Developmental milestones and daily living skills in individuals with Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants. METHODS: Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS. RESULTS: Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25-92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0-13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth. CONCLUSION: Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care.

Development of the data registry for the Cardiac Neurodevelopmental Outcome Collaborative.

Children with congenital heart disease (CHD) can face neurodevelopmental, psychological, and behavioural difficulties beginning in infancy and continuing through adulthood. Despite overall improvements in medical care and a growing focus on neurodevelopmental screening and evaluation in recent years, neurodevelopmental disabilities, delays, and deficits remain a concern. The Cardiac Neurodevelopmental Outcome Collaborative was founded in 2016 with the goal of improving neurodevelopmental outcomes for individuals with CHD and pediatric heart disease. This paper describes the establishment of a centralised clinical data registry to standardize data collection across member institutions of the Cardiac Neurodevelopmental Outcome Collaborative. The goal of this registry is to foster collaboration for large, multi-centre research and quality improvement initiatives that will benefit individuals and families with CHD and improve their quality of life. We describe the components of the registry, initial research projects proposed using data from the registry, and lessons learned in the development of the registry.

Adaptive Skills of Individuals with Angelman Syndrome Assessed Using the Vineland Adaptive Behavior Scales, 2nd Edition.

In the current study, we examined adaptive skills and trajectories over time in 257 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, 2nd Edition. Multilevel linear models were used to examine differences between molecular subtypes over time, from one year to 13 years of age, in the adaptive domains of communication, daily living skills, socialization and motor skills. Individuals with non-deletion subtypes typically demonstrated a higher level of adaptive skills compared to those with deletion subtypes. Statistically significant growth was observed in all adaptive domains through at least early adolescence. Individuals with AS should continue to receive developmental services and educational supports through adolescence and into adulthood given the slow rates of growth being observed across adaptive domains.

Impact of Residual Lesion Severity on Neurodevelopmental Outcomes Following Congenital Heart Surgery in Infancy and Childhood.

Children with congenital heart disease are at increased risk of neurodevelopmental delay throughout their lifespan. This risk is exacerbated following congenital heart surgery (CHS) in infancy. However, there are few modifiable risk factors for postoperative neurodevelopmental delay. In this study, we assessed the Residual Lesion Score (RLS), a quality assessment metric that evaluates residual lesion severity following CHS, as a predictor of neurodevelopmental delay. This was a single-center, retrospective review of patients who underwent CHS from 01/2011 to 03/2021 and post-discharge neurodevelopmental evaluation from 12 to 42 months of age using the Bayley Scales of Infant Development, 3rd Edition (BSID-III). RLS was assigned per published criteria: RLS 1, no residua; RLS 2, minor residua; and RLS 3, major residua or pre-discharge reintervention. Associations between RLS and BSID-III scores, as well as trends in neurodevelopmental outcomes over time, were evaluated. Of 517 patients with median age at neurodevelopmental testing of 20.0 (IQR 18.0-22.7) months, 304 (58.8%), 146 (28.2%), and 67 (13.0%) were RLS 1, 2, and 3, respectively. RLS 3 patients had significantly lower scaled scores in the cognitive, receptive, and expressive communication, and fine and gross motor domains, compared with RLS 1 patients. Multivariable models accounted for 21.5%-31.5% of the variation in the scaled scores, with RLS explaining 1.4-7.3% of the variation. In a subgroup analysis, RLS 3 patients demonstrated relatively fewer gains in cognitive, expressive communication, and gross motor scores over time (all p < 0.05). In conclusion, RLS 3 patients are at increased risk for neurodevelopmental delay, warranting closer follow-up and greater developmental support for cognitive, language, and motor skills soon after surgery.

Factors Associated With Attendance for Cardiac Neurodevelopmental Evaluation.

