Objectives To assess whether copper deficiency plays a role in the recently described cysteamine toxicity in patients with cystinosis, and to examine whether polymorphisms in copper transporters, ...lysyl oxidase, and/or type I procollagen genes could be responsible for the occurrence of cysteamine toxicity in a small subset of patients with cystinosis. Study design Thirty-six patients with cystinosis were included: 22 with Fanconi syndrome (including 7 with cysteamine toxicity), 12 after renal transplantation, 1 receiving hemodialysis, and 1 with ocular cystinosis. Serum copper and ceruloplasmin levels and urinary copper/creatinine ratio were measured. Genes ATP7A and CTR1 (encoding copper transporters), LOX (encoding lysyl oxidase), and COL1A1 and COL1A2 (encoding type I procollagen) were analyzed in patients with (n = 6) and without (n = 5) toxicity. Fibroblast (pro)collagen synthesis was compared in patients with (n = 3) and those without (n = 2) cysteamine toxicity. Results All 22 patients with Fanconi syndrome had increased urinary copper excretion. Serum copper and ceruloplasmin levels were decreased in 9 patients, including all 7 patients with cysteamine toxicity. No specific sequence variations were associated with toxicity. All fibroblasts exhibited normal (pro)collagen synthesis. Conclusion Patients with cystinosis with cysteamine toxicity demonstrate copper deficiency. This can cause decreased activity of lysyl oxidase, the enzyme that generates the aldehydes required for collagen cross-linking. Thus, copper supplementation might prevent cysteamine toxicity.
Cysteamine Toxicity in Patients with Cystinosis Besouw, Martine T.P., MD; Bowker, Richard, MA, MBBS; Dutertre, Jean-Paul, MD ...
The Journal of pediatrics,
12/2011, Letnik:
159, Številka:
6
Journal Article
Recenzirano
Objective To report new adverse effects of cysteamine. Study design Detailed clinical information was obtained from the patients’ physicians. Results New adverse events were reported in 8 of 550 ...patients with cystinosis treated with cysteamine in Europe during the last 5 years. Detailed clinical information was not available for 2 of these patients, 1 of whom died from cerebral ischemia. The 6 evaluable patients developed vascular elbow lesions (6/6), neurologic symptoms (1/6), bone and muscle pain (2/6), and/or skin striae (2/6). Analysis of biopsy specimens from the elbow lesions demonstrated angioendotheliomatosis with irregular collagen fibers. In 3 of the 6 patients, the daily cysteamine dose exceeded the recommended maximum of 1.95 g/m2 /day. Dose reduction led to improvement of signs and symptoms in all 6 patients, suggesting a causal relationship with cysteamine administration. Conclusion Cysteamine administration can be complicated by the development of skin, vascular, neurologic, muscular, and bone lesions. These lesions improve after cysteamine dose reduction. Doses >1.95 g/m2 /day should be prescribed with great caution, but underdosing is not advocated.
Background Nephropathic cystinosis is the most common cause of inherited renal Fanconi syndrome, caused by mutations in lysosomal cystine carrier cystinosin that result in lysosomal cystine ...accumulation throughout the body. How defects in cystinosin cause proximal tubular dysfunction is not known. We hypothesized that cystine accumulation could cause disturbed proximal tubular endocytosis by megalin and cubilin. Study Design Megalin, cubilin, and their ligands were studied in kidney tissue by means of immunohistochemistry. Urinary protein excretion pattern was evaluated. Setting & Participants Kidney tissue from a patient with cystinosis was compared with minimal change nephrotic syndrome tissue, end-stage renal disease tissue, and control renal tissue. Urine from 7 patients with cystinosis was compared with 6 control samples. Results Expression of megalin, cubilin, and ligands (transferrin, albumin, vitamin D–binding protein, α1 -microglobulin, retinol-binding protein, and β2 -microglobulin) in convoluted proximal tubules of cystinotic kidney was similar to that in other kidney specimens. In straight tubules, low-molecular-weight proteins were present in only cystinotic kidney samples. Next to low-molecular-weight proteins and albumin, urinary excretion of immunoglobulin G was increased in patients with cystinosis with Fanconi syndrome compared with controls. This was already observed at an early age, suggesting enhanced glomerular permeability in patients with cystinosis. Limitations This study is essentially observational, and immunohistochemical data are based on 1 cystinotic kidney. Conclusion Our findings indicate that low-molecular-weight proteinuria in patients with cystinosis is not caused by decreased megalin and cubilin expression, and glomerular damage might already be present at early stages of the disease.
Background Seventy percent of children with minimal change nephrotic syndrome (MCNS) have a steroid-dependent or frequent relapsing course of the disease, and most are treated with cyclophosphamide. ...We describe the clinical course of children with biopsy-proven MCNS treated with cyclophosphamide for steroid-dependent or frequently relapsing nephrotic syndrome at our institution from 1971 to 2003. Methods From our pathology registry, we identified 93 patients with biopsy-proven MCNS who received cyclophosphamide therapy. Follow-up information from medical records and mailed questionnaires could be obtained for 80 patients (86%). Results Only 35% of patients experienced no relapse after cyclophosphamide therapy. Twenty-one patients subsequently were treated with cyclosporine, with only 3 (14%) achieving persistent remission. At the end of follow-up, 23 patients (25%) still experienced relapse, and all except 3 patients required continuous immunosuppressive therapy. However, the cumulative incidence of persistent complete remission (>2 years without medication) increased over time (35% at 2 years, 52% at 6 years, and 71% at 15 years after the start of cyclophosphamide therapy), and no patient developed kidney failure. By means of univariate analysis, age younger than 3 years at onset predicted a lower likelihood of attaining remission ( P < 0.05). Conclusion More than a quarter of a selected group of cyclophosphamide-treated patients with steroid-dependent or frequently relapsing MCNS were not in remission after puberty and required prolonged immunosuppressive treatment. There is an urgent need for more effective treatment modalities resulting in persistent remission in these patients.
A search for the pseudoscalar mesons
η
c
and
η
b
, produced by two-photon interactions is performed using the L3 data collected at centre-of-mass energies from 183 GeV to 209 GeV, for a total ...integrated luminosity of 610 pb
−1.
X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization ...of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.
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