Department of Pediatrics, Nationwide Children's Hospital, Ohio State University, 700 Children's Drive, Columbus, OH, 43205, United States.
Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, United States.
Neurosci Lett. 2021 May 1;752:135841. doi: 10.1016/j.neulet.2021.135841. Epub 2021 Mar 22.
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 pre-symptomatic 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.
克拉伯病（球样细胞脑白质营养不良）是一种溶酶体贮积病（LSD），其特征是进行性和深刻的脱髓鞘。已描述了婴儿型、青少年型和成人型克拉伯病，其中婴儿型最常见。婴儿型发病的儿童通常在出生时正常，但在六个月大时开始错过发育里程碑，并且在两到四岁时死亡。克拉伯病是由酸性水解酶半乳糖脑苷脂酶（GALC）缺乏引起的，该酶负责降解半乳糖脑苷脂和神经鞘脂，这些物质在髓鞘膜中含量丰富。GALC 的缺乏导致半乳糖神经酰胺的毒性积累，即半乳糖脑苷脂的溶酶体衍生物，在少突胶质细胞和施旺细胞中导致中枢和周围神经系统脱髓鞘，分别。酶替代、底物减少、酶伴侣和基因治疗等治疗策略已在 LSD 中显示出前景。不幸的是，克拉伯病对大多数单一疗法干预相对耐药。虽然造血干细胞移植可以改变克拉伯病的病程，并且是目前的标准治疗方法，但即使在有症状前的儿童中开始，也只能减缓疾病的进展。然而，最近在克拉伯病的小动物模型中组合治疗方法的成功以及新发病机制的鉴定为开发这种毁灭性疾病的有效治疗方法提供了希望。这篇综述简要介绍了克拉伯病的历史以及单一和联合治疗方法的演变，并讨论了新发病机制以及它们如何影响更有效治疗策略的发展。
