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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(12): 1276-1281, 2021 Dec 15.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34911613

RESUMO

A boy, aged 1 year and 6 months, was found to have persistent positive urine glucose at the age of 4 months, with polydipsia, polyuria, and growth retardation. Laboratory examinations suggested that the boy had low specific weight urine, anemia, hypokalemia, hyponatremia, hypomagnesemia, metabolic acidosis, glycosuria, acidaminuria, increased fractional excretion of potassium, and decreased tubular reabsorption of phosphate. X-ray examinations of the head, thorax, and right hand showed changes of renal rickets. The slit-lamp examination showed a large number of cystine crystals in the cornea. The genetic testing showed a suspected pathogenic homozygous mutation of the CTNS gene, C.922g>A(p.Gly308Arg). The boy was finally diagnosed with cystinosis. At the beginning of treatment, symptomatic supportive treatment was given to maintain the stability of the internal environment, and cysteamine tartaric acid capsules were used after diagnosis to remove cysteine. This article reported a case of cystinosis caused by CTNS gene mutation and summarized the etiology, clinical features, diagnosis, and treatment of this disease, which can provide a reference for the early diagnosis, treatment, and subsequent study of the disease.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Hipopotassemia , Sistemas de Transporte de Aminoácidos Neutros/genética , Córnea , Cistinose/genética , Humanos , Lactente , Masculino , Mutação , Doenças Raras
2.
Cells ; 10(12)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34944047

RESUMO

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.


Assuntos
Cistinose/patologia , Fertilidade , Animais , Biomarcadores/sangue , Cisteamina/metabolismo , Cistinose/sangue , Modelos Animais de Doenças , Humanos , Modelos Biológicos
3.
Cells ; 10(9)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34572146

RESUMO

Bone complications of cystinosis have been recently described. The main objectives of this paper were to determine in vitro the impact of CTNS mutations and cysteamine therapy on human osteoclasts and to carry out a genotype-phenotype analysis related to osteoclastic differentiation. Human osteoclasts were differentiated from peripheral blood mononuclear cells (PBMCs) and were treated with increasing doses of cysteamine (0, 50, 200 µM) and then assessed for osteoclastic differentiation. Results are presented as median (min-max). A total of 17 patients (mainly pediatric) were included, at a median age of 14 (2-61) years, and a eGFR of 64 (23-149) mL/min/1.73 m2. Most patients (71%) were under conservative kidney management (CKM). The others were kidney transplant recipients. Three functional groups were distinguished for CTNS mutations: cystinosin variant with residual cystin efflux activity (RA, residual activity), inactive cystinosin variant (IP, inactive protein), and absent protein (AP). PBMCs from patients with residual cystinosin activity generate significantly less osteoclasts than those obtained from patients of the other groups. In all groups, cysteamine exerts an inhibitory effect on osteoclastic differentiation at high doses. This study highlights a link between genotype and osteoclastic differentiation, as well as a significant impact of cysteamine therapy on this process in humans.


Assuntos
Cisteamina/farmacologia , Cistinose/genética , Osteoclastos/metabolismo , Adolescente , Adulto , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Diferenciação Celular/efeitos dos fármacos , Criança , Pré-Escolar , Cisteamina/metabolismo , Cistinose/metabolismo , Cistinose/fisiopatologia , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Mutação , Osteoclastos/efeitos dos fármacos , Fenótipo
4.
Orphanet J Rare Dis ; 16(1): 387, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521447

RESUMO

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


Assuntos
Cistinose , Síndrome de Fanconi , Cisteamina/uso terapêutico , Cistina , Cistinose/tratamento farmacológico , Síndrome de Fanconi/tratamento farmacológico , Humanos , Qualidade de Vida , Estudos Retrospectivos
5.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502306

