TYPE-C NIEMANN-PICK DISEASE - SPECTRUM OF PHENOTYPIC VARIATION IN DISRUPTION OF INTRACELLULAR LDL-DERIVED CHOLESTEROL PROCESSING
TYPE-C NIEMANN-PICK DISEASE - SPECTRUM OF PHENOTYPIC VARIATION IN DISRUPTION OF INTRACELLULAR LDL-DERIVED CHOLESTEROL PROCESSING
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DOI：
10.1016/0925-4439(91)90069-l
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发表时间：
1991-06-05
期刊：
影响因子：
--
通讯作者：
LOUISOT, P
中科院分区：
文献类型：
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作者：
VANIER, MT;RODRIGUEZLAFRASSE, C;LOUISOT, P
为了研究C型尼曼-匹克病（NPC）的生化异质性，在125例NPC患者的培养皮肤成纤维细胞中研究了两种最具特征性的异常，即（1）LDL刺激的胆固醇酯形成的动力学和（2）LDL衍生的未酯化胆固醇的囊内蓄积，通过组织化学菲律宾染色进行评价。在86%的病例中证实了显著的改变（酯化率< 10%的正常，非常多和强烈荧光的胆固醇-菲律宾颗粒），描绘了“经典”NPC表型。其余细胞系显示出LDL介导的胆固醇酯化诱导的分级不太严重的损伤和更短暂的延迟，沿着未酯化胆固醇的蓄积减弱。特别是，细胞从一小群（7%）的患者，这已被个性化为代表的“变异”的表型，显示只有轻微的改变酯化，限制在早期阶段的LDL摄取和那些在杂合子无法区分。在这些细胞中，LDL衍生的胆固醇的异常细胞化学分布，虽然中等，仍然是明显的提供严格的实验条件下。第三，不太清楚个性化组（7%），从经典的表型主要是胆固醇酯形成率较高的不同，已被指定为一个“中间”表型，以反映更困难的诊断这样的患者。这些研究结果有一个重要的轴承方面的诊断和遗传咨询，虽然这种表型变异的遗传异质性方面的意义仍有待证明。然而，一个给定的生化表型是一个家庭内的一个恒定的观察（14对兄弟姐妹测试到目前为止）。NPC中LDL-胆固醇加工改变的独特特征已从Wolman病和1-细胞病的比较研究中进一步确立，显示在后者疾病中未酯化LDL衍生的胆固醇的正常或不同的细胞内分布。生化和临床NPC表型之间的相关性只是部分的，但胆固醇加工和鞘磷脂酶的变化的严重程度之间的相关性可以建立。
To investigate biochemical heterogeneity within Niemann-Pick type C disease (NPC), the two most characteristic abnormalities, namely (1) kinetics of LDL-stimulated cholesteryl ester formation and (2) intravesicular accumulation of LDL-derived unesterified cholesterol, evaluated by histochemical filipin staining, were studied in cultured skin fibroblasts from a population of 125 NPC patients. Profound alterations (esterification rates < 10% of normal, very numerous and intensely fluorescent cholesterol-filipin granules) were demonstrated in 86% of the cases, depicting the 'classical' NPC phenotype. The remaining cell lines showed a graded less severe impairment and more transient delay in the induction of LDL-mediated cholesteryl esterification, along with an attenuated accumulation of unesterified cholesterol. In particular, cells from a small group (7%) of patients, which have been individualized as representative of a 'variant' phenotype, showed only slight alterations of esterification, restricted to the early phase of LDL uptake and undistinguishable from those in heterozygotes. In these cells, an abnormal cytochemical distribution of LDL-derived cholesterol, although moderate, was still evident provided rigorous experimental conditions were followed. A third, less clearly individualized group (7%), differing from the classical phenotype mostly by higher rates of cholesteryl ester formation, has been designated as an 'intermediary' phenotype to reflect a more difficult diagnosis of such patients. These findings have an important bearing with regard to diagnosis and genetic counselling, although the significance of such a phenotypic variation in terms of genetic heterogeneity has still to be demonstrated. A given biochemical phenotype was however a constant observation within a family (14 pairs of siblings tested so far). The unique feature of LDL-cholesterol processing alterations in NPC has been further established from comparative studies in Wolman disease and 1-cell disease, showing normal or different intracellular distribution of unesterified LDL-derived cholesterol in the latter disorders. Correlation between biochemical and clinical NPC phenotypes was only partial, but a correlation between the severity of alterations in cholesterol processing and sphingomyelin catabolism could be established.