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1.
BMC Nephrol ; 25(1): 275, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39192178

RESUMO

BACKGROUND: Cystinosis is a lysosomal storage disorder characterized by an autosomal recessive phenotype. Intermediate cystinosis, which progresses slowly and causes renal failure, accounts for approximately 5% of all cystinosis cases. Patients with intermediate cystinosis may not exhibit the typical symptoms of cystinosis, such as Fanconi syndrome and ocular symptoms. Because of its diverse clinical presentation and rarity, intermediate cystinosis can be difficult to diagnose. Additionally, few patients can tolerate cystine-depleting drugs, such as cysteamine, because of their complicated administration schedules and side effects. We report a case of intermediate cystinosis that was treated with cysteamine for 10 years. CASE PRESENTATION: Urinary abnormalities were first diagnosed when the patient was 3 years of age during a health examination specifically for 3-year-old children, which is unique to Japan. Cystinosis was diagnosed when the patient was 12 years of age. Cysteamine therapy was initiated and regular cystine concentration measurements were performed. Although proteinuria persisted, the patient's renal function progressed slowly. Two renal biopsies were performed, and multinucleated podocytes and cystine crystals without focal segmental glomerulosclerosis lesions were observed in the biopsy specimens. The patient's renal function remained stable. CONCLUSIONS: This case of intermediate cystinosis was treated with cysteamine over the course of 10 years. Intermediate cystinosis requires an appropriate diagnosis and long-term treatment.


Assuntos
Cisteamina , Eliminadores de Cistina , Cistinose , Humanos , Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Cistinose/complicações , Eliminadores de Cistina/uso terapêutico , Masculino , Criança , Feminino , Resultado do Tratamento , Pré-Escolar
2.
Biomed Pharmacother ; 178: 117236, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39096619

RESUMO

In infantile nephropathic cystinosis, variants of the CTNS gene cause accumulation of cystine in lysosomes, causing progressive damage to most organs. Patients usually present before 1 year of age with signs of renal Fanconi syndrome. Cysteamine therapy allows cystine clearance from lysosomes and delays kidney damage but does not prevent progression to end-stage kidney disease, suggesting that pathways unrelated to cystine accumulation are also involved. Among these, impaired autophagy, altered endolysosomal trafficking, and increased apoptosis have emerged in recent years as potential targets for new therapies. We previously showed that luteolin, a flavonoid compound, improves these abnormal pathways in cystinotic cells and in zebrafish models of the disease. Herein, we have investigated if prolonged luteolin treatment ameliorates kidney damage in a murine model of cystinosis. To this end, we have treated Ctns-/- mice from 2 to 8 months with 150 mg/kg/day of luteolin. No significant side effects were observed. Compared to untreated animals, analyses of kidney cortex samples obtained after sacrifice showed that luteolin decreased p62/SQSTM1 levels (p <0.001), improved the number, size, and distribution of LAMP1-positive structures (p <0.02), and decreased tissue expression of cleaved caspase 3 (p <0.001). However, we did not observe improvements in renal Fanconi syndrome and kidney inflammation. Kidney function remained normal during the time of the study. These results indicate that luteolin has positive effects on the apoptosis and endo-lysosomal defects of cystinotic proximal tubular cells. However, these beneficial effects did not translate into improvement of renal Fanconi syndrome.


Assuntos
Cistinose , Modelos Animais de Doenças , Luteolina , Animais , Luteolina/farmacologia , Luteolina/uso terapêutico , Cistinose/tratamento farmacológico , Camundongos , Camundongos Knockout , Apoptose/efeitos dos fármacos , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética , Camundongos Endogâmicos C57BL , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Fatores de Tempo , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo
3.
J Bone Miner Res ; 39(8): 1094-1102, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-38864569

RESUMO

Nephropathic cystinosis is an orphan autosomal recessive lysosomal storage disease characterized by a deficiency of cystinosin, a cystine transporter protein, leading to tissue damage, primarily in the kidney and cornea. With the introduction of cystine-depleting therapy with cysteamine and the possibility to survive to adulthood, new challenges of skeletal complications are a concern, with sparse data available regarding bone development. The aim of the current study was to gain more information on bone density and geometry in these patients. Fifty-one patients (29 males, 22 females) with genetically proven nephropathic cystinosis were clinically evaluated with a medical history, physical examination, grip strength measurements, and biochemical and imaging studies. Bone mineral density, bone geometry, and muscle cross sectional area were measured, and muscle was evaluated. Results were compared with age- and gender-specific reference data. Z-scores for height (mean [M] = -1.75, standard deviation [SD] = 1.43), weight (M = -1.67, SD = 1.29), and BMI (M = -0.98, SD = 1.29) were lower than reference data. Medullary cross-sectional area (CSA) and cortical density z-scores were not compromised (M = 0.12, SD = 1.56 and M = -0.25, SD = 1.63, respectively), but cortical CSA z-scores and Strength-Strain Index (SSI) were reduced (M = -2.16, SD = 1.08, M = -2.07, SD = 1.08). Muscular deficits were reflected by reduced z-scores for muscle CSA (M = -2.43, SD = 1.27) and grip strength (M = -3.01, SD = 1.10), along with jump force (34% lower than reference value). Multiple regression analyses indicated an association of muscle mass with medullary CSA and SSI, but not with cortical CSA. While bone density parameters were normal, bone geometry was altered, resulting in a thinner cortex with possible impact on bone strength. Muscle weakness be partially responsible for altered bone geometry and could provide a potential treatment target.


