日本队列中与inf2相关的腓骨肌萎缩症:遗传和临床见解

IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY
Chikashi Yano, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Takahiro Hobara, Risa Nagatomo, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Chika Matsuoka, Toru Yamashita, Takashi Kimura, Ayako Miyazaki, Chinatsu Kinjo, Kenji Yokochi, Nanami Yamanaka, Nozomu Matsuda, Tomoki Suichi, Yoshiyuki Hanaoka, Haruka Kojima, Kenichi Todo, Hiroyuki Ishiura, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima
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引用次数: 0

摘要

背景:INF2突变可引起局灶节段性肾小球硬化(FSGS)和腓骨肌萎缩症(CMT)。准确的遗传学诊断是至关重要的,因为inf2相关的FSGS通常对免疫治疗有耐药性,但移植后很少复发,其相关的神经病变可以模拟可治疗的免疫介导疾病,如慢性炎症性脱髓鞘性多根神经病变(CIDP)。方法:我们进行了一项多中心研究,调查了3329名日本遗传性周围神经病变/CMT患者,这些患者在2007年至2024年间接受了基因面板测序或全外显子组分析。临床数据,包括电生理评估,从患者的医疗记录中获得。结果:我们在8例患者中鉴定出6种致病的INF2变异,它们都位于透明抑制结构域内。结构模型显示,在透明的自调节结构域结合口袋附近聚集了变异,这对INF2的自抑制至关重要。临床上,所有病例均为散发性,神经发病的中位年龄为9岁。所有患者均表现为下肢无力,6/8(75%)有感觉障碍。所有患者还出现肾功能障碍,其中7/8(88%)在中位年龄15岁时进展为终末期肾病。此外,所有患者均出现脱髓鞘性神经病变,2/8(25%)患者因疑似免疫介导的神经病变接受了免疫治疗。结论:尽管在日本,INF2变异是CMT的罕见病因,但在患有脱髓鞘神经病变和早发性蛋白尿的儿科患者中,即使没有家族史,也应考虑到这一点。血液和尿液测试评估肾功能障碍可以为适当的基因检测提供指导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
INF2-Related Charcot-Marie-Tooth Disease in a Japanese Cohort: Genetic and Clinical Insights.

Background: INF2 mutations cause focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth disease (CMT). Accurate genetic diagnosis is critical, as INF2-related FSGS is typically resistant to immunotherapy yet rarely recurs after transplantation, and its associated neuropathy can mimic treatable immune-mediated disorders such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Methods: We performed a multicenter study investigating 3329 Japanese patients with inherited peripheral neuropathies/CMT who underwent gene panel sequencing or whole-exome analysis between 2007 and 2024. Clinical data, including electrophysiological assessments, were obtained from the patients' medical records.

Results: We identified six pathogenic INF2 variants in eight patients, all of which were located within the diaphanous inhibitory domain. Structural modeling revealed clustering of variants near the diaphanous autoregulatory domain-binding pocket, which is critical for INF2 autoinhibition. Clinically, all cases were sporadic, with a median age at neurological onset of 9 years. All patients exhibited lower limb weakness, and 6/8 (75%) had sensory disturbances. All patients also developed kidney dysfunction, with 7/8 (88%) progressing to end-stage renal disease at a median age of 15 years. Furthermore, all patients showed demyelinating neuropathy, and 2/8 (25%) received immunotherapy due to suspected immune-mediated neuropathy.

Conclusion: Although INF2 variants are a rare cause of CMT in Japan, they should be considered in pediatric patients with demyelinating neuropathy and early-onset proteinuria, even in the absence of a family history. Blood and urine tests assessing renal dysfunction can provide guidance for appropriate genetic testing.

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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
期刊介绍: Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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