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2.
Int J Mol Sci ; 25(3)2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38338900

RESUMO

Cystinosis is a low-prevalence lysosomal storage disease. The pathomechanism involves abnormal functioning of the cystinosine lysosomal cystine transporter (CTNS), causing intraliposomal accumulation of the amino acid cysteine disulfide, which crystallizes and deposits in several parts of the body. The most common ophthalmic complication of cystinosis is the deposition of "gold dust" cystine crystals on the cornea, which already occurs in infancy and leads to severe photosensitivity and dry eyes as it gradually progresses with age. In the specific treatment of cystinosis, preparations containing cysteamine (CYA) are used. The availability of commercialized eyedrops for the targeted treatment is scarce, and only Cystadrops® are commercially available with strong limitations. Thus, magistral CYA-containing compounded eyedrops (CYA-CED) could have a key role in patient care; however, a rationally designed comprehensive study on the commercialized and magistral products is still missing. This work aims to build up a comprehensive study about commercialized and magistral CYA eye drops, involving pharmacokinetic and physicochemical characterization (applying mucoadhesivity, rheology test, investigation of drug release, and parallel artificial membrane permeability assays), as well as ex vivo tests, well supported by statistical analysis.


Assuntos
Cistinose , Humanos , Cistinose/metabolismo , Cisteamina/uso terapêutico , Cisteamina/metabolismo , Cistina/metabolismo , Soluções Oftálmicas/uso terapêutico , Córnea/metabolismo
3.
Transpl Immunol ; 83: 101993, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38224843

RESUMO

Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by cystine buildup in various tissues, including the kidneys. Renal involvement is the primary manifestation, leading to end-stage renal disease (ESRD) if left untreated. Kidney transplantation (KT) in patients with cystinosis has significantly improved their prognosis for the disease outcome. Detailed reports on preoperative and Long-term postoperative management in these patients remain sparse. This report discusses the outcomes of two young adult patients of Middle Eastern descent with cystinosis who underwent KT. The first patient, diagnosed with infantile nephropathic cystinosis treated by cystine-depleting therapy, was operated by KT at the age of 18. The second patient, diagnosed with juvenile cystinosis, underwent transplantation at the age of 35 after being treated with hemodialysis. Our report describes detailed pre- and postoperative managements, including laboratory results, and pharmacological interventions. Both cases highlighted the varying clinical manifestations and disease severity between infantile and juvenile cystinosis. Pre-transplant conditions included renal dysfunction, growth retardation, secondary hyperparathyroidism, anemia, and extrarenal manifestations. Following KT, both patients experienced regained renal function, resolution of extrarenal complications, and normalization of laboratory parameters. Furthermore, both patients showed excellent postoperative outcomes with no acute rejection or allograft-related complications. KT is the treatment of choice for cystinosis patients with ESRD. Long-term follow-up post-transplantation is crucial to maintain good graft function. Further studies may elucidate optimal pre- and postoperative management protocols for this rare condition.


Assuntos
Cistinose , Falência Renal Crônica , Transplante de Rim , Síndrome Nefrótica , Adulto Jovem , Humanos , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Transplante de Rim/efeitos adversos , Cistina/uso terapêutico
4.
Pediatr Nephrol ; 39(4): 1113-1123, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37978055

RESUMO

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.


Assuntos
Cistinose , Síndrome de Fanconi , Humanos , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Cistinose/epidemiologia , Cisteamina/uso terapêutico , Estudos Transversais , Cistina , Acesso aos Serviços de Saúde
5.
Clin Genet ; 105(3): 323-328, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38009794

RESUMO

Cystinosis is a severe, monogenic systemic disease caused by variants in CTNS gene. Currently, there is growing evidence that exonic variants in many diseases can affect pre-mRNA splicing. The impact of CTNS gene exonic variants on splicing regulation may be underestimated due to the lack of routine studies at the RNA level. Here, we analyzed 59 exonic variants in the CTNS gene using bioinformatics tools and identified candidate variants that may induce splicing alterations by minigene assays. We identified six exonic variants that induce splicing alterations by disrupting the ratio of exonic splicing enhancers/exonic splicing silencers (ESEs/ESSs) or by interfering with the recognition of classical splice sites, or both. Our results help in the correct molecular characterization of variants in cystinosis and inform emerging therapies. Furthermore, our work suggests that the combination of in silico and in vitro assays facilitates to assess the effects of DNA variants driving rare genetic diseases on splicing regulation and will enhance the clinical utility of variant functional annotation.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Humanos , Cistinose/genética , Splicing de RNA/genética , Éxons/genética , Sequências Reguladoras de Ácido Nucleico , RNA , Processamento Alternativo , Sítios de Splice de RNA , Sistemas de Transporte de Aminoácidos Neutros/genética
6.
Lab Invest ; 104(1): 100287, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37949358

