Krabbe disease: New hope for an old disease.
Krabbe disease: New hope for an old disease.
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DOI：
10.1016/j.neulet.2021.135841
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发表时间：
2021-05-01
影响因子：
2.5
通讯作者：
Sands MS
中科院分区：
文献类型：
--
作者：
Bradbury AM;Bongarzone ER;Sands MS
Krabbe病（球样细胞脑白质营养不良）是一种以进行性和严重脱髓鞘为特征的溶酶体贮积病（LSD）。婴儿、青少年和成人发病形式的克拉布病已被描述，其中婴儿是最常见的。患有癫痫发作的儿童通常在出生时表现正常，但在六个月大时开始错过发育里程碑，并在两到四岁时死亡。克拉伯病是由酸水解酶半乳糖神经酰胺酶（GALC）的缺乏引起的，所述酸水解酶半乳糖神经酰胺酶（GALC）负责降解在髓鞘膜中丰富的半乳糖神经酰胺和鞘脂。GALC的缺乏导致半乳糖基鞘氨醇（精神病）（半乳糖基神经酰胺的溶血衍生物）在少突胶质细胞和许旺细胞中的毒性蓄积，分别导致中枢和外周神经系统的脱髓鞘。治疗策略，如酶替代，底物减少，酶伴侣和基因治疗已显示出对LSD的承诺。不幸的是，Krabbe病对大多数单一治疗干预相对难治。虽然造血干细胞移植可以改变Krabbe病的病程，并且是目前的标准治疗，但它只是减缓了病情的进展，即使在症状前儿童中开始。然而，最近在Krabbe病的小动物模型中的组合治疗方法的成功和新的致病机制的鉴定为这种毁灭性疾病的有效治疗的发展提供了希望。本文综述了Krabbe病的简史以及单一和联合治疗方法的演变，并讨论了新的致病机制以及它们如何影响更有效的治疗策略的发展。
Krabbe disease (globoid cell leukodystrophy) is a lysosomal storage disease (LSD) characterized by progressive and profound demyelination. Infantile, juvenile and adult-onset forms of Krabbe disease have been described, with infantile being the most common. Children with an infantile-onset generally appear normal at birth but begin to miss developmental milestones by six months of age and die by two to four years of age. Krabbe disease is caused by a deficiency of the acid hydrolase galactosylceramidase (GALC) which is responsible for the degradation of galactosylceramides and sphingolipids, which are abundant in myelin membranes. The absence of GALC leads to the toxic accumulation of galactosylsphingosine (psychosine), a lysoderivative of galactosylceramides, in oligodendrocytes and Schwann cells resulting in demyelination of the central and peripheral nervous systems, respectively. Treatment strategies such as enzyme replacement, substrate reduction, enzyme chaperones, and gene therapy have shown promise in LSDs. Unfortunately, Krabbe disease has been relatively refractory to most single-therapy interventions. Although hematopoietic stem cell transplantation can alter the course of Krabbe disease and is the current standard-of-care, it simply slows the progression, even when initiated in presymptomatic children. However, the recent success of combinatorial therapeutic approaches in small animal models of Krabbe disease and the identification of new pathogenic mechanisms provide hope for the development of effective treatments for this devastating disease. This review provides a brief history of Krabbe disease and the evolution of single and combination therapeutic approaches and discusses new pathogenic mechanisms and how they might impact the development of more effective treatment strategies.
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DOI：
10.1097/nen.0000000000000117
发表时间：
2014-10
影响因子：
3.2
作者：
Claycomb KI;Winokur PN;Johnson KM;Nicaise AM;Giampetruzzi AW;Sacino AV;Snyder EY;Barbarese E;Bongarzone ER;Crocker SJ
通讯作者：
Crocker SJ
影响因子：
15.9
作者：
Bradbury, Allison M.;Bagel, Jessica H.;Vite, Charles H.
通讯作者：
Vite, Charles H.
影响因子：
3.5
作者：
Corado, Carley R.;Pinkstaff, Jason;Bradbury, Allison M.
通讯作者：
Bradbury, Allison M.
影响因子：
5.3
作者：
Cantuti-Castelvetri, Ludovico;Maravilla, Erick;Bongarzone, Ernesto R.
通讯作者：
Bongarzone, Ernesto R.
影响因子：
3.4
作者：
Dietrich, C;Bagatolli, LA;Gratton, E
通讯作者：
Gratton, E