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Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomal cystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of life through proximal tubular damage followed by progressive glomerular damage and end stage renal failure during mid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS. Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Several lines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacement therapy, hormonal therapy and others; however, no curative treatment is yet available. In the current review we will discuss the most important clinical features of the disease, advantages and disadvantages of the current diagnostic and therapeutic options and the main topics of future research in cystinosis.

Background Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients’ clinical and morphological presentation over the past decades have not yet been thoroughly investigated. Methods Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016). Results In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z -score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z -score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients. Conclusions Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information

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. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Cystinosis is a rare lysosomal storage disease characterised by cystine crystal formation within cells. In the eyes, crystals accumulate in the cornea causing photophobia, loss of visual acuity, and corneal complications. Strict adherence to topical cysteamine treatment is the only therapy that reduces corneal crystal accumulation. Cystinosis, a crystallopathy, is also a disease of inflammation. As the disease progresses the inflammatory processes have a greater impact on the ocular manifestations. The age at which inflammation becomes increasingly significant is dependent on the adequacy of early patient management and adherence with therapy. As patients are living longer with cystinosis, optimising ocular management is increasingly important. No clinical guidelines addressing the long-term ocular management of cystinosis exist. Similarly, there is little recognition in the literature of how to address the inflammatory component of the disease. This paper presents management guidelines, linked to the 3C Classification of severity, used at our centre that provides a framework for optimising care. Adoption of these can help preserve the sight of cystinosis patients. The paper also hypothesises the molecular pathway leading to corneal inflammation.

This study aimed to develop and validate the University of California Irvine Corneal Cystine Crystal Score (UCI CCCS), a novel grading system for objectively assessing corneal crystal deposition in cystinosis patients using a slit lamp biomicroscope. This tool provides a standardized method for monitoring disease progression and evaluating treatment efficacy. This retrospective study analyzed clinical records from 36 cystinosis patients examined at the Day of Hope conference, all with the infantile nephropathic form. The records included evaluations from slit-lamp examinations and Best Corrected Visual Acuity (BCVA). After evaluation, the UCI CCCS was developed by experts in pediatric ophthalmology and cornea specialty; this system differentiates cystine crystal density, iris visibility, and corneal haze on a scale from 0 to 5. For validation, 107 slit-lamp images were assessed by masked graders. Statistical analysis using Intraclass Correlation Coefficient (ICC) and Cohen’s kappa was performed to confirm the tool’s ability to produce consistent, reproducible results across and within graders. The cohort included 23 males and 13 females (mean age: 15.64 years, range: 0–60). A total of 72 eyes were evaluated. In the validation phase, the UCI CCCS demonstrated high inter-rater agreement (κ = 0.869, P < 0.001) and excellent intra-rater reliability (ICC = 0.922, P < 0.001). The UCI CCCS is a validated, reliable, and reproducible tool for assessing corneal crystal involvement in cystinosis, supporting its clinical and research applications.

Cystinosis is a rare autosomal-recessive lysosomal storage disease with high morbidity and mortality. It is caused by mutations in the CTNS gene that encodes the cystine transporter, cystinosin, which leads to lysosomal cystine accumulation. Patients with infantile nephropathic cystinosis, the most common and most severe clinical form of cystinosis, commonly present with renal Fanconi syndrome by 6–12 months of age, and without specific treatment, almost all will develop end-stage renal disease (ESRD) by 10–12 years of age. Early corneal cystine crystal deposition is a hallmark of the disease. Cystinosis also presents with gastrointestinal symptoms (e.g., vomiting, decreased appetite, and feeding difficulties) and severe growth retardation and may affect several other organs over time, including the eye, thyroid gland, gonads, pancreas, muscles, bone marrow, liver, nervous system, lungs, and bones. Cystine-depleting therapy with cysteamine orally is the only specific targeted therapy available for managing cystinosis and needs to be combined with cysteamine eye drops for corneal disease involvement. In patients with early treatment initiation and good compliance to therapy, long-term cysteamine treatment delays progression to ESRD, significantly improves growth, decreases the frequency and severity of extrarenal complications, and is associated with extended life expectancy. Therefore, early diagnosis of cystinosis and adequate life-long treatment with cysteamine are essential for preventing end-organ damage and improving the overall prognosis in these patients.

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.

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 2  = 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.

Key Points Cystinosis is a multi-systemic lysosomal storage disease caused by inactivating mutations in, or the absence of, the lysosomal membrane exporter for cystine, cystinosin; cystinosis is the main cause of hereditary renal Fanconi syndrome Treatment with cysteamine efficiently depletes lysosomal cystine and delays progression to renal insufficiency; however, cysteamine does not reverse established renal Fanconi syndrome, indicating functions of cystinosin beyond cystine transport Insights from mechanistic studies suggest that the pathological mechanisms of Fanconi syndrome in cystinosis are multifactorial, involving oxidative stress and impaired vesicular trafficking, autophagy, and mTORC1 and TFEB signalling Haematopoietic stem cell (HSC) transplantation ameliorates renal Fanconi syndrome in cystinotic mice; HSCs differentiate into macrophages that transfer cystinosin-bearing lysosomes into proximal tubule cells via tunnelling nanotubes that cross the tubular basement membrane Since tunnelling nanotubes contain donor-derived cytosol and carry all types of organelles, this mechanism should be generic and could be used to correct other genetic diseases that affect proximal tubule cells One of the first manifestations of cystinosis is a renal Fanconi syndrome, characterized by severe dysfunction of proximal tubule cells. This Review describes the pathogenesis of renal Fanconi syndrome in cystinosis, focusing on the importance of cystinosin in the maintenance of cellular homeostasis beyond its function in cystine transport. Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. It is caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, a renal Fanconi syndrome is often the first manifestation of cystinosis, usually presenting within the first year of life and characterized by the early and severe dysfunction of proximal tubule cells, highlighting the unique vulnerability of this cell type. The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome. This Review summarizes decades of studies that have fostered a better understanding of the pathogenesis of the renal Fanconi syndrome associated with cystinosis. These studies have unraveled some of the early molecular changes that occur before the onset of tubular atrophy and identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy and the regulation of energy balance. These studies have also led to the identification of new potential therapeutic targets and here, we outline the potential role of stem cell therapy for cystinosis and provide insights into the mechanism of haematopoietic stem cell-mediated kidney protection.

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.