Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterised by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next generation sequencing based assay. Comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. Review of the clinical and genetic features of SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants (p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)). Both SETD2 subgroups demonstrated a methylation episignature which was characterised by hypomethylation and hypermethylation events respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype–phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants

Biological and psychosocial sex and gender differences in patients with epilepsy

EINLEITUNG: In vielen Bereichen der Medizin zeigt sich wachsende Evidenz für relevante Geschlechterunterschiede, Beispiele sind kardiologische und immunologische Erkrankungen oder die weltweit um ca. 10 Jahre niedrigere Lebenserwartung von Männern. Zu Geschlechterunterschieden im Bereich der Epilepsien gibt es bislang kaum Erkenntnisse. Ziel dieser Arbeit ist es daher, in einem explorativen Ansatz Unterschiede in den Bereichen der Epilepsiesyndrome, Pharmakotherapie, Anfallskontrolle und psychosozialen Variablen zu untersuchen. METHODIK: Im Rahmen einer monozentrischen Querschnittsstudie wurden Patienten der Epilepsie-Hochschulambulanzen der Charité mittels eines semistrukturierten Interviews befragt, welches neben Angaben zu Medikation und Soziodemographie auch standardisierte Fragebögen zur Erfassung von Depressionen (PHQ-D), Angststörungen (HADS-A), sozialer Unterstützung (ESSI, MuSK) und gesundheitsspezifischer Lebensqualität (QOLIE-31-P) umfasste. Epilepsiespezifische Variablen wurden mithilfe der Patientenakten verifiziert und vervollständigt. Bei allen Patienten wurde routinemäßig die Serumkonzentration der Antiepileptika bestimmt. ERGEBNISSE: Ausgewertet wurden Datensätze von 302 Patienten (53,3% weiblich). IGEs lagen signifikant häufiger bei Frauen vor (34,2% der Frauen, 11,3% der Männer, p<0,001), fokale Epilepsien häufiger bei Männern (58,4% der Frauen, 85,1% der Männer, p<0,001). Entsprechend der Epilepsiesyndrome verteilten sich die Anfallstypen, unabhängig davon wurden EFA signifikant häufiger von Frauen mit fokaler Epilepsie berichtet (p=0,12). Patienten mit IGE waren signifikant häufiger anfallsfrei als Patienten mit fokaler Epilepsie (p<0,001). Weibliches Geschlecht war ein unabhängiger negativer Prädiktor für Anfallsfreiheit in den letzten 3 Monaten (p=0,030, Exp(B) 0,528). Männer wurden häufiger mit antiepileptischer Polytherapie behandelt (p=0,014). Keine Geschlechterunterschiede zeigten sich bei der Wahl der Substanzen oder den Dosierungen der AED, ebenso wenig wurden signifikante Unterschiede der Serumkonzentrationen nachgewiesen. Nebenwirkungen der antiepileptischen Therapie waren häufig (40,1%) und unterschieden sich zwischen den Geschlechtern: Müdigkeit, Sehstörungen, Hautprobleme und Gewichtszunahme wurden häufiger von Frauen genannt, Gang- und Gleichgewichtsstörungen vornehmlich von Männern. Das Depressionsscreening (PHQ-D) zeigte eine höhere Symptombelastung der Frauen, wobei für Major Depression suggestive Werte bei beiden Geschlechtern gleich häufig vorlagen (insgesamt 11,3%). Auch Angstsymptomatik (HADS-A) war zwischen Männern und Frauen gleich verteilt (grenzwertige/ krankheitswertige HADS-A-Scores bei insgesamt 67,3%). Die subjektiv wahrgenommene soziale Unterstützung (ESSI) war bei Männern signifikant niedriger als bei Frauen (p=0,039), insgesamt jedoch hoch. Umgekehrt zeigte sich die gesundheitsbezogene Lebensqualität (QOLIE-31-P) bei den Frauen geringer (p=0,008). SCHLUSSFOLGERUNG: In vielen klinisch relevanten Bereichen konnten signifikante Unterschiede zwischen Männern und Frauen mit Epilepsie gezeigt werden, in anderen Bereichen (wie den affektiven Störungen) zeigten sich die beiden Gruppen überraschend homogen. Diese Arbeit zu Geschlechterunterschieden bei Epilepsien liefert Ansätze für Interventionen im klinischen Alltag und zeigt zudem den Bedarf für weiterreichende Forschung auf.INTRODUCTION: Mounting evidence exists for relevant sex differences in various medical fields. Examples are cardiologic or immune-mediated diseases as well as general life expectancy, which is 10 years lower for men worldwide. Nevertheless, little is known about sex differences in epilepsies. This study explores sex/gender differences in epilepsy syndromes, pharmacotherapy, response to treatment and psychosocial variables. METHODS: By means of a monocentric cross-sectional study, adult epilepsy outpatients at Charité University Hospital completed a semi-structured interview containing information about AED, response to treatment, sociodemographic situation and standardized questionnaires for depression (PHQ-D), anxiety disorders (HADS-A), social support (ESSI, MuSK) and health-related quality of life (QOLIE-31-P). Epilepsy-related information were verified and completed with patient records. Serum concentration of AED was routinely measured in all patients. RESULTS: Data of 302 patients (53.3% female) were evaluated. Idiopathic generalized epilepsies were significantly more frequent in women (34.2% of all women, 11.3% of all men, p<0.001), while partial epilepsies predominated in men (58.4% of all women, 85.1% of all men, p<0.001). Seizure types were distributed according to epilepsy syndromes, however, in focal epilepsies simple partial seizures were more frequently reported by women (p=0.012). Seizure freedom occurred significantly more often in patients with IGE than in those with partial epilepsies (p<0.001). Female sex was an independent negative predictor for seizure freedom in the preceding 3 months (p=0.030, Exp(B) 0.528). Men were treated more often with antiepileptic polytherapy (p=0.014). Sex differences were found neither in choice of substance nor in AED dosages, also in serum concentrations no significant differences were proven. Adverse effects of antiepileptic therapy were frequent (40.1%) and differed between the sexes: women frequently reported tiredness, visual impairment, skin irritation and weight gain, while disturbances of gait/balance predominantly affected men. Screening for depressive symptoms (PHQ-D) showed higher scores in women, while suggestive scores for major depression equalled in both sexes (total 11.3%). There was no sex/gender difference in anxiety scores (borderline/pathologic HADS-A-scores in 67.3%). Subjectively perceived social support (ESSI) was significantly lower in men (p=0.039), while generally high. Conversely, health-related quality of life (QOLIE-31-P) was lower in women (p=0.008). CONCLUSION: Differences between men and women with epilepsy could be shown in various clinically relevant areas, while in other domains (i.e. affective disorders) both groups seemed surprisingly homogeneous. This study on sex and gender differences in epilepsies gives impulses for interventions in clinical routine and points out the urgent need for further research