RESUMO

Cystinosis is an autosomal recessive disease caused by mutations in the CTNS gene encoding a protein called cystinosine, which is a lysosomal cystine transporter. Disease-causing mutations lead to accumulation of cystine crystals in the lysosomes, thereby causing dysfunction of vital organs. Determination of the increased leukocyte cystine level is one of the most used methods for diagnosis. However, this method is expensive, difficult to perform, and may yield different results in different laboratories. In this study, a disease model was created with CTNS gene-silenced HK2 cells, which can mimic cystinosis in cell culture, and multiomics methods (ie, proteomics, metabolomics, and fluxomics) were implemented at this cell culture to investigate new biomarkers for the diagnosis. CTNS-silenced cell line exhibited distinct metabolic profiles compared with the control cell line. Pathway analysis highlighted significant alterations in various metabolic pathways, including alanine, aspartate, and glutamate metabolism; glutathione metabolism; aminoacyl-tRNA biosynthesis; arginine and proline metabolism; beta-alanine metabolism; ascorbate and aldarate metabolism; and histidine metabolism upon CTNS silencing. Fluxomics analysis revealed increased cycle rates of Krebs cycle intermediates such as fumarate, malate, and citrate, accompanied by enhanced activation of inorganic phosphate and ATP production. Furthermore, proteomic analysis unveiled differential expression levels of key proteins involved in crucial cellular processes. Notably, peptidyl-prolyl cis-trans isomerase A, translation elongation factor 1-beta (EF-1beta), and 60S acidic ribosomal protein decreased in CTNS-silenced cells. Additionally, levels of P0 and tubulin α-1A chain were reduced, whereas levels of 40S ribosomal protein S8 and Midasin increased. Overall, our study, through the utilization of an in vitro cystinosis model and comprehensive multiomics approach, led to the way toward the identification of potential new biomarkers while offering valuable insights into the pathogenesis of cystinosis.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Humanos , Cistinose/genética , Cistinose/metabolismo , Cistina/genética , Cistina/metabolismo , Proteômica , Biomarcadores , Inativação Gênica , RNA Interferente Pequeno/genética , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo
7.
Autophagy ; 20(1): 202-204, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37621073

RESUMO

Differentiation and fate decisions are critical for the epithelial cells lining the proximal tubule (PT) of the kidney, but the signals involved remain unknown. Defective cystine mobilization from lysosomes through CTNS (cystinosin, lysosomal cystine transporter), which is mutated in cystinosis, triggers the dedifferentiation and dysfunction of the PT cells, causing kidney disease and severe metabolic complications. Using preclinical models and physiologically relevant cellular systems, along with functional assays and a generative artificial intelligence (AI)-powered engine, we found that cystine storage imparted by CTNS deficiency stimulates Ragulator-RRAG GTPase-dependent recruitment of MTORC1 and its constitutive activation. In turn, this diverts the catabolic trajectories and differentiating states of PT cells toward growth and proliferation, disrupting homeostasis and their specialized functions. Therapeutic MTORC1 inhibition by using low doses of rapamycin corrects lysosome function and differentiation downstream of cystine storage and ameliorates PT dysfunction in preclinical models of cystinosis. These discoveries suggest that cystine may act as a lysosomal fasting signal that tailors MTORC1 signaling to direct fate decisions in the kidney PT epithelium, highlighting novel therapeutic paradigms for cystinosis and other lysosome-related disorders.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Inteligência Artificial , Autofagia , Cistina/metabolismo , Cistinose/metabolismo , Células Epiteliais/metabolismo , Lisossomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
8.
Pediatr Nephrol ; 39(2): 609-612, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37572116

