The gangliosidoses are a family of neurodegenerative lysosomal storage diseases that have recently seen promising advances in gene therapy. White matter deficits are well established components of gangliosidosis pathology that are now receiving more attention because they are partially refractory to correction by gene therapy. After a brief synopsis of normal myelinogenesis, this review outlines current viewpoints on the origin of white matter deficits in the gangliosidoses and potential obstacles to treating them effectively by gene therapy. Dysmyelinogenesis (failure of myelin sheaths to form properly) is proposed as the predominant contributor to white matter pathology, but precise mechanistic details are not well understood. The involvement of neuronal storage deficits may extend beyond secondary demyelination (destruction of myelin due to axonal loss) and contribute to dysmyelinogenesis. Preclinical studies in animal models of the gangliosidoses have substantially improved lifespan and quality of life, leading to the initiation of several clinical trials. However, improvement of white matter pathology has lagged behind other metrics and few evidence-based explanations have been proposed to date. Research groups in the field are encouraged to include myelin-specific investigations in future gene therapy work to address this gap in knowledge.

中文翻译：

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白质病理学是神经节苷脂沉积症基因治疗的障碍。

神经节苷脂贮积症是一类神经退行性溶酶体贮积病，最近在基因治疗方面取得了有希望的进展。白质缺陷是神经节苷脂病病理学中公认的组成部分，现在受到更多关注，因为它们部分难以通过基因治疗纠正。在简要概述正常髓鞘生成之后，本文概述了目前关于神经节苷脂病中白质缺陷的起源的观点以及通过基因疗法有效治疗它们的潜在障碍。髓磷脂生成障碍（髓鞘无法正常形成）被认为是白质病理学的主要贡献者，但精确的机制细节尚不清楚。神经元储存缺陷的参与可能超出继发性脱髓鞘（由于轴突丢失而导致髓鞘质的破坏），并导致髓鞘质生成障碍。神经节苷脂病动物模型的临床前研究显着改善了寿命和生活质量，从而启动了多项临床试验。然而，白质病理学的改善落后于其他指标，迄今为止几乎没有提出基于证据的解释。鼓励该领域的研究小组将髓磷脂特异性研究纳入未来的基因治疗工作中，以解决这一知识空白。