BACKGROUND AND OBJECTIVES: Neurodevelopmental evaluation of toddlers with complex congenital heart disease is recommended but reported frequency is low. Data on barriers to attending neurodevelopmental follow-up are limited. This study aims to estimate the attendance rate for a toddler neurodevelopmental evaluation in a contemporary multicenter cohort and to assess patient and center level factors associated with attending this evaluation. METHODS: This is a retrospective cohort study of children born between September 2017 and September 2018 who underwent cardiopulmonary bypass in their first year of life at a center contributing data to the Cardiac Neurodevelopmental Outcome Collaborative and Pediatric Cardiac Critical Care Consortium clinical registries. The primary outcome was attendance for a neurodevelopmental evaluation between 11 and 30 months of age. Sociodemographic and medical characteristics and center factors specific to neurodevelopmental program design were considered as predictors for attendance. RESULTS: Among 2385 patients eligible from 16 cardiac centers, the attendance rate was 29.0% (692 of 2385), with a range of 7.8% to 54.3% across individual centers. In multivariable logistic regression models, hospital-initiated (versus family-initiated) scheduling for neurodevelopmental evaluation had the largest odds ratio in predicting attendance (odds ratio = 4.24, 95% confidence interval, 2.74-6.55). Other predictors of attendance included antenatal diagnosis, absence of Trisomy 21, higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category, longer postoperative length of stay, private insurance, and residing a shorter distance from the hospital. CONCLUSIONS: Attendance rates reflect some improvement but remain low. Changes to program infrastructure and design and minimizing barriers affecting access to care are essential components for improving neurodevelopmental care and outcomes for children with congenital heart disease.

Inpatient Screening for Early Identification of Developmental Risk in Infants with Congenital Heart Defects.

OBJECTIVE: To assess the utility of an inpatient standardized developmental screener for early identification of developmental risk in infants with a congenital heart defect (CHD). STUDY DESIGN: This was a retrospective, observational study with convenience sample of postoperative infants with CHD (aged 3-12 months) who underwent neurodevelopmental screening with the Bayley Scales of Infant and Toddler Development Screening Test, Third Edition (Bayley-III Screener) just before discharge. Follow-up testing included outpatient Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) (12-42 mo). RESULTS: The Bayley-III Screener was administered to 325 infants at a median of 5 months, 8 days (IQR 3 months, 28 days, to 7 months, 17 days). Infants scored below age expectations on the Gross Motor (79%), Fine Motor (63%), Receptive Communication (50%), Expressive Communication (38%), and Cognitive (38%) domains. In each domain, children with CHD had greater rates of scores below expectations than the normative sample (each P <.001). The odds of scoring in a greater risk category were increased for infants with genetic syndromes and longer length of hospital stay across all domains. The outpatient Bayley-III (n = 74, 23% follow-up) was completed at a median of 19 months, 9 days (IQR: 17 months, 3 days, to 23 months, 37 days). Individuals falling in greater-risk categories on their initial Bayley-III Screener were significantly more likely to have worse performance on their follow-up outpatient Bayley-III (each domain P < .01). CONCLUSIONS: Inpatient standardized neurodevelopmental screening provides important clinical utility in identifying infants at risk for developmental concern, allows for provision of recommendations for developmental services, and potentially overcomes barriers often noted in returning for outpatient post-discharge assessments.

Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS).

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits. RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports. CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations.

Preterm congenital heart disease and neurodevelopment: the importance of looking beyond the initial hospitalization.

Congenital heart disease (CHD) and prematurity are leading causes of infant mortality in the United States. Infants with CHD born prematurely are often described as facing "double jeopardy" with vulnerability from their underlying heart disease and from organ immaturity. They endure additional complications of developing in the extrauterine environment while healing from interventions for heart disease. While morbidity and mortality for neonates with CHD have declined over the past decade, preterm neonates with CHD remain at higher risk for adverse outcomes. Less is known about their neurodevelopmental and functional outcomes. In this perspective paper, we review the prevalence of preterm birth among infants with CHD, highlight the medical complexity of these infants, and emphasize the importance of exploring outcomes beyond survival. We focus on current knowledge regarding overlaps in the mechanisms of neurodevelopmental impairment associated with CHD and prematurity and discuss future directions for improving neurodevelopmental outcomes.

Telehealth services for cardiac neurodevelopmental care during the COVID-19 pandemic: a site survey from the Cardiac Neurodevelopmental Outcome Collaborative.

