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Genetic testing and counselling are increasingly important in epilepsy care, aiming at finding a diagnosis, understanding aetiology and improving treatment and outcome. The psychological impact of genetic counselling from patients' or parents' perspectives is, however, unknown. We studied the counselee-reported outcome of genetic counselling before and after genetic testing for epilepsy by evaluating empowerment – a key outcome goal of counselling reflecting cognitive, decisional and behavioural control, emotional regulation and hope – and anxiety. We asked patients or their parents (for those <16 years or intellectually disabled) referred for genetic testing for epilepsy in two university hospitals between June 2014 and 2017 to complete the same two questionnaires at three timepoints: before and after pre-test counselling and after post-test counselling. Empowerment was measured with the Genetic Counselling Outcome Scale (GCOS-18); anxiety with the short State Trait Anxiety Inventory (STAI-6). A total of 63 participants (55 parents with the age of 29–66 years; 8 patients with the age of 21–42 years) were included in our study. Empowerment significantly increased during the genetic counselling trajectory with a medium effect size (p < 0.001 , d = 0.57). A small but significant increase in empowerment was already seen after pre-test counselling (p = 0.038 , d = 0.29). Anxiety did not change significantly during the counselling trajectory (p = 0.223, d = −0.24). Our study highlights that patients with epilepsy or their parents show a clinically relevant increase in empowerment after genetic counselling. Empowerment was already increased after pre-test counselling, suggesting the importance of counselling before initiating genetic testing for epilepsy. However, individual differences in changes in empowerment and anxiety were seen, suggesting that counselling could be further improved, based on individual needs. • Genetic testing and counselling are increasingly essential in epilepsy care. • Our study gives insight in outcomes of genetic counselling for epilepsy. • Counselees for epilepsy show an increase in empowerment after genetic counselling. • Counselling sessions can be further improved based on individual needs. [ABSTRACT FROM AUTHOR]

We describe an 18-year-old male patient with myoclonic astatic epilepsy (MAE), moderate to severe intellectual disability, behavioural problems, several dysmorphisms and a 1.2-Mb de novo deletion on chromosome 16p11.2. This deletion results in haploinsufficiency of STX1B and other genes. Recently, variants in the STX1B gene have been associated with a wide spectrum of fever-related epilepsies ranging from single febrile seizures to severe epileptic encephalopathies. Two previously reported patients with a STX1B missense variant or deletion were diagnosed with MAE. Our observation of a STX1B deletion in a third patient with MAE therefore supports that STX1B gene variants or deletions can be involved in the aetiology of MAE. Furthermore, STX1B encodes for syntaxin-1B, of which interaction with the protein encoded by the STXBP1 gene is essential for the regulation of the synaptic transmission of neurotransmitters. STXBP1 gene variants have been identified in patients with many different types of epilepsy, including Dravet syndrome and epileptic encephalopathies, suggesting STX1B plays a similar role. We recommend that analysis of STX1B should be considered in the diagnostic work-up of individuals with MAE. [ABSTRACT FROM AUTHOR]

