PDF(Pubmed)
Abstract：
Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.
摘要：
运动神经元疾病和周围神经病变是神经退行性疾病的异质组，由于在不同的发育阶段进行性功能障碍或特定神经元亚群的丧失而表现出不同的症状。几个单基因，最近发现了与鞘脂生物合成的原发性代谢破坏相关的神经退行性疾病。鞘脂是脂质的亚类,其形成包括神经系统细胞的膜组分的所有细胞和亚细胞细胞器膜的关键结构单元。它们在髓磷脂的脂质部分中特别丰富。在这次审查中,我们将专注于我们目前对三种单基因疾病表型的理解，与丝氨酸棕榈酰转移酶成分致病变异相关的神经肌肉疾病，鞘脂生物合成的第一步。这些包括遗传性感觉和自主神经病变1型（HSAN1），感觉型周围神经病,和两种神经退行性疾病：幼年肌萎缩性侧索硬化症，影响上下运动神经元，保留感觉神经元，以及一种复杂的遗传性痉挛性截瘫，选择性地累及上运动神经元和更广泛的中枢神经系统神经变性。我们还将回顾我们目前对疾病病理机制的理解，治疗方法，以及在未来研究中探索的未解决的问题。