Nephropathic cystinosis is a rare lysosomal storage disease affecting primarily the kidney and cornea. With new treatment options, patients survive to adulthood and challenges such as bone development and fracture risk become a matter of concern. In this study, we investigated bone density, bone geometry, and muscle mass and function using peripheral quantitative-computed tomography. We included 51 patients with genetically proven cystinosis at an age between 6.6 and 39.6 yr. Beside height impairment and low body weight, patients had a thinner bone cortex leading to a reduced stress­strain index. This index represents the resistance of bone against torsional load and, therefore, is considered to be a good marker of bone strength: with low values fracture risk might increase. Furthermore, patients had lower muscle mass and muscle function, the latter evaluated by grip strength and jump force. Looking for the interaction of muscle and bone multiple regression analyses indicated an association of muscle mass with strength strain index. The muscle weakness might be partially responsible for altered bone geometry and lower bone strength and is possibly a treatment target, which has to be investigated in the future.


Assuntos
Cistinose , Humanos , Masculino , Feminino , Cistinose/patologia , Cistinose/fisiopatologia , Cistinose/tratamento farmacológico , Cistinose/complicações , Criança , Adolescente , Adulto , Adulto Jovem , Densidade Óssea , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Tamanho do Órgão , Osso Cortical/patologia , Osso Cortical/diagnóstico por imagem , Osso Cortical/fisiopatologia , Pré-Escolar
4.
Mol Genet Metab ; 142(1): 108454, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38603816

RESUMO

BACKGROUND: Cystine-depleting therapy in nephropathic cystinosis is currently monitored via the white blood cell cystine assay, although its application and usefulness are limited by practical and technical issues. Therefore, alternative biomarkers that are widely available, more economical and less technically demanding, while reliably reflecting long-term adherence to cysteamine treatment, are desirable. Recently, we proposed chitotriosidase enzyme activity as a potential novel biomarker for the therapeutic monitoring of cysteamine treatment in cystinosis. In this study, we aimed to validate our previous findings and to confirm the value of chitotriosidase in the management of cystinosis therapy. MATERIALS & METHODS: A retrospective study was conducted on 12 patients treated at the National Institutes of Health Clinical Center and followed up for at least 2 years. Plasma chitotriosidase enzyme activity was correlated with corresponding clinical and biochemical data. RESULTS: Plasma chitotriosidase enzyme activity significantly correlated with WBC cystine levels, cysteamine total daily dosage and a Composite compliance score. Moreover, plasma chitotriosidase was a significant independent predictor for WBC cystine levels, and cut-off values were established in both non-kidney transplanted and kidney transplanted cystinosis patients to distinguish patients with a good versus poor compliance with cysteamine treatment. Our observations are consistent with those of our previous study and validate our findings. CONCLUSIONS: Chitotriosidase enzyme activity is a valid potential alternative biomarker for monitoring cysteamine treatment in nephropathic cystinosis patients. SYNOPSIS: Chitotriosidase enzyme activity is a valid potential alternative biomarker for monitoring cysteamine treatment in nephropathic cystinosis patients.


Assuntos
Cisteamina , Cistina , Cistinose , Hexosaminidases , Humanos , Cisteamina/uso terapêutico , Masculino , Feminino , Cistinose/tratamento farmacológico , Cistinose/sangue , Estudos Retrospectivos , Hexosaminidases/sangue , Adolescente , Cistina/sangue , Criança , Adulto , Biomarcadores/sangue , Adulto Jovem , Monitoramento de Medicamentos/métodos , Eliminadores de Cistina/uso terapêutico , Pré-Escolar , Transplante de Rim
5.
Eye Contact Lens ; 50(7): 321-328, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38630953

