Evaluation of QTc in Rett syndrome: Correlation with age, severity, and genotype

Abstract

Rett syndrome (RTT) is caused by MECP2 mutations, resulting in various neurological symptoms. Prolonged corrected QT interval (QTc) is also reported and is a speculated cause of sudden death in RTT. The purpose of this study was to correlate QTc in RTT patients with age, clinical severity, and genotype. 100 RTT patients (98 females, 2 males) with MECP2 mutations underwent baseline neurological evaluation (KKI-RTT Severity Scale) and QTc measurement (standard 12 lead electrocardiogram) as part of our prospective natural history study. Mean QTc of the cohort was 422.6 msec, which did not exceed the normal values for age. 7/100 patients (7%) had QTc prolongation (>450 msec). There was a trend for increasing QTc with age and clinical severity (p=0.09). No patients with R106C, R106W, R133C, R168*, R270*, R294*, R306C, R306H, and R306P mutations demonstrated QTc prolongation. There was a relatively high proportion of QTc prolongation in patients with R255* mutations (2/8, 25%) and large deletions (1/4, 25%). The overall presence of QTc prolongation did not correlate with mutation category (p=0.52). Our findings demonstrate that in RTT, the prevalence of QTc prolongation is lower than previously reported. Hence, all RTT patients warrant baseline ECG; if QTc is prolonged, then cardiac followup is warranted. If initial QTc is normal, then annual ECGs, particularly in younger patients, may not be necessary. However, larger sample sizes are needed to solidify the association between QTc and age and clinical severity. The biological and clinical significance of mild QTc prolongation above the normative data remains undetermined.

Serial follow‐up of corrected QT interval in Rett syndrome

“…The identification of those patients with RTT at risk for development of QTc prolongation may result in the enhanced screening of patients who may be at a higher risk of sudden cardiac death from cardiac electrical abnormalities. Crosson et al described a cohort of 100 patients with RTT, with a mean QTc of 422ms . In their cohort only seven of 100 patients had QTc greater than 450ms, a cut‐off lower than that used in our cohort and likely overestimates the incidence.…”

Rett syndrome: a neurological disorder with metabolic components

“…Given the association between MeCP2 and HDAC3, non-specific HDAC inhibitors, commonly prescribed for seizure maintenance, should be approached cautiously as a treatment in RTT. Additionally, both RTT patients and Mecp2 mutant mice present with metabolic syndrome [ 15 , 180 ], oxidative stress [ 27 , 29 ], cardiac defects [ 211 , 212 ], decreased bone density [ 174 , 213 ] and urological dysfunction [ 214 , 215 ]. As CNS-targeted gene therapy becomes a more realistic therapeutic approach, peripheral deficiency of MeCP2 must be considered more than ever as these symptoms are likely to persist following targeted genetic treatment to the brain.…”

Diurnal variation in autonomic regulation among patients with genotyped Rett syndrome

“…A key feature of RTT is the dysregulation of autonomic circuits that may contribute to sudden death 16–22. Previous research has characterised heart rate variability (HRV),23 24 cardiac repolarisation measures,25 26 and cardiorespiratory coupling as measures of autonomic dysregulation 18 19 23 27–29. However, many studies were conducted before MECP2 genotype information was available, and they were conducted in hospital settings, where the full range of autonomic behaviour may not be observable 26.…”