiation of cysteamine ( p = 0.006), with the dose of cysteamine ( p = 0.04), and with the use of angiotensin-converting enzyme inhibitors ( p = 0.01). Nonrenal long-term complications are similar to previously reported data. Of note, 3/23 patients developed rare forms of primary tumors that were successfully treated. In conclusion, our experience shows a significant improvement in the renal and nonrenal complications of cystinosis over the past decades and highlights the importance of early diagnosis in order to initiate cysteamine as soon as possible. [ABSTRACT FROM AUTHOR]

Background/Aims: Nephrogenic diabetes insipidus (NDI) is a serious condition with large water losses in the urine and the risk of hypernatremic dehydration. Unrecognized, repeated episodes of hypernatremic dehydration can lead to permanent brain damage. Primary NDI is due to mutations in either AVPR2 or AQP2. NDI can also occur as a secondary complication, most commonly from obstructive uropathy or chronic lithium therapy. We observed NDI in patients with inherited tubulopathies and aimed to define the clinical and molecular phenotype. Methods: We reviewed the medical notes of 4 patients with clinical NDI and an underlying molecularly confirmed diagnosis of nephropathic cystinosis, Bartter syndrome, nephronophthisis and apparent mineralocorticoid excess, respectively. Results: The patients all failed to concentrate their urine after administration of 1-desamino[8-D-arginine] vasopressin. None had an identifiable mutation in AVPR2 or AQP2, consistent with secondary NDI. Patients experienced repeated episodes of hypernatremic dehydration, and in 2 cases, NDI was initially thought to be the primary diagnosis, delaying recognition of the underlying problem. Conclusion: The recognition of this potential complication is important as it has direct implications for clinical management. The occurrence of NDI in association with these conditions provides clues for the etiology of aquaporin deficiency. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis (NC) is an autosomal recessive disorder caused by mutations of the CTNS gene that encodes for a cystine transmembrane transporter. Several mutations have been described in the coding and promoter regions of the CTNS gene in affected individuals. We selected three patients with NC from two unrelated families, in whom sequence analysis of the CTNS gene detected only one or no mutations. Total RNA was isolated from peripheral blood mononuclear cells or fibroblasts and CTNS transcripts were analyzed. We observed a skipping of exon 5 (85 bp) in two siblings and an intron 9 retention of 75 bp associated with partial replication of exon 9 in the third patient. Genomic DNA analysis of intron regions surrounding exon 5 showed a point mutation in the hypothetical lariat branch site of intron 4 at position –24 (c.141–24 T > C) in the first two patients and a duplication of 266 bp including a part of exon and intron 9 in the third patient. Analysis of CTNS gene transcripts allowed identification of mutations in patients in whom CTNS mutations could not be detected by traditional DNA sequencing. These results support the hypothesis that cystinosis is a monogenic disorder. [ABSTRACT FROM AUTHOR]

Abstract: The cysteine/cystine (Cys/CySS) couple represents one of the major cell thiol/disulfide systems and is involved in the regulation of several metabolic pathways and the cell redox state. Nephropathic cystinosis (NC) is an autosomal recessive disease characterized by renal cellular dysfunction due to mutations in the CTNS gene, which encodes cystinosin, a CySS lysosomal transporter. To analyze the mechanisms involved in cell damage in NC, we have investigated the effects of CTNS gene overexpression or inhibition on cell thiol/disulfide systems and vice versa. Overexpression of the CTNS gene had no remarkable effect on intracellular Cys/CySS and GSH/GSSG redox state. Silencing the CTNS gene increased cell CySS and Cys and decreased cell GSH and GSSG and increased mildly the redox state of the Cys/CySS-couple. Extracellular CySS and Cys deprivation for 48 h caused an oxidation of the Cys/CySS (73 mV) and GSH/GSSG (100 mV) redox couples and increased CTNS mRNA levels by 1.9±0.2-fold (p <0.001). Conversely, a reduced cell environment associated with a GSH/GSSG reduction from −250.1±3.10 to −330.6±4.70 mV (p <0.001) and a Cys/CySS reduction from −167.0±11.30 to −240.0±8.17 mV (p <0.005) was associated with a 40% decrease in CTNS mRNA levels (p <0.05). By regression analysis, CTNS gene expression was correlated with intracellular Cys level and with Cys/CySS redox state. [Copyright &y& Elsevier]