RESUMO

PURPOSE: To report the clinical course and compare the utility of Scheimpflug tomography (ST) and anterior segment optical coherence tomography (AS-OCT) for central corneal thickness (CCT) and corneal densitometry (CD) assessment in patients with corneal crystals owing to nephropathic cystinosis. METHODS: A retrospective chart analysis of three patients with nephropathic cystinosis and the presence of corneal cystine crystals in both eyes was performed. All patients underwent clinical examination and anterior segment photography, ST, and AS-OCT scans. Corneal densitometry was exported from built-in proprietary software for ST and from custom-made validated software for AS-OCT. Anterior segment optical coherence tomography images were rescaled to grayscale units from 0 (maximum transparency) to 100 (minimum transparency) to match built-in ST densitometry readings. Furthermore, the mean pixel intensity, representative of CD, was calculated from the pixels corresponding to the segmented cornea. RESULTS: All three patients had pathognomonic cystine crystals deposits in the cornea and were treated with cysteamine medications that resulted in clinical improvement. The CCT measured using ST exhibited a range from 560 to 958 µm. Conversely, when assessed with AS-OCT, the CCT varied within the range of 548 to 610 µm. Both examinations could be performed, but in the more severe cases, AS-OCT showed far greater utility to estimate CD. In four of six eyes examined, ST showed disproportionate CCT values, compared with the AS-OCT, whereas reliable CD measurements were only available in AS-OCT. CONCLUSION: The AS-OCT could be considered a baseline ocular measurement in cystinosis and in the evaluation of disease progression and treatment efficacy.


Assuntos
Córnea , Doenças da Córnea , Cistinose , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Estudos Retrospectivos , Masculino , Feminino , Córnea/patologia , Córnea/diagnóstico por imagem , Doenças da Córnea/diagnóstico , Doenças da Córnea/diagnóstico por imagem , Segmento Anterior do Olho/diagnóstico por imagem , Segmento Anterior do Olho/patologia , Adolescente , Adulto , Criança , Adulto Jovem , Densitometria/métodos , Acuidade Visual/fisiologia
6.
Pediatr Nephrol ; 39(8): 2429-2433, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38462547

RESUMO

BACKGROUND: The objective of this report is to identify and characterize cases of fibrosing colonopathy, a rare and underrecognized adverse event, associated with cysteamine delayed-release (DR) in patients with nephropathic cystinosis. METHODS: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the medical literature for postmarketing reports of fibrosing colonopathy associated with cysteamine through August 2, 2023. RESULTS: We identified four cases of fibrosing colonopathy reported with the use of cysteamine DR. The time to onset ranged from 12 to 31 months. In one case, the patient required surgery to have a resection of a section of the strictured colon and a diverting ileostomy. Fibrosing colonopathy was diagnosed by histopathology in two of the cases. CONCLUSIONS: Our case series identified the risk of fibrosing colonopathy in patients taking cysteamine DR and prompted regulatory action by the FDA. As outlined in changes to the U.S. prescribing information for cysteamine DR, healthcare professionals should be aware of the potential risk of fibrosing colonopathy with cysteamine DR, especially as symptoms can be non-specific leading to misdiagnosis or delayed diagnosis. If the diagnosis of fibrosing colonopathy is confirmed, consideration should be given to permanently discontinuing cysteamine DR and switching to cysteamine immediate-release treatment.


Assuntos
Cisteamina , Cistinose , Preparações de Ação Retardada , Humanos , Cisteamina/efeitos adversos , Cisteamina/administração & dosagem , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Preparações de Ação Retardada/efeitos adversos , Feminino , Masculino , Criança , Doenças do Colo/induzido quimicamente , Doenças do Colo/diagnóstico , Doenças do Colo/patologia , Doenças do Colo/etiologia , Adolescente , Eliminadores de Cistina/administração & dosagem , Eliminadores de Cistina/efeitos adversos , Estados Unidos , Fibrose , Colo/patologia , Colo/efeitos dos fármacos , Colo/diagnóstico por imagem , Cápsulas , Pré-Escolar , Sistemas de Notificação de Reações Adversas a Medicamentos
8.
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
9.
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
10.
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 , Acessibilidade aos Serviços de Saúde
11.
J Neurol Sci ; 456: 122841, 2024 01 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
12.
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
13.
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
14.
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
15.
Orphanet J Rare Dis ; 18(1): 162, 2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37353838

RESUMO

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.


Assuntos
Cistinose , Síndrome de Fanconi , Humanos , Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Estudos Retrospectivos , Cápsulas , Síndrome de Fanconi/tratamento farmacológico
16.
Ocul Surf ; 29: 432-443, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37355021

