Electrocardiographic findings in Rett syndrome: An explanation for sudden death?

Sekul, Elizabeth A.; Moak, Jeffrey P.; Schultz, Rebecca; Glaze, Daniel G.; Dunn, Jonathan; Percy, Alan K.

doi:10.1016/s0022-3476(94)70128-8

Cited by 100 publications

(88 citation statements)

References 4 publications

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“…The authors found that 18.5% of these patients had long corrected QT interval (QTc), consistent with previous reports [23,31,32]. They thought that these 18.5% of affected individuals are likely at risk for sudden death since 26% of deaths in RTT are sudden and unexpected [24].…”

supporting

confidence: 85%

Rett Syndrome: Translate Medicine from Brain to Heart

Wang¹

2012

Brain Disord Ther

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Rett syndrome (RTT) is a X-linked neurodevelopmental disorder that affects approximately 1 in 10,000 live female births and is characterized by delayed-onset loss of spoken language, loss of hand use, problems with ambulation, and the development of distinctive hand stereotypes [1][2][3][4][5][6][7][8][9][10][11][12]. RTT is typically caused by mutations in methyl-CpG-binding protein 2 (MECP2) [1,2,5,[8][9][10]13,14], a gene encoding a protein involved in regulation of gene expression [3,13,15,16]. In addition to the cognitive and motor abnormalities, RTT patients also show autonomic dysfunction, with breathing and heart rate irregularities [17][18][19][20]. Boys with mutations in MECP2 show more severe autonomic dysfunction, with marked breathing and heart rate abnormalities that usually result in death within the first year of life [21]. RTT patients have a high incidence of sudden unexpected deaths (26% of all deaths) [22], which are probably of cardiac origin. Previous studies have shown that some RTT patients have prolonged QT intervals (LQT) on electrocardiograms (ECGs) [23]. In patients with other diseases, LQT is a significant risk factor for sudden arrhythmic cardiac death [24]. However, so far the causes for LQT in RTT and its contribution to the high proportion of sudden death are still unknown. As reported recently in Science Translational Medicine, McCauley et al. [25] tested the hypothesis that these sudden deaths in RTT patients may be due to cardiac dysfunction.In most cases, inherited LQT are caused by mutations in the voltage-gated potassium channels KVLQT1 (LQT1) and HERG (LQT2) and in the voltage-gated sodium channel SCN5A (LQT3) [26][27][28][29]. Rare mutations in genes encoding other channel subunits and other cardiac proteins such as caveolin-3 [30], may also contribute to some cases of inherited LQT. Since RTT patients have MeCP2 dysfunction, which causes the LQT phenotype, McCauley et al. [25] aimed at understanding whether (I) MeCP2 dysfunction in mice can recapitulate the long QT phenotype and cause predisposition to arrhythmic-induced death after programmed electrical stimulation (PES); (II) neuronal tissue specific MeCP2 dysfunction is sufficient to reproduce the LQT phenotype; and (III) alterations in the sodium current contribute to the LQT phenotype in this mouse model of RTT.Firstly, McCauley et al. [25] examined ECGs in 379 female patients with typical RTT to define the prevalence of electrophysiological abnormalities in RTT. The authors found that 18.5% of these patients had long corrected QT interval (QTc), consistent with previous reports [23,31,32]. They thought that these 18.5% of affected individuals are likely at risk for sudden death since 26% of deaths in RTT are sudden and unexpected [24]. The authors then tried to identify electrophysiological abnormalities in mouse models of RTT. They found that hemizygous male Mecp2Null/Y mice have severe early-onset LQT and QRS prolongation, and heterozygous female Mecp2 Null /+ show prolongation of both parameters that becomes...