Nephropathic cystinosis is a lysosomal disorder caused by functional defects of cystinosin, which mediates cystine efflux into the cytosol. The protein sequence contains at least two signals that target the protein to the lysosomal compartment, one of which is located at the carboxy terminal tail (GYDQL). We have isolated from a human kidney cDNA library a cystinosin isoform, which is generated by an alternative splicing of exon 12 that removes the GYDQL motif. Based on its last three amino acids, we have termed this protein cystinosin-LKG. Contrary to the lysosomal cystinosin isoform, expression experiments performed by transient transfection of green fluorescent protein fusion plasmids in HK2 cells showed that cystinosin-LKG is expressed in the plasma membrane, in lysosomes, and in other cytosolic structures. This subcellular localization of the protein was confirmed by transmission electron microscopy. In addition, immunogold labeling was observed in the endoplasmic reticulum and in the Golgi apparatus. Expression of the protein in renal tubular structures was also directly demonstrated by immunostaining of normal human kidney sections. The plasma membrane localization of cystinosin-LKG was directly tested by [35S]cys- tine flux experiments in COS-1 cells. In the presence of a proton gradient, a marked enhancement of intracellular cystine transport was observed in cells overexpressing this isoform. These data indicate that the expression of the gene products encoded by the CTNS gene is not restricted to the lysosomal compartment. These finding may help elucidate the mechanisms of cell dysfunction in this disorder. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis is a lysosomal storage disorder, which, if untreated, results in renal failure by age 10 years. Oral cysteamine has been shown to preserve renal function in these patients. In this study, a 2-year-old girl with nephropathic cystinosis and severe gastrointestinal dysmotility was treated with intravenous (i.v.) administration of cysteamine hydrochloride (HCl). This is only the second report of long-term i.v. cysteamine therapy for nephropathic cystinosis. Unlike the treatment in the previous case, however, treatment in our patient was limited by liver toxicity. [ABSTRACT FROM AUTHOR]

In children, dilated coronary arteries are usually caused by Kawasaki’s disease. We report four children with dilated coronary arteries and nephropathic cystinosis. [ABSTRACT FROM AUTHOR]

Background: We aimed to identify diagnosed cases of ocular cystinosis and describe clinical, epidemiological and therapeutic characteristics. Methods: This is a descriptive and retrospective case series. All patients underwent a full check-up examination every 4–6 months by ophthalmologists, nephrologists and other required specialists. Results: Of the seven cases, six (85.7%) were females and one (14.2%) was male. The infantile nephropathic form of cystinosis was observed in five patients and the juvenile nephropathic form in two patients. No patients with the ocular form of cystinosis were identified. Corneal cystine crystals (CCC) were found in all analyzed patients. Severe ocular and general complications of the disease that had been standing for years, connected to the infantile nephropathic form, delayed diagnosis or inappropriate treatment, were observed only in two patients. All patients received topical therapy. No adverse events related to the therapy were observed. Conclusions: Cystinosis is a rare, progressive disease. Early diagnosis and treatment prevent serious complications from numerous systemic organs. Patients require constant systematic monitoring by various specialists. [ABSTRACT FROM AUTHOR]

Cystinosis is a rare autosomal recessive disease caused by mutations of the CTNS gene in which cystine accumulates throughout the body as a result of a defective efflux of cystine from lysosomes. Three phenotypic forms have been described according to the age of onset and the severity of the clinical symptoms: infantile, intermediate, and ocular non-nephropathic cystinosis. Here we report the natural history of cystinosis in a 55-year-old man with intermediate nephropathic cystinosis diagnosed at 9 years of age. Although tubulopathy was unnoticed in the early years, he required transplantation at age 16. Sequencing analysis of all the CTNS exons revealed that the proband is homozygous for a 21-bp in-frame deletion in exon 5 (c. 198_218del21), resulting in an in-frame deletion of 7 amino acids from the N-terminal domain of the cystinosin protein. Our patient has had relatively mild extra-renal disease despite lack of early cysteamine therapy. He has been able to attend university and pursue a professional career into the 6th decade. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of "cystinosis metabolic bone disease" is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both CTNS mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nephropathic cystinosis is a severe autosomal recessive inherited metabolic disease characterized by accumulation of free cystine in lysosomes. Cystinosis can lead to renal failure and multiorgan impairment. Only five cases of cystinosis with associated Bartter syndrome are reported in the literature, and no genetic evaluation has been reported. We describe two siblings with nephropathic cystinosis presenting with features of Bartter syndrome and their genetic pattern. [ABSTRACT FROM AUTHOR]