Serotonin Transporter Abnormality in the Dorsal Motor Nucleus of the Vagus in Rett Syndrome: Potential Implications for Clinical Autonomic Dysfunction

Paterson, David S.; Thompson, Eric G.; Belliveau, Richard A.; Antalffy, Barbara; Trachtenberg, Felicia; Armstrong, Dawna; Kinney, Hannah C.

doi:10.1097/01.jnen.0000187054.59018.f2

Cited by 42 publications

(31 citation statements)

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“…Studies in a mouse model for RS indicate that the irregular respiratory rhythm is explained by disturbed medullary levels of norepinephrine and serotonin (31). These animal studies are consistent with disturbances in serotonin transporter as described in human patients with RS (32). Further elucidation of the mechanisms underlying cardiorespiratory dysregulation and their neurochemical basis will ideally lead to intervention strategies to modify the cardiorespiratory phenotype in RS.…”

Section: Discussionsupporting

confidence: 49%

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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Section: Discussionsupporting

confidence: 49%

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

et al. 2006

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“…Postmortem analysis did not reveal significant differences in 5-HT cell numbers in the medulla oblongata, between the RTT group and controls, although it revealed a significant reduction in serotonin transporter (SERT) binding in the dorsal motor nucleus of the vagus (Paterson et al 2005). This result indicates a deficit in 5-HT innervation or uptake in this major autonomic nucleus which is responsible for controlling the cardiorespiratory systems.…”

Section: Biogenic Amines and The Autonomic Nervous System In Rett Synmentioning

confidence: 49%

“…No significant differences in 5-HT cell numbers was found between the RTT cases and seven controls, although binding to the serotonin transporter (SERT) in RTT patients differed significantly in the dorsal motor nucleus of the vagus (DMX) (Paterson et al 2005), suggesting an altered 5-HT innervation. These observations are particularly interesting, given that the DMX nucleus is involved in the innervation of organs such as the lungs, gastrointestinal tract or heart, which do not function normally in Rett syndrome patients.…”

Section: Serotoninergic Deficitsmentioning

confidence: 98%

Biogenic Amines in Rett Syndrome: The Usual Suspects

Roux

Villard

2009

Behav Genet

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Rett syndrome (RTT) is a severe postnatal neurological disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. In affected children, most biological parameters, including brain structure, are normal (although acquired microcephaly is usually present). However, in recent years, a deficit in bioaminergic metabolism has been identified at the cellular and molecular levels, in more than 200 patients. Recently available transgenic mouse strains with a defective Mecp2 gene also show abnormalities, strongly suggesting that there is a direct link between the function of the MECP2 protein and the metabolism of biogenic amines. Biogenic amines appear to have an important role in the pathophysiology of Rett syndrome, for several reasons. Firstly, biogenic amines modulate a large number of autonomic and cognitive functions. Secondly, many of these functions are affected in RTT patients. Thirdly, biogenic amines are the only neurotransmitters that have repeatedly been found to be altered in RTT patients. Importantly, pharmacological interventions can be envisaged to try to counteract the deficits observed. Here, we review the available human and mouse data and present how they have been and could be used in the development of pharmacological treatments for children affected by the syndrome. Given our current knowledge and the tools available, modulating biogenic amine metabolism may prove to be the most promising strategy for improving the life quality of Rett syndrome patients in the short term.

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“…In the developing brain stem, this impairment will more than likely have downstream effects such as perturbations in excitatory [19] and inhibitory [20] pathways, which in turn will have knock-on effects on vital brain regions implicated in sympathetic and parasympathetic elements of the autonomic nervous system (ANS). Any imbalance will result in dysautonomia; however whilst, autonomic manifestations in RTT include anxiety, pupillary dilation [21], raised serotonin receptor binding in brain stem nuclei [22], low vagal tone with poor vagal response to hyperventilation [23], lower heart rate variability with prolonged QTcF [15] and uncontrolled albeit normal sympathetic tone due to minimal negative feedback of the parasympathetic system [24], due to the inherent heterogeneous plasticity of RTT particularly in terms of maturity-related brainstem functioning [25], these manifestations are more than likely to differ between individuals and so the precise trajectory in terms of the developmental progression of dysautonomia in RTT is at the moment unclear.…”

Section: Introductionmentioning

confidence: 99%

Paradoxical physiological responses to propranolol in a Rett syndrome patient: a case report

et al. 2016

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BackgroundRett Syndrome (RTT), caused by a loss-of-function in the epigenetic modulator: X-linked methyl-CpG binding protein 2 (MeCP2), is a pervasive neurological disorder characterized by compromised brain functions, anxiety, severe mental retardation, language and learning disabilities, repetitive stereotyped hand movements and developmental regression. An imbalance in the sympathetic and the parasympathetic nervous system (dysautonomia) and the resulting autonomic storms is a frequent occurrence in patients with RTT. The prototypical beta blocker propranolol has been used to manage sympathetic hyperactivity in patients with RTT.Case presentationA 13 year old girl with RTT was referred to the Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust. Her clinical picture included disordered breathing with concomitant hyperventilation and apnoea, epilepsy, scoliosis, no QT prolongation (QT/QTc [372/467 ms on automated electrocardiogram [ECG], but manually calculated to be 440 ms]), no cardiac abnormalities (PR interval: 104 ms, QRS duration: 78 ms), and generalised anxiety disorder (ICD-10-CM Diagnosis Code F41.1). She was also constipated and was fed via percutaneous endoscopic gastrostomy (PEG). To manage the dysautonomia, propranolol was given (5 mg and 10 mg) and in parallel her physiological parameters, including heart rate, skin temperature and skin transpiration, were monitored continuously for 24 h as she went about her activities of daily living. Whilst her skin temperature increased and skin transpiration decreased, unexpectedly there was a significant paradoxical increase in the patient’s average heart rate following propranolol treatment.ConclusionHere, we present a unique case of a paradoxical increase in heart rate response following propranolol treatment for managing dysautonomia in a child with RTT. Further studies are warranted to better understand the underlying dysautonomia in patients with RTT and the impact this might have on treatment strategies in rare disorders such as RTT.

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Serotonin Transporter Abnormality in the Dorsal Motor Nucleus of the Vagus in Rett Syndrome: Potential Implications for Clinical Autonomic Dysfunction

Cited by 42 publications

References 42 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

Biogenic Amines in Rett Syndrome: The Usual Suspects

Paradoxical physiological responses to propranolol in a Rett syndrome patient: a case report

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