Long-term follow-up of well-treated nephropathic cystinosis patients

Kleta, Robert; Bernardini, Isa; Ueda, Masako; Varade, William S.; Phornphutkul, Chanika; Krasnewich, Donna M.; Gahl, William A.

doi:10.1016/j.jpeds.2004.03.056

Cited by 114 publications

(85 citation statements)

References 40 publications

(19 reference statements)

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“…The most common type in our study, the c.451A>G mutation, was previously described in Turkey and associated with a moderate clinical course 16 . Similarly, all of our patients with the c.451A>G mutation (2,3,4,10,11,12,14,16,20) were diagnosed between the ages of 2 to 14 years with renal tubular acidosis (RTA), excluding only one patient. Patient 16, who was on Three out of seven patients with the c.681G>A mutation are on the CAPD program due to renal failure.…”

Section: Discussionmentioning

confidence: 97%

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Genotypic and phenotypic features of the cystinosis patients from the South Eastern part of Turkey

et al. 2016

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Section: Discussionmentioning

confidence: 97%

“…Early diagnosis and treatment with appropriate doses of cysteamine provide considerable reduction in the cystine level in the lysosomes, and in addition, may prevent development of renal dysfunction and extrarenal complications 9,10 . They also increase the growth rate.…”

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confidence: 99%

Genotypic and phenotypic features of the cystinosis patients from the South Eastern part of Turkey

et al. 2016

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“…19 When renal Fanconi's syndrome occurs as a result of multisystem disease, early diagnosis may facilitate therapy directed at the basic defect. 20 When Fanconi's syndrome is isolated, however, treatment is largely symptomatic because the basic defect is generally unknown. Exceptions include genetic disorders causing a partial Fanconi's syndrome 4,21 (e.g., renal glucosuria due to biallelic SGLT2 mutations 22 and phosphaturia associated with autosomal recessive deficiency of phosphate transport 23 ).…”

Section: Discussionmentioning

confidence: 99%

Mistargeting of Peroxisomal EHHADH and Inherited Renal Fanconi's Syndrome

et al. 2014

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Background: In renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown. Methods: We clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance (1H-NMR) spectroscopy. Results: We linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. 1H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency. Conclusions: Mistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Seventh Framework Programme and others.)

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“…Patient adherence with Cystagon is challenging due to its dosing frequency, significant adverse effects, and the need for lifelong treatment from the age of diagnosis (13). Because Cystagon must be taken every 6 hours (Q6H) around the clock based on the pharmacoefficiency of cystine depletion, patients must be awakened in the middle of the night to be fully adherent.…”

Section: Introductionmentioning

confidence: 99%

“…One study demonstrated that ,25% of patients (5 of 22) were actually adhering to this regimen (14). There is evidence that failure to adhere to this strict Q6H dosing regimen results in more rapid deterioration of kidney function as WBC cystine levels rise (13). A small pilot trial suggested that a delayed-release Q12H formulation of cysteamine, EC-Cysteamine, was able to maintain WBC cystine levels comparable with the marketed immediaterelease Q6H formulation (15,16).…”

Section: Introductionmentioning

confidence: 99%

A Randomized Controlled Crossover Trial with Delayed-Release Cysteamine Bitartrate in Nephropathic Cystinosis

Langman

Greenbaum

Sarwal

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Immediate-release cysteamine bitartrate (Cystagon; Mylan Pharmaceuticals, Canonsburg, PA) may prevent or delay kidney transplantation and other serious outcomes in patients with cystinosis, but has never been subjected to a prospective clinical trial. Cystagon efficacy requires strict lifelong dosing every 6 hours. Such a dosing schedule and Cystagon-associated side effects are often cited by patients as reasons for nonadherence. Design, setting, participants, & measurementsThis open-label, randomized, controlled, crossover trial was powered to show that a new delayed-release formulation of cysteamine bitartrate, RP103, taken every 12 hours, was noninferior to Cystagon for maintenance of white blood cell (WBC) cystine at levels associated with optimal outcomes in the disease.Results Forty-three patients were randomized. Using a mixed-effects statistical analysis model, the least-squares mean peak value of WBC cystine level was 0.6260.05 nmol 1/2 cystine/mg protein after 12 hours under RP103 and 0.5460.05 nmol 1/2 cystine/mg protein after 6 hours under Cystagon, a difference of 0.0860.04 nmol 1/2 cystine/mg protein (95.8% confidence interval, 0-0.16). The average steady-state total daily dose of RP103 was 82% of the incoming steady-state total daily dose of Cystagon. There were three-fold more gastrointestinal side effects compared with using Cystagon.Conclusions A new delayed-release Q12H formulation of cysteamine bitartrate is not inferior to the Q6H formulation (Cystagon) in maintaining low WBC cystine levels in patients with cystinosis but at a lower total daily dose.

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Long-term follow-up of well-treated nephropathic cystinosis patients

Cited by 114 publications

References 40 publications

Genotypic and phenotypic features of the cystinosis patients from the South Eastern part of Turkey

Genotypic and phenotypic features of the cystinosis patients from the South Eastern part of Turkey

Mistargeting of Peroxisomal EHHADH and Inherited Renal Fanconi's Syndrome

A Randomized Controlled Crossover Trial with Delayed-Release Cysteamine Bitartrate in Nephropathic Cystinosis

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