RESUMO

Cystinosis is a rare, incurable, autosomal recessive disease caused by mutations in the CTNS gene. This gene encodes the lysosomal cystine transporter cystinosin, leading to lysosomal cystine accumulation in all cells of the body, with kidneys being the first affected organs. The current treatment with cysteamine decreases cystine accumulation, but does not reverse the proximal tubular dysfunction, glomerular injury or loss of renal function. In our previous study, we have developed a zebrafish model of cystinosis through a nonsense mutation in the CTNS gene and have shown that zebrafish larvae recapitulate the kidney phenotype described in humans. In the current study, we characterized the adult cystinosis zebrafish model and evaluated the long-term effects of the disease on kidney and extra renal organs through biochemical, histological, fertility and locomotor activity studies. We found that the adult cystinosis zebrafish presents cystine accumulation in various organs, altered kidney morphology, impaired skin pigmentation, decreased fertility, altered locomotor activity and ocular anomalies. Overall, our data indicate that the adult cystinosis zebrafish model reproduces several human phenotypes of cystinosis and may be useful for studying pathophysiology and long-term effects of novel therapies.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Cistina/metabolismo , Cistinose/patologia , Modelos Animais de Doenças , Rim/patologia , Mutação , Proteínas de Peixe-Zebra/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética , Animais , Cistinose/etiologia , Humanos , Rim/metabolismo , Fenótipo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
6.
Cells ; 10(8)2021 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-34440723

RESUMO

Mice lacking the functional cystinosin gene (Ctns-/-), a model of infantile nephropathic cystinosis (INC), exhibit the cachexia phenotype with adipose tissue browning and muscle wasting. Elevated leptin signaling is an important cause of chronic kidney disease-associated cachexia. The pegylated leptin receptor antagonist (PLA) binds to but does not activate the leptin receptor. We tested the efficacy of this PLA in Ctns-/- mice. We treated 12-month-old Ctns-/- mice and control mice with PLA (7 mg/kg/day, IP) or saline as a vehicle for 28 days. PLA normalized food intake and weight gain, increased fat and lean mass, decreased metabolic rate and improved muscle function. It also attenuated perturbations of energy homeostasis in adipose tissue and muscle in Ctns-/- mice. PLA attenuated adipose tissue browning in Ctns-/- mice. PLA increased gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in Ctns-/- mice. This was accompanied by correcting the increased expression of muscle wasting signaling while promoting the decreased expression of myogenesis in gastrocnemius of Ctns-/- mice. PLA attenuated aberrant expressed muscle genes that have been associated with muscle atrophy, increased energy expenditure and lipolysis in Ctns-/- mice. Leptin antagonism may represent a viable therapeutic strategy for adipose tissue browning and muscle wasting in INC.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Caquexia/prevenção & controle , Cistinose/tratamento farmacológico , Antagonistas de Hormônios/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Receptores para Leptina/antagonistas & inibidores , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/patologia , Cistinose/complicações , Cistinose/metabolismo , Cistinose/patologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Receptores para Leptina/metabolismo , Transdução de Sinais
7.
J Cachexia Sarcopenia Muscle ; 12(5): 1296-1311, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34196133

