4qA 特异性远端 D4Z4 低甲基化与面肩肱型肌营养不良症疾病严重程度和进展的关联。
Association of 4qA-Specific Distal D4Z4 Hypomethylation With Disease Severity and Progression in Facioscapulohumeral Muscular Dystrophy.
机构信息
From the Department of Neurology and Institute of Neurology of First Affiliated Hospital (F.Z., L.Q., L.C., Y.Z., Xiaodan Lin, J.H., Xin Lin, Q.H., Yuhua Lin, L.L., L.W., F.L., K.Y., M.L., Yi Lin, Y.F., N.W., Z.W.), Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou; and Department of Neurology (L.Q., Xin Lin, F.L., M.L., Yi Lin, Y.F., N.W., Z.W.), National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
出版信息
Neurology. 2023 Jul 18;101(3):e225-e237. doi: 10.1212/WNL.0000000000207418. Epub 2023 May 24.
BACKGROUND AND OBJECTIVES
The objective of this study was to examine whether the regional methylation levels at the most distal D4Z4 repeat units (RU) in the 4qA-permissive haplotype were associated with disease severity and progression in facioscapulohumeral muscular dystrophy type 1 (FSHD1).
METHODS
This 21-year, retrospective, observational cohort study was conducted at the Fujian Neuromedical Center (FNMC) in China. Methylation levels of the most distal D4Z4 RU, including 10 CpGs, were assessed in all participants by bisulfite sequencing. Patients with FSHD1 were stratified into 4 groups based on methylation percentage quartiles, including LM1 (low methylation), LM2 (low to intermediate methylation), LM3 (intermediate to high methylation), and highest methylation (HM) levels. Patients received evaluations of motor function focusing on lower extremity (LE) progression at baseline and in follow-ups. FSHD clinical score (CS), age-corrected clinical severity scale (ACSS), and modified Rankin scale were used to assess motor function.
RESULTS
The methylation levels of the 10 CpGs were significantly lower in all 823 patients with genetically confirmed FSHD1 than in 341 healthy controls (HCs). CpG6 methylation levels could distinguish the following: (1) patients with FSHD1 from HCs; (2) symptomatic from asymptomatic/unaffected patients; (3) patients with LE involvement from those without LE involvement, with AUCs (95% CI) of 0.9684 (0.9584-0.9785), 0.7417 (0.6903-0.7931), and 0.6386 (0.5816-0.6956), respectively. Lower CpG6 methylation levels were correlated with higher CS (r = -0.392), higher ACSS (r = -0.432), and earlier onset age of first-ever muscle weakness (r = 0.297). For the LM1, LM2, LM3, and HM groups, the respective proportions of LE involvement were 52.9%, 44.2%, 36.9%, and 23.4%; and onset ages of LE involvement were 20, 26.5, 25, and 26.5 years. Cox regression analysis-adjusted for sex, age at examination, D4Z4 RU, and 4qA/B haplotype-showed that the LM1, LM2, and LM3 groups (i.e., groups with lower methylation levels) had a higher risk of independent ambulation loss, with HRs (95% CI) of 3.523 (1.565-7.930), 3.356 (1.458-7.727), and 2.956 (1.245-7.020), respectively.
DISCUSSION
4q35 distal D4Z4 hypomethylation is correlated with disease severity and progression to lower extremity involvement.
背景与目的
本研究旨在探讨 4qA 许可单倍型中最远端 D4Z4 重复单位（RU）的区域甲基化水平是否与 1 型面肩肱型肌营养不良症（FSHD1）的疾病严重程度和进展相关。
方法
这是一项在中国福建神经医学中心（FNMC）进行的 21 年回顾性观察队列研究。通过亚硫酸氢盐测序法评估所有参与者中最远端 D4Z4 RU 的甲基化水平，包括 10 个 CpG。根据甲基化百分比四分位数将 FSHD1 患者分为 4 组，包括低甲基化（LM1）、低到中甲基化（LM2）、中到高甲基化（LM3）和最高甲基化（HM）水平。患者在基线和随访时接受了以下针对下肢（LE）进展的运动功能评估：FSHD 临床评分（CS）、年龄校正临床严重程度评分（ACSS）和改良 Rankin 量表。
结果
与 341 名健康对照者（HCs）相比，所有 823 名经基因证实的 FSHD1 患者的 10 个 CpG 的甲基化水平显著降低。CpG6 甲基化水平可区分：（1）FSHD1 患者与 HCs；（2）有症状与无症状/未受影响的患者；（3）LE 受累患者与无 LE 受累患者，AUC（95%CI）分别为 0.9684（0.9584-0.9785）、0.7417（0.6903-0.7931）和 0.6386（0.5816-0.6956）。较低的 CpG6 甲基化水平与较高的 CS（r=-0.392）、较高的 ACSS（r=-0.432）和首次肌肉无力的发病年龄较早（r=0.297）相关。对于 LM1、LM2、LM3 和 HM 组，LE 受累的比例分别为 52.9%、44.2%、36.9%和 23.4%；LE 受累的发病年龄分别为 20、26.5、25 和 26.5 岁。Cox 回归分析（校正性别、检查时年龄、D4Z4 RU 和 4qA/B 单倍型）显示，LM1、LM2 和 LM3 组（即甲基化水平较低的组）独立丧失独立行走能力的风险更高，HR（95%CI）分别为 3.523（1.565-7.930）、3.356（1.458-7.727）和 2.956（1.245-7.020）。
讨论
4q35 远端 D4Z4 低甲基化与疾病严重程度和下肢受累进展相关。
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