PART 16 : LYSOSOMAL DISORDERS Chapter 145 : Niemann-Pick Disease Type C : A Lipid Trafficking Disorder-猫眼课题宝

DOI：

发表时间：

2007

期刊：

Plant Physiology

影响因子：

7.4

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

M. Patterson;M. Vanier;Kinuko Suzuki;Jill A. Morris;E. Carstea;E. Neufeld;J. Blanchette-Mackie

1. 尼曼-匹克病C型（NP-C）是一种常染色体隐性脂质病，临床表现为蛋白质，其生物化学特征是外源性胆固醇在细胞运输中的独特错误，这与未酯化胆固醇的溶酶体积累有关。大多数患有这种表型的患者与18号染色体有关，即尼曼-匹克病1型基因（NPC1）的位点。NPC1是一个新基因，其预测蛋白产物包含13 - 16个跨膜结构域，以及一个与Patched、HMG-CoA还原酶和甾醇调节元件结合蛋白（SREBP）裂解激活蛋白（SCAP）同源的甾醇感应结构域。一个被称为NPC结构域的区域，保存在酵母、线虫和小鼠中，包含亮氨酸拉链。NP-C在临床、生化和分子水平上不同于原发性鞘磷脂脂质病（尼曼-匹克病A型[NP-A]和尼曼-匹克病B型[NP-B]分别），传统上将其归为一类。尼曼-匹克病D型（NP-D）与NP-C具有等位基因，应被视为一种与遗传分离物相关的变异表型，而不是一种独特的实体。一小群患者属于第二个基因互补组，与18号染色体无关。这些个体被认为具有暂时指定为尼曼-匹克病2型基因（NPC2）的基因突变。2. NP-C的临床表现具有异质性。大多数NP-C患者有进行性神经系统疾病，尽管在某些病例中肝损害突出，并且在一些病例中可能是致命的。可变肝脾肿大、垂直核上眼麻痹、进行性共济失调、肌张力障碍和痴呆是“经典”表型的特征。这些儿童在儿童时期出现，并在第二或第三个十年死亡。其他表型包括胎儿腹水、致命性新生儿肝病、婴儿早期发病伴张力低下和运动发育迟缓，以及以精神疾病和痴呆为主的成人变异。3. NP-C是泛民族的。在新斯科舍省（以前称为尼曼-匹克病D型）和科罗拉多州南部描述了遗传分离株。互补研究显示了两种不同的群体。大约95%的患者与18q11染色体有关，因此与NPC1有关；其余的人被认为在第二个基因上发生了突变，这个基因暂时被命名为NPC2。4. NP-C的患病率估计约为1:15万，使其成为比NP-A和NP-B加起来更常见的表型。由于术语混乱，在发现细胞胆固醇加工异常之前缺乏明确的诊断测试，以及未能识别临床表型，很可能低估了该疾病的真实患病率。5. 泡沫细胞或海蓝色组织细胞存在于许多组织中。这些细胞不是NP-C特异性的，可能不存在，特别是在没有内脏肿大的情况下。特征性包涵体（多形性细胞质体）可在皮肤和结膜活检中发现。在整个神经系统中，存在细胞质膨胀和各种包涵体的神经元储存。神经原纤维缠结、巨动脉瘤和轴突球体也可见。任何使用均须遵守www.ommbid.com上的使用条款。版权所有©麦格劳-希尔公司。版权所有。第145章：尼曼-匹克病C型：一种脂质转运紊乱

1. Niemann-Pick disease type C (NP-C) is an autosomal recessive lipidosis with protean clinical manifestations, distinguished biochemically by a unique error in cellular trafficking of exogenous cholesterol that is associated with lysosomal accumulation of unesterified cholesterol. A majority of patients with this phenotype are linked genetically to chromosome 18, the locus of Niemann-Pick disease type 1 gene (NPC1). NPC1 is a novel gene whose predicted protein product contains between 13 and 16 transmembrane domains, and a sterol-sensing domain with homologies to Patched, HMG-CoA reductase, and sterol regulatory element binding protein [SREBP] cleavage-activating protein (SCAP). A region designated the NPC domain, conserved in yeast, nematode, and mouse, contains a leucine zipper. NP-C is distinct at clinical, biochemical, and molecular levels from the primary sphingomyelin lipidoses (Niemann-Pick disease types A [NP-A] and Niemann-Pick disease types B [NP-B], respectively]), with which it has traditionally been grouped. Niemann-Pick disease type D (NP-D) is allelic with NP-C, and should be regarded as a variant phenotype associated with a genetic isolate, rather than a distinct entity. A small group of patients belong to a second genetic complementation group that does not link to chromosome 18. These individuals are believed to have mutations in a gene provisionally designated Niemann-Pick disease type 2 gene (NPC2). 2. The clinical manifestations of NP-C are heterogeneous. Most patients with NP-C have progressive neurologic disease, although hepatic damage is prominent in certain cases, and may be lethal in some. Variable hepatosplenomegaly, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia characterize the “classic” phenotype. These children present in childhood, and die in the second or third decade. Other phenotypes include presentations with fetal ascites, fatal neonatal liver disease, early infantile onset with hypotonia and delayed motor development, and adult variants in which psychiatric illness and dementia predominate. 3. NP-C is panethnic. Genetic isolates have been described in Nova Scotia (formerly Niemann-Pick disease type D) and southern Colorado. Complementation studies have demonstrated two distinct groups. About 95 percent of patients link to chromosome 18q11, and thus to NPC1; the remainder are believed to have mutations in a second gene, provisionally designated NPC2. 4. NP-C has an estimated prevalence of approximately 1:150,000, making it a more common phenotype than NP-A and NP-B combined. It is likely that the true prevalence of the disease has been underestimated because of confusing terminology, the lack of a definitive diagnostic test prior to the discovery of the abnormalities of cellular cholesterol processing, and failure to recognize the clinical phenotypes. 5. Foam cells or sea-blue histiocytes are found in many tissues. Such cells are not specific for NP-C and may be absent, particularly in cases lacking visceromegaly. Characteristic inclusions (polymorphous cytoplasmic bodies) may be identified in skin and conjunctival biopsies. Neuronal storage with cytoplasmic ballooning and a variety of inclusions is present throughout the nervous system. Neurofibrillary tangles, meganeurites, and axonal spheroids are also seen. Any use is subject to the Terms of Use on www.ommbid.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved. 1 Chapter 145: Niemann-Pick Disease Type C: A Lipid Trafficking Disorder

PART 16 : LYSOSOMAL DISORDERS Chapter 145 : Niemann-Pick Disease Type C : A Lipid Trafficking Disorder

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