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A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single‐center cohort study, we assessed the impact of different initial treatment strategies for metastatic RCC (mRCC) on the development of BM. All consecutive patients diagnosed with mRCC between 2011 and 2022 were included at the Erasmus MC Cancer Institute, the Netherlands, and a subgroup of patients with BM was selected. In total, 381 patients with mRCC (ECM, BM, or both) were identified. Forty‐six patients had BM of whom 39 had metachronous BM (diagnosed ≥1 month after ECM). Twenty‐five (64.1%) of these 39 patients with metachronous BM had received prior systemic treatment for ECM and 14 (35.9%) patients were treatment naive at BM diagnosis. The median BM‐free survival since ECM diagnosis was significantly longer (p =.02) in previously treated patients (29.0 [IQR 12.6–57.0] months) compared to treatment naive patients (6.8 [IQR 1.0–7.0] months). In conclusion, patients with mRCC who received systemic treatment for ECM prior to BM diagnosis had a longer BM‐free survival as compared to treatment naïve patients. These results emphasize the need for careful evaluation of treatment strategies, and especially AS, for patients with mRCC. [ABSTRACT FROM AUTHOR]

To investigate the association between the presence and severity of seizures in asphyxiated newborns and their neurodevelopmental outcome at ages two and five years. Retrospective data analysis from a prospectively collected multicenter cohort of 186 term-born asphyxiated newborns undergoing therapeutic hypothermia (TH) in 11 centers in the Netherlands and Belgium. Seizures were diagnosed by amplitude-integrated electroencephalography (EEG) and raw EEG signal reading up to 48 hours after rewarming. Neurodevelopmental outcome was assessed by standardized testing at age two and five years. Primary outcome was death or long-term neurodevelopmental impairment (NDI) including cerebral palsy. Associations were calculated using univariate and multivariate logistic regression analyses adjusting for Thompson score and a validated brain magnetic resonance imaging (MRI) score. Seventy infants (38%) had seizures during TH or rewarming, and 44 (63%) of these needed two or more antiseizure medications (ASMs). Overall mortality was 21%. Follow-up data from 147 survivors were available for 137 infants (93%) at two and for 94 of 116 infants (81%) at five years. NDI was present in 26% at two and five years. Univariate analyses showed a significant association between seizures and death or NDI, but this was no longer significant after adjusting for Thompson and MRI score in the multivariate analysis; this was also true for severe seizures (need for two or more ASMs) or seizures starting during rewarming. The presence or severity of seizures in newborns undergoing TH for hypoxic-ischemic encephalopathy was not independently associated with death or NDI up to age five years after adjusting for several confounders. [ABSTRACT FROM AUTHOR]

This study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of 159 patients with a neurodevelopmental disorder (NDD), in which WES analysis and reanalysis were performed between January 1, 2014, and December 31, 2021, was retrospectively collected. Patients were included if they were under the age of 18 years at initial analysis and if this initial analysis did not result in a diagnosis. Demographic, phenotypic, and genotypic characteristics of patients were collected and analyzed. The primary outcomes of our study were (i) diagnostic yield at reanalysis, (ii) reasons for detecting a new possibly causal variant at reanalysis, (iii) unsolicited findings, and (iv) factors associated with positive result of reanalysis. In addition, we conducted a questionnaire study amongst the 7 genetic department in the Netherlands creating an overview of used techniques, yield, and organization of WES reanalysis. The single-center data show that in most cases, WES reanalysis was initiated by the clinical geneticist (65%) or treating physician (30%). The mean time between initial WES analysis and reanalysis was 3.7 years. A new (likely) pathogenic variant or VUS with a clear link to the phenotype was found in 20 initially negative cases, resulting in a diagnostic yield of 12.6%. In 75% of these patients, the diagnosis had clinical consequences, as for example, a screening plan for associated signs and symptoms could be devised. Most (32%) of the (likely) causal variants identified at WES reanalysis were discovered due to a newly described gene-disease association. In addition to the 12.6% diagnostic yield based on new diagnoses, reclassification of a variant of uncertain significance found at initial analysis led to a definite diagnosis in three patients. Diagnostic yield was higher in patients with dysmorphic features compared to patients without clear dysmorphic features (yield 27% vs. 6%; p = 0.001). Conclusions: Our results show that WES reanalysis in patients with NDD in standard patient care leads to a substantial increase in genetic diagnoses. In the majority of newly diagnosed patients, the diagnosis had clinical consequences. Knowledge about the clinical impact of WES reanalysis, clinical characteristics associated with higher yield, and the yield per year after a negative WES in larger clinical cohorts is warranted to inform guidelines for genetic reanalysis. These guidelines will be of great value for pediatricians, pediatric rehabilitation specialists, and pediatric neurologists in daily care of patients with NDD. What is Known: • Whole exome sequencing can cost-effectively identify a genetic cause of intellectual disability in about 30–40% of patients. • WES reanalysis in a research setting can lead to a definitive diagnosis in 10–20% of previously exome negative cases. What is New: • WES reanalysis in standard patient care resulted in a diagnostic yield of 13% in previously exome negative children with NDD. • The presence of dysmorphic features is associated with an increased diagnostic yield of WES reanalysis. [ABSTRACT FROM AUTHOR]

Background: Causes of childhood behavior problems remain poorly understood. Enriched family environments and corresponding brain development may reduce the risk of their onset, but research investigating white matter neurodevelopmental pathways explaining associations between the family environment and behavior remains limited. We hypothesized that more positive prenatal and mid-childhood family functioning – a measure of a family's problem solving and supportive capacity – would be associated with two markers of preadolescent white matter neurodevelopment related to reduced behavior problems: higher global fractional anisotropy (FA) and lower global mean diffusivity (MD). Methods: Data are from 2727 families in the Generation R Study, the Netherlands. Mothers reported family functioning (McMaster Family Assessment Device, range 1–4, higher scores indicate healthier functioning) prenatally and in mid-childhood (mean age 6.1 years). In preadolescence (mean age 10.1), the study collected diffusion-weighted scans. We computed standardized global MD and FA values by averaging metrics from 27 white matter tracts, and we fit linear models adjusting for possible confounders to examine global and tract-specific outcomes. Results: Prenatal and mid-childhood family functioning scores were moderately correlated, r = 0.38. However, only prenatal family functioning – and not mid-childhood functioning – was associated with higher global FA and lower global MD in preadolescence in fully adjusted models: β global FA = 0.11 (95% CI 0.00, 0.21) and β global MD = −0.15 (95% CI −0.28, −0.03) per one-unit increase in functioning score. Sensitivity and tract-specific analyses supported these global findings. Conclusions: These results suggest high-functioning prenatal or perinatal family environments may confer lasting white matter neurodevelopmental benefits into preadolescence. [ABSTRACT FROM AUTHOR]

Previous studies have found significant associations between estimated autozygosity - the proportion of an individual's genome contained in homozygous segments due to distant inbreeding - and multiple traits, including educational attainment (EA) and cognitive ability. In one study, estimated autozygosity showed a stronger association with parental EA than the subject's own EA. This was likely driven by parental EA's association with mobility: more educated parents tended to migrate further from their hometown, and because of the strong correlation between ancestry and geography in the Netherlands, these individuals chose partners farther from their ancestry and therefore more different from them genetically. We examined the associations between estimated autozygosity, cognitive ability, and parental EA in a contemporary sub-sample of adolescents from the Adolescent Brain Cognitive Development Study℠ (ABCD Study®) (analytic N = 6,504). We found a negative association between autozygosity and child cognitive ability consistent with previous studies, while the associations between autozygosity and parental EA were in the expected direction of effect (with greater levels of autozygosity being associated with lower EA) but the effect sizes were significantly weaker than those estimated in previous work. We also found a lower mean level of autozygosity in the ABCD sample compared to previous autozygosity studies, which may reflect overall decreasing levels of autozygosity over generations. Variation in spousal similarities in ancestral background in the ABCD study compared to other studies may explain the pattern of associations between estimated autozygosity, EA, and cognitive ability in the current study. [ABSTRACT FROM AUTHOR]