OBJECTIVE: COVID-19 has markedly impacted the provision of neurodevelopmental care. In response, the Cardiac Neurodevelopmental Outcome Collaborative established a Task Force to assess the telehealth practices of cardiac neurodevelopmental programmes during COVID-19, including adaptation of services, test protocols and interventions, and perceived obstacles, disparities, successes, and training needs. STUDY DESIGN: A 47-item online survey was sent to 42 Cardiac Neurodevelopmental Outcome Collaborative member sites across North America within a 3-week timeframe (22 July to 11 August 2020) to collect cross-sectional data on practices. RESULTS: Of the 30 participating sites (71.4% response rate), all were providing at least some clinical services at the time of the survey and 24 sites (80%) reported using telehealth. All but one of these sites were offering new telehealth services in response to COVID-19, with the most striking change being the capacity to offer new intervention services for children and their caregivers. Only a third of sites were able to carry out standardised, performance-based, neurodevelopmental testing with children and adolescents using telehealth, and none had completed comparable testing with infants and toddlers. Barriers associated with language, child ability, and access to technology were identified as contributing to disparities in telehealth access. CONCLUSIONS: Telehealth has enabled continuation of at least some cardiac neurodevelopmental services during COVID-19, despite the challenges experienced by providers, children, families, and health systems. The Cardiac Neurodevelopmental Outcome Collaborative provides a unique platform for sharing challenges and successes across sites, as we continue to shape an evidence-based, efficient, and consistent approach to the care of individuals with CHD.

Sleep Patterns in Young Children with Congenital Heart Disease.

Sleep patterns of 419 toddlers with congenital heart disease were comparable with the normative population except for increased likelihood across the cohort of sleeping in parents' room and increased disrupted sleep in children aged 18-23 months. Disrupted sleep patterns were associated with lower maternal education and increased medical complexity.

Developmental Skills of Individuals with Angelman Syndrome Assessed Using the Bayley-III.

We describe the development of 236 children with Angelman syndrome (AS) using the Bayley Scales of Infant and Toddler Development, Third Edition. Multilevel linear mixed modeling approaches were used to explore differences between molecular subtypes and over time. Individuals with AS continue to make slow gains in development through at least age 12 years of age at about 1-2 months/year based on age equivalent score and 1-16 growth score points/year depending on molecular subtype and domain. Children with a deletion have lower scores at baseline and slower rate of gaining skills while children with UBE3A variant subtype demonstrated higher scores as well as greater rates of skill attainment in all domains. The developmental profiles of UPD and ImpD were similar.

Impact of tight glycemic control and hypoglycemia after pediatric cardiac surgery on neurodevelopmental outcomes at three years of age: Findings from a randomized clinical trial.

BACKGROUND: Studies examining the impact of randomization As per standard instruction, city is required for affiliations; however, this information is missing in affiliation 6. Please check if the provided city is correct and amend if necessary. to tight glycemic control (TGC) and resultant hypoglycemia on later neurodevelopmental outcomes have produced mixed results. Our study examined this association in children undergoing cardiac surgery. METHODS: Participants who were enrolled in the Safe Pediatric Euglycemia after Cardiac Surgery (SPECS) trial returned for neurodevelopmental (ND) follow-up between 30 to 42.5 months of age. ND outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. ND scores were compared between the TGC and standard care treatment groups and between patients with moderate to severe and no to mild hypoglycemia. As a secondary analysis, to increase sample size and power, we combined the three-year-old assessments with previously collected assessments done at < 30 months of age to further examine differences between groups longitudinally. RESULTS: Among the 269 participants who completed neurodevelopmental evaluation (in-person testing or questionnaires) at three years of age (follow-up rate, 31%), there were no statistically significant differences in ND outcomes according to treatment group or hypoglycemia status. In the combined analysis of all evaluations (from 9 to 42.5 months of age), we found no treatment group differences. However, in these longitudinal analyses, children who experienced moderate to severe hypoglycemia had lower scores on the Bayley-III cognitive and motor domains compared to children with no to mild hypoglycemia. CONCLUSIONS: For infants undergoing cardiac surgery, there was no impact of tight glycemic control on neurodevelopmental outcomes. Moderate to severe hypoglycemia was associated with worse ND outcomes in longitudinal analyses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00443599. Registered: November 2016.

Integrating Telehealth Into Neurodevelopmental Assessment: A Model From the Cardiac Neurodevelopmental Outcome Collaborative.

