Serial follow‐up of corrected QT interval in Rett syndrome

Abstract

Aim To identify factors associated with baseline prolonged corrected QT (QTc) and higher risk of QTc prolongation during follow‐up in patients with Rett syndrome (RTT). Method A retrospective review of patients receiving an electrocardiogram (ECG) between June 2012 and June 2018 was performed. Age, methyl‐CpG binding protein 2 gene (MECP2) mutation, RTT Severity Scale (RSSS) score, breathing abnormalities, seizure frequency, medications, and ECG parameters were collected. Prolonged QTc was defined as greater than or equal to 460ms. Comparisons at baseline and during follow‐up were made. Results In total, 129 unique patients (all female) had 349 ECGs. At baseline, 12 (9.3%) had a prolonged QTc (median 474ms, interquartile range 470–486ms) and were more likely to have moderate/severe breathing abnormalities (66.7% vs 24.8%; p=0.005) and take selective serotonin reuptake inhibitors (SSRIs) (41.7% vs 15.4%; p=0.04). There was no difference in age, RSSS score, seizures, or mutation. Twenty‐six developed prolonged QTc during a median follow‐up of 1 year 7 months (interquartile range 0–3y 6mo). QTc prolongation was associated with p.(Thr158Met) mutation versus the remaining six common mutations (hazard ratio 4.1, 95% confidence interval 1.4–12.0; p=0.01) but not with age, RSSS score, seizures, breathing abnormalities, or SSRIs. Interpretation Breathing abnormalities and SSRIs were associated with baseline QTc prolongation and those with p.(Thr158Met) mutation were more likely to develop prolonged QTc over time. Identification of patients with prolonged QTc warrants increased clinical monitoring. What this paper adds Breathing abnormalities and selective serotonin reuptake inhibitors are associated with prolonged baseline corrected QT (QTc). Development of QTc prolongation is associated with the p.(Thr158Met) mutation.

Consensus guidelines on managing Rett syndrome across the lifespan

“… 48 There is evidence suggesting increased risk for prolonged QTc interval that may be present from a young age 49–51 and may develop with time. 52 The frequency of epileptic and non-epileptic spells 53 54 waxes and wanes throughout the course. 53 55 Individuals with RTT generally respond to anticonvulsants, 53 55 56 but there have been no randomised controlled trials of specific anticonvulsants for RTT.…”

Long QT interval in Rett syndrome: expanding the knowledge of a poorly understood phenomenon

“…An association with the common p.Arg255X MECP2 mutation was also reported. The current longitudinal study by Clark et al 3 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.…”

“…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 …”

“…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. 3,4 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.…”

“…5 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. 5 While Clark et al's 3 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).…”