Understanding neurodevelopmental trajectories and behavioral profiles in SCN1A-related epilepsy syndromes.

BACKGROUND: A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + ) syndrome. Dravet syndrome (DS) is associated with refractory seizures, developmental delay, intellectual disability (ID), motor impairment, and challenging behavior(1,2). GEFS + is a less severe phenotype in which cognition is often normal and seizures are less severe. Challenging behavior largely affects quality of life of patients and their families. This study describes the profile and course of the behavioral phenotype in patients with SCN1A-related epilepsy syndromes, explores correlations between behavioral difficulties and potential risk factors. METHODS: Data were collected from questionnaires, medical records, and semi-structured interviews. Behavior difficulties were measured using the Adult/Child Behavior Checklist (C/ABCL) and Adult self-report (ASR). Other questionnaires included the Pediatric Quality of Life Inventory (PedsQL), the Functional Mobility Scale (FMS) and the Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP). To determine differences in behavioral difficulties longitudinally, paired T-tests were used. Pearson correlation and Spearman rank test were used in correlation analyses and multivariable regression analyses were employed to identify potential risk factors. RESULTS: A cohort of 147 participants, including 107 participants with DS and 40 with genetic epilepsy with febrile seizures plus (GEFS + ), was evaluated. Forty-six DS participants (43.0 %) and three GEFS + participants (7.5 %) showed behavioral problems in the clinical range on the A/CBCL total problems scale. The behavioral profile in DS exists out of withdrawn behavior, aggressive behavior, and attention problems. In DS patients, sleep disturbances (ß = 1.15, p < 0.001) and a lower age (ß = -0.21, p = 0.001) were significantly associated with behavioral difficulties. Between 2015 and 2022, behavioral difficulties significantly decreased with age (t = -2.24, CI = -6.10 - -0.15, p = 0.04) in DS participants aging from adolescence into adulthood. A decrease in intellectual functioning (ß = 3.37, p = 0.02) and using less antiseizure medications in 2022 than in 2015, (ß = -1.96, p = 0.04), were identified as possible risk factors for developing (more) behavioral difficulties. CONCLUSIONS: These findings suggest that, in addition to epilepsy, behavioral difficulties are a core feature of the DS phenotype. Behavioral problems require personalized management and treatment strategies. Further research is needed to identify effective interventions.

Psychiatric and neurological manifestations in adults with Smith-Magenis syndrome: A scoping review.

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by a 17p11.2 deletion or a pathogenic variant of the RAI1 gene, which lies within the 17p11.2 region. Various psychiatric and neurological disorders have been reported in SMS, with most literature focusing on children and adolescents. To provide an overview of the current knowledge on this topic in adults with SMS, we performed a comprehensive scoping review of the relevant literature. Our findings suggest that many manifestations that are common in childhood persist into adulthood. Neuropsychiatric manifestations in adults with SMS include intellectual disability, autism spectrum- and attention deficit hyperactivity disorder-related features, self-injurious and physical aggressive behaviors, sleep-wake disorders, and seizures. Findings of this review may facilitate optimization of management strategies in adults with SMS, and may guide future studies exploring late-onset psychiatric and neurological comorbidities in SMS.

Challenging behavior in children and adolescents with Dravet syndrome: Exploring the lived experiences of parents.

BACKGROUND: Dravet syndrome (DS) is a monogenic syndrome associated with SCN1A mutations in the majority of patients and characterized by devastating epilepsy, that may be life-threatening. Aside from refractory seizures, core symptoms of DS include behavioral difficulties, developmental delay, cognitive impairment, and motor dysfunction. Previous DS research has mainly focused on epileptic seizures and pharmacological management and less on behavioral difficulties. This study aims to explore the lived experience of parents supporting a child with DS, with a focus on behavioral aspects. METHODS: We performed a qualitative study using focus groups and following the consolidated criteria for reporting qualitative research (COREQ) guidelines. We organized three focus groups with parents of children and adults with DS and used a pre-defined topic list of open questions, similar for each focus group to ensure comparability. The focus groups were video recorded, transcribed, and anonymized. Data were analyzed using an iterative coding process where codes were sorted into themes. Differences in coding among the researchers were discussed until a consensus was reached. RESULTS: In total, twenty parents (mothers only) participated in the study. The age of children with DS ranged between 3 to 22 years with a mean age of 11.8 years. A range of behavioral difficulties emerged from the thematic analysis. Overall, the most commonly mentioned behavioral difficulties were aggression, dangerous behavior, impulsivity, hyperactivity, routinized and compulsive habits. Our results showed different behavior per age group, with more externalizing behaviors such as aggression and impulsivity in children aged 3-13 years; and more internalizing behavior such as routinized and compulsive habits in adolescents and young adults (14-22 years). This results in a different kind of support these families need and should be acknowledged when in consult with a healthcare professional. Parents reported that challenging behavior was a source of stress and impacted negatively on their family's quality of life. Parents reported feeling alone in their search for solutions, and many explored options outside the traditional medical context. CONCLUSION: Our results suggest that the challenging behavior associated with DS leads to a huge burden of care. Healthcare professionals working with DS patients may need to develop shared decision-making strategies that take into account challenging behavior.

Atypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins.

The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of >1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal 'allelic' homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2.

The ethics of polygenic scores in psychiatry: minefield or opportunity for patient-centered psychiatry?

Recent advancements in psychiatric genetics have sparked a lively debate on the opportunities and pitfalls of incorporating polygenic scores into clinical practice. Yet, several ethical concerns have been raised, casting doubt on whether further development and implementation of polygenic scores would be compatible with providing ethically responsible care. While these ethical issues warrant thoughtful consideration, it is equally important to recognize the unresolved need for guidance on heritability among patients and their families. Increasing the availability of genetic counseling services in psychiatry should be regarded as a first step toward meeting these needs. As a next step, future integration of novel genetic tools such as polygenic scores into genetic counseling may be a promising way to improve psychiatric counseling practice. By embedding the exploration of polygenic psychiatry into the supporting environment of genetic counseling, some of the previously identified ethical pitfalls may be prevented, and opportunities to bolster patient empowerment can be seized upon. To ensure an ethically responsible approach to psychiatric genetics, active collaboration with patients and their relatives is essential, accompanied by educational efforts to facilitate informed discussions between psychiatrists and patients.

Intellectual and Behavioral Phenotypes of Smith-Magenis Syndrome: Comparisons between Individuals with a 17p11.2 Deletion and Pathogenic RAI1 Variant.

AIM: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder caused by a 17p11.2 deletion or pathogenic variant in the RAI1 gene. SMS is associated with developmental delay, intellectual disability (ID), and major sleep and behavioral disturbances. To explore how genetic variants may affect intellectual functioning and behavior, we compared intellectual and behavioral phenotypes between individuals with a 17p11.2 deletion and pathogenic RAI1 variant. METHOD: We reviewed available clinical records from individuals (aged 0-45 years) with SMS, ascertained through a Dutch multidisciplinary SMS specialty clinic. RESULTS: We included a total of 66 individuals (n = 47, 71.2% with a 17p11.2 deletion and n = 19, 28.8% with a pathogenic RAI1 variant) for whom data were available on intellectual functioning, severity of ID (n = 53), and behavioral problems assessed with the Child Behavior Checklist (CBCL, n = 39). Median full-scale IQ scores were lower (56.0 vs. 73.5, p = 0.001) and the proportion of individuals with more severe ID was higher (p = 0.01) in the 17p11.2 deletion group. Median total CBCL 6-18 scores (73.5 vs. 66.0, p = 0.02) and scores on the sub-scales somatic complaints (68.0 vs. 57.0, p = 0.001), withdrawn/depressed behavior (69.5 vs. 55.0, p = 0.02), and internalizing behavior (66.0 vs. 55.0, p = 0.002) were higher in the RAI1 group. CONCLUSION: The results of this study suggest that 17p11.2 deletions are associated with a lower level of intellectual functioning and less internalizing of problems compared to pathogenic RAI1 variants. The findings of this study may contribute to personalized-management strategies in individuals with SMS.

Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review.

Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms. Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035). Results: The literature search yielded 208 reports for data-extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta-propeller protein-associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic-lysosomal and ubiquitin-proteasome system. Conclusion: Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism.

Vitamin D status in children with a psychiatric diagnosis, autism spectrum disorders, or internalizing disorders.