OBJECTIVE: In the wake of the COVID-19 pandemic, psychologists were pushed to look beyond traditional in-person models of neurodevelopmental assessment to maintain continuity of care. A wealth of data demonstrates that telehealth is efficacious for pediatric behavioral intervention; however, best practices for incorporating telehealth into neurodevelopmental assessment are yet to be developed. In this topical review, we propose a conceptual model to demonstrate how telehealth can be incorporated into various components of neurodevelopmental assessment. METHODS: Harnessing existing literature and expertise from a multidisciplinary task force comprised of clinicians, researchers, and patient/parent representatives from the subspecialty of cardiac neurodevelopmental care, a conceptual framework for telehealth neurodevelopmental assessment was developed. Considerations for health equity and access to care are discussed, as well as general guidelines for clinical implementation and gaps in existing literature. RESULTS: There are opportunities to integrate telehealth within each stage of neurodevelopmental assessment, from intake to testing, through to follow-up care. Further research is needed to determine whether telehealth mitigates or exacerbates disparities in access to care for vulnerable populations as well as to provide evidence of validity for a wider range of neurodevelopmental measures to be administered via telehealth. CONCLUSIONS: While many practices are returning to traditional, face-to-face neurodevelopmental assessment services, psychologists have a unique opportunity to harness the momentum for telehealth care initiated during the pandemic to optimize the use of clinical resources, broaden service delivery, and increase access to care for pediatric neurodevelopmental assessment.

Methylation analysis and developmental profile of two individuals with Angelman syndrome due to mosaic imprinting defects.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternally-inherited UBE3A on chromosome 15q11.2. In AS due to a chromosomal deletion that encompasses UBE3A, paternal uniparental disomy of chromosome 15, or imprinting defects (ImpD), the SNRPN locus is unmethylated, while in neurotypical individuals, it is ∼50% methylated. We present the developmental profile of two adults with mild AS assessed using standardized behavioral and neurodevelopmental measures. Both had intellectual disability with unusually advanced verbal communication skills compared to other individuals with AS. Methylation of the SNRPN locus was examined using Methylation Specific Quantitative Melt Analysis (MS-QMA) in different tissues at one time point for participant A (22 years) and two time points for participant B (T1: 22 years, T2: 25 years), and these levels were compared to a typical AS cohort. While participant A showed methylation levels comparable to the typical AS cohort, participant B showed methylation mosaicism in all tissues at both time points and changes in methylation levels from T1 to T2. AS should be considered in individuals with intellectual disability and verbal speech who may not have the typical symptoms of AS.

Fetal Brain Volume Predicts Neurodevelopment in Congenital Heart Disease.

BACKGROUND: Neurodevelopmental impairment is common in children with congenital heart disease (CHD), but postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedents for neurodevelopmental disabilities might begin in utero, we analyzed whether fetal brain volume predicted subsequent neurodevelopmental outcome in children with CHD. METHODS: Fetuses with isolated CHD and sociodemographically comparable healthy control fetuses underwent fetal brain magnetic resonance imaging and 2-year neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and the Adaptive Behavior Assessment System, Third Edition (ABAS-3). Hierarchical regression evaluated potential predictors of Bayley-III and ABAS-3 outcomes in the CHD group, including fetal total brain volume adjusted for gestational age and sex, sociodemographic characteristics, birth measures, and medical history. RESULTS: The CHD group (n=52) had lower Bayley-III cognitive, language, and motor scores than the control group (n=26), but fetal brain volumes were similar. Within the CHD group, larger fetal total brain volume correlated with higher Bayley-III cognitive, language, and motor scores and ABAS-3 adaptive functioning scores (r=0.32-0.47; all P<0.05), but this was not noted in the control group. Fetal brain volume predicted 10% to 21% of the variance in neurodevelopmental outcome measures in univariate analyses. Multivariable models that also included social class and postnatal factors explained 18% to 45% of the variance in outcome, depending on developmental domain. Moreover, in final multivariable models, fetal brain volume was the most consistent predictor of neurodevelopmental outcome across domains. CONCLUSIONS: Small fetal brain volume is a strong independent predictor of 2-year neurodevelopmental outcomes and may be an important imaging biomarker of future neurodevelopmental risk in CHD. Future studies are needed to support this hypothesis. Our findings support inclusion of fetal brain volume in risk stratification models and as a possible outcome in fetal neuroprotective intervention studies.

A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. METHODS: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. RESULTS: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. CONCLUSION: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Anxiety in Angelman Syndrome.

