RESUMO
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.
Assuntos
Cobre/deficiência , Cisteamina/efeitos adversos , Cistinose/complicações , Substâncias Protetoras/efeitos adversos , Fármacos Renais/efeitos adversos , Adenosina Trifosfatases/genética , Adolescente , Adulto , Biomarcadores/metabolismo , Proteínas de Transporte de Cátions/genética , Ceruloplasmina/metabolismo , Criança , Pré-Escolar , Colágeno/metabolismo , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Cobre/metabolismo , Transportador de Cobre 1 , ATPases Transportadoras de Cobre , Cisteamina/uso terapêutico , Cistinose/tratamento farmacológico , Cistinose/genética , Cistinose/metabolismo , Síndrome de Fanconi/complicações , Síndrome de Fanconi/tratamento farmacológico , Síndrome de Fanconi/genética , Síndrome de Fanconi/metabolismo , Feminino , Marcadores Genéticos , Humanos , Masculino , Polimorfismo Genético , Substâncias Protetoras/uso terapêutico , Proteína-Lisina 6-Oxidase/genética , Fármacos Renais/uso terapêutico , Análise de Sequência de DNA , Adulto JovemRESUMO
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/m(2)/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/m(2)/day should be prescribed with great caution, but underdosing is not advocated.