Rett Syndrome: Specific MECP2 Variants are Associated With Elevated Serum Neurofilament Light Chain

IF 2.1 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology Pub Date : 2025-08-05 DOI:10.1016/j.pediatrneurol.2025.07.016

Emma Hirn MD , Brenda Huppke MD , Bernd Wilken MD , Michael Kiehntopf MD , Peter Huppke MD

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引用次数: 0

Abstract

Background

Rett syndrome, a neurodevelopmental disorder predominantly affecting females, is caused by variants in MECP2. Individuals experience a decline in skills, particularly involving language and hand function; nevertheless, studies of brain pathology suggest that neurodegeneration is not involved. To further investigate the presence of neurodegeneration, we measured serum neurofilament light chain (sNfL), a sensitive biomarker of neuronal damage.

Methods

Cross-sectional study performed in a cohort of Rett syndrome females with a confirmed pathogenic MECP2 variant. sNfL levels were measured using single-molecule array assay, converted to an age-adjusted z-score, and compared with MECP2 variant type and clinical characteristics.

Results

Included were 77 patients; mean age 14 years, median sNfL level 6.8 pg/mL. sNfL z-scores were higher in the Rett cohort compared to healthy age-matched females (P < 0.001). Elevated sNfL levels were associated with pathogenic variant type; only patients carrying variants affecting the nuclear receptor corepressor interaction domain had elevated sNfL z-scores (P < 0.001) greater than healthy age-matched females, while those with C-terminal deletions or missense variants outside this domain did not. Consistently, patients unable to walk independently and without residual hand function had higher sNfL levels than patients with residual function in these respective areas (P = 0.04).

Conclusions

sNfL levels were elevated in our Rett syndrome cohort, irrespective of age, indicating ongoing neuronal damage. However, on closer inspection, this finding was true only for a subset of patients with more severe pathogenic variants affecting the nuclear receptor corepressor interaction domain. sNfL may prove a useful biomarker in upcoming therapeutic trials.

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Rett综合征：特定MECP2变异与血清神经丝轻链升高相关

drett综合征是一种主要影响女性的神经发育障碍，由MECP2变异引起。个人的技能会下降，尤其是语言和手部功能；然而，脑病理学研究表明，与神经变性无关。为了进一步研究神经变性的存在，我们测量了血清神经丝轻链（sNfL），这是神经元损伤的敏感生物标志物。方法横断面研究在Rett综合征女性确诊致病MECP2变异队列中进行。采用单分子阵列法测量sNfL水平，并将其转换为年龄调整后的z评分，并比较MECP2变异类型和临床特征。结果纳入77例患者；平均年龄14岁，中位sNfL水平6.8 pg/mL。Rett队列的sNfL z得分高于健康同龄女性（P < 0.001）。sNfL水平升高与致病变异类型相关；只有携带影响核受体协同抑制因子相互作用域的变异的患者sNfL z-score高于健康年龄匹配的女性（P < 0.001），而c端缺失或该区域外的错义变异的患者则没有升高。同样，不能独立行走和无残手功能的患者在这些区域的sNfL水平高于残手功能患者（P = 0.04）。结论：在我们的Rett综合征队列中，snfl水平升高，与年龄无关，表明正在进行的神经元损伤。然而，经过仔细检查，这一发现仅适用于影响核受体辅抑制因子相互作用域的更严重致病变异的一小部分患者。sNfL可能在即将到来的治疗试验中被证明是一种有用的生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pediatric neurology 医学-临床神经学

CiteScore

4.80

自引率

2.60%

发文量

176

审稿时长

78 days

期刊介绍： Pediatric Neurology publishes timely peer-reviewed clinical and research articles covering all aspects of the developing nervous system. Pediatric Neurology features up-to-the-minute publication of the latest advances in the diagnosis, management, and treatment of pediatric neurologic disorders. The journal''s editor, E. Steve Roach, in conjunction with the team of Associate Editors, heads an internationally recognized editorial board, ensuring the most authoritative and extensive coverage of the field. Among the topics covered are: epilepsy, mitochondrial diseases, congenital malformations, chromosomopathies, peripheral neuropathies, perinatal and childhood stroke, cerebral palsy, as well as other diseases affecting the developing nervous system.