Key issues in Rett syndrome: emotional, behavioural and autonomic dysregulation (EBAD) - a target for clinical trials

Jatinder Singh,Paramala Santosh

doi:10.1186/s13023-018-0873-8

Abstract

Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with rare genetic syndromes with multisystem morbidity. Emotional and behavioural dysregulation is common across many neurodevelopmental disorders. It can manifest in children across multiple diagnostic groups, including those on the autism spectrum and in rare genetic syndromes such as Rett Syndrome (RTT). There is, however a remarkable scarcity in the literature on the impact of the autonomic component on emotional and behavioural regulation in these disorders, and on the longer-term outcomes on disorder burden.RTT is a debilitating and often life-threatening disorder involving multiple overlapping physiological systems. Autonomic dysregulation otherwise known as dysautonomia is a cardinal feature of RTT characterised by an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system. Unlocking the autonomic component of emotional and behavioural dysregulation would be central in reducing the impairment seen in patients with RTT. In this vein, Emotional, Behavioural and Autonomic Dysregulation (EBAD) would be a useful construct to target for treatment which could mitigate burden and improve the quality of life of patients.RTT can be considered as a congenital dysautonomia and because EBAD can give rise to impairments occurring in multiple overlapping physiological systems, understanding these physiological responses arising out of EBAD would be a critical part to consider when planning treatment strategies and improving clinical outcomes in these patients. Biometric guided pharmacological and bio-feedback therapy for the behavioural and emotional aspects of the disorder offers an attracting perspective to manage EBAD in these patients. This can also allow for the stratification of patients into clinical trials and could ultimately help streamline the patient care pathway for optimal outcomes.The objectives of this review are to emphasise the key issues relating to the management of EBAD in patients with RTT, appraise clinical trials done in RTT from the perspective of autonomic physiology and to discuss the potential of EBAD as a target for clinical trials.

Highlights

The Autonomic Nervous System (ANS) can be separated into the sympathetic and parasympathetic nervous system and through multiple overlapping hierarchical networks; these systems continuously orchestrate and fine-tune numerous voluntary and involuntary bodily processes
The longitudinal trajectory of EBAD has never been evaluated and in this view, one could have a model whereby EBAD could be tracked from childhood to adolescence where the neuro-anatomical and neuro-physiological profiles of Rett Syndrome (RTT) would be different. This may seem as an ambitious undertaking; given the multifaceted nature of RTT, new tangible outcome measures would be of benefit in terms of how we evaluate the efficacy of drugs in future clinical trials in RTT patients
The take home message from this review is that clinical trials undertaken in patients with RTT have met with limited success

Summary

Introduction

The Autonomic Nervous System (ANS) can be separated into the sympathetic and parasympathetic nervous system and through multiple overlapping hierarchical networks; these systems continuously orchestrate and fine-tune numerous voluntary and involuntary bodily processes. Autonomic dysregulation presents with a constellation of abnormalities in different components of the sympathetic and parasympathetic nervous system This leads to imbalances in cardiac, enteric, motor and respiratory systems resulting in an autonomic crisis. Riley-Day syndrome otherwise known as familial dysautonomia is a rare hereditary autonomic neuropathy caused in the majority of cases by a mutation in the IKBKAP/ELP1 gene [2]. This gene encodes the protein IKAP that is a crucial component for elongator genes, which are thought to be responsible for the development and maintenance of the ANS [3]. Under its umbrella, more than 30 names have been coined such as central autonomic dysfunction, paroxysmal sympathetic hyperactivity and hypothalamic–midbrain dysregulation syndrome [11]

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