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Orphanet Journal of Rare Diseases Apr 2016Cystinosis 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... (Review)
Review
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.
Topics: Amino Acid Transport Systems, Neutral; Child; Cystine; Cystinosis; Humans
PubMed: 27102039
DOI: 10.1186/s13023-016-0426-y -
Cells Dec 2021Cystinosis is a rare inheritable lysosomal storage disorder characterized by cystine accumulation throughout the body, chronic kidney disease necessitating renal... (Review)
Review
Cystinosis is a rare inheritable lysosomal storage disorder characterized by cystine accumulation throughout the body, chronic kidney disease necessitating renal replacement therapy mostly during adolescence, and multiple extra-renal complications. The majority of male cystinosis patients are infertile due to azoospermia, in contrast to female patients who are fertile. Over recent decades, the fertility status of male patients has evolved from a primary hypogonadism in the era before the systematic treatment with cysteamine to azoospermia in the majority of cysteamine-treated infantile cystinosis patients. In this review, we provide a state-of-the-art overview on the available clinical, histopathological, animal, and in vitro data. We summarize current insights on both cystinosis males and females, and their clinical implications including the potential effect of cysteamine on fertility. In addition, we identify the remaining challenges and areas for future research.
Topics: Animals; Biomarkers; Cysteamine; Cystinosis; Disease Models, Animal; Fertility; Humans; Models, Biological
PubMed: 34944047
DOI: 10.3390/cells10123539 -
Nature Dec 2020Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the...
Dozens of genes contribute to the wide variation in human pigmentation. Many of these genes encode proteins that localize to the melanosome-the organelle, related to the lysosome, that synthesizes pigment-but have unclear functions. Here we describe MelanoIP, a method for rapidly isolating melanosomes and profiling their labile metabolite contents. We use this method to study MFSD12, a transmembrane protein of unknown molecular function that, when suppressed, causes darker pigmentation in mice and humans. We find that MFSD12 is required to maintain normal levels of cystine-the oxidized dimer of cysteine-in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation. Tracing and biochemical analyses show that MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Indeed, loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter cystinosin. Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes.
Topics: Biological Transport; Cell Fractionation; Cell Line; Cysteine; Cystine; Cystinosis; Fibroblasts; Humans; Lysosomes; Melanins; Melanosomes; Membrane Proteins; Oxidation-Reduction
PubMed: 33208952
DOI: 10.1038/s41586-020-2937-x -
Journal of the American Society of... Mar 2015Crystalline nephropathy refers to renal parenchymal deposition of crystals leading to kidney damage. The most common forms of crystalline nephropathy encountered in...
Crystalline nephropathy refers to renal parenchymal deposition of crystals leading to kidney damage. The most common forms of crystalline nephropathy encountered in renal pathology are nephrocalcinosis and oxalate nephropathy. Less frequent types include urate nephropathy, cystinosis, dihydroxyadeninuria, and drug-induced crystalline nephropathy (e.g., caused by indinavir or triamterene). Monoclonal proteins can also deposit in the kidney as crystals and cause tissue damage. This occurs in conditions such as light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulinemia. The latter is a rare complication of multiple myeloma that results from crystallization of monoclonal proteins in the systemic vasculature, leading to vascular injury, thrombosis, and occlusion. In this report, we describe a case of crystalglobulin-induced nephropathy and discuss its pathophysiology and the differential diagnosis of paraprotein-induced crystalline nephropathy.
