Gaucher disease and other storage disorders
Gaucher disease and other storage disorders
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DOI：
10.1182/asheducation-2012.1.13
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发表时间：
2012-12-01
期刊：
影响因子：
--
通讯作者：
Grabowski, Gregory A.
中科院分区：
文献类型：
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作者：
Grabowski, Gregory A.
1882年，Philippe Gaucher描述了一位32岁的女性，她患有巨大的脾肿大，脾细胞异常大，他称之为“原发性脾上皮瘤”。“在接下来的世纪，人们描述了这种疾病的系统性和遗传性及其涉及内脏和中枢神经系统的变异。对致病酶缺陷、遗传学、分子病理学和基因组学的描述为表型谱的致病性提供了见解，并为现在称为戈谢病的特定疗法的开发提供了基础。作为一个原型，临床和经济上成功的细胞内酶疗法为其他溶酶体贮积病（LSD）和孤儿病（包括法布里病、庞贝病和尼曼-皮克病）以及几种粘多糖病的类似研究和治疗开发的扩展提供了动力。此类LSD作为一组在7000多例活产中发生，其持续研究揭示了自噬和凋亡途径以及蛋白质稳态的复杂分子交错，并且已经认识到溶酶体/自噬和蛋白质稳态系统的破坏对更常见疾病的影响。示例包括年龄相关性神经退行性疾病（如帕金森病和戈谢病）、特发性肥厚性心肌病、卒中和肾衰竭（如法布里病）、非酒精性脂肪肝/非酒精性脂肪性肝炎（NAFLD/NASH）和动脉粥样硬化（如溶酶体酸性脂肪酶缺乏症）。虽然被认为是罕见的，但治疗的可用性和LSD对更常见疾病的影响需要将其纳入常规临床实践。
In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a "primary epithelioma of the spleen." The systemic nature and inheritance of the disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage diseases (LSDs) and orphan diseases, including Fabry, Pompe, and Niemann-Pick diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common diseases has been recognized. Examples include age-related neurodegenerative diseases (eg, Parkinson disease and Gaucher disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice.