Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Psychosocial experiences of clinicians providing care for children with severe neurological impairment.

AIM: To investigate clinicians' psychosocial experiences navigating interdisciplinary care for children with severe neurological impairment (SNI), for example children with a developmental epileptic encephalopathy; secondarily, to identify preferences for future interventions to support clinicians caring for children with SNI. METHOD: We conducted a qualitative descriptive study with interdisciplinary clinicians by using a purposeful sampling recruitment strategy. Twenty-four participants with expertise caring for children with SNI completed in-depth, semi-structured interviews. We transcribed the interviews, de-identified them, and performed inductive thematic analysis. RESULTS: Thematic analysis elicited interrelated themes. Clinicians experienced immense professional barriers providing patient-centred care across fragmented healthcare contexts. Physical, emotional, and psychological impacts were attributed to inadequate reflective practice training and a paucity of integrated resources to support clinicians over time. Multipronged strategies were prioritized by clinicians, incorporating psychoeducation, interdisciplinary peer mentorship, and psychological resources to build reflective practice skills for clinicians providing complex care in an advancing era of medicine. INTERPRETATION: This study provides novel and in-depth insight into clinicians' experiences navigating care for children with SNI. The results will be used to inform future integrated and multipronged co-developed resources tailored for clinicians, on the basis of their recommendations.

Understanding the ongoing learning needs of Australian paediatricians: Evaluation of a pilot paediatric video teaching programme.

AIM: The purpose of this study was to evaluate whether pre-recorded video-based lectures (VBLs) covering a range of paediatric topics are an acceptable means of providing ongoing education for consultant and trainee paediatricians in Australia. METHODS: Previous participants (paediatric consultants and junior medical officers) of a neurology outreach teleconference programme offered by a paediatric neurologist between 2017 and 2020 were invited to participate in a multi-specialty pre-recorded video-based education programme. Acceptability was explored by assessing relevance, likelihood of utilising VBL's in the future, uptake and learning activity preferences. The impact of VBLs on confidence, currency and practice was also explored. Additional data including topics of interest, preferred video format, duration, viewing method and frequency of delivery were captured, to better understand participant preferences to inform future efforts. RESULTS: A total of 135 consented; 116 returned baseline; 94 returned follow-up surveys. Preferred learning activities included a live/interactive component. Videos were considered relevant. Preferences for pre-recorded videos improved from ninth to sixth most preferred learning activity post-intervention. VBL convenience and accessibility were valued. Practice was altered in: approach to management, use of treatments, confidence in decision-making, and discussion with families and patients. The average view duration was 16 min. Longer videos yielded slightly lower audience retention rates. For future offerings, the majority endorsed a preference for a 'mixed' video format and duration of 20-40 min, offered monthly. CONCLUSION: Video-based medical education is an appealing and sustainable alternative, given the convenience of unrestricted accessibility, in meeting ongoing learning needs of Australian paediatricians and trainees.

Hope in the uncertainties and certainty for parents of children with rare neurological disorders: Part 3 (of 3): Hope.

This is the third article of a three-part series and addresses how clinicians provide hopefulness meaningfully to families coping with life-limiting and quality of life impairing neurological conditions. The first two articles addressed the enormous challenges faced by carers and also explored the struggles of clinicians trying to provide relief and comfort. Can these families, and those helping clinically, legitimately hope? It is expectation that consolidates desire into a substantial hope that may motivate finding a way forward. Hope must be realistic and directed to something in particular and in someone in particular. Hope and despair are not monolithic but often travel together for both children, families and clinicians. Hope is not denial but a belief that there are positive possibilities. Finding what can be helpfully hoped for and what must be realistically despaired of, is the discerning struggle. Clinicians aim to change what we can and accept what we cannot. Acceptance and grief are arrived at slowly for carers and families. Similarly, clinicians struggle with the hopes of bringing meaningful solace and are supported by trusted colleagues who have shared the same experience. Clinicians strive to respond appropriately and effectively in a dynamic process based on trust, providing presence and compassion when cure is not possible. Clinicians help find the small doable things that foster hope and lessen isolation and abandonment, mindful of the limits of their medical expertise. Surprisingly these modest hopes and faltering acceptances often provide a different form of strength and comfort to sustain a family.

