Arginine:glycine amidinotransferase (AGAT) deficiency: an easy-to-miss treatable adult-onset myopathy.

Arginine:glycine amidinotransferase (AGAT) deficiency is an ultrarare disorder of creatine metabolism, presenting with developmental delay, characteristic biochemical findings and muscle weakness. Most known cases have been identified and treated in early childhood. We describe a 27-year-old woman with learning difficulties and significant myopathy who was diagnosed through genetic investigation in adulthood. Treatment with creatine (10-15 g/day) led to a significant and rapid improvement of muscle strength. A literature review of the few reported adult cases confirms that progressive myopathy is a prominent feature that responds well to creatine supplementation. AGAT deficiency, a partially treatable condition, should be considered in the differential diagnosis of a genetic myopathy, particularly in people with developmental delay and progressive myopathy.

ImprintSeq, a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance.

PURPOSE: Disruptions of genomic imprinting are associated with congenital imprinting disorders (CIDs) and other disease states, including cancer. CIDs are most often associated with altered methylation at imprinted differentially methylated regions (iDMRs). In some cases, multiple iDMRs are affected causing multilocus imprinting disturbances (MLIDs). The availability of accurate, quantitative, and scalable high-throughput methods to interrogate multiple iDMRs simultaneously would enhance clinical diagnostics and research. METHODS: We report the development of a custom targeted methylation sequencing panel that covered most relevant 63 iDMRs for CIDs and the detection of MLIDs. We tested it in 70 healthy controls and 147 individuals with CIDs. We distinguished loss and gain of methylation per differentially methylated region and classified high and moderate methylation alterations. RESULTS: Across a range of CIDs with a variety of molecular mechanisms, ImprintSeq performed at 98.4% sensitivity, 99.9% specificity, and 99.9% accuracy (when compared with previous diagnostic testing). ImprintSeq was highly sensitive for detecting MLIDs and enabled diagnostic criteria for MLID to be proposed. In a child with extreme MLID profile a probable genetic cause was identified. CONCLUSION: ImprintSeq provides a novel assay for clinical diagnostic and research studies of CIDs, MLIDs, and the role of disordered imprinting in human disease states.

Further delineation of phenotypic spectrum of SCN2A-related disorder.

SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype-genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype-phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.

Sociodemographic characteristics associated with parenthood amongst patients with a psychotic diagnosis: a cross-sectional study using patient clinical records.

PURPOSE: Estimates of parenthood in individuals with psychosis range from 27 to 63%. This number has likely increased due to the introduction of newer anti-psychotics and shorter hospital stays. The problems of psychosis can affect patients' capacity to offer the consistent, responsive care required for healthy child development. The following research questions were assessed: (1) what proportion of these patients have their children correctly recorded in their clinical notes, (2) what proportion of patients in secondary care with a psychotic diagnosis have children, and (3) what sociodemographic characteristics are associated with parenthood in this population. METHODS: This study used CRIS (Clinical Record Interactive Search) to search for patients with a diagnosis of non-affective or affective psychosis (F20-29, F31.2 or F31.5) within a UK NHS Trust. A binomial regression model was fitted to identify the variables associated with parenthood. RESULTS: Fewer than half of the parents in the sample had their children recorded in the correct field in their clinical notes. Of 5173 patients with psychosis, 2006 (38.8%) were parents. Characteristics associated with parenthood included being female, older age, higher socioeconomic status, renting or owning, having ever been married, being unemployed, not being White (British) and not having a diagnosis of schizophrenia. CONCLUSION: Over one-third of patients with psychosis were parents, and the study indicates that not all NHS Trusts are recording dependants accurately. Many variables were strongly associated with parenthood and these findings may help target interventions for this population.

Parenting and psychosis: An experience sampling methodology study investigating the inter-relationship between stress from parenting and positive psychotic symptoms.

OBJECTIVES: There is a strong association between stress and psychotic symptoms, and this study examined the bidirectional nature of this relationship in parents with psychosis, with negative affect as a mediator and a range of other psychosocial factors included as covariates. It also examined whether stress from parenting had a larger impact on psychosis than non-parenting stress. DESIGN: The study used a within-participants repeated measures design, using experience sampling methodology (ESM). ESM is a self-report surveying technique completed over an intensive longitudinal period. Participants completed six surveys a day, for 10 days. METHODS: Thirty-five participants with psychosis who were a parent to a child between the ages of 2 and 16 took part. Study phones alerted participants to complete surveys by beeping at semi-random intervals over 10 days. Multi-level modelling was used with surveys at Level-1 and participants at Level-2. Predictor variables were time-lagged in order to infer directionality. RESULTS: Parenting stress was found to predict psychotic symptoms, and this relationship was mediated by negative affect. The reverse direction was also confirmed. Few of the additional psychosocial factors were found to have a significant impact on the models' estimations. Parenting stress was not found to have a larger impact on psychosis than other sources of stress. CONCLUSIONS: This study provides further evidence of the bidirectional relationship between stress and psychosis in the context of parenting. Further research should explore if parenting stress plays a unique role in predicting psychotic symptoms by comparing parents and non-parents with psychosis.

Isolated- and Beckwith-Wiedemann syndrome related- lateralised overgrowth (hemihypertrophy): Clinical and molecular correlations in 94 individuals.

The congenital imprinting disorder, Beckwith-Wiedemann syndrome (BWS) is associated with variable clinical features including hemihypertrophy/lateralised overgrowth (LO) and embryonal tumour predisposition. BWS-associated (epi)genetic alterations occur in a subset of patients with isolated LO (ILO), leading to the concept of BWS spectrum disorder (BWSp). We investigated the relationship between clinical features and molecular diagnostic results in a cohort with LO using the BWSp international consensus group (BWSICG) clinical scoring system. Clinical/molecular findings in 94 previously-unreported patients with LO referred for BWSp molecular studies were reviewed retrospectively. The BWSICG score was assigned and diagnostic rate calculated. BWSp-associated (epi)genetic alteration was identified in 15/94 (16%). The molecular diagnostic rate by MS-MLPA (blood DNA) for BWS-related molecular findings in patients with LO was positively correlated with the BWSICG score. 3/48 with ILO had a molecular alteration. No individuals with ILO had developed an embryonal tumour at last follow up. Among a cohort of individuals with LO referred for BWSp molecular testing, the BWSICG score correlated with diagnostic yield. The embryonal tumour risk in children with ILO and negative molecular testing appeared very low, however longer- and more complete follow up is required to better define tumour risks in this group.

Parenting interventions for people with schizophrenia or related serious mental illness.

BACKGROUND: Around a third of people with schizophrenia or related serious mental illness will be a parent. Both the parents and the children in this population are at increased risk of adverse outcomes due to parental mental illness. Parenting interventions are known to improve parenting skills and decrease child disruptive behaviour. This systematic review aimed to synthesise the evidence base for parenting interventions designed specifically for parents who have schizophrenia or related serious mental illness. OBJECTIVES: To assess the effects of parenting interventions for people with schizophrenia or related serious mental illness. SEARCH METHODS: On 10 February 2021 we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on the following: Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), ClinicalTrials.Gov, Embase, International Standard Randomised Controlled Trial Number (ISRCTN), MEDLINE, PsycINFO, PubMed, and the World Health Organization International Clinical Trials Registry Platform. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs) that compared parenting interventions with a control condition for people with schizophrenia or related serious mental illness with a child between the ages of 0 and 18 years. DATA COLLECTION AND ANALYSIS: We independently inspected citations, selected studies, extracted data and appraised study quality. We assessed risk of bias for included studies. MAIN RESULTS: We only included one trial (n = 50), and it was not possible to extract any data because the authors did not provide any means and standard deviations for our outcomes of interest; they only reported whether outcomes were significant or not at the 0.05 level. Three domains of the trial were rated as having a high risk of bias. AUTHORS' CONCLUSIONS: The only included trial provided inconclusive evidence. There is insufficient evidence to make recommendations to people with schizophrenia (or related serious mental illness) or clinicians, or for policy changes. Although there is no RCT evidence, parenting interventions for people with schizophrenia or related serious mental illness have been developed. Future research should test these in RCTs in order to improve the evidence base for this population.

Mental health professionals' experiences of working with parents with psychosis and their families: a qualitative study.

BACKGROUND: Healthcare service users who are parents with psychosis form part of the caseload of most community mental health teams. Mental health professionals can experience uncertainty about how to work with and ask about the children of these parents, and often report difficulties when collaborating with other agencies. This study focused on professionals' experiences of working with parents with psychosis and their families to gain an understanding of these parents' needs from a service-level perspective, and to identify barriers that professionals may experience in meeting those needs. METHODS: Qualitative focus groups were conducted with four to eight mental health professionals per group. Data were analysed using reflexive thematic analysis. JR familiarised herself with the transcripts and then coded each salient unit within the text. Themes were then identified and discussed amongst all authors until there was agreement. RESULTS: We developed two overarching themes: 1) Diversity of need in parents with psychosis and 2) Role boundaries. The first explored mental health professionals' perceived range of experiences that parents with psychosis and their families have, and the range of potential effects of parental psychosis on a child. The second theme described how some mental health professionals emphasised the importance of supporting service users in terms of their parenting status and others felt it was more critical to treat the person's symptomatic expression. This theme also included issues with communication both with their service users and with other agencies. CONCLUSIONS: Mental health professionals identified that the needs of parents with psychosis were diverse and reflected significant variation in the experiences of service users. Mental health professionals across different types of team (early intervention and community mental health) expressed contrasting viewpoints about how achievable it was to respond to a service user's parenting status in an adult mental health setting. Future research should aim to determine where training is needed to enhance mental health professionals' ability to work holistically with families in an adult mental health setting, and how to enhance collaboration with other agencies.

Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype.

Whole-exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2-related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients. This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2-related disorder and the Angelman-/Rett-/Pitt-Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2-related disorder.

FOXP1-related intellectual disability syndrome: a recognisable entity.

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

A family perspective on parental psychosis: An interpretative phenomenological analysis study.

OBJECTIVES: While one third of people with a psychotic disorder are a parent, there has been little research to date examining the consequences of this from a whole family perspective. This study investigates families where a parent has experienced an episode of psychosis and compares and contrasts the family members' perspectives. DESIGN: This study was rooted in phenomenology and data were derived from in-depth semi-structured interviews. METHODS: Parents with a psychotic disorder who had a child aged between 3 and 11 in a UK NHS Trust were invited to take part in the study. Semi-structured interviews were conducted with these parents, with their child (if they were between the ages of 8 and 11), and with their partner or another close family member. Data were analysed using multiperspectival interpretive phenomenological analysis (m-IPA). RESULTS: Thirteen participants took part comprising of five parents, four children, three partners and one grandmother. Four themes were developed using m-IPA: (1) Parental psychosis impacts the whole family, (2) Psychosis and my role as a parent, (3) Secrecy and concealment surrounding parental psychosis, and (4) Pressures and vulnerabilities within the family system. CONCLUSION: Psychosis had a negative impact on all family members and secrecy existed between family members. The children in particular only had partial information about their parent's mental illness, which left them worried and confused. More work is needed to support these families to explain psychosis to the children.

Parental health in the context of public family care proceedings: A scoping review of evidence and interventions.

BACKGROUND: Child protective services (CPS), or their equivalent, have statutory power to remove children from birth parents in instances of child abuse, neglect, or concerns around parenting capacity via public family care proceedings. Parents who have children subject to proceedings, 'birth parents', often have complex health and social care needs. OBJECTIVE: We aimed to review what is known about the health needs of birth parents and the interventions implemented to support these health needs. METHODS: We searched PubMed, Scopus, and grey literature using a systematic strategy of key concepts "health", "care proceedings", and "parents". We included all publications in English that reported parental health in the context of care proceedings from the 1st of January 2000 to the 1st of March 2021. RESULTS: Included studies (n = 61) reported on maternal health (57 %) or the health of both parents (40 %), with only one study reporting on fathers alone. We conceptually categorised parental health need (n = 41) into i) mental health, ii) physical health, iii) substance misuse, iv) developmental disorders, and v) reproductive health. Health inequities and poor access to services were described across all categories, with longstanding issues often pre-dating proceedings or the child's birth. All interventions supporting parental health (n = 20) were targeted at mothers, with some supporting fathers (n = 8), formally or informally. We grouped similar interventions into three types: alternative family courts, wrap-around services, and specialist advocacy/peer support. CONCLUSIONS: Parents who have children subject to care proceedings have complex health needs that pre-date CPS concerns. The studies included in our review strongly suggest that health issues are exacerbated by child removal, triggering deteriorations in mental health, poor antenatal health for subsequent pregnancies, and avoidable mortality. Findings highlight the need for targeted and timely intervention for parents to improve whole-family outcomes. There are models that have been designed, implemented, and tested using relationship-based, trauma-informed, multidisciplinary, family-focused, and long-term approaches.

The Phenotypic Continuum of ATP1A3-Related Disorders.

BACKGROUND AND OBJECTIVES: ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process. METHODS: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021. RESULTS: Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint. DISCUSSION: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

A Scoping Review of Interventions Designed to Support Parents With Mental Illness That Would Be Appropriate for Parents With Psychosis.