RESUMO

BACKGROUND: Ctns-/- mice, a mouse model of infantile nephropathic cystinosis, exhibit hypermetabolism with adipose tissue browning and profound muscle wasting. Inflammatory cytokines such as interleukin (IL)-1 trigger inflammatory cascades and may be an important cause for cachexia. We employed genetic and pharmacological approaches to investigate the effects of IL-1 blockade in Ctns-/- mice. METHODS: We generated Ctns-/- Il1ß-/- mice, and we treated Ctns-/- and wild-type control mice with IL-1 receptor antagonist, anakinra (2.5 mg/kg/day, IP) or saline as vehicle for 6 weeks. In each of these mouse lines, we characterized the cachexia phenotype consisting of anorexia, loss of weight, fat mass and lean mass, elevation of metabolic rate, and reduced in vivo muscle function (rotarod activity and grip strength). We quantitated energy homeostasis by measuring the protein content of uncoupling proteins (UCPs) and adenosine triphosphate in adipose tissue and skeletal muscle. We measured skeletal muscle fiber area and intramuscular fatty infiltration. We also studied expression of molecules regulating adipose tissue browning and muscle mass metabolism. Finally, we evaluated the impact of anakinra on the muscle transcriptome in Ctns-/- mice. RESULTS: Skeletal muscle expression of IL-1ß was significantly elevated in Ctns-/- mice relative to wild-type control mice. Cachexia was completely normalized in Ctns-/- Il1ß-/- mice relative to Ctns-/- mice. We showed that anakinra attenuated the cachexia phenotype in Ctns-/- mice. Anakinra normalized UCPs and adenosine triphosphate content of adipose tissue and muscle in Ctns-/- mice. Anakinra attenuated aberrant expression of beige adipose cell biomarkers (UCP-1, CD137, Tmem26, and Tbx1) and molecules implicated in adipocyte tissue browning (Cox2/Pgf2α, Tlr2, Myd88, and Traf6) in inguinal white adipose tissue in Ctns-/- mice. Moreover, anakinra normalized gastrocnemius weight and fiber size and attenuated muscle fat infiltration in Ctns-/- mice. This was accompanied by correction of the increased muscle wasting signalling pathways (increased protein content of ERK1/2, JNK, p38 MAPK, and nuclear factor-κB p65 and mRNA expression of Atrogin-1 and Myostatin) and the decreased myogenesis process (decreased mRNA expression of MyoD and Myogenin) in the gastrocnemius muscle of Ctns-/- mice. Previously, we identified the top 20 differentially expressed skeletal muscle genes in Ctns-/- mice by RNAseq. Aberrant expression of these 20 genes have been implicated in muscle wasting, increased energy expenditure, and lipolysis. We showed that anakinra attenuated 12 of those top 20 differentially expressed muscle genes in Ctns-/- mice. CONCLUSIONS: Anakinra may provide a targeted novel therapy for patients with infantile nephropathic cystinosis.


Assuntos
Cistinose , Atrofia Muscular , Animais , Caquexia/tratamento farmacológico , Caquexia/etiologia , Caquexia/patologia , Cistinose/patologia , Humanos , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular/patologia
8.
BMJ Case Rep ; 14(7)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312133

RESUMO

Cystinosis is a multisystem disorder with varied presentations secondary to deposition of cystine crystals in different organ systems. Children with cystinosis typically present with renal tubular acidosis and failure to thrive. We report a 3-year-old girl, born to a third-degree consanguineous couple, who presented with failure to thrive and polyuria. Laboratory investigations showed metabolic alkalosis suggestive of a Bartter-like syndrome and acquired hypothyroidism. Although metabolic alkalosis is a rare manifestation of cystinosis, the presence of renal tubular dysfunction and hypothyroidism prompted consideration of a probable diagnosis of cystinosis in the index child. Slit-lamp examination revealed cystine crystals in the cornea and genetic analysis showed a mutation in exon 9 of the CTNS (cystinosin, lysosomal cystine transporter) gene on chromosome 17. We highlight the importance of considering cystinosis as a differential diagnosis for Bartter syndrome and hypothyroidism.


Assuntos
Acidose Tubular Renal , Síndrome de Bartter , Cistinose , Hipotireoidismo , Síndrome de Bartter/complicações , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Criança , Pré-Escolar , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/genética , Feminino , Humanos , Hipotireoidismo/diagnóstico , Doenças Raras
9.
Kidney Int ; 100(5): 1112-1123, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34237326

RESUMO

Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.


Assuntos
Cistinose , Síndrome de Fanconi , Adulto , Pré-Escolar , Estudos de Coortes , Cisteamina/uso terapêutico , Cistina , Eliminadores de Cistina , Cistinose/genética , Humanos
10.
EMBO Mol Med ; 13(7): e13067, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34165243

RESUMO

Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis. We identified alpha-ketoglutarate as a potential metabolite to bridge cystinosin loss to autophagy, apoptosis and kidney proximal tubule impairment in cystinosis. This insight combined with a drug screen revealed a bicalutamide-cysteamine combination treatment as a novel dual-target pharmacological approach for the phenotypical correction of cystinotic kidney proximal tubule cells, patient-derived kidney tubuloids and cystinotic zebrafish.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Sistemas de Transporte de Aminoácidos Neutros/genética , Anilidas , Animais , Cisteamina , Cistinose/tratamento farmacológico , Humanos , Nitrilas , Fenótipo , Compostos de Tosil , Peixe-Zebra
11.
Hum Reprod ; 36(5): 1191-1204, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33822926