RESUMO

BACKGROUND  : Cystinosis is a rare autosomal recessive lysosomal disorder that mainly affects the kidney and eye. Early treatment with cysteamine significantly improves the prognosis. However, early diagnosis of cystinosis, especially the juvenile nephropathic form, remains challenging because typical symptoms only become apparent in adulthood. We herein describe a 13-year-old girl who presented with proteinuria only but was diagnosed with juvenile nephropathic cystinosis based on multinucleated podocytes in her kidney biopsy specimen. We also studied the nephropathology of another case to determine the features of the multinucleated podocytes. CASE DIAGNOSIS: A previously healthy 13-year-old girl presented to our hospital because proteinuria had been detected in her school urine screening. She had been noted to have proteinuria on her school urine screening when she was 11 years of age but there was no consultation with her physician at that time. She was asymptomatic and had no other abnormalities on examination other than a relatively high urinary ß-2 microglobulin level. Her kidney biopsy showed 15 multinucleated podocytes in 34 glomeruli, and the mean number of nuclei per multinucleated podocyte was 4.4. Ophthalmological examination showed cystine crystals in her cornea. Her white blood cell cystine level was high, and she was diagnosed with juvenile nephropathic cystinosis. She started oral cysteamine treatment and showed almost no progression of the disease after 2 years. In another patient with juvenile nephropathic cystinosis, there were 25 multinucleated podocytes in 63 glomeruli, and the mean number of nuclei per multinucleated podocyte was 2.9. CONCLUSION: Early diagnosis is crucial to improve the prognosis of patients with cystinosis. This report emphasizes the importance of recognizing the unique pathological feature of multinucleated podocytes as an essential clue to the diagnosis of cystinosis.


Assuntos
Cistinose , Podócitos , Feminino , Humanos , Adolescente , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Cisteamina/uso terapêutico , Cistina , Proteinúria/etiologia
9.
J Neurol Sci ; 456: 122841, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38101161

RESUMO

Nephropathic cystinosis is a rare autosomal recessive storage disorder caused by CTNS gene mutations, leading to autophagy-lysosomal pathway impairment and cystine crystals accumulation. Neurologic involvement is highly variable and includes both neurodevelopmental and neurodegenerative disturbances, as well as focal neurologic deficits. By presenting longitudinal data of a 28-year-old patient with a large infratentorial lesion, we summarized the pathology, clinical and imaging features of neurological involvement in cystinosis patients. Brain damage in form of cystinosis-related cerebral lesions occurs in advanced disease phases and is characterized by the accumulation of cystine crystals, subsequent inflammation with vasculitis-like features, necrosis, and calcification. Epilepsy is a frequent comorbidity in affected individuals. Steroids might play a role in the symptomatic treatment of "stroke-like" episodes due to edematous-inflammatory lesions, but probably do not change the overall prognosis. Lifelong compliance to depleting therapy with cysteamine still represents the main therapeutic option. However, consequences of CTNS gene defects are not restricted to cystine accumulation. New evidence of four-repeat (4R-) Tau immunoreactivity suggests concurrent progressive neurodegeneration in cystinosis patients, highlighting the need of innovative therapeutic strategies, and shedding light on the crosstalk between proteinopathies and autophagy-lysosomal system defects. Eventually, emerging easily accessible biomarkers such as serum neurofilament light chains (NfL) might detect subclinical neurologic involvement in cystinosis patients.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Humanos , Adulto , Cistinose/complicações , Cistinose/genética , Cistinose/tratamento farmacológico , Cistina/metabolismo , Cistina/uso terapêutico , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/uso terapêutico , Cisteamina/uso terapêutico , Inflamação/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo
10.
Int J Mol Sci ; 24(23)2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38069326

RESUMO

Cystinosis is an autosomal recessive disease resulting from mutations in ctns, which encodes for cystinosin, a proton-coupled cystine transporter that exports cystine from lysosomes. The major clinical form, infantile cystinosis, is associated with renal failure due to the malfunctioning of the renal proximal tubule (RPT). To examine the hypothesis that the malfunctioning of the cystinotic RPT arises from defective differentiation, human-induced pluripotent stem cells (hiPSCs) were generated from human dermal fibroblasts from an individual with infantile cystinosis, as well as a normal individual. The results indicate that both the cystinotic and normal hiPSCs are pluripotent and can form embryoid bodies (EBs) with the three primordial germ layers. When the normal hiPSCs were subjected to a differentiation regime that induces RPT formation, organoids containing tubules with lumens emerged that expressed distinctive RPT proteins, including villin, the Na+/H+ Exchanger (NHE) isoform 3 (NHE3), and the NHE Regulatory Factor 1 (NHERF1). The formation of tubules with lumens was less pronounced in organoids derived from cystinotic hiPSCs, although the organoids expressed villin, NHE3, and NHERF1. These observations can be attributed to an impairment in differentiation and/or by other defects which cause cystinotic RPTs to have an increased propensity to undergo apoptosis or other types of programmed cell death.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Células-Tronco Pluripotentes Induzidas , Humanos , Cistinose/genética , Cistina/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Trocador 3 de Sódio-Hidrogênio/genética , Mutação , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Lisossomos/metabolismo
11.
Orphanet J Rare Dis ; 18(1): 389, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38087330