Background Increasing evidence suggests that long-chain polyunsaturated fatty acid (LCPUFA) availability in utero could program later health. Objective The objective of the study was to explore whether prenatal LCPUFA availability could be involved in programming cardiometabolic disease risk at childhood. Methods Data of 242 mother–child pairs from the Maastricht Essential Fatty Acid Birth (MEFAB) cohort were used. Multi-variable linear regression analysis was applied to identify associations between maternal LCPUFA concentrations around weeks 11, 22 and 32 of pregnancy and at time of delivery and cardiometabolic risk factors of their children (glucose metabolism, blood lipids, and blood pressure) at age 7. Results Maternal eicosapentaenoic acid (20:5 n −3) at week 11 of pregnancy was negatively associated with children׳s glucose ( B =−0.34 mmol/L; 95% CI: −0.56, −0.12). Positive associations were found between maternal linoleic acid (18:2 n −6) at time of delivery and children׳s proinsulin ( B =0.25 pmol/L; 95% CI: 0.08, 0.41); maternal 3-docosapentaenoic acid (22:5 n −3) at week 11 and children׳s total cholesterol ( B =1.23 mmol/L; 95% CI: 0.45, 2.01) and low-density-lipoprotein cholesterol ( B =1.12 mmol/L; 95% CI: 0.42, 1.82); and maternal osbond acid (22:5 n −6) at week 22 and tetracosadienoic acid (24:2 n −6) at week 32 and children׳s diastolic blood pressure ( B =16.86 mmHg; 95% CI: 7.63, 26.08 and B =17.75 mmHg; 95% CI: 6.37, 29.94, respectively). Conclusion Our findings suggest that maternal omega-6 ( n −6) fatty acids may be of particular importance in relation to children׳s glucose metabolism and blood pressure, whereas omega-3 ( n −3) fatty acids seem particularly related to blood lipids at childhood. In general, the strength of the associations appeared stronger with fatty acid concentrations in early pregnancy compared to late pregnancy. [ABSTRACT FROM AUTHOR]

Prenatal polyunsaturated fatty acid (PUFA) concentrations may be involved in the prenatal programming of adiposity. In this study we therefore explored the association between maternal PUFA concentrations, measured up to four times during pregnancy, and offspring adiposity at age 7 in 234 mother-child pairs of the Maastricht Essential Fatty Acid Birth cohort. Only dihomo-gamma-linolenic acid (DGLA, an n-6 fatty acid) concentration was associated with adiposity: per standard deviation increase in relative DGLA concentration, BMI increased by 0.44kg/m2 (CI95: 0.16, 0.72), sum of skinfolds increased by 3.41mm (CI95: 1.88, 4.95), waist circumference increased by 1.09cm (CI95: 0.40, 1.78), and plasma leptin concentration increased by 0.66µg/l (CI95: 0.20, 1.11). In conclusion, maternal DGLA throughout gestation was associated with increased BMI and some additional measures of adiposity at age 7. This suggests that maternal DGLA might play a role in or reflect the prenatal programming of adiposity. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the association between insulin resistance and physical fitness, leptin concentration, body composition and family history for diabetes in non-selected young children. Physical fitness, fasting plasma glucose, insulin and leptin concentrations, anthropometric characteristics and medical history were available in two hundred and fifty-seven 7-year-old Dutch children. Correlations with the homeostasis model assessment (HOMA) index for insulin resistance were studied. A multiple regression model was calculated for HOMA. The differences between children with or without a family history for diabetes were not significant. Boys scored higher on glucose concentration and aerobic fitness and lower on sum of skin folds and leptin concentration (p<.05). After adjustment for sum of skin folds, HOMA was significantly associated with leptin in both genders (boys r=.184 p=.031; girls r=.430 p=.000). The association between physical fitness and HOMA was mediated by sum of skin folds. The associations were stronger in girls than in boys. In the regression model (R(2)=.205) the leptin concentration was the only significant predictor for HOMA. The influence of family history for diabetes on insulin resistance is shown as a trend at this age. Our findings suggest that plasma leptin concentration is independently associated with the development of insulin resistance in a non-selected prepubertal population. The association of physical fitness with insulin resistance seems to be mediated by the sum of skin folds. [ABSTRACT FROM AUTHOR]

Background: To improve the effective prevention and treatment of obesity, it is important to focus on body weight (BW) development and its determinants during childhood. Objective: The aim of the present study was to investigate the effects of early development, parental and genetic variables, and behavioral determinants on overweight at 12 y. Design: In a Dutch cohort of 105 children, anthropometric measurements were conducted from birth until age 7 y. At age 12 y, anthropometric measurements were obtained again, as were measurements of body composition, leptin concentration, 3 polymorphisms, and physical activity, and the Three-Factor Eating Questionnaire was conducted. In addition, parental body mass indexes (BMIs, in kg/m2) and Three-Factor Eating Questionnaire scores were determined. Results: The children's mean (±SD) BMI at 12 y was 19.0 ± 2.6, and 15.2% were classified as overweight. From the first year of life, BMI tracked significantly with BMI at age 12 y (r=0.24, P<0.05). Linear regression analyses showed that a rapid increase in BW during the first year of life, a high BMI of the father, and a high dietary restraint score of the mother were significantly associated with overweight at age 12 y (P < 0.05). No significant genetic relation was observed. In addition, overweight was positively associated with dietary restraint of the child, and percentage body fat was negatively associated with the child's activity score (P < 0.05). Conclusions: In this homogeneous cohort of normal-weight to moderately overweight children, tracking of BMI during childhood took place from the first year of life. Overweight at age 12 y was predicted by an early rapid increase in BW and parental influences. Overweight during childhood may be maintained or even promoted by a high dietary restraint score and low physical activity. [ABSTRACT FROM AUTHOR]

Background: Essential fatty acids (EFAs) in umbilical cord blood samples are associated with attained birth weight in pre-mature infants and low-birth-weight neonates. Objective: The objective was to investigate relations between the EFA composition of cord and maternal plasma phospholipids and birth weight in term neonates. Design: This was a cross-sectional study in 627 singletons born at term. The plasma phospholipid EFA composition of the mothers was determined by gas-liquid chromatography at study entry (≤ 16 wk gestation), at delivery, and in cord plasma at birth. Birth weights were normalized to SD scores. Results: In cord plasma, the dihomo-γ-linolenic acid concentration was positively related to weight SD scores. Both arachidonic acid (AA) and docosahexaenoic acid (DHA) were negatively related to weight SD scores. EFA-status indicators showed similar negative associations, whereas eicosatrienoic acid concentrations were positively related to neonatal size. In maternal plasma, proportions of n-3 long-chain polyenes (LCPs) and n-6 LCPs decreased during pregnancy. Larger decreases in AA, DHA, n-3 LCP, and n-6 LCP fractions were observed in mothers of heavier babies. Higher concentrations of LCPs in maternal plasma were, however, not related to a larger infant size at birth. Conclusions: A lower biochemical EFA status in umbilical cord plasma and a larger decrease in maternal plasma LCP concentrations are associated with a higher weight-for-gestational-age at birth in term neonates. Our findings do not support a growth-stimulating effect of AA or DHA; however, they do suggest that maternal-to-fetal transfer of EFAs might be a limiting factor in determining neonatal EFA status. [ABSTRACT FROM AUTHOR]

Abstract We studied the presence of benign infantile epilepsy (BIE), paroxysmal kinesigenic dyskinesia (PKD), and PKD with infantile convulsions (PKD/IC) in patients with a 16p11.2 deletion including PRRT2 or with a PRRT2 loss-of-function sequence variant. Index patients were recruited from seven Dutch university hospitals. The presence of BIE, PKD and PKD/IC was retrospectively evaluated using questionnaires and medical records. We included 33 patients with a 16p11.2 deletion: three (9%) had BIE, none had PKD or PKD/IC. Twelve patients had a PRRT2 sequence variant: BIE was present in four (p = 0.069), PKD in six (p < 0.001) and PKD/IC in two (p = 0.067). Most patients with a deletion had undergone genetic testing because of developmental problems (87%), whereas all patients with a sequence variant were tested because of a movement disorder (55%) or epilepsy (45%). BIE, PKD and PKD/IC clearly showed incomplete penetrance in patients with 16p11.2 deletions, but were found in all and 95% of patients with a PRRT2 sequence variant in our study and a large literature cohort, respectively. Deletions and sequence variants have the same underlying loss-of-function disease mechanism. Thus, differences in ascertainment have led to overestimating the frequency of BIE, PKD and PKD/IC in patients with a PRRT2 sequence variant. This has important implications for counseling if genome-wide sequencing shows such variants in patients not presenting the PRRT2 -related phenotypes. [ABSTRACT FROM AUTHOR]

Summary: Background: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals. Methods: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR. Findings: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis. Interpretation: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24. Funding: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research. [Copyright &y& Elsevier]