RESUMO

STUDY QUESTION: Do males with the rare lysosomal storage disease infantile nephropathic cystinosis (INC) have a chance of biological fatherhood? SUMMARY ANSWER: Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval from the centre of the testes providing additional opportunities for fatherhood. WHAT IS KNOWN ALREADY: Biallelic mutations in the cystinosin (CTNS) gene in INC cause dysfunction in cystine transport across lysosomal membranes and cystine accumulation throughout the body. Spontaneous paternity in cystinosis has not been described, despite the availability of cysteamine treatment. Azoospermia has been diagnosed in small case series of males with INC. ART using ICSI requires few spermatozoa, either from semen or extracted surgically from the testes of azoospermic men. However, there is limited evidence to suggest this could be successful in INC. STUDY DESIGN, SIZE, DURATION: In this prospective cohort study performed between 2018 and 2019, we performed a cross-sectional investigation of 18 male patients with INC to delineate endocrine and spermatogenic testicular function. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum hormone levels, semen samples (according to World Health Organization 2010 standards), and testicular ultrasound images were analysed in 18 male patients aged 15.4-40.5 years. Surgical sperm extraction was performed in two, and their testicular biopsies were investigated by light and electron microscopy. Past adherence to cysteamine treatment was assessed from medical record information, using a composite scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: Adherence to cysteamine treatment was high in most patients. Testicular volumes and testosterone levels were in the normal ranges, with the exception of two and three older patients, respectively. Serum LH levels were above the normal range in all subjects aged ≥20 years. FSH levels were elevated in all but four males: three with spermatozoa in semen and one adolescent. Inhibin B levels were shown to be lower in older men. Testicular ultrasound revealed signs of obstruction in 67% of patients. Reduced fructose and zinc seminal markers were found in 33%, including two patients with azoospermia who underwent successful surgical sperm retrieval. Histology identified fully preserved spermatogenesis in the centre of their testes, but also tubular atrophy and lysosomal overload in Sertoli and Leydig cells of the testicular periphery. LIMITATIONS, REASONS FOR CAUTION: Limitations of this study are the small number of assessed patients and the heterogeneity of their dysfunction in cystine transport across lysosomal membranes. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that testicular degeneration in cystinosis results from the lysosomal overload of Sertoli and Leydig cells of the testicular periphery, and that this can possibly be delayed, but not prevented, by good adherence to cysteamine treatment. Endocrine testicular function in INC may remain compensated until the fourth decade of life; however, azoospermia may occur during adolescence. Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval providing additional opportunities for biological fatherhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Cystinosis Foundation Germany. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: n/a.


Assuntos
Cistinose , Adolescente , Adulto , Idoso , Estudos Transversais , Alemanha , Humanos , Masculino , Estudos Prospectivos , Análise do Sêmen , Recuperação Espermática , Espermatozoides , Testículo , Adulto Jovem
12.
Orphanet J Rare Dis ; 16(1): 177, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849633

RESUMO

BACKGROUND: Cystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function in adulthood. We previously demonstrated intact auditory sensory processing, accompanied by mild sensory memory difficulties, in children and adolescents with cystinosis. METHODS: We investigated whether further progressive decrements in these processes would be observed in adults with cystinosis, comparing high-density auditory-evoked potential (AEP) recordings from adults with cystinosis (N = 15; ages: 19-38 years) to those of age-matched controls (N = 17). We employed a duration oddball paradigm with different stimulation rates, in which participants passively listened to regularly occurring standard tones interspersed with infrequently occurring deviant tones. Analyses focused on AEP components reflecting auditory sensory-perceptual processing (N1 and P2), sensory memory (mismatch negativity, MMN), and attentional orienting (P3a). RESULTS: Overall, adults with cystinosis produced highly similar sensory-perceptual AEP responses to those observed in controls suggesting intact early auditory cortical processing. However, significantly increased P2 and P3a amplitudes and reduced MMN at slower stimulation rates were observed, suggesting mild-to-moderate changes in auditory sensory memory and attentional processing. While cognitive testing revealed lower scores on verbal IQ and perceptual reasoning in cystinosis, these did not correlate with the AEP measures. CONCLUSIONS: These neurophysiological data point to the emergence of subtle auditory processing deficits in early adulthood in cystinosis, warranting further investigation of memory and attentional processes in this population, and of their consequences for perceptual and cognitive function.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Cistinose , Adolescente , Adulto , Percepção Auditiva , Eletroencefalografia , Potenciais Evocados Auditivos , Humanos , Mutação , Adulto Jovem
13.
Nefrología (Madrid) ; 41(2): 182-190, mar.-abr. 2021. tab
Artigo em Espanhol | IBECS | ID: ibc-201571