RESUMO

BACKGROUND: Cystinosis, a rare lysosomal storage disease caused by mutations in the CTNS gene, is characterized by cystine crystallization and accumulation within multiple tissues, including kidney and brain. Its impact on neural function appears mild relative to its effects on other organs during early disease, but since therapeutic advances have led to substantially increased life expectancy, neurological implications are of increasing interest, necessitating deeper understanding of the impact of cystinosis on neurocognitive function. Behavioral difficulties have been reported in cystinosis in the visual domain. Very little is known, however, about how the brains of people living with cystinosis process visual information. This is especially interesting given that cystine accumulation in the cornea and posterior ocular structures is a hallmark of cystinosis. METHODS: Here, high-density scalp electrophysiology was recorded to visual stimuli (during a Go/No-Go task) to investigate visual processing in individuals with cystinosis, compared to age-matched controls. Analyses focused on early stages of cortical visual processing. RESULTS: The groups differed in their initial cortical response, with individuals with cystinosis exhibiting a significantly larger visual evoked potential (VEP) in the 130-150 ms time window. The groups also differed in the associations between neural responses and verbal abilities: While controls with higher IQ scores presented larger neural responses, that relationship was not observed in cystinosis. CONCLUSIONS: The enlarged VEP in cystinosis could be the result of cortical hyperexcitability and/or differences in attentional engagement and explain, at least partially, the visual and visual-spatial difficulties described in this population.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Oftalmopatias , Criança , Adulto , Humanos , Cistinose/genética , Cistinose/tratamento farmacológico , Cistina/genética , Cistina/metabolismo , Cistina/uso terapêutico , Potenciais Evocados Visuais , Mutação/genética , Percepção Visual , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/uso terapêutico
12.
BMC Nephrol ; 24(1): 351, 2023 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-38031005

RESUMO

BACKGROUND: Nephropathic Cystinosis (NC), a rare disease characterised by intra-lysosomal accumulation of cystine, results in progressive kidney failure (KF). Compliance to lifelong oral cysteamine, the only therapy, is often compromised. The relationship between compliance and costs of NC has not been previously formally assessed. The present study evaluates the impact of compliance on lifetime (direct) costs of treating KF in NC patients in the United Kingdom. METHODS: A three-state (KF-free, post-KF, death) partitioned survival model was developed for hypothetical 'Good Compliance' (GC) and 'Poor Compliance' (PC) cohorts. Survival in the KF-free state was determined by a published regression function of composite compliance score (CCS). The CCS is a summation of annual compliance scores (ACS) over treatment duration prior to KF. ACSs are indexed on annual (average) leukocyte cystine levels (LCL). The Poor Compliance cohort was defined to reflect NC patients in a previous study with a mean LCL of 2.35 nmols nmol half-cystine/mg protein over the study period - and an estimated mean ACS of 1.64 over a 13.4 year treatment duration. The Good Compliance cohort was assumed to have an ACS of 2.25 for 21 years. Major KF costs were evaluated - i.e., dialysis, kidney transplants, and subsequent monitoring. RESULTS: The mean CCS was 47 for the GC and 22 for the PC cohort respectively, corresponding to estimated lifetime KF costs of £92,370 and £117,830 respectively - i.e., a cost saving of £25,460/patient, or £1,005/patient for every 1-unit improvement in CCS. CONCLUSION: This analysis indicates that lifetime costs of KF in NC can be reduced through improved treatment compliance with oral cysteamine.


Assuntos
Cistinose , Síndrome de Fanconi , Insuficiência Renal , Humanos , Cistinose/complicações , Cistinose/tratamento farmacológico , Cistinose/metabolismo , Cisteamina/uso terapêutico , Cistina/metabolismo , Diálise Renal , Cooperação do Paciente , Reino Unido
13.
J Biosci ; 482023.
Artigo em Inglês | MEDLINE | ID: mdl-38018544