The Impact of Demographic Characteristics on Parenting Stress among Parents of Children with Disabilities: A Cross-Sectional Study

Even though it is already known that parents of children with developmental delays or disabilities experience higher parenting stress than families of typically developing children, the contributing factors need to be analyzed in more detail. The aim of this cross-sectional study was to examine the influence of demographic characteristics on parenting stress from caring for a disabled child and to identify possible protective or additional stressful social factors. A total of 611 mothers and fathers of children with developmental delays, chronic diseases, or disabilities completed two questionnaires during their medical appointments at the Children’s Development Center (CDC) of Leipzig University Hospital between June 2020 and February 2021. These consisted of the German versions of the Parenting Stress Index (PSI) and the Impact on Family Scale (IOFS). To determine differences between the various groups, we used parametric and non-parametric tests. Mothers and single parents are significantly more strained than fathers and non-single parents. Parents with vocational training, those who graduated with a higher-level diploma, and those within employment report a higher financial burden. While unemployed and full-time workers experience the lowest stress, parents who work part-time or exclusively take care of their child show higher levels of stress. Looking at the age of the child, parents of children of young primary school age are the most stressed, and those of infants are the least stressed. These findings suggest that mothers and single parents especially should receive more support, and parents need to be provided with more attention during their child’s entry into school. Possible limitations and the influence of the COVID-19 pandemic are discussed