The experience of psychosis can present additional difficulties for parents, over and above the normal challenges of parenting. Although there is evidence about parenting interventions specifically targeted at parents with affective disorders, anxiety, and borderline personality disorder, there is currently limited evidence for parents with psychotic disorders. It is not yet known what, if any, interventions exist for this population, or what kinds of evaluations have been conducted. To address this, we conducted a scoping review to determine (1) what parenting interventions have been developed for parents with psychosis (either specifically for, or accessible by, this client group), (2) what components these interventions contain, and (3) what kinds of evaluations have been conducted. The eligibility criteria were broad; we included any report of an intervention for parents with a mental health diagnosis, in which parents with psychosis were eligible to take part, that had been published within the last 20 years. Two reviewers screened reports and extracted the data from the included reports. Thirty-eight studies of 34 interventions were included. The findings show that most interventions have been designed either for parents with any mental illness or parents with severe mental illness, and only two interventions were trialed with a group of parents with psychosis. After noting clusters of intervention components, five groups were formed focused on: (1) talking about parental mental illness, (2) improving parenting skills, (3) long-term tailored support for the whole family, (4) groups for parents with mental illness, and (5) family therapy. Twenty-three quantitative evaluations and 13 qualitative evaluations had been conducted but only eight interventions have or are being evaluated using a randomized controlled trial (RCT). More RCTs of these interventions are needed, in addition to further analysis of the components that are the most effective in changing outcomes for both the parent and their children, in order to support parents with psychosis and their families.

Evaluating 'Enhancing Pragmatic Language skills for Young children with Social communication impairments' (E-PLAYS): a feasibility cluster-randomised controlled trial.

BACKGROUND: This article reports the results from a feasibility study of an intervention ('E-PLAYS') aimed at supporting children who experience difficulties with social communication. E-PLAYS is based around a dyadic computer game, which aims to develop collaborative and communication skills. A pilot study found that when E-PLAYS was delivered by researchers, improvements on communication test scores and on collaborative behaviours were observed. The aim of this study was to ascertain the feasibility of running a full-scale trial to test the effectiveness of E-PLAYS in a National Health Service (NHS) setting with delivery by speech and language therapists and teaching assistants. METHODS: The study was a two-arm feasibility cluster-randomised controlled trial of the E-PLAYS intervention with a treatment as usual control arm. Data relating to recruitment and retention, treatment fidelity, acceptability to participants, suitability of outcomes and feasibility of collecting health economic measures and of determining cost-effectiveness were collected. Speech and language therapists selected suitable children (ages 4-7 years old) from their caseload. E-PLAYS intervention (experimental group) was then delivered by teaching assistants overseen by speech and language therapists. The control group received usual care. Assessments included blinded language measures and observations, non-blinded teacher-reported measures of peer relations and classroom behaviour and non-blinded parent-reported use of health and education resources and quality of life. RESULTS: Planned recruitment was for 70 children, in the event, 50 children were recruited which was sufficient for feasibility purposes. E-PLAYS was very highly rated by children, teaching assistants and speech and language therapists and treatment fidelity did not pose any issues. We were able to collect health economic data which suggests that E-PLAYS would be a low-cost intervention. CONCLUSION: Based on recruitment, retention and adherence rates and our outcome measures, a full-scale randomised controlled trial estimated appears feasible and warranted to assess the effectiveness of E-PLAYS for use by the NHS and schools. TRIAL REGISTRATION: ISRCTN 14818949 (retrospectively registered).

Evaluating 'enhancing pragmatic language skills for young children with social communication impairments' (E-PLAYS): protocol for a feasibility randomised controlled trial study.

BACKGROUND: A number of children experience difficulties with social communication and this has long-term deleterious effects on their mental health, social development and education. The proposal presented in this article describes a feasibility study for a trial to test an intervention ('E-PLAYS') aimed at supporting children with social communication impairments. E-PLAYS harnesses technology in the form of a novel computer game in order to develop collaborative and communication skills. Preliminary studies by the authors show that when E-PLAYS was administered by the research team, children with social communication impairments showed improvements on communication test scores and on observed collaborative behaviours. The study described here is a pragmatic trial to test the application of E-PLAYS delivered by NHS speech and language therapists together with schools. METHODS: This protocol outlines a two-arm feasibility cluster-randomised controlled trial of the E-PLAYS intervention with treatment as usual control arm, with randomisation at the level of the speech and language therapist. The aim of this study is to ascertain whether it will be feasible to progress to running a full-scale definitive trial to test the effectiveness of E-PLAYS in an NHS setting. Data relating to recruitment and retention, the appropriateness of outcomes and the acceptability of E-PLAYS to participants will be collected.Speech and language therapists will select suitable children (ages 4-7 years old) from their caseloads and deliver either the E-PLAYS intervention (experimental group) or treatment as usual (control group). Assessments will include blinded language measures and observations, non-blinded teacher-reported measures of peer relations and classroom behaviour and parent-reported use of resources and quality of life. There will also be a qualitative process evaluation. DISCUSSION: The findings of this study will inform the decision as to whether to progress to a full-scale definitive randomised controlled trial to test the effectiveness of E-PLAYS when delivered by speech and language therapists and teaching assistants within schools. The use of technology in game form is a novel approach in an area where there are currently few available interventions. TRIAL REGISTRATION: ISRCTN 14818949 (retrospectively registered).