Hope in the uncertainties and certainty for parents of children with rare neurological disorders: Part 2 (of 3): Certainty.

This is the second of a three-part series that explores different aspects of uncertainty, certainty and hope in the context of providing clinical care for children with rare and life-limiting neurological disorders. When caring for families impacted by an overwhelming complex disorder in a child, complicated by threatening uncertainties and potentially more threatening certainties, clinicians utilise skills drawn from differing fields to make the load of information, and the emotional impact more manageable. The first article in this series addressed how clinicians might manage the 'accumulation of uncertainties' and to provide compassionate care not only to their patients, and their families, but also to themselves. This second paper delves into the less helpful aspects of 'certainty', including the associated losses and griefs endured by parents responding to threatening fears associated with their child's condition. In the extreme, disconnection and psychological isolation borne by parents can lead to a sense of hopelessness and desperation. Facing unwelcome certainties - clinicians and parents together - forms the basis of future trust and hope. Clinicians who share the field of trust with families and show commitment to helping parents, even when cure remains elusive, build a sense of hope. This is the sort of hopefulness that clinicians need to have and to offer as they share the journey with families. In this series, we seek to harness a shared approach to face unwelcome certainties and to kindle a sense of hope that is both credible and meaningful to the parents, family and clinician.

Hope in the uncertainties and certainty for parents of children with rare neurological disorders. Part I (of 3): Uncertainty.

This is the first of three articles exploring the aspects of clinical care for children with rare neurological disorders including uncertainties old and new. The disruptive technologies of genomic sequencing and advanced therapeutics such as gene-based therapies offer parents of children with severe but rare neurological conditions for the first-time unprecedented opportunities for 'precision medicine'. At the same time, the realities of limited genomic diagnostic yields and not infrequent detection of variants of uncertain significance, lack of natural history study data and management guidelines for individually rare neurogenetic conditions, means that high pre-genomic test expectations are all too often replaced by an accumulation of new uncertainties. This can add to the chronic traumatic stress experienced by many families but may also have under-recognised impacts for their clinicians, contributing to 'burn-out' and attendant negative psychosocial impacts. This first article aims to address how clinicians might manage the accumulation of uncertainties to be more helpful to patients and their families. Moreover, it seeks to address how clinicians can move forward providing compassionate care to their patients and a little more consideration for themselves.

What we have learnt about trauma, loss and grief for children in response to COVID-19.

The disruption of daily life resulting from COVID-19 and its precautions has taken an enormous emotional toll on children and families. The consequences of disrupted schooling, changed social interactions and altered family dynamics has had some unanticipated positives such as improved on-line educational upskilling and personal resilience. However, the potential longer term implications for educational outcomes, economic impacts of job loss and prolonged financial insecurity, physical wellbeing and mental health remain unclear. The potential for post-traumatic stress disorders from what is experienced by children with imposed isolation from friends and extended family, domestic violence and death of relatives remains concerning. Confronting images and stories relayed through social media and the popular press will challenge children's views of safety, security, trust and potentially rob them of much of the innocence of youth. In an overwhelming global response to the "adult" problems of the COVID-19 pandemic, this article reflects on the consequences of trauma, loss and grief through the perspective of children and how they may alter their view of the world.

Consequences of physical distancing emanating from the COVID-19 pandemic: An Australian perspective.

The sobering reality of the COVID-19 pandemic is that it has brought people together at home at a time when we want them apart in the community. This will bring both benefits and challenges. It will affect people differently based upon their age, health status, resilience, family support structures, and socio-economic background. This article will assess the impact in high income countries like Australia, where the initial wave of infection placed the elderly at the greatest risk of death whilst the protective measures of physical distancing, self-isolation, increased awareness of hygiene practices, and school closures with distance learning has had considerable impact on children and families acutely and may have ramifications for years to come.

Keeping our children safe and calm in troubled times.