Angelman Syndrome (AS) is a neurodevelopmental disorder most commonly caused by the impaired expression of the maternal UBE3A gene on chromosome 15. Though anxiety has been identified as a frequently present characteristic in AS, there are limited studies examining anxiety in this population. Studies of anxiety in other neurodevelopmental disorders have found disorder specific symptoms of anxiety and age specific displays of anxiety symptoms. However, there is a consistent challenge in identifying anxiety in people with neurodevelopmental disorders given the lack of measurement instruments specifically designed for this population. Given the limited information about AS and anxiety, the aims of the current project were to (a) examine symptoms of anxiety in children with AS and (b) determine the correlates of anxiety in children with AS. Participants included 42 adult caregivers of youth with AS in the AS Natural History study who completed the Developmental Behavior Checklist (DBC). The results found that 26% of the sample demonstrated elevated symptoms of anxiety and established a relationship between elevated anxiety in youth with AS and higher levels of irritability, hyperactivity, self-absorbed behaviors, and disruptive/antisocial behaviors. Findings from this research provide a foundation for tailoring evidence-based assessments and treatments for youth with AS and anxiety.

Neurological features in infants with congenital heart disease.

AIM: To report neurological examination findings at 5 to 12 months of age in infants with congenital heart disease (CHD) and to identify predictors of abnormal neurological examination. METHOD: This retrospective observational study included infants who required cardiac surgery at less than 3 months of age and underwent a standard neurological examination from a neurologist in the cardiac neurodevelopmental outpatient clinic between age 5 months and 12 months. Predictors for abnormal neurological examination (concerns on structured developmental history, demographic factors, medical history, and newborn neurodevelopmental assessment) were considered for multivariate regression. RESULTS: The sample included 127 infants (mean age 7mo 2wks), who underwent first cardiac surgery at 7 days (4-49 interquartile range [IQR]) of age and were seen for a neurological examination in the cardiac neurodevelopmental clinic. Neurological abnormalities were common; 88% of infants had an abnormal neurological examination in at least one domain assessed. The most common abnormalities were abnormal axial (48%) and extremity (44%) tone, mostly hypotonia. Abnormal neurological examination was associated with concerns on the concurrent structured developmental history, genetic condition, extracardiac anomaly, longer length of stay, more than one cardiac surgery, ongoing early intervention services, and abnormalities on newborn neurodevelopmental assessment. INTERPRETATION: Neurological examination abnormalities are common in infants with CHD after infant heart surgery, supporting the need for early and ongoing therapeutic developmental services and adherence to American Heart Association recommendations for developmental follow-up for children with CHD. What this paper adds Neurological examination abnormalities are common in infants who undergo open-heart surgery. Medical complications in infancy increase risk for neurological abnormalities. Family-reported concerns on structured developmental history may predict abnormal neurological examination at 5 to 12 months of age. Abnormal newborn neurodevelopmental assessment may predict abnormal neurological examination at 5 to 12 months of age.

Characterisation of neurodevelopmental and psychological outcomes in CHD: a research agenda and recommendations from the cardiac neurodevelopmental outcome collaborative.

The Neurodevelopmental and Psychological Outcomes Working Group of the Cardiac Neurodevelopmental Outcome Collaborative was formed in 2018 through support from an R13 grant from the National Heart, Lung, and Blood Institute with the goals of identifying knowledge gaps regarding the neurodevelopmental and psychological outcomes of individuals with CHD and investigations needed to advance science, policy, clinical care, and patient/family outcomes. Accurate characterisation of neurodevelopmental and psychological outcomes in children with CHD will drive improvements in patient and family outcomes through targeted intervention. Decades of research have produced a generalised perspective about neurodevelopmental and psychological outcomes in this heterogeneous population. Future investigations need to shift towards improving methods, measurement, and analyses of outcomes to better inform early identification, prevention, and intervention. Improved definition of underlying developmental, neuropsychological, and social-emotional constructs is needed, with an emphasis on symptom networks and dimensions. Identification of clinically meaningful outcomes that are most important to key stakeholders, including patients, families, schools and providers, is essential, specifically how and which neurodevelopmental differences across the developmental trajectory impact stakeholders. A better understanding of the discontinuity and patterns of neurodevelopment across the lifespan is critical as well, with some areas being more impactful at some ages than others. Finally, the field needs to account for the impact of race/ethnicity, socio-economic status, cultural and linguistic diversity on our measurement, interpretation of data, and approach to intervention and how to improve generalisability to the larger worldwide population of patients and families living with CHD.

Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.

Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.