RESUMO

ANTECEDENTES Y OBJETIVO: Las tubulopatías primarias son raras y se presentan habitualmente en la edad pediátrica. Avances recientes en diagnóstico genético y tratamiento han cambiado su historia natural. Este estudio presenta el espectro clínico de una serie de tubulopatías primarias diagnosticadas en una Unidad de Nefrología Pediátrica y ofrece datos de seguimiento a largo plazo sobre crecimiento, filtrado glomerular estimado y complicaciones intercurrentes. PACIENTES Y MÉTODOS: Estudio observacional en 53 pacientes con tubulopatías primarias y defecto genético identificado: síndrome de Gitelman (36%), acidosis tubular renal distal (15%), cistinuria (11%), raquitismo hipofosfatémico ligado al X (7%), síndrome de Dent-Lowe (7%), cistinosis (6%), y uno o 2 casos de otras tubulopatías. Se recogieron datos demográficos, analíticos y clínicos al diagnóstico, durante la evolución y en el momento del estudio. RESULTADOS: La edad (mediana y rango intercuartílico) al diagnóstico fue de 5,08 años (1,33-8,50). Las manifestaciones de presentación más frecuentes fueron descompensaciones metabólicas asociadas a procesos intercurrentes (40%) y talla baja (38%). La talla (media ± DE) fue de -1,39 ± 1,49 al diagnóstico y 1,07 ± 1,54 tras un seguimiento de 18,92 (6,25-24,33) años. Dieciséis (32%) desarrollaron filtrado glomerular estimado < 90 mL/min/1,73 m2. Tres pacientes requirieron reemplazo renal sustitutivo. Once enfermos tuvieron descompensaciones metabólicas que requirieron hospitalización, 9 cólicos nefríticos y/o cálculos renales y 10 problemas mentales. Seis de 8 pacientes con acidosis tubular renal desarrollaron sordera neurosensorial. CONCLUSIONES: Las tubulopatías primarias son un grupo heterogéneo de enfermedades que ocasionan afectación del crecimiento, reversible en gran medida con tratamiento, riesgo de reducción de filtrado glomerular estimado e importantes complicaciones extrarrenales derivadas o asociadas


BACKGROUND AND OBJECTIVE: Primary tubulopathies are rare and usually present at pediatric age. Recent advances in genetic diagnosis and treatment have changed its natural history. This study provides the clinical spectrum of a series of primary tubulopathies diagnosed in a Pediatric Nephrology Unit and to offer long-term follow-up data regarding growth, estimated glomerular filtration and intercurrent complications. PATIENTS AND METHODS: Observational study in 53 patients with primary tubulopathies and identified genetic defect: Gitelman syndrome (36%), distal renal tubular acidosis (15%), cystinuria (11%), X-linked hypophosphatemic rickets (7%), Dent-syndrome Lowe (7%), cystinosis (6%), and 1-2 cases of other tubulopathies. Demographic, analytical and clinical data were collected at diagnosis, during evolution and at the time of the study. RESULTS: The age (median and interquartile range) at diagnosis was 5.08 years (1.33-8.50). The most frequent presentation manifestations were metabolic decompensations associated with intercurrent processes (40%) and short stature (38%). Height (mean±SD) was - 1.39 ± 1.49 at diagnosis and 1.07 ± 1.54 after a follow-up of 18.92 (6.25-24.33) years. Sixteen (32%) developed an estimated glomerular filtration < 90 ml / min / 1.73 m2. Three patients required replacement renal replacement. Eleven patients had metabolic decompensations that required hospitalization, 9 renal colic and / or kidney stones and 10 mental problems. Six of 8 patients with distal renal tubular acidosis developed sensorineural deafness. CONCLUSIONS: Primary tubulopathies are a heterogeneous group of diseases that cause growth impairment, largely reversible with treatment, risk of estimated glomerular filtration reduction and significant extrarenal complications derived or associated


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Erros Inatos do Transporte Tubular Renal/patologia , Progressão da Doença , Erros Inatos do Transporte Tubular Renal/fisiopatologia , Estudos Longitudinais , Seguimentos , Cistinose/patologia , Cistinose/fisiopatologia , Taxa de Filtração Glomerular/fisiologia
14.
PLoS One ; 16(3): e0247846, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661986

RESUMO

IMPORTANCE: Development of noninvasive methodology to reproducibly measure tissue cystine crystal load to assess disease status and guide clinical care in cystinosis, an inherited lysosomal storage disorder characterized by widespread cystine crystal accumulation. OBJECTIVE: To develop an unbiased and semi-automated imaging methodology to quantify dermal cystine crystal accumulation in patients to correlate with disease status. DESIGN, SETTING AND PARTICIPANTS: 101 participants, 70 patients and 31 healthy controls, were enrolled at the University of California, San Diego, Cystinosis Clinics, Rady Children's Hospital, San Diego and at the annual Cystinosis Research Foundation family conference for an ongoing prospective longitudinal cohort study of cystinosis patients with potential yearly follow-up. EXPOSURES: Intradermal reflectance confocal microscopy (RCM) imaging, blood collection via standard venipuncture, medical record collection, and occasional skin punch biopsies. MAIN OUTCOMES AND MEASURES: The primary outcome was to establish an automated measure of normalized confocal crystal volume (nCCV) for each subject. Secondary analysis examined the association of nCCV with various clinical indicators to assess nCCV's possible predictive potential. RESULTS: Over 2 years, 57 patients diagnosed with cystinosis (median [range] age: 15.1 yrs [0.8, 54]; 41.4% female) were intradermally assessed by RCM to produce 84 image stacks. 27 healthy individuals (38.7 yrs [10, 85]; 53.1% female) were also imaged providing 37 control image stacks. Automated 2D crystal area quantification revealed that patients had significantly elevated crystal accumulation within the superficial dermis. 3D volumetric analysis of this region was significantly higher in patients compared to healthy controls (mean [SD]: 1934.0 µm3 [1169.1] for patients vs. 363.1 µm3 [194.3] for controls, P<0.001). Medical outcome data was collected from 43 patients with infantile cystinosis (media [range] age: 11 yrs [0.8, 54]; 51% female). nCCV was positively associated with hypothyroidism (OR = 19.68, 95% CI: [1.60, 242.46], P = 0.02) and stage of chronic kidney disease (slope estimate = 0.53, 95%CI: [0.05, 1.00], P = 0.03). CONCLUSIONS AND RELEVANCE: This study used non-invasive RCM imaging to develop an intradermal cystine crystal quantification method. Results showed that cystinosis patients had increased nCCV compared to healthy controls. Level of patient nCCV correlated with several clinical outcomes suggesting nCCV may be used as a potential new biomarker for cystinosis to monitor long-term disease control and medication compliance.


Assuntos
Cistina/análise , Cistinose/diagnóstico por imagem , Derme/diagnóstico por imagem , Adolescente , Adulto , Criança , Cristalização , Cistinose/patologia , Feminino , Humanos , Imageamento Tridimensional , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Adulto Jovem
15.
EBioMedicine ; 63: 103166, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33341443

RESUMO

Lysosomal storage disorders (LSDs), which number over fifty, are monogenically inherited and caused by mutations in genes encoding proteins that are involved in lysosomal function. Lack of the functional protein results in storage of a distinctive material within the lysosomes, which for years was thought to determine the pathophysiology of the disorder. However, our current view posits that the primary storage material disrupts the normal role of the lysosome in the autophagic pathway resulting in the secondary storage of autophagic debris. It is this "collateral damage" which is common to the LSDs but nonetheless intricately nuanced in each. We have selected five LSDs resulting from defective proteins that govern widely different lysosomal functions including glycogen degradation (Pompe), lysosomal transport (Cystinosis), lysosomal trafficking (Danon), glycolipid degradation (Gaucher) and an unidentified function (Batten) and argue that despite the disparate functions, these proteins, when mutant, all impair the autophagic process uniquely.


