Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies.

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes (KCNC2, STXBP6, DHRS9) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs.

STXBP6 Gene Mutation: A New Form of SNAREopathy Leads to Developmental Epileptic Encephalopathy.

Syntaxin-binding protein 6 (STXBP6), also known as amysin, is an essential component of the SNAP receptor (SNARE) complex and plays a crucial role in neuronal vesicle trafficking. Mutations in genes encoding SNARE proteins are often associated with a broad spectrum of neurological conditions defined as "SNAREopathies", including epilepsy, intellectual disability, and neurodevelopmental disorders such as autism spectrum disorders. The present whole exome sequencing (WES) study describes, for the first time, the occurrence of developmental epileptic encephalopathy and autism spectrum disorders as a result of a de novo deletion within the STXBP6 gene. The truncated protein in the STXBP6 gene leading to a premature stop codon could negatively modulate the synaptic vesicles' exocytosis. Our research aimed to elucidate a plausible, robust correlation between STXBP6 gene deletion and the manifestation of developmental epileptic encephalopathy.

Specific Learning Disorders: Variation Analysis of 15 Candidate Genes in 9 Multiplex Families.

Background and Objectives: Specific Learning Disorder (SLD) is a complex neurobiological disorder characterized by a persistent difficult in reading (dyslexia), written expression (dysgraphia), and mathematics (dyscalculia). The hereditary and genetic component is one of the underlying causes of SLD, but the relationship between genes and the environment should be considered. Several genetic studies were performed in different populations to identify causative genes. Materials and Methods: Here, we show the analysis of 9 multiplex families with at least 2 individuals diagnosed with SLD per family, with a total of 37 persons, 21 of whom are young subjects with SLD, by means of Next-Generation Sequencing (NGS) to identify possible causative mutations in a panel of 15 candidate genes: CCPG1, CYP19A1, DCDC2, DGKI, DIP2A, DYM, GCFC2, KIAA0319, MC5R, MRPL19, NEDD4L, PCNT, PRMT2, ROBO1, and S100B. Results: We detected, in eight families out nine, SNP variants in the DGKI, DIP2A, KIAA0319, and PCNT genes, even if in silico analysis did not show any causative effect on this behavioral condition. In all cases, the mutation was transmitted by one of the two parents, thus excluding the case of de novo mutation. Moreover, the parent carrying the allelic variant transmitted to the children, in six out of seven families, reports language difficulties. Conclusions: Although the present results cannot be considered conclusive due to the limited sample size, the identification of genetic variants in the above genes can provide input for further research on the same, as well as on other genes/mutations, to better understand the genetic basis of this disorder, and from this perspective, to better understand also the neuropsychological and social aspects connected to this disorder, which affects an increasing number of young people.

Migraine and handedness.

Migraine is a typically unilateral disorder in adulthood; however, the reasons for painful lateralization have been little investigated. The possible influence of manual dominance was suggested. We aimed to investigate the localization of pain in migraine attacks in right-handed and left-handed subjects. The retrospective study collected 546 patients with migraine aged between 16 and 65 years, reporting the manual dominance to the Edinburgh test. We included 466 right-handed and 80 left-handed subjects with migraine. We registered 4215 unilateral painful attacks. The right-handers had 3412 unilateral episodes; 62.8% of the attacks were characterized by pain on the right side and 37.2% by pain on the left. The left-handed subjects reported 803 unilateral pain with 63.5% of unilateral pain episodes on the left side and 36.5% of attacks with lateralized pain on the right (p < 0.001). Our data suggest that manual dominance may influence the side of pain lateralization in migraine.

Prader-Willi Syndrome with Angelman Syndrome in the Offspring.

We report the second case, to the best of our knowledge, of a mother with Prader-Willi syndrome (PWS) who gave birth to a daughter with Angelman syndrome (AS). The menarche occurred when she was 16, and the following menstrual cycles were irregular, but she never took sexual hormone replacement therapy. At the age of 26, our patient with PWS became pregnant. The diagnosis was confirmed by molecular genetic testing that revealed a ~5.7 Mb deletion in the 15q11.1-15q13 region on the paternal allele in the mother with PWS and the maternal one in the daughter with AS, respectively. Both the mother with PWS and the daughter with AS showed peculiar clinical and genetic features of the two syndromes. Our case report reaffirms the possible fertility in PWS; therefore, it is very important to develop appropriate socio-sexual education programs and fertility assessments in order to guarantee the expression of a healthy sexuality.

Reading-writing disorder in children with idiopathic epilepsy.

Several studies have documented learning disabilities (LDs) in subjects with epilepsy, who have been shown to be at greater risk of mild neuropsychological damage, with the consequent risk of academic failure. This retrospective study aimed to investigate the peculiarities of reading and writing disorders in subjects with idiopathic epilepsy. The reading and writing performance of 35 children affected by reading and writing disorders and idiopathic epilepsy (R/WD + E group) has been compared with the performance of 37 children with only reading and writing disorders (R/WD group). A comparison group of 22 typical developing healthy children (TDC group) was also included in the study. As expected, the TDC group reached better performances in the reading and writing tests administered. Between R/WD + E and R/WD groups, there was a substantial analogy in reading and writing disabilities. The differences between the two clinical groups concern writing ability in sentences dictation and verbal and visuospatial short-term memory in digit span and memory-for-location (MFL) tests.

