Globoid cell leukodystrophy (Krabbe's disease): Update
Globoid cell leukodystrophy (Krabbe's disease): Update
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DOI：
10.1177/08830738030180090201
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发表时间：
2003-09-01
影响因子：
1.9
通讯作者：
Suzuki, K
中科院分区：
文献类型：
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作者：
Suzuki, K
典型的球状细胞白质营养不良（克拉伯氏病）是由一种溶酶体酶半乳糖神经酰胺酶的遗传缺陷引起的。它是两种典型的遗传性脑白质营养不良之一，另一种是异色性脑白质营养不良。遗传方式为常染色体隐性遗传。这种疾病通常发生在婴儿中，并采取迅速致命的过程，但也存在罕见的晚发形式。临床表现仅为神经系统，有明显的白质征象。其病理是独特的，包括髓磷脂和髓磷脂形成细胞（中枢神经系统的少突胶质细胞和周围神经系统的Schwarm细胞）的迅速和几乎完全消失，反应性星形胶质增生，以及独特的、通常是多核巨噬细胞（“球状细胞”）的浸润，这些巨噬细胞含有强周期性酸-希夫（PAS）阳性物质。一种通常不显著但具有高度细胞毒性的代谢物，半乳糖神经酰胺酶（psychosine），也是半乳糖神经酰胺酶的底物，被认为在发病机制中起关键作用。半乳糖神经酰胺酶基因已被克隆，并鉴定出大量致病突变。同样的遗传性半乳糖神经酰胺酶缺乏症发生在一些哺乳动物物种中，如老鼠、狗和猴子。最近，至少在小鼠中，鞘脂激活蛋白之一皂苷A的缺乏被证明会导致晚发性、缓慢进展的球状细胞白质营养不良，并伴有半乳糖神经酰胺酶底物降解受损的所有表型后果。在排除其他可能性的情况下，半乳糖神经酰胺酶活性正常的晚发性脑白质营养不良患者可能会出现由皂苷A缺乏引起的人球状细胞脑白质营养不良。治疗人类患者的唯一认真尝试是骨髓移植，它可以显著减轻症状，特别是对于那些发病较晚、进展较慢的球状细胞白质营养不良的患者。
The classic globoid cell leukodystrophy (Krabbe's disease) is caused by genetic defects in a lysosomal enzyme, galactosyl-ceramidase. It is one of the two classic genetic leukodystrophies, together with metachromatic leukodystrophy. The mode of inheritance is autosomal recessive. Typically the disease occurs among infants and takes a rapidly fatal course, but rarer late-onset forms also exist. Clinical manifestations are exclusively neurologic with prominent white-matter signs. The pathology is unique, consisting of a rapid and nearly complete disappearance of myelin and myelin-forming cells-the oligodendrocytes in the central nervous system and the Schwarm cells in the peripheral nervous system, reactive astroytic gliosis, and infiltration of the unique and often multinucleated macrophages ("globoid cells") that contain strongly periodic acid-Schiff (PAS)-positive materials. A normally insignificant but highly cytotoxic metabolite, galactosylsphingosine (psychosine), is also a substrate of galactosylceramidase and is considered to play a critical role in the pathogenesis. The galactosylceramidase gene has been cloned, and a large number of disease-causing mutations have been identified. Equivalent genetic galactosylceramidase deficiency occurs in several mammalian species, such as mouse, dog, and monkey. Recently, deficiency of one of the sphingolipid activator proteins, saposin A, was demonstrated to cause a late-onset, slowly progressive globoid cell leukodystrophy at least in the mouse, with all of the phenotypic consequences of impaired degradation of galactosylceramidase substrates. Human globoid cell leukodystrophy owing to saposin A deficiency might be anticipated and should be suspected in human patients with a late-onset leukodystrophy with normal galactosylceramidase activity when other possibilities are also excluded. The only serious attempt at treating human patients is bone marrow transplantation, which can provide significant alleviation of symptoms, particularly in those patients with later-onset, more slowly progressive globoid cell leukodystrophy.