Assuntos
Autofagia , Suscetibilidade a Doenças , Doenças por Armazenamento dos Lisossomos/etiologia , Doenças por Armazenamento dos Lisossomos/metabolismo , Lisossomos/metabolismo , Animais , Autofagia/genética , Biomarcadores , Cistinose/etiologia , Cistinose/metabolismo , Cistinose/patologia , Gerenciamento Clínico , Humanos , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/terapia , Especificidade de Órgãos/genética
16.
Acta Ophthalmol ; 99(2): e189-e195, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32833325

RESUMO

PURPOSE: The purpose of the present study was to establish a semi-automated threshold-based image segmentation algorithm to detect and objectively quantify corneal cystine crystal deposition in ocular cystinosis with anterior segment optical coherence tomography (AS-OCT). METHODS: This prospective, observational, comparative study included 88 eyes of 45 patients from the German Cystinosis Registry Study as well as 68 eyes of 35 healthy control subjects. All eyes were imaged with AS-OCT (Cirrus HD-OCT 5000, Carl Zeiss Meditec AG, Jena, Germany). As an initial step, B-scan images were subjectively analysed for typical changes in morphology in comparison to healthy controls. Based on the experience gained, an objective semi-automated B-scan image segmentation algorithm was developed using a grey scale value-based threshold method to automatically quantify corneal crystals. RESULTS: On AS-OCT B-scans, corneal crystals appeared as hyperreflective deposits within the corneal stroma. The crystals were distributed either in all stromal layers (43 eyes, 49%) or confined to the anterior (23 eyes, 26%) or posterior stroma (22 eyes, 25%), respectively. The novel automatic B-scan image segmentation algorithm was most efficient in delineating corneal crystals at higher grey scale thresholds (e.g. 226 of a maximum of 255). Significant differences in suprathreshold grey scale pixels were observable between cystinosis patients and healthy controls (p < 0.001). In addition, the algorithm was able to detect an age-dependent depth distribution profile of crystal deposition. CONCLUSION: Objective quantification of corneal cystine crystal deposition is feasible with AS-OCT and can serve as a novel biomarker for ocular disease control and topical treatment monitoring.


Assuntos
Algoritmos , Córnea/patologia , Doenças da Córnea/diagnóstico , Cistinose/diagnóstico , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Microscopia Confocal/métodos , Estudos Prospectivos , Adulto Jovem
17.
Br J Ophthalmol ; 105(5): 608-613, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32593979

RESUMO

BACKGROUND/AIMS: Cystinosis is a rare, autosomal recessive disorder causing defective transport of cystine out of lysosomes. Cystadrops (0.55% cysteamine hydrochloride in viscous solution) has been used on a named-patient basis to treat the accumulation of cystine crystals in the cornea in patients with cystinosis. METHODS: Retrospective analysis of the Temporary Authorisation for Use cohort of 130 patients who received Cystadrops between 2013 and 2017 in France. RESULTS: Patients received an average dosage of 3.3 (±0.94) instillations per eye per day. Over the duration of follow-up, of up to 45 months, patients maintained visual acuity scores of 0.0, which approximated normal. Corneal cystine crystal scores tended to decrease over time, stabilising after around 27 months between 1.22 and 1.87. Photophobia decreased within 3 months, stabilising on scores of around 1.5 and 1.7. 47 non-serious adverse reactions were reported, which were generally transient irritation, stinging or blurred vision. Four serious adverse events were reported, including keratitis and corneal ulcer, but these may have been caused by the underlying disease. CONCLUSION: This large safety cohort confirms the efficacy, safety and tolerability of Cystadrops in real-world clinical practice.


