Abstract：
OBJECTIVE: Pathogenic variants in the NARS1 gene, which encodes for the asparaginyl-tRNA synthetase1 (NARS1) enzyme, were associated with complex central and peripheral nervous system phenotypes. Recently, Charcot-Marie-Tooth (CMT) disease has been linked to heterozygous pathogenic variants in NARS1 in nine patients. Here, we report two brothers and their mother from a French family with distal hereditary motor neuropathy (dHMN) carrying a previously unreported NARS1 variant.
METHODS: The NARS1 variant (c.1555G>C; p.(Gly519Arg)) was identified through whole-genome sequencing (WGS) performed on the family members. Clinical findings, nerve conduction studies (NCS), needle electromyography (EMG), and functional assays in yeast complementation assays are reported here.
RESULTS: The family members showed symptoms of dHMN, including distal weakness and osteoarticular deformities. They also exhibited brisk reflexes suggestive of upper motor neuron involvement. All patients were able to walk independently at the last follow-up. NCS and EMG confirmed pure motor neuropathy. Functional assays in yeast confirmed a loss-of-function effect of the variant on NARS1 activity.
CONCLUSIONS: Our findings expand the clinical spectrum of NARS1-associated neuropathies, highlighting the association of NARS1 mutations with dHMN. The benign disease course observed in our patients suggests a slowly progressive phenotype. Further reports could contribute to a more comprehensive understanding of the spectrum of NARS1-associated neuropathies.
METHODS: The NARS1 variant (c.1555G>C; p.(Gly519Arg)) was identified through whole-genome sequencing (WGS) performed on the family members. Clinical findings, nerve conduction studies (NCS), needle electromyography (EMG), and functional assays in yeast complementation assays are reported here.
RESULTS: The family members showed symptoms of dHMN, including distal weakness and osteoarticular deformities. They also exhibited brisk reflexes suggestive of upper motor neuron involvement. All patients were able to walk independently at the last follow-up. NCS and EMG confirmed pure motor neuropathy. Functional assays in yeast confirmed a loss-of-function effect of the variant on NARS1 activity.
CONCLUSIONS: Our findings expand the clinical spectrum of NARS1-associated neuropathies, highlighting the association of NARS1 mutations with dHMN. The benign disease course observed in our patients suggests a slowly progressive phenotype. Further reports could contribute to a more comprehensive understanding of the spectrum of NARS1-associated neuropathies.
摘要：
目的：NARS1基因的致病变异，它编码天冬酰胺酰-tRNA合成酶1（NARS1）酶，与复杂的中枢和周围神经系统表型有关。最近,Charcot-Marie-Tooth（CMT）疾病已与9例NARS1中的杂合致病变异有关。这里,我们报道了来自一个法国家庭的两名兄弟和他们的母亲,他们患有远端遗传性运动神经病(dHMN),携带一个以前未报道的NARS1变异体.
方法:通过对家族成员进行全基因组测序(WGS)鉴定NARS1变体(c.1555G>C;p.(Gly519Arg))。临床发现，神经传导研究（NCS），针肌电图（EMG），这里报道了酵母互补测定中的功能测定。
结果：家庭成员出现dHMN症状，包括远端无力和骨关节畸形。他们还表现出活跃的反射，提示上运动神经元受累。所有患者在最后一次随访时都能够独立行走。NCS和EMG证实了纯运动神经病。酵母中的功能测定证实了变体对NARS1活性的功能丧失作用。
结论：我们的发现扩大了NARS1相关神经病的临床范围，强调NARS1突变与dHMN的关联。在我们的患者中观察到的良性疾病过程表明了缓慢进展的表型。进一步的报告可能有助于更全面地了解NARS1相关神经病变的频谱。
方法:通过对家族成员进行全基因组测序(WGS)鉴定NARS1变体(c.1555G>C;p.(Gly519Arg))。临床发现，神经传导研究（NCS），针肌电图（EMG），这里报道了酵母互补测定中的功能测定。
结果：家庭成员出现dHMN症状，包括远端无力和骨关节畸形。他们还表现出活跃的反射，提示上运动神经元受累。所有患者在最后一次随访时都能够独立行走。NCS和EMG证实了纯运动神经病。酵母中的功能测定证实了变体对NARS1活性的功能丧失作用。
结论：我们的发现扩大了NARS1相关神经病的临床范围，强调NARS1突变与dHMN的关联。在我们的患者中观察到的良性疾病过程表明了缓慢进展的表型。进一步的报告可能有助于更全面地了解NARS1相关神经病变的频谱。
