Department of Neurology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands.
Expertise Center Movement Disorders Groningen, University Medical Center Groningen (UMCG), PO Box 30.001, 9700 RB, Groningen, The Netherlands.
Clin Epigenetics. 2022 Dec 11;14(1):170. doi: 10.1186/s13148-022-01384-7.
Dystonia is a rare movement disorder, in which patients suffer from involuntary twisting movements or abnormal posturing. Next to these motor symptoms, patients have a high prevalence of psychiatric comorbidity, suggesting a role for serotonin in its pathophysiology. This study investigates the percentage of DNA methylation of the gene encoding for the serotonin reuptake transporter (SLC6A4) in dystonia patients and the associations between methylation levels and presence and severity of psychiatric symptoms.
Patients with cervical dystonia (n = 49), myoclonus dystonia (n = 41) and dopa-responsive dystonia (DRD) (n = 27) and a group of healthy controls (n = 56) were included. Psychiatric comorbidity was evaluated with validated questionnaires. Methylation levels of 20 CpG sites situated 69 to 213 base pairs upstream of the start codon of SLC6A4 were investigated. Methylation in dystonia patients was compared to healthy controls, correcting for age, and correlated with psychiatric comorbidity.
Bootstrapped quantile regression analysis showed that being a dystonia patient compared to a healthy control significantly explains the methylation level at two CpG sites (CpG 24: pseudo-R = 0.05, p = 0.04, CpG 32: pseudo-R = 0.14, p = 0.03). Subgroup analysis revealed that being a DRD patient significantly explained a part of the variance of methylation levels at two CpG sites (CpG 21: pseudo-R = 0.03, p = 0.00, CpG 24: pseudo-R = 0.06, p = 0.03). Regression analysis showed that methylation level at CpG 38 significantly explained a small proportion of the variance of severity score for anxiety (R = 0.07, p = 0.04) and having a diagnosis of depression (Nagelkerke R: 0.11, p = 0.00). Genotype of the 5-HTTLPR polymorphism had no additional effect on these associations.
This study showed an association between percentage of methylation at several specific sites of the promoter region of SLCA64 and (dopa-responsive) dystonia patients compared to healthy controls. Furthermore, methylation levels were associated with severity of anxiety and presence of a depressive disorder in the dystonia group. This study suggests alterations in the serotonergic metabolism in dystonia patients, and its relation with the non-motor symptoms.
肌张力障碍是一种罕见的运动障碍，患者会出现不自主的扭曲运动或异常姿势。除了这些运动症状外，患者还普遍存在精神共病，这表明 5-羟色胺在其病理生理学中起作用。本研究调查了肌张力障碍患者中编码 5-羟色胺再摄取转运体（SLC6A4）的基因的 DNA 甲基化百分比，以及甲基化水平与精神症状的存在和严重程度之间的关联。
纳入了 49 例颈肌张力障碍患者、41 例肌阵挛性肌张力障碍患者和 27 例多巴反应性肌张力障碍（DRD）患者，以及 56 名健康对照组。使用经过验证的问卷评估精神共病。研究了位于 SLC6A4 起始密码子上游 69 到 213 个碱基对的 20 个 CpG 位点的甲基化水平。将肌张力障碍患者的甲基化水平与健康对照组进行比较，并校正年龄，同时与精神共病相关联。
Bootstrapped 分位数回归分析表明，与健康对照组相比，肌张力障碍患者的两个 CpG 位点（CpG 24：伪 R=0.05，p=0.04，CpG 32：伪 R=0.14，p=0.03）的甲基化水平明显不同。亚组分析表明，DRD 患者的两个 CpG 位点（CpG 21：伪 R=0.03，p=0.00，CpG 24：伪 R=0.06，p=0.03）的甲基化水平差异有统计学意义。回归分析表明，CpG 38 的甲基化水平与焦虑严重程度评分（R=0.07，p=0.04）和抑郁诊断（Nagelkerke R：0.11，p=0.00）呈显著相关。5-HTTLPR 多态性的基因型对这些关联没有额外的影响。
本研究显示，与健康对照组相比，SLC6A4 启动子区域的几个特定 CpG 位点的甲基化百分比与（多巴反应性）肌张力障碍患者之间存在关联。此外，在肌张力障碍组中，甲基化水平与焦虑严重程度和抑郁障碍的存在有关。本研究表明，肌张力障碍患者的 5-羟色胺代谢发生改变，与非运动症状有关。