RESUMO

Cystinosis is an autosomally inherited rare genetic disorder in which cystine accumulates in the lysosome. The defect arises from a mutation in the lysosomal efflux pump, cystinosin (or CTNS). Despite the disease being known for more than a century, research, diagnosis, and treatment in India have been very minimal. In recent years, however, some research on cystinosis has been carried out on understanding the pathophysiology and in the development of a humanized yeast model for interrogating the CTNS protein. There has also been a greater awareness of the disease that has been facilitated by the formation of the Cystinosis Foundation of India just over a decade ago. Awareness among primary physicians is critical for early diagnosis, which in turn is critical for proper treatment. Eight different mutations have been observed in cystinosis patients in India, and the mutation spectrum seems different to what has been seen in the US and Europe. Despite these positive developments, there are immense hurdles still to be surmounted. This includes ensuring that the diagnosis is done sooner, making cysteamine more easily available, and, also for the future, to make accessible the promise of gene therapy to cystinosis patients.


Assuntos
Cistinose , Humanos , Cistinose/diagnóstico , Cistinose/epidemiologia , Cistinose/genética , Cistina/genética , Cistina/metabolismo , Cisteamina/efeitos adversos , Mutação , Índia/epidemiologia
14.
Sci Rep ; 13(1): 20961, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-38016974

RESUMO

Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to treat the genetic defect in cystinosis using synthetic mRNA in cell models and ctns-/- zebrafish embryos. Cystinosis is a prototype lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal cystine-H+ symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and the most severely affected organs, presenting glomerular and proximal tubular dysfunction, progressing to end-stage kidney failure. The current therapeutic standard cysteamine, reduces cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA can restore lysosomal cystinosin expression following lipofection into CTNS-/- kidney cells and injection into ctns-/- zebrafish. A single CTNS mRNA administration decreases cellular cystine accumulation for up to 14 days in vitro. In the ctns-/- zebrafish, CTNS mRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. Therefore, this proof-of-principle study takes the first steps in establishing an mRNA-based therapy to restore cystinosin expression, resulting in cystine reduction in vitro and in the ctns-/- larvae, and restoration of the zebrafish pronephros function.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Animais , Cistinose/genética , Cistinose/terapia , Cistina/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/uso terapêutico , Modelos Teóricos , Suplementos Nutricionais , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo
15.
Sci Rep ; 13(1): 17276, 2023 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-37828038

RESUMO

Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Using surface plasmon resonance, we first showed that both dAAs compete for protein ligand binding to immobilized megalin in a concentration-dependent manner, with identical inhibition curves by L- and D-stereoisomers. In cystinotic mice, 2-month diets with 5x-L-lysine and 5x-L-arginine were overall well tolerated, while 5x-D-lysine induced strong polyuria but no weight loss. All diets induced a marked increase of dAA urinary excretion, most prominent under 5x-D-lysine, without sign of kidney insufficiency. Renal cystine accumulation was slowed down approx. twofold by L-dAAs, and totally suppressed by D-lysine. We conclude that prolonged dietary manipulation of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo.


Assuntos
Cistina , Cistinose , Adulto , Humanos , Animais , Camundongos , Cistina/metabolismo , Cistinose/metabolismo , Lisina , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Rim/metabolismo , Suplementos Nutricionais
16.
Turk J Pediatr ; 65(4): 611-619, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37661676

RESUMO

BACKGROUND: Hereditary renal tubular disorders (HRTD) represent a group of genetic diseases characterized by disturbances in fluid, electrolyte, and acid-base homeostasis. There is a paucity of studies on pediatric HRTD in Egypt. In this study, we aimed to study the pattern, characteristics, and growth outcome of HRTD at an Egyptian medical center. METHODS: This study included children from one month to < 18-years of age with HRTD who were diagnosed and followed up at the Pediatric Nephrology Unit of Sohag University Hospital from January 2015 to December 2021. Data on patients` demographics, clinical features, growth profiles, and laboratory characteristics were collected. RESULTS: Fifty-eight children (57% males; 72% parental consanguinity; 60% positive family history) were diagnosed with seven HRTD types. The most commonly encountered disorders were distal renal tubular acidosis (distal renal tubular acidosis [RTA] 27 cases, 46.6%) and Bartter syndrome (16 cases 27.6%). Other identified disorders were Fanconi syndrome (6 cases with cystinosis), isolated proximal RTA (4 cases), nephrogenic diabetes insipidus (3 cases), and one case for each RTA type IV and Gitelman syndrome. The median age at diagnosis was 17 months with a variable diagnostic delay. The most common presenting features were failure to thrive (91.4%), developmental delay (79.3%), and dehydration episodes (72.4%). Most children showed marked improvement in growth parameters in response to appropriate management, except for cases with Fanconi syndrome. Last, only one case (with cystinosis) developed end-stage kidney disease. CONCLUSIONS: HRTD (most commonly distal RTA and Bartter syndrome) could be relatively common among Egyptian children, and the diagnosis seems challenging and often delayed.