Assuntos
Córnea/metabolismo , Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Acuidade Visual , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Córnea/diagnóstico por imagem , Eliminadores de Cistina/farmacologia , Cistinose/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
19.
Am J Ophthalmol ; 223: 275-285, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32888903

RESUMO

PURPOSE: To evaluate safety and efficacy of topical cysteamine ophthalmic solution for corneal cystinosis. METHODS: Seven databases were searched (PubMed, OVID, EMBASE, Web of Science, Cochrane Central, Google Scholar, and ClinicalTrials.gov) for relevant studies, using appropriate keywords. Comparative observational studies and randomized controlled trials comparing cysteamine with control or other formulations for treatment of corneal or ophthalmic cystinosis were included. Outcome measurements were improvement or response to therapy, change in corneal cystine crystal score (CCCS), in vivo confocal microscopy score (IVCM), cystine crystal depth, contrast sensitivity (CS), photophobia score, and safety. DESIGN: Systematic review and meta-analysis. RESULTS: Seven studies were included. Compared to placebo and control, the cysteamine arm was better in terms of improvements and responses to therapy (2 studies showed a risk ratio [RR] of 16; 95% confidence interval [CI]: 2.30-111.37) and crystal density score (1 study showed a mean difference [MD] of -0.80; 95% CI: -1.56 to -0.04). No significant differences were observed in terms of improvement in CS (1 study showed an RR of 7.00; 95% CI: 0.47-103.27). Compared to cystamine, cysteamine showed benefits in terms of crystal density score (MD -0.94; 95% CI: -1.64 to -0.24). Compared to a newer formulation, the standard formulation (cysteamine [Cystaran]; 0.55% cysteamine hydrochloride + benzalkonium chloride 0.01%) performed better in terms of decreasing CCCS. Another newer, viscous formulation, Cystadrops, performed better than the standard formulation in terms of change in CCCS, IVCM score, corneal crystal depth, and photophobia score; however, local adverse effects and blurring were higher in the group receiving Cystadrops. CONCLUSIONS: Conventional cysteamine (0.1% to 0.3%) performed better than placebo (control) in terms of response to therapy. In terms of decreasing corneal cystine density, cysteamine (0.55%) was better than cystamine (0.55%), and the viscous Cystadrops (0.55%) was better than the standard formulation (0.1%).


Assuntos
Cisteamina/administração & dosagem , Cistinose/tratamento farmacológico , Acuidade Visual , Doenças da Córnea/tratamento farmacológico , Eliminadores de Cistina/administração & dosagem , Humanos , Soluções Oftálmicas/administração & dosagem
20.
BMC Med Genet ; 21(1): 240, 2020 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-33308164

RESUMO

BACKGROUND: In Morocco, consanguinity rate is very high; which lead to an increase in the birth prevalence of infants with autosomal recessive disorders. Previously, it was difficult to diagnose rare autosomal recessive diseases. Next Generation Sequencing (NGS) techniques have considerably improved clinical diagnostics. A genetic diagnosis showing biallelic causative mutations is the requirement for targeted carrier testing in parents, prenatal and preimplantation genetic diagnosis in further pregnancies, and also for targeted premarital testing in future couples at risk of producing affected children by a known autosomal recessive disease. METHODS: In this report, we present our strategy to advise a future couple of first cousins, whose descendants would risk cystinosis; an autosomal recessive lysosomal disease caused by mutations in the CTNS gene. Indeed, our future husband's sister is clinically and biochemically diagnosed with cystinosis in early childhood. First, we opted to identify the patient's CTNS gene abnormality by using (NGS), then we searched for heterozygosity in the couple's DNA, which allows us to predict the exact risk of this familial disease in the future couple's offspring. RESULTS: We have shown that the future husband, brother of the patient is heterozygous for the familial mutation. On the other hand, his future wife did not inherit the familial mutation. Therefore, genetic counseling was reassuring for the risk of familial cystinosis in this couple's offspring. CONCLUSIONS: We report in this study, one of the major applications of (NGS), an effective tool to improve clinical diagnosis and to provide the possibility of targeted premarital carrier testing in couples at risk.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Consanguinidade , Cistinose/genética , Aconselhamento Genético , Mutação , Adulto , Sistemas de Transporte de Aminoácidos Neutros/deficiência , Cistinose/diagnóstico , Cistinose/patologia , Feminino , Expressão Gênica , Testes Genéticos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Marrocos , Linhagem , Risco
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