Background and objective: Multiple studies suggest that children with Autism Spectrum Disorders (ASD) have significantly lower vitamin D3 levels than typically developing children. However, whether vitamin D3 deficiency is more common in children with ASD than in children with other psychiatric disorders remains unclear. This study was conducted to explore the prevalence of vitamin D3 in children with a psychiatric diagnosis including children with ASD or with internalizing disorders (mood and anxiety disorders). In addition, this study investigated the potential associations between vitamin D3 and Body Mass Index (BMI). Materials and methods: Clinical data, including BMI and vitamin D3 levels, of 93 children (6-18 years; n = 47; 51% female) with ASD (n = 58) and internalizing disorders (n = 37) were retrospectively analyzed. Results: In the overall sample, the prevalence of vitamin D3 deficiency (<50 nmol/L) was 77.4%. Additionally, 75.9% of the children with ASD and 79.5% with internalizing disorders had vitamin D3 deficiency. BMI was inversely related to vitamin D3 in the total group (p = 0.016). The multiple regression model for the total group significantly predicted vitamin D3 (p = 0.022). Age contributed significantly to the prediction. Stratified for sex and primary diagnosis, multiple regression models showed that for boys with ASD, higher BMI levels were associated with lower vitamin D3 levels (p = 0.031); in boys with internalizing disorders and in girls, no relation was found between BMI and vitamin D3 levels. Conclusion: In this this cross-sectional, explorative study high rates of vitamin D3 deficiency in children with different psychiatric disorders were found. The results showed an inverse relation between BMI and vitamin D3 levels in the total group. Vitamin D3 deficiency was particularly common in boys with ASD and obesity. Lifestyle factors may contribute to the association between high BMI and low vitamin D3 levels in boys with ASD. Vitamin D3 deficiency is common in patients with psychiatric disorders and it is highly recommended to increase clinicians' awareness of this common and remediable risk factor.

Untargeted metabolic analysis in dried blood spots reveals metabolic signature in 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with increased risk of neurodevelopmental phenotypes including autism spectrum disorders (ASD) and intellectual impairment. The typically deleted region in 22q11.2DS contains multiple genes with the potential of altering metabolism. Deficits in metabolic processes during early brain development may help explain the increased prevalence of neurodevelopmental phenotypes seen in 22q11.2DS. However, relatively little is known about the metabolic impact of the 22q11.2 deletion, while such insight may lead to increased understanding of the etiology. We performed untargeted metabolic analysis in a large sample of dried blood spots derived from 49 22q11.2DS patients and 87 controls, to identify a metabolic signature for 22q11.2DS. We also examined trait-specific metabolomic patterns within 22q11.2DS patients, focusing on intelligence (intelligence quotient, IQ) and ASD. We used the Boruta algorithm to select metabolites distinguishing patients from controls, patients with ASD from patients without, and patients with an IQ score in the lowest range from patients with an IQ score in the highest range. The relevance of the selected metabolites was visualized with principal component score plots, after which random forest analysis and logistic regression were used to measure predictive performance of the selected metabolites. Analysis yielded a distinct metabolic signature for 22q11.2DS as compared to controls, and trait-specific (IQ and ASD) metabolomic patterns within 22q11.2DS patients. The metabolic characteristics of 22q11.2DS provide insights in biological mechanisms underlying the neurodevelopmental phenotype and may ultimately aid in identifying novel therapeutic targets for patients with developmental disorders.

A normative chart for cognitive development in a genetically selected population.

Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.

COMT Val(158) met genotype and striatal D(2/3) receptor binding in adults with 22q11 deletion syndrome.

Although catechol-O-methyltransferase (COMT) activity evidently affects dopamine function in prefrontal cortex, the contribution is assumed less significant in striatum. We studied whether a functional polymorphism in the COMT gene (Val(158) Met) influences striatal D(2/3) R binding ratios (D(2/3) R BP(ND) ) in 15 adults with 22q11 deletion syndrome and hemizygous for this gene, using single photon emission computed tomography and the selective D(2/3) radioligand [(123) I]IBZM. Met hemizygotes had significantly lower mean D(2/3) R BPND than Val hemizygotes. These preliminary data suggest that low COMT activity may affect dopamine levels in striatum in humans and this may have implications for understanding the contribution of COMT activity to psychiatric disorders.

Neurobiological perspective of 22q11.2 deletion syndrome.

22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson's disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders.1 Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised.2 Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain.3-5 Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype.3,5 In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population.

Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings.

BACKGROUND: The dystrobrevin-binding protein 1 (DTNBP1) gene is a susceptibility gene for schizophrenia. There is growing evidence that DTNPB1 contributes to intelligence and cognition. In this study, we investigated association between single nucleotide polymorphisms (SNPs) in the DTNBP1 gene and intellectual functioning in patients with a first episode of schizophrenia or related psychotic disorder (first-episode psychosis, FEP), their healthy siblings, and unrelated controls. METHODS: From all subjects IQ measurements were obtained (verbal IQ [VIQ], performance IQ [PIQ], and full scale IQ [FSIQ]). Seven SNPs in the DTNBP1 gene were genotyped using single base primer extension and analyzed by matrix-assisted laser deionization mass spectrometry (MALDI-TOF). RESULTS: Mean VIQ, PIQ, and FSIQ scores differed significantly (p < 0.001) between patients, siblings, and controls. Using a family-based and a case-control design, several single SNPs were significantly associated with IQ scores in patients, siblings, and controls. CONCLUSION: Although preliminary, our results provide evidence for association between the DTNBP1 gene and intelligence in patients with FEP and their unaffected siblings. Genetic variation in the DTNBP1 gene may increase schizophrenia susceptibility by affecting intellectual functioning.

The effect of Ecstasy on memory is moderated by a functional polymorphism in the cathechol-O-methyltransferase (COMT) gene.

There is ample evidence for decreased verbal memory in heavy Ecstasy users. However, findings on the presence of a dose-response relation are inconsistent, possibly due to individual differences in genetic vulnerability. Catechol-O-methyltransferase (COMT) is involved in the catabolism of Ecstasy. Therefore, COMT gene polymorphisms may moderate this vulnerability. We prospectively assessed verbal memory in subjects with a high risk for future Ecstasy use, and compared 59 subjects after first Ecstasy use with 60 subjects that remained Ecstasy-naive. In addition, we tested the interaction effect of Ecstasy and the functional val (158)met polymorphism on verbal memory. Met-allele carriers were somewhat more sensitive to the effects of Ecstasy on verbal learning than homozygous val-subjects. After correction for the use of other substances this effect was no longer statistically significant. The findings suggest that the COMT gene moderates the negative effect of Ecstasy on memory, but also other drug use seems to play a role.

AMPT-induced monoamine depletion in humans: evaluation of two alternative [123I]IBZM SPECT procedures.

PURPOSE: Acute monoamine depletion paradigms using alpha-methyl-para-tyrosine (AMPT) combined with single photon emission computed tomography (SPECT) have been used successfully to evaluate disturbances in central dopaminergic neurotransmission. However, severe side effects due to relatively high doses (4,500 to 8,000 mg) of AMPT have been reasons for study withdrawal. Thus, we assessed the effectiveness and tolerability of two alternative procedures, using lower doses of AMPT. METHODS: Six healthy subjects underwent three measurements of striatal dopamine D(2) receptor (D(2)R)-binding potential (BP(ND)) with SPECT and the selective radiolabeled D(2)R antagonist [(123)I]IBZM. All subjects were scanned in the absence of pharmacological intervention (baseline) and after two different depletion procedures. In the first depletion session, over 6 h, subjects were administered 1,500 mg of AMPT before scanning. In the second depletion session, over 25 h, subjects were administered 40 mg AMPT/kg body weight. We also administered the Subjective Well-being Under Neuroleptic Treatment Scale, a self-report instrument designed to measure the subjective experience of patients on neuroleptic medication. RESULTS: We found no change of mean D(2)R BP(ND) after the first and short AMPT challenge compared to the baseline. However, we found a significant increase in striatal D(2)R BP(ND) binding after the AMPT challenge adjusted for bodyweight compared to both other regimen. Although subjective well-being worsened after the prolonged AMPT challenge, no severe side effects were reported. CONCLUSIONS: Our results imply a low-dosage, suitable alternative to the common AMPT procedure. The probability of side effects and study withdrawal can be reduced by this procedure.