Disease relevance of Cystinosis

• Nephropathic cystinosis, an autosomal recessive disorder resulting from defective lysosomal transport of cystine, is the most common inherited cause of renal Fanconi syndrome [1].
• Myopathy and cystine storage in muscles in a patient with nephropathic cystinosis [2].
• We treated 93 children with nephropathic cystinosis with oral cysteamine (mean dose, 51.3 mg per kilogram of body weight per day) for up to 73 months [3].
• A patient with nephropathic cystinosis and end-stage renal disease was treated with cysteamine, both intravenously and orally [4].
• CONCLUSIONS: Cystinosis is a lysosomal storage disease due to impaired transport of cystine out of lysosomes [5].

High impact information on Cystinosis

• Improved renal function in children with cystinosis treated with cysteamine [6].
• Heterozygote detection in cystinosis, using leukocytes exposed to cystine dimethyl ester [7].
• Ineffectiveness of ascorbic acid therapy in nephropathic cystinosis [8].
• Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis [9].
• 11 children with either cystinosis or Lowe's syndrome had a reduced content of plasma and muscle carnitine due to renal Fanconi syndrome [10].

Chemical compound and disease context of Cystinosis

• Successful pregnancy despite placental cystine crystals in a woman with nephropathic cystinosis [11].
• Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome [10].
• Metabolism of pantethine in cystinosis [12].
• Seven of 10 patients with cystinosis had elevations in LH or follicle-stimulating hormone (FSH) levels, suggesting testicular failure [13].
• MAIN RESULTS: Although testosterone levels were within normal limits in 7 of 10 patients with cystinosis, the mean testosterone level in patients with cystinosis was 11.5 +/- 2.0 nmol/L compared with 24.2 +/- 3.0 nmol/L in control patients (P < 0.005) [13].

Biological context of Cystinosis

• Cystinosin-DeltaGYDQL is directly involved in the observed cystine transport, since this activity is highly reduced when the GYDQL motif is restored and is abolished upon introduction of a point mutation inducing early-onset cystinosis [14].
• The gene for cystinosis, CTNS, has 12 exons [15].
• These findings suggest that the CTNS promoter region should be examined in patients with cystinosis who have fewer than two coding-sequence mutations [16].
• This gene-dosage effect strongly supports previous findings demonstrating that the basic defect in cystinosis is impaired cystine transport across the lysosomal membrane [17].
• Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin [18].

Anatomical context of Cystinosis

• Similar treatment of normal fibroblasts and fibroblasts from patients heterozygous for cystinosis resulted in a 6- to 7-fold increase in cystine content [19].
• Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis [20].
• Sorted muscle cells, cultured from a patient with nephropathic cystinosis, stored 100 times normal amounts of cystine [21].
• Two cell lines from children with nephropathic cystinosis containing 1-6 micronmol half-cystine/g protein gave a family of curves similar to those of the normal [22].
• Esomeprazole therapy for gastric acid hypersecretion in children with cystinosis [23].

Gene context of Cystinosis

• Although >55 CTNS mutations occur in patients with the lysosomal storage disorder cystinosis, no regulatory mutations have been reported, because the promoter has not been defined [16].
• Interestingly, both CTNS and CARKL are absent in nearly half of all cystinosis patients (i.e., those homozygous for the common deletion) [24].
• Intralysosomal cystine accumulation in mice lacking cystinosin, the protein defective in cystinosis [25].
• In the current study, we compared the catalytic rate constants for the conversion of palmitoyl-CoA (a PPT substrate) and cystine (which accumulates in cystinosis) by cysteamine [26].
• Although ATP-dependent lysosomal cystine efflux is not demonstrable in cultured lymphoblasts from individuals with nephropathic cystinosis, ATPase activity and acidification in lysosomes from these cells is comparable to that in noncystinotic lysosomes [27].

Analytical, diagnostic and therapeutic context of Cystinosis

• All these late complications of nephropathic cystinosis contribute to a description of the natural history of the disease and provide a rationale for the therapeutic use of cystine-depleting agents after renal transplantation [28].
• OBJECTIVE: The objective was to assess the efficacy and safety of growth hormone (GH) treatment in severely growth retarded children with nephropathic cystinosis during conservative treatment and during renal replacement therapy [29].
• A patient with nephropathic cystinosis developed gingival hyperplasia secondary to cyclosporine-A therapy for his renal allograft [30].
• Metabolic studies were performed on two HLA identical 9 1/2-year-old twins with nephropathic cystinosis during 14 months' participation in a double-blind study to evaluate ascorbic acid treatment for cystinosis [31].

References