Topics: Biopsy; Crystallization; Female; Humans; Kidney; Kidney Diseases; Middle Aged; Multiple Myeloma; Serum Globulins
PubMed: 25190731
DOI: 10.1681/ASN.2014050509 -
Cells Feb 2022Cystinosis is a lethal autosomal recessive disease that has been known clinically for over 100 years. There are now specific treatments including dialysis, renal... (Review)
Review
Cystinosis is a lethal autosomal recessive disease that has been known clinically for over 100 years. There are now specific treatments including dialysis, renal transplantation and the orphan drug, cysteamine, which greatly improve the duration and quality of patient life, however, the cellular mechanisms responsible for the phenotype are unknown. One cause, programmed cell death, is clearly involved. Study of extant literature via Pubmed on "programmed cell death" and "apoptosis" forms the basis of this review. Most of such studies involved apoptosis. Numerous model systems and affected tissues in cystinosis have shown an increased rate of apoptosis that can be partially reversed with cysteamine. Proposed mechanisms have included changes in protein signaling pathways, autophagy, gene expression programs, and oxidative stress.
Topics: Apoptosis; Autophagy; Cysteamine; Cystinosis; Humans; Kidney Transplantation
PubMed: 35203319
DOI: 10.3390/cells11040670 -
Cells Jun 2022Early diagnosis and effective therapy are essential for improving the overall prognosis and quality of life of patients with nephropathic cystinosis. The severity of... (Review)
Review
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.
Topics: Biomarkers; Cysteamine; Cystine; Cystinosis; Fanconi Syndrome; Humans; Quality of Life
PubMed: 35681534
DOI: 10.3390/cells11111839 -
Cells Mar 2022Cystinosis is a rare lysosomal storage disease that is tightly linked with the name of the American physician and scientist Dr. Jerry Schneider. Dr. Schneider...
Cystinosis is a rare lysosomal storage disease that is tightly linked with the name of the American physician and scientist Dr. Jerry Schneider. Dr. Schneider (1937-2021) received his medical degree from Northwestern University, followed by a pediatrics residency at Johns Hopkins University and a fellowship in inherited disorders of metabolism. He started to work on cystinosis in J. Seegmiller's laboratory at the National Institutes of Health (NIH) and subsequently moved to the UC San Diego School of Medicine, where he devoted his entire career to people suffering from this devastating lysosomal storage disorder. In 1967, Dr. Schneider's seminal paper 'Increased cystine in leukocytes from individuals homozygous and heterozygous for cystinosis' opened a new era of research towards understanding the pathogenesis and finding treatments for cystinosis patients. His tremendous contribution transformed cystinosis from a fatal disorder of childhood to a treatable chronic disease, with a new generation of cystinosis patients being now in their 40th and 50th years. Dr. Schneider wrote a fascinating 'Personal History of Cystinosis' highlighting the major milestones of cystinosis research. Unfortunately, he passed away before this manuscript could be published. Fifty-five years after his first paper on cystinosis, the 'Personal History of Cystinosis' by Dr. Schneider is a tribute to his pioneering discoveries in the field and an inspiration for young doctors and scientists who have taken over the torch of cystinosis research towards finding a cure for cystinosis.
Topics: Child; Cystinosis; Heterozygote; History, 21st Century; Homozygote; Humans; Leukocytes; Male; Medicine; United States
PubMed: 35326395
DOI: 10.3390/cells11060945 -
Cells Jan 2022The activation of several inflammatory pathways has recently been documented in patients and different cellular and animal models of nephropathic cystinosis. Upregulated... (Review)
Review
The activation of several inflammatory pathways has recently been documented in patients and different cellular and animal models of nephropathic cystinosis. Upregulated inflammatory signals interact with many pathogenic aspects of the disease, such as enhanced oxidative stress, abnormal autophagy, inflammatory cell recruitment, enhanced cell death, and tissue fibrosis. Cysteamine, the only approved specific therapy for cystinosis, ameliorates many but not all pathogenic aspects of the disease. In the current review, we summarize the inflammatory mechanisms involved in cystinosis and their potential impact on the disease pathogenesis and progression. We further elaborate on the crosstalk between inflammation, autophagy, and apoptosis, and discuss the potential of experimental drugs for suppressing the inflammatory signals in cystinosis.
Topics: Animals; Autophagy; Cystinosis; Humans; Inflammasomes; Inflammation; Kidney Diseases; Molecular Targeted Therapy
PubMed: 35053306
DOI: 10.3390/cells11020190