Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to scarcity of supporting evidence. In our study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite Reticulon-2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with Reticulon-2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN, and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

中文翻译：

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Reticulon 2 缺陷导致常染色体隐性遗传性远端运动神经病并伴有下肢痉挛

此前已在有限的受常染色体显性痉挛性截瘫 (SPG12-OMIM:604805) 影响的家庭中发现了杂合 RTN2 变异，且发病年龄各异。尽管如此，由于缺乏支持证据，SPG12 的最终有效性仍有待确定。在我们的研究中，我们使用外显子组、基因组和桑格测序结合深度表型分析，在来自七个患有远端遗传性运动神经病 (dHMN) 的近亲家庭的 14 名个体中鉴定并验证了 7 个新型或超罕见的纯合性功能丧失性 RTN2 变异。所有受影响的个体（7名男性和7名女性，年龄9-50岁）均表现出上肢和下肢远端无力、下肢痉挛、反射亢进，发病于生命的第一个十年。神经传导研究显示轴突运动神经病伴有肌电图神经源性变化。尽管病程缓慢进展，但所有患者在平均病程为 19.71 ± 13.70 年的时间内仍能行走。秀丽隐杆线虫 RTN2 同源物功能丧失变体的表征表明，与亲本菌株相比，存在形态和行为差异。用内质/肌浆网 Ca2+ 再摄取抑制剂（2,5-二叔丁基氢醌）治疗突变体可挽救关键的表型差异，表明对 RTN2 疾病具有潜在的治疗益处。尽管 Reticulon-2 是一种内质网 (ER) 驻留膜成形蛋白，但我们对患者成纤维细胞的分析并未发现 ER 结构或对 ER 应激反应的显着改变。我们的研究结果描绘了一种独特形式的常染色体隐性遗传 dHMN，其具有与 Reticulon-2 缺陷相关的锥体特征。该表型与 SIGMAR1 相关 dHMN 和 Silver 样综合征有相似之处，为 RTN2 相关 dHMN 的临床谱和潜在治疗策略提供了宝贵的见解。