RESUMEN
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.
Asunto(s)
Cobre/deficiencia , Cisteamina/efectos adversos , Cistinosis/complicaciones , Sustancias Protectoras/efectos adversos , Fármacos Renales/efectos adversos , Adenosina Trifosfatasas/genética , Adolescente , Adulto , Biomarcadores/metabolismo , Proteínas de Transporte de Catión/genética , Ceruloplasmina/metabolismo , Niño , Preescolar , Colágeno/metabolismo , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Cobre/metabolismo , Transportador de Cobre 1 , ATPasas Transportadoras de Cobre , Cisteamina/uso terapéutico , Cistinosis/tratamiento farmacológico , Cistinosis/genética , Cistinosis/metabolismo , Síndrome de Fanconi/complicaciones , Síndrome de Fanconi/tratamiento farmacológico , Síndrome de Fanconi/genética , Síndrome de Fanconi/metabolismo , Femenino , Marcadores Genéticos , Humanos , Masculino , Polimorfismo Genético , Sustancias Protectoras/uso terapéutico , Proteína-Lisina 6-Oxidasa/genética , Fármacos Renales/uso terapéutico , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
A neonate who received vitamin K (VK) supplementation then developed severe late-onset bleeding with abnormal prothrombin time and activated partial thromboplastine time. The bleeding was corrected after intravenous VK. Molecular analysis of the gamma-glutamylcarboxylase gene revealed a heterozygous single nucleotide polymorphism, which decreases carboxylase activity and induces VK-dependent coagulation deficiency.