RESUMO
Niemann-Pick type C disease (NPC) is a hereditary neurovisceral atypical lipid storage disorder produced by mutations in the NPC1 and NPC2 genes. The disease is characterized by unesterified cholesterol accumulation in late endosomal/lysosomal compartments and oxidative stress. The most affected tissues are the cerebellum and the liver. The lysotropic drug U18666A (U18) has been widely used as a pharmacological model to induce the NPC phenotype in several cell culture lines. It has already been reported that there is an increase in copper content in hepatoma Hu7 cells treated with U18. We confirmed this result with another human hepatoma cell line, HepG2, treated with U18 and supplemented with copper in the media. However, in mouse hippocampal primary cultures treated under similar conditions, we did not find alterations in copper content. We previously reported increased copper content in the liver of Npc1 (-/-) mice compared to control animals. Here, we extended the analysis to the copper content in the cerebella, the plasma and the bile of NPC1 deficient mice. We did not observe a significant change in copper content in the cerebella, whereas we found increased copper content in the plasma and decreased copper levels in the bile of Npc1(-/-) mice. Finally, we also evaluated the plasma content of ceruloplasmin, and we found an increase in this primary copper-binding protein in Npc1 (-/-) mice. These results indicate cell-type dependence of copper accumulation in NPC disease and suggest that copper transport imbalance may be relevant to the liver pathology observed in NPC disease.
Assuntos
Cobre/sangue , Cobre/metabolismo , Doenças de Niemann-Pick/sangue , Doenças de Niemann-Pick/metabolismo , Androstenos , Animais , Western Blotting , Linhagem Celular Tumoral , Células Cultivadas , Ceruloplasmina/metabolismo , Colesterol/metabolismo , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos BALB C , Proteína C1 de Niemann-Pick , Proteínas/genética , Proteínas/metabolismo , RatosRESUMO
OBJECTIVE: To characterize the lipid profiles in patients with types A and B Niemann Pick disease (NPD) and determine if lipid abnormalities are associated with evidence of early cardiovascular disease or correlate with genotype. STUDY DESIGN: The study was a cross-sectional analysis of 10 patients with NPD type A and 30 patients with NPD type B that was carried out in the General Clinical Research Center. For each patient, fasting lipid profile and glucose, T4, height or length, weight, resting blood pressure, and acid sphingomyelinase deficiency genotype were measured. In type B patients, electrocardiograhic-gated helical computed tomography of the heart also was obtained. RESULTS: Lipid abnormalities included low (<35 mg/dL) high-density lipoprotein cholesterol in 100% of patients and hypertriglyceridemia and increased low-density lipoprotein cholesterol in 62% (25/40) and 67% (27/40) of patients, respectively. Coronary artery calcium scores were positive (>1.0) in 10 of 18 type B patients studied. There was no correlation of the Delta R608 genotype with a milder phenotype for the lipid abnormalities, as has been observed for a number of other NPD manifestations. CONCLUSIONS: Lipid abnormalities are part of the phenotype in types A and B NPD and may be associated with early atherosclerotic heart disease.
Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Hipertrigliceridemia/sangue , Doenças de Niemann-Pick/sangue , Cálcio/análise , Criança , Pré-Escolar , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/química , Estudos Transversais , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Doenças de Niemann-Pick/genética , FenótipoRESUMO
OBJECTIVES: To compare growth of children with type B Niemann-Pick disease (NPD) with disease variables including genotype, organomegaly, bone age, and serum insulin-like growth factor-1 (IGF-1). STUDY DESIGN: A cross-sectional analysis of growth was performed in 23 children and adolescents with enzymatically and genotypically confirmed NPD. Liver and spleen volumes were measured by quantitative computed tomography and skeletal age by a wrist radiograph. RESULTS: The mean Z scores for height and weight were -1.24 (29th percentile) and -0.75 (34th percentile). The mean liver and spleen volumes were 2.06 and 13.46 times normal for weight, respectively. Skeletal age was delayed by an average of 2.5 years, and serum IGF-1 level was at or below the 2nd percentile in 8 of 12 patients. Short stature and low weight were significantly correlated with large organ volumes, delayed bone age, and low IGF-1 levels. In contrast to patients with other mutations, individuals homozygous for the DeltaR608 mutation had normal height and weight, markedly less hepatosplenomegaly and bone age delay, and normal IGF-1 levels. CONCLUSIONS: Abnormal linear growth and delayed skeletal maturation are common in children and adolescents with type B NPD; however, homozygosity for DeltaR608 is associated with normal growth.