Keeping children safe and keeping children free from worry are usually tasks that parents do without any sense of cross-purpose. In times of threat and very real danger, these two parental goals come into conflict. This article articulates the confusion of intentions amidst the pandemic. It alludes to previous crises such as happened in both World Wars to protect children including Operation Pied Piper to evacuate them from London in World War 2. The aim of this paper is to give parents and clinicians an awareness of the child's and young person's point of view, in particular, the worry of children for parents. The burden on children of fearing that they may infect parents, grandparents and loved ones generally is considerable. Parents who deny what is happening lack credibility. Parents who fail to manage their own anxieties burden their children with burdens they themselves cannot bear. Honesty about the need for safety and courage as parents to promote calm are what good parents have been doing throughout history. Telling children what they are doing that is right helps them to know what 'the right' is. The possibility is considered that we will come through the pandemic with a greater sense of what matters to our children and what should matter to us.

Sensory dysregulation in tic disorders is associated with executive dysfunction and comorbidities.

BACKGROUND: Tics are conceptualized as a sensorimotor phenomenon with a premonitory urge typically described by patients. As observed in other neurodevelopmental disorders, we have observed sensory dysregulation symptoms, such as tactile hypersensitivity to clothing, in children with tic disorders; however, formal clinical research in this area is limited. OBJECTIVE: To define the presence of sensory dysregulation symptoms in tic disorders, and their clinical associations. METHODS: Prevalence of sensory dysregulation in 102 children with tic disorders was compared to 61 age- and sex-matched healthy controls. Sensory dysregulation, executive function, and quality of life data were obtained through the Short Sensory Profile-2, Sensory Profile-2, Sensory Processing Measure, Behaviour Rating Inventory of Executive Function-2, and Strength and Difficulties Questionnaire and Pediatric Quality of Life Inventory. Tics were assessed with the Yale Global Tic Severity Scale. RESULTS: Children with tics, in the presence of comorbidity, had elevated sensory dysregulation compared to healthy controls (P < 0.001). There was a positive correlation between sensory dysregulation and global executive difficulties in children with tics and comorbidity (n = 87; rho = 0.716; P < 0.001) and a negative correlation of sensory dysregulation with quality of life (n = 87; rho = -0.595; P < 0.001). In children with tics, there was an association between sensory dysregulation and number of comorbidities (P < 0.001). CONCLUSION: In the presence of comorbidity, children with tic disorders have broad sensory dysregulation symptoms beyond the premonitory urge. There was a statistically significant association between sensory dysregulation and executive function difficulties and the presence of neurodevelopmental and psychiatric comorbidity. Sensory dysregulation can be considered neurodevelopmental symptoms, providing insight into the neurobiology of tics and opportunities for therapeutic intervention. © 2019 International Parkinson and Movement Disorder Society.

Delivering bad news.

News in medicine has an obligation to be helpful, accurate, comprehensible for the intended audience and part of an on-going professional relationship that enables the best outcomes available. These obligations have special poignancy when the news is bad, the patient is a child and the news scene is a busy medical practice, clinic or hospital. This paper aims to outline specific ways of being helpful when delivering bad news, within the constraints of daily practice, to a wide variety of developmentally different children at different stages in the family life cycle. The paper specifies the purpose, tasks, obstacles and practicalities of giving adverse information about the health of children in our clinical work. Adverse news needs to be embedded within delivering news more generally in our work. This presupposes a trusting relationship, an accurate understanding of the news to be delivered and a capacity to communicate medical complexity to the intended audience. There are multiple audiences for our medical news, at different developmental stages, each of whom needs help to 'hear the news' in different ways. Each developmental period within a broader family life cycle is briefly addressed. The limited evidence-base is outlined with a view to what the clinician can do to foster maximal support, understanding and on-going cooperation. The interplay between realism and optimism is highlighted so that accuracy and helpfulness are wedded as meaningfully and sensitively as possible. The aim is to be helpful rather than pursue an ideal of the unfaltering, polished and flawlessly performing clinician.

The consequences of chronic cannabis smoking in vulnerable adolescents.

Cannabis, like the mythic shape-shifter, presents in various guises, morphing with the perspective and context of the observer. Arguments about cannabis are confused by a myriad of debates-medical, social, ethical and political-as if a single conceptual umbrella can capture the variety and granularity of marijuana-related issues. This paper responds to marijuana use as it is commonly practised by youth in Australia. It has little to say about synthetic cannabinoids, specific medicinal cannabinoids, or medicinal properties of marijuana. We address those adolescents genetically and environmentally vulnerable to mental illness, with specific emphasis on indigenous and neurodevelopmentally impaired young people who show patterns of usage and response very different to adults and more resilient members of the population. Specifically, the practice of mixing tobacco with marijuana by aboriginal youth, and the resultant coalition of dependencies, will likely presage a rise in pulmonary and central nervous system pathology over the coming decades. Aboriginal youth begin using earlier, persist longer, and take greater quantities of cannabis than non-indigenous youth. This paper recommends practical interventions to reduce the multiple health consequences of chronic cannabis use in young people, especially indigenous young people.

