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

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.

Surface‐ and voxel‐based brain morphologic study in Rett and Rett‐like syndrome with MECP2 mutation

“…Rett syndrome (RTT) (OMIM 312750) is a rare congenital disorder characterized by autistic features, acquired microcephaly, habitual hand clapping, loss of purposeful hand skill, and autonomic dysfunction (Neul et al, 2010; Singh and Santosh, 2018). Mutations of methyl‐CpG binding protein 2 ( MECP2 ) on the X chromosome are identified in over 90% of patients with a typical RTT phenotype.…”

Gratification Disorder as an Early Marker of Rett Syndrome: Two Pediatric Case Reports

“…As a result of the dysautonomia, they may also suffer from impaired swallowing (including aerophagia), abnormalities of the gastroesophageal tract, urinary bladder disorders, mood disorders, sleep disorders, and abnormalities of breathing (breath-holding or hyperventilation spells). 19 Dystonia is not an early feature of Rett syndrome and rarely appears before 5 years of age, and when present, it is usually distal initially. 20 We concluded these episodes are manifestations of GD.…”

Re-thinking treatment targets in child and adolescent psychiatry

“…Biological underpinnings of these deficits include decreased activation of striatal and frontal regions in response to frustrative non-reward and altered amygdala response modulation in response to threat [11]. These alterations underlying emotional and behavioural dysregulation linked to irritability also affect the cardiac-respiratory output via the autonomic nervous system [12].…”

“…A clinicianrated version of this instrument (CL-ARI) has also shown good psychometric properties for assessing behavioural and mood components of irritability across diagnostic groups [14], which makes it a good candidate for use in clinical trials. The emotional, behavioural and autonomic dysregulation (EBAD) linked to irritability, which can be empirically measured, would also be a relevant target for treatment outcome and stratification [12].…”