Loss of synaptic Zn²⁺ transporter function increases risk of febrile seizures

Febrile seizures (FS) are the most common seizure syndrome and are potentially a prelude to more severe epilepsy. Although zinc (Zn(2+)) metabolism has previously been implicated in FS, whether or not variation in proteins essential for Zn(2+) homeostasis contributes to susceptibility is unknown. Synaptic Zn(2+) is co-released with glutamate and modulates neuronal excitability. SLC30A3 encodes the zinc transporter 3 (ZNT3), which is primarily responsible for moving Zn(2+) into synaptic vesicles. Here we sequenced SLC30A3 and discovered a rare variant (c.892C > T; p.R298C) enriched in FS populations but absent in population-matched controls. Functional analysis revealed a significant loss-of-function of the mutated protein resulting from a trafficking deficit. Furthermore, mice null for ZnT3 were more sensitive than wild-type to hyperthermia-induced seizures that model FS. Together our data suggest that reduced synaptic Zn(2+) increases the risk of FS and more broadly support the idea that impaired synaptic Zn(2+) homeostasis can contribute to neuronal hyperexcitability

Physical Health, Media Use, and Mental Health in Children and Adolescents With ADHD During the COVID-19 Pandemic in Australia

Objective: To examine the impact of COVID-19 restrictions among children with attention-deficit/hyperactivity disorder (ADHD). Methods: Parents of 213 Australian children (5–17 years) with ADHD completed a survey in May 2020 when COVID-19 restrictions were in place (i.e., requiring citizens to stay at home except for essential reasons). Results: Compared to pre-pandemic, children had less exercise (Odds Ratio (OR) = 0.4; 95% CI 0.3–0.6), less outdoor time (OR = 0.4; 95% 0.3–0.6), and less enjoyment in activities (OR = 6.5; 95% CI 4.0–10.4), while television (OR = 4.0; 95% CI 2.5–6.5), social media (OR = 2.4; 95% CI 1.3–4.5), gaming (OR = 2.0; 95% CI 1.3–3.0), sad/depressed mood (OR = 1.8; 95% CI 1.2–2.8), and loneliness (OR = 3.6; 95% CI 2.3–5.5) were increased. Child stress about COVID-19 restrictions was associated with poorer functioning across most domains. Most parents (64%) reported positive changes for their child including more family time. Conclusions: COVID-19 restrictions were associated with both negative and positive impacts among children with ADHD

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

BACKGROUND:Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS:We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS:We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes. INTERPRETATION:We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING:National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK

The feasibility and acceptability of AllPlay Dance for autistic children:a pilot randomised controlled trial

Purpose: Few studies have explored the potential for community dance programs to act as a feasible and acceptable avenue for improving the physical, social, and mental health outcomes of autistic children. This randomised waitlist-controlled pilot trial examined the feasibility, acceptability and preliminary efficacy of the classical/contemporary AllPlay Dance program for autistic children. Methods: Twenty-seven autistic children aged 7–12 were randomised to either the intervention group or waitlist control group. Primary outcomes were the acceptability and feasibility of the program, as measured by general study metrics (e.g., enrolment rate, drop out, session attendance) and the participants’ subjective ratings of their experiences (e.g., enjoyment, willingness to do more sessions/recommend the program, etc.). Secondary outcomes included changes in children's motor proficiency, quality of life, and social, emotional and behavioural functioning. Results: The AllPlay Dance program was feasible to conduct and acceptable to young autistic dancers, their parents, and the elite dancers/buddies whose role was to support their participation. There were also promising trends towards improvement in aspects of motor functioning (i.e., aiming and catching). Conclusion: Overall, the findings support the need to conduct a full-scale randomised-controlled trial to confirm the potential gains that this inclusive and creative community-based activity can offer autistic children.</p

Sleeping Sound Autism Spectrum Disorder (ASD):a randomised controlled trial of a brief behavioural sleep intervention in primary school-aged autistic children

BACKGROUND: Behavioural sleep problems are common in children with autism spectrum disorder (ASD); however, evidence for the efficacy of behavioural sleep interventions is limited. This study examined the efficacy of a brief behavioural sleep intervention in autistic children. It was hypothesised that the intervention would reduce overall child sleep problems (primary outcome), in addition to improvements in children’s social, emotional, cognitive, academic functioning, and quality of life, and parent/caregivers’ stress, quality of life, and mental health (secondary outcomes). METHODS: A randomised controlled trial was conducted with participants randomised via a computer‐generated sequence to the sleeping sound intervention (n = 123) or treatment as usual (n = 122) group. Participants comprised 245 children with an ASD diagnosis. Inclusion criteria were as follows: confirmation of DSM IV or DSM‐5 diagnosis of ASD, participants aged between 5 and 13 years and parent/caregiver report of moderate–severe sleep problems. Exclusion criteria were as follows: parent/caregiver intellectual disability or lacking sufficient English to complete questionnaires; and child participant with co‐occurring medical conditions known to impact sleep. The intervention group received the sleeping sound intervention (2 × 50‐min face‐to‐face sessions plus follow‐up phone call) by a trained clinician. RESULTS: Change in children’s sleep problems was measured by the Children’s Sleep Habits Questionnaire (CSHQ) at 3 months post randomisation. Parents/caregivers of children in the intervention group reported a reduction in child sleep problems at 3 months post randomisation (effect size: E.S −0.7). There were also small effects in a number of child (internalising symptoms, emotional behavioural disturbance and quality of life) and parent/caregiver (mental health, parenting stress and quality of life) outcomes; however, these did not remain significant when controlling for multiple comparisons. CONCLUSIONS: The sleeping sound ASD intervention is an efficacious and practical way to reduce sleep problems for autistic children. This brief behavioural intervention has the potential to be embedded easily into the Australian healthcare system

Sleeping sound with autism spectrum disorder (ASD): study protocol for an efficacy randomised controlled trial of a tailored brief behavioural sleep intervention for ASD

Introduction Sleep problems are a characteristic feature of children with autism spectrum disorder (ASD) with 40% to 80% of children experiencing sleep difficulties. Sleep problems have been found to have a pervasive impact on a child\u27s socio-emotional functioning, as well as on parents\u27 psychological functioning. The Sleeping Sound ASD project aims to evaluate the efficacy of a brief behavioural sleep intervention in reducing ASD children\u27s sleep problems in a fully powered randomised controlled trial (RCT). Intervention impact on child and family functioning is also assessed. Methods and analysis The RCT aims to recruit 234 children with a diagnosis of ASD, aged 5-13 years, who experience moderate to severe sleep problems. Participants are recruited from paediatrician clinics in Victoria, Australia, and via social media. Families interested in the study are screened for eligibility via phone, and then asked to complete a baseline survey online, assessing child sleep problems, and child and family functioning. Participants are then randomised to the intervention group or treatment as usual comparator group. Families in the intervention group attend two face-to-face sessions and a follow-up phone call with a trained clinician, where families are provided with individually tailored behavioural sleep strategies to help manage the child\u27s sleep problems. Teacher reports of sleep, behavioural and social functioning are collected, and cognitive ability assessed to provide measures blind to treatment group. The primary outcome is children\u27s sleep problems as measured by the Children\u27s Sleep Habits Questionnaire at 3 months post-randomisation. Secondary outcomes include parent and child quality of life; child social, emotional, behavioural and cognitive functioning; and parenting stress and parent mental health. Cost-effectiveness of the intervention is also evaluated. Ethics and dissemination Findings from this study will be published in peer-reviewed journals and disseminated at national and international conferences, local networks and online. Trial registration number ISRCTN14077107 (ISRCTN registry dated on 3 March 2017)