University of Sydney, Sydney, NSW, Australia.
Curr Mol Med. 2011 Nov;11(8):650-65. doi: 10.2174/156652411797536714.
The distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders that primarily affect motor neurons, without significant sensory involvement. New dHMN genes continue to be identified. There are now 11 causative genes described for dHMN, and an additional five genetic loci with unidentified genes. This genetic heterogeneity has further delineated the classification of dHMN, which was previously classified according to mode of inheritance, age at onset, and additional complicating features. Some overlap between phenotypically distinct forms of dHMN is also apparent. The mutated genes identified to-date in dHMN include HSPB1, HSPB8, HSPB3, DCTN1, GARS, PLEKHG5, BSCL2, SETX, IGHMBP2, ATP7A and TRPV4. The pathogenesis of mutations remains to be fully elucidated, however common pathogenic mechanisms are emerging. These include disruption of axonal transport, RNA processing defects, protein aggregation and inclusion body formation, disrupted calcium channel activity, and loss of neuroprotective signalling. Some of these dHMN genes are also mutated in Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). This review examines the growing number of identified dHMN genes, discusses recent insights into the functions of these genes and possible pathogenic mechanisms, and looks at the increasing overlap between dHMN and the other neuropathies CMT2 and SMA.
远端遗传性运动神经病（dHMN）是一组临床和遗传异质性的疾病，主要影响运动神经元，而感觉神经受累不明显。新的 dHMN 基因不断被发现。目前已有 11 个 dHMN 的致病基因被描述，另外还有 5 个遗传位点存在未鉴定的基因。这种遗传异质性进一步划分了 dHMN 的分类，此前根据遗传方式、发病年龄和其他复杂特征进行分类。一些表型不同的 dHMN 之间也存在明显的重叠。迄今为止在 dHMN 中鉴定出的突变基因包括 HSPB1、HSPB8、HSPB3、DCTN1、GARS、PLEKHG5、BSCL2、SETX、IGHMBP2、ATP7A 和 TRPV4。突变的发病机制仍有待充分阐明，但常见的发病机制正在出现。这些机制包括轴突运输中断、RNA 处理缺陷、蛋白质聚集和包含体形成、钙通道活性紊乱以及神经保护信号丢失。这些 dHMN 基因中的一些也在遗传性运动感觉神经病（CMT）和脊髓性肌萎缩症（SMA）中发生突变。这篇综述检查了越来越多已鉴定出的 dHMN 基因，讨论了这些基因功能和可能的发病机制的最新见解，并研究了 dHMN 与其他神经病 CMT2 和 SMA 之间日益增加的重叠。