Mental health of health professionals.

Helping medical colleagues with depression and suicidal thoughts and feelings can be more difficult than helping those who are not in the caring professions. The current systems of notification of impairment and supporting troubled doctors, especially in the public sector, are not working well and can make help seeking and help accepting harder. Accessing effective psychiatric help confidentially and in a timely way is difficult unless it is anticipated, facilitated, tenacious and resistant to initial rebuff. When suicide occurs, it is frequently associated with unhelpful generalisations on the value of psychiatric intervention among colleagues that makes others less likely to seek help or believe that the 'the help will help'. The needs of the children of those who take their lives are often overlooked.

Principles of medicating children with neurodevelopmental and sleep disorders--a review.

Conflict between the demands of the environment in which a child lives and the child's intrinsic sleep signature, produces stress-behaviour difficulties in the child. Distorted development, especially distorted brain development, often leads to distorted intrinsic sleep signatures. The sleep-behaviour outcome, arising from the conflict between each child's sleep signature and the environmental niche in which they live, can be modified by medications, on the one hand, and taking the role of kin, peer and social networks seriously. Medications alter the intrinsic sleep signature of the child and the stress response. Non-medical interventions address the demands and constraints of the child's environmental niche. When the main medication strategy to address distorted sleep involves brain stimulation, those children that do not respond will often need a reversal of medication priorities; an inhibitory strategy as a short to medium term support, sleep regulation being primary for longer term management, and stimulatory strategies used sparingly, if at all. We are often dealing with vulnerable populations, not all of which are reliable or accurate sources of information. Features of a presentation alerting the clinician to non-medication factors contributing to the failure of treatment are discussed.

Pervasive refusal syndrome (PRS) 21 years on: a re-conceptualisation and a renaming.

Twenty-one years ago, Lask and colleagues first described pervasive refusal syndrome (PRS) as a child's "dramatic social withdrawal and determined refusal to walk, talk, eat, drink, or care for themselves in any way for several months" in the absence of an organic explanation. PRS has been conceptualised in a variety of ways since then. These have included a form of post-traumatic stress disorder, learnt helplessness, 'lethal mothering', loss of the internal parent, apathy or the 'giving-up' syndrome, depressive devitalisation, primitive 'freeze', severe loss of activities of daily living and 'manipulative' illness, meaning the possibility that the children have been drugged to increase chances of asylum in asylum-seeking families. Others have insisted that PRS is simply depression, conversion disorder, catatonia or a factitious condition. This paper reviews these conceptualisations, explores some of the central complexities around PRS and proposes a neurobiological explanatory model, based upon autonomic system hyper-arousal. It touches upon the clinical implications and suggests a new name for the condition reflecting what we believe to be a more sophisticated understanding of the disorder than was available when it was first described.

Helping Young People in Out-of-Home Care: Basic Elements.

Children and adolescents (young people) who experience maltreatment early in life and are subsequently placed in out-of-home care (OOHC) are specifically at risk for poor mental health outcomes.1 Although rates vary by survey and location, up to half of these young people have clinical-level mental health difficulties, and another 20% to 25% have difficulties approaching clinical significance.2 These difficulties are characterized by high symptom complexity and severity, and include maltreatment-related mental health symptoms.2 Many young people in OOHC are difficult to engage with and retain in treatment, compounded by a lack of specialized mental health services3 and a history of problematic social interactions with supports.4 They are often reluctant to seek help because of stigmatization and confidentiality concerns, limited opportunities for decision making, service inaccessibility, distrust of mental health services, and their perception that professionals do not understand their circumstances.5 We propose 6 clinical practice modifications for mental health services working with young people in OOHC to enhance therapeutic engagement and to maximize their therapeutic outcomes.