Dietary trans fatty acids (TFAs) are primarily industrially produced and remain abundant in processed food, particularly in low- and middle-income countries. Although TFAs are a cause of adverse cardiometabolic outcomes, little is known about exposure to TFAs in relation to brain development. We aimed to investigate the effect of maternal TFA concentration during pregnancy on offspring head growth in utero and during childhood. In a prospective population-based study in Rotterdam, the Netherlands, with 6900 mother–child dyads, maternal plasma TFA concentration was assessed using gas chromatography in mid-gestation. Offspring head circumference (HC) was measured in the second and third trimesters using ultrasonography; childhood brain morphology was assessed using magnetic resonance imaging at age 10 years. We performed regression analyses adjusting for sociodemographic and lifestyle confounders and instrumental variable (IV) analyses. Our IV analysis leveraged a national policy change that led to a substantial reduction in TFA and occurred mid-recruitment. After adjusting for covariates, maternal TFA concentration during pregnancy was inversely related to fetal HC in the third trimester (mean difference per 1% wt:wt increase: − 0.33, 95% CI − 0.51, − 0.15, cm) and to fetal HC growth from the second to the third trimester (− 0.04, 95% CI − 0.06, − 0.02, cm/week). Consistent findings were obtained with IV analyses, strengthening a causal interpretation. Association between prenatal TFA exposure and HC in the second trimester or global brain volume at age 10 years was inconclusive. Our findings are of important public health relevance as TFA levels in food remain high in many countries. [ABSTRACT FROM AUTHOR]

Evidence suggests that maltreatment shapes the child's brain. Little is known, however, about how normal variation in parenting influences the child neurodevelopment. We examined whether harsh parenting is associated with the brain morphology in 2,410 children from a population-based cohort. Mothers and fathers independently reported harsh parenting at child age 3 years. Structural and diffusion-weighted brain morphological measures were acquired with MRI scans at age 10 years. We explored whether associations between parenting and brain morphology were explained by co-occurring adversities, and whether there was a joint effect of both parents' harsh parenting. Maternal harsh parenting was associated with smaller total gray (β = −0.05 (95%CI = −0.08; −0.01)), cerebral white matter and amygdala volumes (β = −0.04 (95%CI = −0.07; 0)). These associations were also observed with the combined harsh parenting measure and were robust to the adjustment for multiple confounding factors. Similar associations, although non-significant, were found between paternal parenting and these brain outcomes. Maternal and paternal harsh parenting were not associated with the hippocampus or the white matter microstructural metrics. We found a long-term association between harsh parenting and the global brain and amygdala volumes in preadolescents, suggesting that adverse rearing environments common in the general population are related to child brain morphology. [ABSTRACT FROM AUTHOR]

Background: Treatment development for neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) is impeded by heterogeneity in clinical manifestation and underlying etiologies. Symptom traits such as aberrant sensory reactivity are present across NDDs and might reflect common mechanistic pathways. Here, we test the effectiveness of repurposing a drug candidate, bumetanide, on irritable behavior in a cross-disorder neurodevelopmental cohort defined by the presence of sensory reactivity problems. Methods: Participants, aged 5–15 years and IQ ≥ 55, with ASD, ADHD, and/or epilepsy and proven aberrant sensory reactivity according to deviant Sensory Profile scores were included. Participants were randomly allocated (1:1) to bumetanide (max 1 mg twice daily) or placebo tablets for 91 days followed by a 28-day wash-out period using permuted block design and minimization. Participants, parents, healthcare providers, and outcome assessors were blinded for treatment allocation. Primary outcome was the differences in ABC-irritability at day 91. Secondary outcomes were differences in SRS-2, RBS-R, SP-NL, BRIEF parent, BRIEF teacher at D91. Differences were analyzed in a modified intention-to-treat sample with linear mixed models and side effects in the intention-to-treat population. Results: A total of 38 participants (10.1 [SD 3.1] years) were enrolled between June 2017 and June 2019 in the Netherlands. Nineteen children were allocated to bumetanide and nineteen to placebo. Five patients discontinued (n = 3 bumetanide). Bumetanide was superior to placebo on the ABC-irritability [mean difference (MD) −4.78, 95%CI: −8.43 to −1.13, p = 0.0125]. No effects were found on secondary endpoints. No wash-out effects were found. Side effects were as expected: hypokalemia (p = 0.046) and increased diuresis (p = 0.020). Conclusion: Despite the results being underpowered, this study raises important recommendations for future cross-diagnostic trial designs. [ABSTRACT FROM AUTHOR]

The placenta is the largest fetal organ, which connects the mother to the fetus and supports most aspects of organogenesis through the transport of nutrients and gases. However, further studies are needed to assess placental pathology as a reliable predictor of long-term physical growth or neural development in newborns. The Consensus Statement of the Amsterdam Placental Workshop Group (APWGCS) on the sampling and definition of placental lesions has resulted in diagnostic uniformity in describing the most common pathological lesions of the placenta and contributed to the international standardization of descriptions of placental pathology. In this narrative review, we reclassified descriptions of placental pathology from previously published papers according to the APWGCS criteria and comparatively assessed the relationship with infantile physical and/or neural development. After reclassification and reevaluation, placental pathology of maternal vascular malperfusion, one of the APWGCS criteria, emerged as a promising candidate as a universal predictor of negative infantile neurodevelopmental outcomes, not only in term and preterm deliveries but also in high-risk groups of very low birthweight newborns. However, there are few studies that examined placental pathology according to the full categories of APWGCS and also included low-risk general infants. It is necessary to incorporate the assessment of placental pathology utilizing APWGCS in the design of future birth cohort studies as well as in follow-up investigations of high-risk infants.

Importance: The association of poor family functioning, a potent stressor, with child behavior is potentially long term and relevant for a person's well-being later in life. Whether changes in brain development underlie the associations with preadolescent behavior and help identify periods of vulnerability is unclear.Objective: To assess the associations of poor family functioning from pregnancy onward with cortical, white matter, and subcortical volumes, and to examine the extent to which, in particular, hippocampal volume mediates the association of prenatal parental environmental exposures with child problem behavior in preadolescence.Design, Setting, and Participants: This population-based cohort study, conducted from April 2002 to January 2006, was embedded in Generation R, a multiethnic population-based cohort from fetal life onward. All pregnant women living in Rotterdam, the Netherlands, with an expected delivery date between April 2002 and January 2006 were invited to participate. Of the 8879 pregnant women enrolled during pregnancy, 1266 mothers with no partner data and 490 with missing family functioning data were excluded, as well as 1 sibling of 32 twin pairs. After excluding an additional 657 children with poor imaging data quality or incidental findings, the final sample consisted of 2583 mother-child pairs. Data analysis was performed from March 1, 2019, to June 28, 2019.Exposures: Mother- and father-rated poor family functioning was repeatedly measured by the General Functioning subscale of the Family Assessment Device.Main Outcomes and Measures: Our primary hypothesis, formulated after data collection but before analysis, was that poor prenatal family functioning would be associated with smaller hippocampal and amygdala volumes in late childhood. High-resolution structural neuroimaging data of children aged 10 years were collected with a single 3-T magnetic resonance imaging system. Child emotional and behavioral problems were assessed with the Child Behavior Checklist.Results: Data were available for 2583 children (mean [SD] age, 10.1 [0.6] years; 1315 girls [50.9%]). Data for parents included 2583 mothers (mean [SD] age, 31.1 [4.7] years; 1617 Dutch race/ethnicity [62.6%]) and 1788 fathers (mean [SD] age, 33.5 [5.3] years; 1239 Dutch race/ethnicity [69.3%]). Children exposed to prenatal maternal-reported poor family functioning had smaller hippocampal (B = -0.08; 95% CI, -0.13 to -0.02) and occipital lobe (B = -0.70; 95% CI, -1.19 to -0.21) volumes in preadolescence. There was no evidence for an association of exposure to poor family functioning at mid- or late childhood with brain morphology. Hippocampal volumes partially mediated the association of prenatal maternal-reported poor family functioning with preadolescent problem behavior (B = 0.08; 95% CI, 0.03-0.13), even after adjusting for prior child problems at age 1.5 years. Analyses of combined maternal and paternal family functioning ratings showed similar results, but associations were largely driven by maternal family functioning reports.Conclusions and Relevance: In this population-based cohort study, prenatal maternal-reported poor family functioning was associated with a smaller hippocampus in preadolescents. This difference in brain structure may underlie behavioral problems and is a possible neurodevelopmental manifestation of the long-term consequences of poor family functioning for the child. [ABSTRACT FROM AUTHOR]

Brain development and deterioration across the lifespan are integral to the etiology of late-life neurodegenerative disease. Factors that influence the health of the adult brain remain to be elucidated and include risk factors, protective factors, and factors related to cognitive and brain reserve. To address this knowledge gap we designed a life-course study on brain health, which received funding through the EU ERC Programme under the name Origins of Alzheimer's Disease Across the Life course (ORACLE) Study. The ORACLE Study is embedded within Generation R, a prospective population-based cohort study of children and their parents, and links this with the Rotterdam Study, a population-based study in middle-aged and elderly persons. The studies are based in Rotterdam, the Netherlands. Generation R focuses on child health from fetal life until adolescence with repeated in-person examinations, but has also included data collection on the children's parents. The ORACLE Study aims to extend the parental data collection in nearly 2000 parents with extensive measures on brain health, including neuroimaging, cognitive testing and motor testing. Additionally, questionnaires on migraine, depressive symptoms, sleep, and neurological family history were completed. These data allow for the investigation of longitudinal influences on adult brain health as well as intergenerational designs involving children and parents. As a secondary focus, the sampling is enriched by mothers (n = 356) that suffered from hypertensive disorders during pregnancy in order to study brain health in this high-risk population. This article provides an overview of the rationale and the design of the ORACLE Study. [ABSTRACT FROM AUTHOR]

Objective: The authors examined associations of exposure to maternal depressive symptoms at different developmental stages from fetal life to preadolescence with child brain development, including volumetrics and white matter microstructure.Methods: This study was embedded in a longitudinal birth cohort in Rotterdam, the Netherlands. Participants were 3,469 mother-child pairs with data on maternal depressive symptoms and child neuroimaging at age 10. The authors also measured child emotional and behavioral problems at the time of neuroimaging. The association of maternal depressive symptoms with child brain development at each assessment was examined. Maternal depressive symptom trajectories were modeled across fetal life and childhood to determine the association of maternal depressive symptom patterns over time with child brain development.Results: The single-time-point analyses showed that maternal depressive symptoms at child age 2 months were associated with smaller total gray matter volume and lower global fractional anisotropy (FA), whereas maternal depressive symptoms assessed prenatally or in childhood were not. The trajectory analyses suggested in particular that children exposed to persistently high levels of maternal depressive symptoms across the perinatal period had smaller gray and white matter volumes as well as alterations (i.e., lower FA) in white matter microstructure compared with nonexposed children. Furthermore, the gray matter volume differences mediated the association between postnatal maternal depressive symptoms and child attention problems.Conclusions: Perinatal maternal depressive symptoms were consistently associated with child brain development assessed 10 years later. These results suggest that the postnatal period is a window of vulnerability for adversities such as maternal depressive symptoms. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to estimate long-term impairment attributable to congenital cytomegalovirus infection (cCMV).Method: This nationwide cohort study retrospectively assessed cCMV in children born in 2008 in the Netherlands, testing 31 484 stored neonatal dried blood spots. Extensive medical data of cCMV-positive children (n=133) and matched cCMV-negative comparison children (n=274) up to 6 years of age were analysed.Results: Moderate to severe long-term impairment was diagnosed in 24.8% (33 out of 133) of all cCMV-positive children (53.8% in symptomatic, 17.8% in asymptomatic), compared with 12.0% (33 out of 274) of cCMV-negative children. Sensorineural hearing loss was seen only in five cCMV-positive children (3.8%). Developmental delays were diagnosed more often in cCMV-positive children than cCMV-negative children: motor (12.0% vs 1.5%), cognitive (6.0% vs 1.1%), and speech-language (16.5% vs 7.3%). Long-term impairment in multiple domains was more frequent in symptomatic (19.2%) and asymptomatic (8.4%) cCMV-positive children than cCMV-negative children (1.8%).Interpretation: Children with cCMV were twice as likely to have long-term impairment up to the age of 6 years, especially developmental delays and sensorineural hearing loss, than cCMV-negative comparison children, with a risk difference of 12.8%. These insights into the risk of cCMV-associated impairment can help optimize care and stimulate preventive measures.What This Paper Adds: Congenital cytomegalovirus infection (cCMV) leads to impairment in 25% of cases. Fifty per cent of children with cCMV symptoms at birth have long-term impairment. The risk difference of moderate to severe long-term impairment between children with and without cCMV is 13%, attributable to cCMV. cCMV leads to motor, cognitive, and speech-language developmental delay in children. [ABSTRACT FROM AUTHOR]

It is well known that smoking during pregnancy can affect offspring health. Prenatal tobacco exposure has been associated with negative behavioral and cognitive outcomes in childhood, adolescence, and young adulthood. These associations between prenatal tobacco exposure and psychopathology in offspring could possibly be explained by the influence of prenatal tobacco exposure on brain development. In this prospective study, we investigated the association between prenatal tobacco exposure, behavioral and emotional functioning and brain morphology in young children. On the basis of age and gender, we matched 113 children prenatally exposed to tobacco with 113 unexposed controls. These children were part of a population-based study in the Netherlands, the Generation R Study, and were followed from pregnancy onward. Behavioral and emotional functioning was assessed at age 6 with the Child Behavior Checklist. We assessed brain morphology using magnetic resonance imaging techniques in children aged 6-8 years. Children exposed to tobacco throughout pregnancy have smaller total brain volumes and smaller cortical gray matter volumes. Continued prenatal tobacco exposure was associated with cortical thinning, primarily in the superior frontal, superior parietal, and precentral cortices. These children also demonstrated increased scores of affective problems. In addition, thickness of the precentral and superior frontal cortices was associated with affective problems. Importantly, brain development in offspring of mothers who quit smoking during pregnancy resembled that of nonexposed controls (no smaller brain volumes and no thinning of the cortex). Our findings suggest an association between continued prenatal tobacco exposure and brain structure and function in school-aged children. [ABSTRACT FROM AUTHOR]

A fundamental task in neuroscience is to characterize the brain's developmental course. While replicable group-level models of structural brain development from childhood to adulthood have recently been identified, we have yet to quantify and understand individual differences in structural brain development. The present study examined inter-individual variability and sex differences in changes in brain structure, as assessed by anatomical MRI, across ages 8.0–26.0 years in 269 participants (149 females) with three time points of data (807 scans), drawn from three longitudinal datasets collected in the Netherlands, Norway, and USA. We further investigated the relationship between overall brain size and developmental changes, as well as how females and males differed in change variability across development. There was considerable inter-individual variability in the magnitude of changes observed for all examined brain measures. The majority of individuals demonstrated decreases in total gray matter volume, cortex volume, mean cortical thickness, and white matter surface area in mid-adolescence, with more variability present during the transition into adolescence and the transition into early adulthood. While most individuals demonstrated increases in white matter volume in early adolescence, this shifted to a majority demonstrating stability starting in mid-to-late adolescence. We observed sex differences in these patterns, and also an association between the size of an individual's brain structure and the overall rate of change for the structure. The present study provides new insight as to the amount of individual variance in changes in structural morphometrics from late childhood to early adulthood in order to obtain a more nuanced picture of brain development. The observed individual- and sex-differences in brain changes also highlight the importance of further studying individual variation in developmental patterns in healthy, at-risk, and clinical populations. [ABSTRACT FROM AUTHOR]

• Epilepsy is significantly associated with people with intellectual disability (PwID). • People with intellectual disability with treatment-resistant epilepsy in the UK and the Netherlands were reviewed. • Significant mental, physical, behavioral, and neurodevelopmental comorbidities exist. • Polypharmacy of AEDs and psychotropics was commonly in use. • People with intellectual disability & epilepsy need a different approach to managing their health needs. Around 25% of people with Intellectual Disability (PwID) have comorbid epilepsy with seizures in up to two-thirds being drug-resistant. Little is known of the general characteristics and prescribing practices to this population. Describe and compare characteristics of two cohorts of PwID and epilepsy in two different countries to inform clinical practice better. An explorative, retrospective, case-note review in a specialist ID community service in England and in an expert center for PwID and epilepsy in the Netherlands was conducted. Information on ID severity, medical/behavioral/psychiatric/neurodevelopmental/genetic comorbidities, psychotropic, and antiepileptic drugs (AEDs) for each cohort was collected. The English cohort consisted of 167 people (98 males; age range 18–73 years; mild/moderate ID- 35%) and the Dutch cohort of 189 people (111 males; age range 18–85 years; mild/moderate ID – 51%). The two cohorts were comparable in their baseline characteristics. The Dutch had higher rates of physical comorbidity, but less mental or behavioral disorders and were more likely to be on anti-psychotic medication. The mean dosages between three most common AEDs prescribed were similar. The most frequently prescribed drug in both centers is valproate. Three-quarters of the Dutch were on three or more AEDs compared to a third in the English cohort. Structured description of the characteristics, differences, and commonalities of PwID, treatment, and services of both countries is presented. This is the first real-world study to reveal unique characteristics of managing epilepsy for a complex ID population. In particular, it highlights the considerable comorbid psychiatric burden and psychotropic prescribing. [ABSTRACT FROM AUTHOR]

Background & Aims: Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by absence of enteric ganglia in the distal part of the gut. Variants in ret proto-oncogene (RET) have been associated with up to 50% of familial and 35% of sporadic cases. We searched for variants that affect disease risk in a large, multigenerational family with history of HSCR in a linkage region previously associated with the disease (4q31.3-q32.3) and exome wide., Methods: We performed exome sequencing analyses of a family in the Netherlands with 5 members diagnosed with HSCR and 2 members diagnosed with functional constipation. We initially focused on variants in genes located in 4q31.3-q32.3; however, we also performed an exome-wide analysis in which known HSCR or HSCR-associated gene variants predicted to be deleterious were prioritized for further analysis. Candidate genes were expressed in HEK293, COS-7, and Neuro-2a cells and analyzed by luciferase and immunoblot assays. Morpholinos were designed to target exons of candidate genes and injected into 1-cell stage zebrafish embryos. Embryos were allowed to develop and stained for enteric neurons., Results: Within the linkage region, we identified 1 putative splice variant in the lipopolysaccharide responsive beige-like anchor protein gene (LRBA). Functional assays could not confirm its predicted effect on messenger RNA splicing or on expression of the mab-21 like 2 gene (MAB21L2), which is embedded in LRBA. Zebrafish that developed following injection of the lrba morpholino had a shortened body axis and subtle gut morphological defects, but no significant reduction in number of enteric neurons compared with controls. Outside the linkage region, members of 1 branch of the family carried a previously unidentified RET variant or an in-frame deletion in the glial cell line derived neurotrophic factor gene (GDNF), which encodes a ligand of RET. This deletion was located 6 base pairs before the last codon. We also found variants in the Indian hedgehog gene (IHH) and its mediator, the transcription factor GLI family zinc finger 3 (GLI3). When expressed in cells, the RET-P399L variant disrupted protein glycosylation and had altered phosphorylation following activation by GDNF. The deletion in GDNF prevented secretion of its gene product, reducing RET activation, and the IHH-Q51K variant reduced expression of the transcription factor GLI1. Injection of morpholinos that target ihh reduced the number of enteric neurons to 13% ± 1.4% of control zebrafish., Conclusions: In a study of a large family with history of HSCR, we identified variants in LRBA, RET, the gene encoding the RET ligand (GDNF), IHH, and a gene encoding a mediator of IHH signaling (GLI3). These variants altered functions of the gene products when expressed in cells and knockout of ihh reduced the number of enteric neurons in the zebrafish gut., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)