Rett syndrome (RTT) is a complex neurodevelopmental disorder affecting multiple neurological functions. Autonomic abnormalities are highly prevalent and constitute supportive diagnostic criteria for variant RTT. In a study validating the diagnostic criteria, Percy et al. reported that patients with classic and variant RTT, 77% and 61% respectively, had breathing abnormalities, while 42% and 21% respectively had cold extremities. Cardiac dysautonomia has also been a major concern since the early decades of RTT research. Multiple cardiac rhythm abnormalities have been described, including T-wave abnormalities, reduced heart rate variability, and a prolonged (heart rate) corrected QT (QTc) interval. The study by Clark et al. represents the first longitudinal examination of long QTc in RTT. The QT interval is calculated from the beginning of the Q wave to the end of the T wave, representing the period from onset of ventricular contraction to the end of ventricular relaxation. Extension of the repolarization period in prolonged QTc increases the possibility of premature ventricular contraction and the development of a ventricular arrhythmia; manifesting symptoms range from fainting to sudden death. The development of long QTc into an arrhythmia is multifactorial. While the longer the QTc, the higher the risk, there is no elevation of QTc that is completely safe. Using Bazett’s correction, 450ms to 460ms are considered cut-offs, and scoring systems combining clinical and electrocardiographic features have been developed for diagnosis and management. Several factors have increased interest in prolonged QTc in RTT: a relatively high prevalence of sudden death; use of medications linked to long QTc (selective serotonin reuptake inhibitors [SSRIs]), and the need for QTc surveillance in drug trials. In 2017, Crosson et al. published the largest cohort evaluated for prolonged QTc in RTT. This cross-sectional investigation concluded that, at 7%, the prevalence of long QTc was lower than previously reported and that it was associated with increased age and clinical severity. An association with the common p.Arg255X MECP2 mutation was also reported. The current longitudinal study by Clark et al. expands these findings by evaluating a larger sample. Despite using a more stringent definition of long QTc (>460ms vs >450ms), it reports a similar prevalence rate but does not confirm the association with older age and clinical severity. However, since long QTc was linked to SSRI use and severity of breathing abnormalities, this suggests that prolonged QTc is part of a complex dysautonomia. Notably, approximately 20% of participants developed long QTc during the next 2 years. Although no clinical predictors were identified, participants with a p.Thr158Met mutation were more likely to develop prolonged QTc. Data suggest prolonged QTc is a component of a complex dysautonomia in RTT, and a combination of genetic predisposition and environmental factors contribute to its development. While Clark et al.’s contributions are important and unique, because of the lack of agreement between studies, many questions remain: How stable are QTc measurements? (None of the published studies in RTT specifies the number of evaluations that led to the reported values). Do drug interactions, in a population with frequent polypharmacology, increase the risk of developing long QTc? To what extent is severity of clinical features (other than breathing abnormalities) linked to long QTc? Would biomarkers, such as low serotonin plasma levels, differentiate RTT groups with different risks of prolonged QTc? And, ultimately, what is the risk of sudden death in individuals with RTT and long QTc? In terms of RTT management, the present study underscores the importance of surveying for prolonged QTc on an annual or biannual basis. Future studies could delineate risk factors that require closer follow-up or alternative treatment strategies.

中文翻译：

---

Rett 综合征中的长 QT 间期：扩展对鲜为人知的现象的认识

Rett 综合征 (RTT) 是一种复杂的神经发育障碍，影响多种神经功能。自主神经异常非常普遍，构成了变异 RTT 的支持性诊断标准。在一项验证诊断标准的研究中，Percy 等人。据报道，经典和变异 RTT 患者分别有 77% 和 61% 有呼吸异常，而分别有 42% 和 21% 有四肢发冷。自 RTT 研究的最初几十年以来，心脏自主神经功能障碍也一直是一个主要问题。已经描述了多种心律异常，包括 T 波异常、心率变异性降低和延长的（心率）校正 QT (QTc) 间期。克拉克等人的研究。代表了 RTT 中长 QTc 的首次纵向检查。QT间期是从Q波开始到T波结束计算的，代表从心室收缩开始到心室舒张结束的时间段。延长 QTc 中复极期的延长增加了室性早搏和室性心律失常的可能性；症状从昏厥到猝死不等。长 QTc 发展为心律失常是多因素的。虽然 QTc 越长，风险越高，但没有绝对安全的 QTc 升高。使用 Bazett 校正，450ms 到 460ms 被认为是截止时间，并且已经开发了结合临床和心电图特征的评分系统用于诊断和管理。几个因素增加了对 RTT 中延长 QTc 的兴趣：猝死发生率相对较高；使用与长 QTc 相关的药物（选择性 5-羟色胺再摄取抑制剂 [SSRIs]），以及需要在药物试验中监测 QTc。2017 年，克罗森等人。发表了最大的队列评估 RTT 中延长的 QTc。该横断面调查得出结论，长 QTc 的患病率为 7%，低于先前报告的，并且与年龄和临床严重程度的增加有关。还报告了与常见 p.Arg255X MECP2 突变的关联。克拉克等人目前的纵向研究。通过评估更大的样本来扩展这些发现。尽管使用了更严格的长 QTc 定义（>460ms 与 >450ms），但它报告了相似的患病率，但并未证实其与年龄和临床严重程度的关联。然而，由于长 QTc 与 SSRI 的使用和呼吸异常的严重程度有关，这表明延长的 QTc 是复杂的自主神经功能障碍的一部分。值得注意的是，大约 20% 的参与者在接下来的 2 年中出现了长 QTc。虽然没有确定临床预测因素，但具有 p.Thr158Met 突变的参与者更有可能出现 QTc 延长。数据表明延长的 QTc 是 RTT 中复杂的自主神经功能障碍的一个组成部分，遗传易感性和环境因素的组合有助于其发展。虽然克拉克等人的贡献是重要且独特的，但由于研究之间缺乏一致性，许多问题仍然存在：QTc 测量的稳定性如何？（RTT 中已发表的研究均未指定导致报告值的评估数量）。做药物相互作用，在频繁出现多种药理学的人群中，是否会增加发生长 QTc 的风险？临床特征（呼吸异常除外）的严重程度在多大程度上与长 QTc 相关？生物标志物，例如低血清素血浆水平，能否区分具有不同 QTc 延长风险的 RTT 组？最后，RTT 和长 QTc 患者猝死的风险是多少？在 RTT 管理方面，本研究强调了每年或每两年对延长的 QTc 进行调查的重要性。未来的研究可以描述需要更密切随访或替代治疗策略的风险因素。例如低血清素血浆水平，区分具有不同 QTc 延长风险的 RTT 组？最后，RTT 和长 QTc 患者猝死的风险是多少？在 RTT 管理方面，本研究强调了每年或每两年对延长的 QTc 进行调查的重要性。未来的研究可以描述需要更密切随访或替代治疗策略的风险因素。例如低血清素血浆水平，区分具有不同 QTc 延长风险的 RTT 组？最后，RTT 和长 QTc 患者猝死的风险是多少？在 RTT 管理方面，本研究强调了每年或每两年对延长的 QTc 进行调查的重要性。未来的研究可以描述需要更密切随访或替代治疗策略的风险因素。