RESUMO

PURPOSE: Cystinosis is an autosomal recessive lysosomal storage disease (LSDs) caused by mutations in the gene encoding cystinosin (CTNS) that leads to cystine crystal accumulation in the lysosome that compromises cellular functions resulting in tissue damage and organ failure, especially in kidneys and eyes. However, the underlying molecular mechanism of its pathogenesis remains elusive. Two novel mice lines created via CRISPR are used to examine the pathogenesis of cystinosis in the kidney and cornea and the treatment efficacy of corneal pathology using self-complimentary Adeno-associated viral (scAAV-CTNS) vector. METHODS: The CRISPR technique generated two novel cystinotic mouse lines, Ctnsis1 (an insertional mutation) and Ctnsis2 (a nonsense mutation). Immune histochemistry, renal functions test and HRT2 in vivo confocal microscopy were used to evaluate the age-related renal pathogenesis and treatment efficacy of the scAAV-CTNS virus in corneal pathology. RESULTS: Both mutations lead to the production of truncated Ctns proteins. Ctnsis1 and Ctnsis 2 mice exhibit the characteristic of cystinotic corneal crystal phenotype at four-week-old. Treatment with the scAAV-CTNS viral vector decreased the corneal crystals in the treated mice cornea. Ctnsis 1 show renal abnormalities manifested by increased urine volume, reduced urine osmolality, and the loss of response to Desmopressin (dDAVP) at 22-month-old but Ctnsis2 don't manifest renal pathology up to 2 years of age. CONCLUSIONS: Both Ctnsis1 and Ctnsis2 mice exhibit phenotypes resembling human intermediate nephropathic and ocular cystinosis, respectively. scAAV-CTNS viral vectors reduce the corneal cystine crystals and have a great potential as a therapeutic strategy for treating patients suffering from cystinosis.


Assuntos
Cistinose , Humanos , Animais , Camundongos , Lactente , Cistinose/terapia , Cistinose/tratamento farmacológico , Cistina/genética , Cistina/metabolismo , Cistina/uso terapêutico , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Edição de Genes , Córnea/patologia , Terapia Genética
17.
Pediatr Nephrol ; 38(11): 3671-3679, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37219641

RESUMO

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


Assuntos
Cistinose , Síndrome de Fanconi , Adulto , Humanos , Criança , Cistinose/tratamento farmacológico , Cisteamina/efeitos adversos , Estudos Retrospectivos , Cistina/metabolismo
19.
Klin Monbl Augenheilkd ; 240(3): 251-259, 2023 Mar.
Artigo em Inglês, Alemão | MEDLINE | ID: mdl-36977426

RESUMO

Cystinosis is a very rare autosomal recessive lysosomal storage disorder with an incidence of 1 : 150,000 - 1 : 200,000, and is caused by mutations in the CTNS gene encoding the lysosomal membrane protein cystinosin, which transports cystine out of the lysosome into the cytoplasm. As a result, accumulation of cystine occurs in almost all cells and tissues, especially in the kidneys, leading to multiple organ involvement. Introduction of drug therapy with cysteamine in the mid 1980s, along with the availability of renal replacement therapy in childhood, have dramatically improved patient outcome. Whereas patients used to die without therapy with end-stage renal failure during the first decade of life, nowadays most patients live well into adulthood without renal replacement therapy, and several reach 40 years. There is robust evidence that early initiation and sustained lifelong therapy with cysteamine are both essential for morbidity and mortality. The rarity of the disease and the multi-organ involvement present an enormous challenge for those affected and the providers of care for this patient group.


Assuntos
Cistinose , Humanos , Cistinose/diagnóstico , Cistinose/tratamento farmacológico , Cistinose/genética , Cistina/genética , Cistina/metabolismo , Cistina/uso terapêutico , Cisteamina/uso terapêutico , Mutação
20.
Klin Monbl Augenheilkd ; 240(3): 266-275, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36977427

RESUMO

Cystinosis is a rare lysosomal storage disease with a prevalence of 1 : 100 000 - 1 : 200 000 cases. It is caused by biallelic mutations in the CTNS gene, which encodes cystinosin, that transport cystine out of the lysosomes. Due to its dysfunction, cystine crystals accumulate in the lysosomes and ultimately cause apoptosis of the cell. Since cystinosin is ubiquitously present in the body, cystine crystals are deposited in every body structure and lead to the dysfunction of various organ systems in the course of time. Cystine crystals deposited in the cornea are a clinical hallmark of the disease, while there is less awareness of concomitant posterior segment alterations. Symmetrical pigment epithelial mottling and patches of depigmentation frequently start in the periphery and progress towards the posterior pole and can be encountered upon fundus biomicroscopy. Spectral-domain optical coherence tomography (SD-OCT) is an elegant tool for visualizing chorioretinal cystine crystals at the posterior pole. An SD-OCT-based clinical grading of the severity of the chorioretinal manifestation can potentially be applied as a biomarker for systemic disease status and for monitoring oral therapy adherence in the future. Along with previous histological examinations, it may also give information about the location of cystine crystals in the choroid and retina. This review aims to increase the awareness of vision-threatening retinal and choroidal changes in cystinosis and the concomitant findings in SD-OCT.


Assuntos
Cistinose , Humanos , Cistinose/diagnóstico , Cistinose/genética , Cistinose/tratamento farmacológico , Cistina/uso terapêutico , Retina , Córnea
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