Assuntos
Acidose Tubular Renal , Síndrome de Bartter , Cistinose , Anemia de Fanconi , Síndrome de Fanconi , Masculino , Humanos , Criança , Lactente , Feminino , Acidose Tubular Renal/diagnóstico , Acidose Tubular Renal/epidemiologia , Acidose Tubular Renal/genética , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/epidemiologia , Síndrome de Bartter/genética , Egito/epidemiologia , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/epidemiologia , Síndrome de Fanconi/genética , Diagnóstico Tardio
17.
J Clin Invest ; 133(19)2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37561577

RESUMO

Cystinosis is a lysosomal storage disease that is characterized by the accumulation of dipeptide cystine within the lumen. It is caused by mutations in the cystine exporter, cystinosin. Most of the clinically reported mutations are due to the loss of transporter function. In this study, we identified a rapidly degrading disease variant, referred to as cystinosin(7Δ). We demonstrated that this mutant is retained in the ER and degraded via the ER-associated degradation (ERAD) pathway. Using genetic and chemical inhibition methods, we elucidated the roles of HRD1, p97, EDEMs, and the proteasome complex in cystinosin(7Δ) degradation pathway. Having understood the degradation mechanisms, we tested some chemical chaperones previously used for treating CFTR F508Δ and demonstrated that they could facilitate the folding and trafficking of cystinosin(7Δ). Strikingly, chemical chaperone treatment can reduce the lumenal cystine level by approximately 70%. We believe that our study conclusively establishes the connection between ERAD and cystinosis pathogenesis and demonstrates the possibility of using chemical chaperones to treat cystinosin(7Δ).


Assuntos
Cistinose , Humanos , Cistinose/tratamento farmacológico , Cistinose/genética , Cistinose/metabolismo , Cistina/genética , Cistina/metabolismo , Degradação Associada com o Retículo Endoplasmático , Medicina de Precisão , Mutação , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Lisossomos/metabolismo
18.
Nat Commun ; 14(1): 3994, 2023 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-37452023

RESUMO

Differentiation is critical for cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in preclinical models of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Humanos , Cistina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Rim/metabolismo , Células Epiteliais/metabolismo , Lisossomos/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética
19.
Pediatr Nephrol ; 38(12): 3989-3999, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37415042

RESUMO

BACKGROUND: Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk. METHODS: Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models. RESULTS: Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17 years). CONCLUSION: Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.


Assuntos
Cistinose , Síndrome de Fanconi , Insuficiência Renal Crônica , Humanos , Criança , Pré-Escolar , Adolescente , Cistinose/complicações , Rim , Síndrome de Fanconi/complicações , Insuficiência Renal Crônica/complicações
20.
Orphanet J Rare Dis ; 18(1): 173, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37391835

RESUMO

BACKGROUND: While thyroid dysfunction develops in about 50% of untreated children with cystinosis, there is no data about how the sonography of thyroid tissue appears in this disease. Therefore, the purpose of this study was to assess the sonographic appearance, color doppler findings in this disease and to evaluate how cystine crystal accumulation affect tissue stiffness using shear wave elastography (SWE). METHODS: Sixteen children diagnosed with cystinosis and a control group consisting of 34 healthy children were included in this study. B mode ultrasound, color doppler imaging and real-time SWE of thyroid tissue were performed. RESULTS: Ultrasound imaging revealed lower echogenicity and diffuse heterogeneous echotexture in 7 of the 16 cystinosis patients. Thyroid gland volumes were lower in cystinosis patients (p 0.005). Doppler ultrasound demonstrated increased flow in 8 patients. On SWE, the thyroid tissue stiffness was established to be lower in patients compared to healthy children (p 0.003). CONCLUSIONS: This is the first study evaluating thyroid gland B mode, color doppler ultrasonography, and SWE findings in cystinosis. Our findings indicate that cysteamine treatment still cannot completely prevent the disease infiltration process of thyroid gland. The other important finding-that thyroid tissue stiffness was established to be lower than that of the controls-also demonstrates the ongoing disease infiltration process.


Assuntos
Cistinose , Técnicas de Imagem por Elasticidade , Criança , Humanos , Glândula Tireoide/diagnóstico por imagem , Ultrassonografia , Ultrassonografia Doppler
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