Adult complications of nephropathic cystinosis: a systematic review

Kasimer, Rachel; Langman, Craig B.

doi:10.1007/s00467-020-04487-6

Cited by 23 publications

(21 citation statements)

References 118 publications

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“…Symptoms begin with renal Fanconi syndrome in the first year of life, followed by cystine crystal depositions in the cornea [ 2 ]. In time, patients develop other symptoms, including hypothyroidism, pancreatic insufficiency, gonadal failure, poor growth, myopathy, cholestatic liver disease, and central and peripheral nervous system involvement [ 3 ]. Kidney damage is characterized in part by increased apoptosis of proximal tubular cells in mice [ 4 ], confirming previous in vitro studies showing that cystinotic cells are more sensitive to apoptotic stimuli [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Taranta

Elmonem

Bellomo

et al. 2021

Cells

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Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Current therapy with cysteamine only partially reverts some of these changes, highlighting the need to develop additional treatments. Among compounds that were identified in a previous drug-repositioning study, disulfiram (DSF) was selected for in vivo studies. The cystine depleting and anti-apoptotic properties of DSF were confirmed by secondary in vitro assays and after treating Ctns-/- mice with 200 mg/kg/day of DSF for 3 months. However, at this dosage, growth impairment was observed. Long-term treatment with a lower dose (100 mg/kg/day) did not inhibit growth, but failed to reduce cystine accumulation, caused premature death, and did not prevent the development of renal lesions. In addition, DSF also caused adverse effects in cystinotic zebrafish larvae. DSF toxicity was significantly more pronounced in Ctns-/- mice and zebrafish compared to wild-type animals, suggesting higher cell toxicity of DSF in cystinotic cells.

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Section: Introductionmentioning

confidence: 99%

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Taranta

Elmonem

Bellomo

et al. 2021

Cells

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“…It usually manifests in patients from the second decade of life and progresses after kidney transplantation [8]. It is estimated to occur in 24 to 69% of adult patients with cystinosis [18]. It has been rarely reported to occur in the first decade of life [17,19].…”

Section: Discussionmentioning

confidence: 99%

“…EMG findings include reduced amplitude of the motor unit action, brief duration, polyphasic potentials, and spontaneous activity [13,18]. Neurophysiological evidence of myopathy could be detected in asymptomatic patients, before clinically overt muscle weakness develops [8].…”

Section: Discussionmentioning

confidence: 99%

“…Neurophysiological evidence of myopathy could be detected in asymptomatic patients, before clinically overt muscle weakness develops [8]. It is suggested that cysteamine therapy started before 5 years of age can significantly delay the development of myopathy compared to untreated patients [19], and it is also suggested that cysteamine therapy started after its development can stabilize the course of myopathy or slightly improve it [18,19].…”

Section: Discussionmentioning

confidence: 99%

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Clinical and neurophysiological characterization of early neuromuscular involvement in children and adolescents with nephropathic cystinosis

et al. 2021

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Background Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by kidney and extra-renal complications due to the accumulation of cystine crystals in various tissues and organs. Herein, we describe the early neuromuscular complications in a cohort of pediatric nephropathic cystinosis patients. Methods We prospectively evaluated the clinical, biochemical, and neurophysiological data of 15 cystinosis patients. Neurophysiological evaluation was performed to confirm or exclude presence of neuropathy and/or myopathy. Results Patients' age ranged between 20 and 216 months at time of examination. Nine patients were males. Three patients had early abnormal neurophysiological features consistent with neuromuscular involvement (clinically asymptomatic proximal myopathy with a patchy distribution in one patient and isolated asymptomatic sensory nerve conduction changes in two patients). A fourth patient had mixed abnormal motor and sensory axonal neuropathic changes associated with overt clinical features (predominantly motor symptoms). Patients with abnormal neuromuscular features were significantly older in age than the unaffected group (P = 0.005) and had a diagnosis of cystinosis with subsequent cysteamine therapy at a significantly older age than the unaffected group (P = 0.027 and 0.001, respectively). Conclusions We expanded the recognized phenotypes of cystinosis neuromuscular complications with early proximal skeletal myopathy and symptomatic motor and sensory axonal neuropathy. Early asymptomatic neuromuscular complications could develop in pediatric patients and would require neurophysiological studies for early detection prior to development of overt clinical manifestations. Prompt diagnosis and timely initiation of cysteamine therapy with recommended dose can delay the development of neuromuscular complications.

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“…A primary defect in cystinotic osteoblasts and osteoclasts as well as secondary implications of INC account for the so-called cystinosis-associated metabolic bone disease ( 22 , 24 , 25 ). Varying individually, neurological ( 26 ), hematological, dermatological, cardiac, and psychosocial implications of the disease have also been reported ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

Patients With Infantile Nephropathic Cystinosis in Germany and Austria: A Retrospective Cohort Study

O'Connell

Arbeiter

et al. 2022

Front. Med.

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BackgroundInfantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder resulting in progressive chronic kidney disease (CKD) and a variety of extrarenal manifestations. This orphan disease remains a challenge for patients, their families and health care providers. There is currently no comprehensive study on patients' clinical course in Germany and Austria.MethodsA retrospective cohort study including 74 patients at eleven centers of care was conducted. Data on time of diagnosis, CKD stage, leukocyte cystine levels (LCL), extrarenal manifestations, and treatment was collected from medical charts and subsequently analyzed using explorative statistics. Age at initiation of kidney replacement therapy (KRT) was evaluated by Kaplan–Meier analyses for different groups of patients.ResultsPatients were diagnosed at a median age of 15 months (IQR: 10–29, range: 0–110), more recent year of birth was not associated with earlier diagnosis. Oral cystine-depleting therapy (i.e., cysteamine) was prescribed at a median dose of 1.26 g/m2 per day (IQR: 1.03–1.48, range: 0.22–1.99). 69.2% of all 198 LCL measurements of 67 patients were within the desired target range (≤ 1 nmol cystine/mg protein). Median time-averaged LCLs per patient (n = 65) amounted to 0.57 nmol cystine/mg protein (IQR: 0.33–0.98, range: 0.07–3.13) when considering only values at least 1 year after initiation of therapy. The overall median height of 242 measurements of 68 patients was at the 7th percentile (IQR: 1–25, range: 1–99). 40.5% of the values were ≤ the 3rd percentile. Patient sex and year of birth were not associated with age at initiation of KRT, but patients diagnosed before the age of 18 months required KRT significantly later than those patients diagnosed at the age of ≥ 18 months (p = 0.033): median renal survival was 21 years (95% CI: 16, -) vs. 13 years (95% CI, 10, -), respectively.ConclusionEarly diagnosis and initiation of cystine depleting therapy is important for renal survival in children with INC. Cysteamine doses and LCL showed that treatment in this cohort met international standards although there is great interindividual variety. Patient growth and other aspects of the disease should be managed more effectively in the future.

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Adult complications of nephropathic cystinosis: a systematic review

Cited by 23 publications

References 118 publications

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Benefits and Toxicity of Disulfiram in Preclinical Models of Nephropathic Cystinosis

Clinical and neurophysiological characterization of early neuromuscular involvement in children and adolescents with nephropathic cystinosis

Patients With Infantile Nephropathic Cystinosis in Germany and Austria: A Retrospective Cohort Study

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