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supporting

confidence: 85%

Rett Syndrome: Translate Medicine from Brain to Heart

Wang¹

2012

Brain Disord Ther

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“…Considering the frequent reoccurrence of breathholds, with associated overshoot and lag in heart rate response, one could hypothesize that cardiorespiratory homeostasis would be threatened in the most severely affected girls thereby increasing their risk of sudden death (25). The known decreased heart rate variability and prolonged QT c (19,20,23), together with these repeated breathholds, could potentially explain the incidence of sudden death during wakefulness in RS. Some otherwise healthy individuals with long QT syndrome manifest symptoms when swimming (28,29), an activity associated with repetitive breathholds, though the specific arrhythmogenic influence of swimming is unknown.…”

Section: Ans Dysregulation In Rett Syndromementioning

confidence: 99%

Autonomic Nervous System Dysregulation: Breathing and Heart Rate Perturbation During Wakefulness in Young Girls with Rett Syndrome

et al. 2006

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This study characterizes cardiorespiratory dysregulation in young girls with MECP2 mutation-confirmed Rett syndrome (RS). Respiratory inductance plethysmography of chest/abdomen and ECG was obtained during daytime wakefulness in 47 girls with MECP2 mutation-confirmed RS and 47 age-, gender-, and ethnicitymatched controls (ages 2-7 y). An in-home breath-to-breath and beat-to-beat characterization was conducted and revealed that breathing was more irregular, with an increased breathing frequency, mean airflow, and heart rate in RS versus controls. There was a decreased correlation between normal breathing and heart rate variability, and an exaggerated increase in heart rate response to breathholds in RS versus controls. We conclude that girls with RS have cardiorespiratory dysregulation during breathholds as well as during "normal" breaths and during breaths before and subsequent to breathholds. This dysregulation may offer insight into the mechanisms that render girls with RS more vulnerable to sudden death. R S is one of a growing number of disorders characterized by autonomic nervous system dysfunction/dysregulation (1). Diagnosis of RS is based on clinical criteria (2-4), with more than 85% of identified girls having mutations in MECP2 on the X chromosome (5; B. Roa, personal communication). The RS phenotype includes normal development until 6 -18 mo of age, then regression with slowing of head circumference growth, loss of language, development of stereotypical hand movements, gait and truncal apraxia, EEG abnormalities, seizures, spasticity, and scoliosis (2).Breathing irregularities consistent with autonomic dysregulation in RS include characteristic patterns variably described as hyperventilation, Valsalva maneuvers, apnea, apneusis, breathholding, and rapid shallow breathing (6 -17). These irregularities are reported to occur near-exclusively during wakefulness (8,17). Age may play a role, as more breathholds and forceful breathing are reported in 5-10-y-old patients compared with more of a Valsalva pattern in young adults (13). Conclusions regarding imbalance of sympathovagal input have been made primarily from heart rate and blood pressure monitoring during spontaneously occurring breathholds, coupled with analytical measures derived from these signals (4,11,13). Julu and others proposed a disturbance in cardiovascular and respiratory system integration, describing their findings as central autonomic dysfunction (4,11,13). Further support for autonomic dysregulation comes from observations of decreased heart rate variability, longer corrected QT intervals, sinus bradycardia, gaseous abdominal distension, sweating, cool extremities (3,7,18 -23), flushing and temperature dysregulation (M. Coenraads, personal communication).Despite survival into adulthood, Kerr and colleagues (24,25) reported that 20 -26% of RS deaths are sudden and unexpected, and that the deaths occur primarily during wakefulness. QT prolongation and nonspecific ST changes in RS suggest cardiac causes for sudden death, though ...

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“…73 RTT patients have an increased risk of life threatening arrhythmias associated with a prolonged QT interval, 74 and so avoidance of a number of drugs is recommended, including prokinetic agents (eg, cisapride), antipsychotics (eg, thioridazine), tricyclic antidepressants (eg, imipramine), antiarrhythmics (eg, quinidine, sotolol, and amiodarone), anaesthetic agents (eg thiopental and succinylcholine), and antibiotics (eg erythromycin and ketoconazole). In addition, careful evaluation for evidence of central autonomic function using noninvasive methods may be of value in identifying specific patterns of disturbance, and may ultimately lead to specific therapies for this sometimes very distressing set of clinical problems.…”

Section: Managementmentioning

confidence: 99%