More than 80 genes are known to be associated with Charcot-Marie-Tooth disease (CMT). Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families. Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment. The patients harbored ten different variants in LRSAM1, seven of which were novel. Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging. The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant. Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance. Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein. In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy. ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene.

中文翻译：

---

位置很重要 - LRSAM1 突变与罕见的 Charcot-Marie-Tooth 神经病 CMT2P 相关的基因型-表型相关性

已知有 80 多个基因与 Charcot-Marie-Tooth 病 (CMT) 相关。LRSAM1 的突变被确定为一种罕见的原因，并定义了轴突神经病 CMT2P 的亚组。我们从 12 个家庭中确定了另外 14 名患者。临床和电生理数据证实了迟发性轴索神经病，主要是感觉运动障碍。患者在 LRSAM1 中包含 10 个不同的变体，其中 7 个是新的。由于可变的遗传模式和 3´-prime 外显子中致病变异的聚类，LRSAM1 中遗传变异的解释具有挑战性。大多数遵循显性遗传，而隐性遗传已被描述为一种变体。3`末端的变体可能会也可能不会从无意义介导的衰变中逃脱，从而定义了遗传模式。我们的数据强调了 C 端 RING 域的重要性，每当受到改变或截断的蛋白质影响时，它都会对蛋白质功能产生显性负效应。总之，CMT2P 是成人发病的轴突和疼痛性神经病的一种罕见但仍然相关的原因。ACMG（美国医学遗传学和基因组学学会）标准应谨慎应用于变异解释，特别注意引入终止密码子的变异及其在基因中的位置。