Assessment of the maturity-related brainstem functions reveals the heterogeneous phenotypes and facilitates clinical management of Rett syndrome

Julu, Peter O.O.; Engerström, Ingegerd Witt

doi:10.1016/j.braindev.2005.02.012

Cited by 60 publications

(80 citation statements)

References 16 publications

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“…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).…”

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confidence: 99%

“…Diagnosis of RS is based on clinical criteria (2)(3)(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).…”

mentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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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confidence: 99%

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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 age distribution is likely coincidental since previous studies showed no significant age difference between the different cardiorespiratory phenotypes (Julu and Engerstr€ om 2005). At present, it is uncertain whether an altered carbon dioxide metabolism affects the creatine metabolism in females with RTT.…”

Section: Discussionmentioning

confidence: 67%

Altered Carbon Dioxide Metabolism and Creatine Abnormalities in Rett Syndrome

et al. 2011

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Despite their good appetite, many females with Rett syndrome (RTT) meet the criteria for moderate to severe malnutrition. Although feeding difficulties may play a part in this, other constitutional factors such as altered metabolic processes are suspected. Irregular breathing is a common clinical feature, leading to chronic respiratory alkalosis or acidosis. We assumed that these changes in intracellular pH cause disturbances in the metabolic equilibrium, with important nutritional consequences. The study population consisted of a group of thirteen well-defined RTT girls with extended clinical, molecular and neurophysiological assessments. Despite normal levels of total dietary energy and protein intakes, malnutrition was confirmed based on significantly low fat-free mass index (FFMI) values. Biochemical screening of multiple metabolic pathways showed significantly elevated plasma creatine concentrations and increased urinary creatine/ creatinine ratio in five RTT girls. Four girls, 10 years and older, were forceful breathers, one 13-year-old girl had an undetermined cardiorespiratory phenotype. An isolated increase of the urinary creatine/creatinine ratio was seen in two girls, a 9-year old forceful and a 4-year old feeble breather. Given that the young girls are feeble breathers and the older girls are forceful breathers, it is impossible to determine whether the elevated creatine concentrations are due to increasing age or cardiorespiratory phenotype. Furthermore, MeCP2 deficiency may cause epigenetic aberrations affecting the expression of the creatine-transporter gene, which is located at Xq28. Further studies are required to confirm these findings and to provide greater insight into the pathogenesis of the abnormal creatine metabolism in RTT. Abbreviations

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“…Baroreceptor sensitivity was also determined from spontaneous blood pressure fluctuations and was less in RTT subjects (Julu et al, 2001). More recently Julu and Engerstrom (2005) have described 72 RTT cases who's CVT was significantly less than that of the 11 control subjects reported earlier (Julu et al, 2001). It is unfortunate that only a small number of controls have been studied in these reports.…”

Section: Discussionmentioning

confidence: 95%

Autonomic cardiovascular control in methyl-CpG-binding protein 2 (Mecp2) deficient mice

Bissonnette

Knopp

Maylie

et al. 2007

Autonomic Neuroscience

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Methyl-CpG-binding protein 2 is a transcription factor that is involved in gene silencing. It is mutated in the majority of cases of Rett syndrome. This X-linked neurodevelopmental disorder is reported to involve abnormalities in autonomic cardiovascular regulation. As an initial step in understanding the basis for these abnormalities we have characterized autonomic cardiovascular function in Mecp2 deficient mice. Arterial pressure waves were recorded in freely moving animals using telemetry. Baseline blood pressure and pulse interval (PI) as well as indices of heart rate variability (HRV): standard deviation of PI (SDNN), range encompassing 90% of PIs (PI90) and standard deviation of adjacent PIs (SDSD) were similar in Mecp2 +/+ and Mecp2 +/− animals. Spectral analysis of mean arterial pressure (MAP) and PI in the frequency domain showed similar relative power in low frequency 1 (LF1, 08-0.4 Hz), low frequency 2 (LF2, 0.4-1.0 Hz), middle frequency (MF, 1-3 Hz) and high frequency (HF, 3.0-10.0 Hz) bands. Autonomic blockade with atropine or propranolol as well as elevation in ambient temperature to 32 °C resulted in changes in blood pressure, PI and HRV that did not differ between the strains. Atropine, propranolol and elevated temperature resulted in similar changes in both MAP and PI spectral power. Baroreceptor function was tested using intravenous injections of nitroprusside followed by phenylephrine. Maximum gain was not different. These results do not reveal any disturbance of autonomic cardiovascular regulation in the Mecp2 deficient mouse genotype.

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Assessment of the maturity-related brainstem functions reveals the heterogeneous phenotypes and facilitates clinical management of Rett syndrome

Cited by 60 publications

References 16 publications

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

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

Altered Carbon Dioxide Metabolism and Creatine Abnormalities in Rett Syndrome

Autonomic cardiovascular control in methyl-CpG-binding protein 2 (Mecp2) deficient mice

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