On the Playing Field to Improve: A Goal for Autism.

In recent years, there has been a renewed attention to lifestyle-based interventions in people with autism spectrum disorder. The positive effects of physical exercise programs have been well documented both in healthy people and in people with disabilities in the fields of psychological well-being, cognitive outcome and medical health. There is much less evidence about the opportunity to attempt a team-group sport for people with autism. Although researchers seem to suggest an overall positive effect, playing team sports for people with autism spectrum disorder (ASD) means dealing with difficulties in social interactions and limitations in motor functions. This narrative review aims to report studies about the effects, improvements and difficulties that people with autism have to face when they play the world's most popular team sport: soccer.

Are Mutations in the DHRS9 Gene Causally Linked to Epilepsy? A Case Report.

The DHRS9 gene is involved in several pathways including the synthesis of allopregnanolone from progesterone. Allopregnanolone is a positive modulator of gamma aminobutyric acid (GABA) action and plays a role in the control of neuronal excitability and seizures. Whole-exome sequencing performed on a girl with an early onset epilepsy revealed that she was a compound heterozygote for two novel missense mutations of the DHRS9 gene likely to disrupt protein function. No previous studies have reported the implication of this gene in epilepsy. We discuss a new potential pathogenic mechanism underlying epilepsy in a child, due to a defective progesterone pathway.

Emotional-Behavioral Disorders in Healthy Siblings of Children with Neurodevelopmental Disorders.

Background and Objectives: Siblings of disabled children are more at risk of developing mental illnesses. More than 50 international studies show that about 8% of children and adolescents suffer from a mental disorder, which is almost always a source of difficulties both at the interpersonal level (in the family and with peers) and at school. Healthy siblings of children with disabilities are one of the groups most at risk for consequences in psychological health and well-being. As some authors suggest, siblings build their idea of "being people", in terms of character and personality, by continuously and daily confronting themselves with the theme of disability and a family context subjected to continuous stress. The following contribution aims to compare emotional-behavioral disorders in healthy siblings of children with autism spectrum disorder, in healthy siblings of children with Down's syndrome and in healthy siblings of children with typical development. Materials and Methods: The results involve 153 children from the region of Campania and their caregivers through the administration of the Strength and Difficulties Questionnaire. Results: From the data, it emerged that siblings of children with autism spectrum disorder and siblings of children with Down's syndrome have a greater emotional fragility, especially among male subjects. Conclusions: Our results require us to reflect on the clinical and policy measures needed to ensure the well-being of siblings of disabled children, mainly through appropriate sibling coping training.

Electroencephalographic Abnormalities in Autism Spectrum Disorder: Characteristics and Therapeutic Implications.

A large body of literature reports the higher prevalence of epilepsy in subjects with Autism Spectrum Disorder (ASD) compared to the general population. Similarly, several studies report an increased rate of Subclinical Electroencephalographic Abnormalities (SEAs) in seizure-free patients with ASD rather than healthy controls, although with varying percentages. SEAs include both several epileptiform discharges and different non-epileptiform electroencephalographic abnormalities. They are more frequently associated with lower intellectual functioning, more serious dysfunctional behaviors, and they are often sign of severer forms of autism. However, SEAs clinical implications remain controversial, and they could represent an epiphenomenon of the neurochemical alterations of autism etiology. This paper provides an overview of the major research findings with two main purposes: to better delineate the state-of-the-art about EEG abnormalities in ASD and to find evidence for or against appropriateness of SEAs pharmacological treatment in ASD.

Oral Health and Quality of Life in People with Autism Spectrum Disorder.

This article delves into the intricate relationship between oral health, quality of life, and behavioral characteristics in individuals with autism spectrum disorder (ASD). Background/Objectives: Autism has been associated with various challenges, and this study seeks to elucidate the impact of ASD on oral health outcomes and overall well-being. The research focuses on assessing overall oral health by evaluating various parameters, such as the condition of lips, tongue, gums and tissues, natural teeth, dentures, oral hygiene, and dental pain in individuals with ASD. Additionally, the study explores the influence of age, sex, and certain variables, like basic daily living skills on oral health practices, aiming to identify potential correlations between these factors and oral health outcomes. Methods: We employed standardized instruments to quantitatively measure and analyze the impact of oral health status on the overall quality of life experienced by individuals with ASD. Results: The study found a statistically significant positive association between oral health, measured by the Oral Health Assessment Tool (OHAT), and quality of life, as indicated by EuroQol 5-Dimensions Youth version (EQ-5D-Y) total scores (ß = 0.13045, p = 0.00271). This suggests that better oral health is linked to higher quality of life. When adjusting for age and sex in a multiple linear regression model, the association remained significant but with a slightly reduced effect size (ß = 0.10536, p = 0.0167). Age also showed a marginally significant positive association with quality-of-life scores. ANOVA results indicated that participants with advanced oral health status reported significantly higher quality-of-life scores than those with poorer oral health (p = 0.00246). The study also found that intelligence quotient (IQ) does not substantially influence dental health status, while the "Autonomy" subscale of the EQ-5D-Y is positively related to the OHAT. Conclusions: Unhealthy oral conditions significantly impact the overall quality of life in individuals with ASD. Therefore, it is crucial to include regular dental assessments and treatments in therapeutic protocols for patients with ASD.

Neurodevelopmental Disorders and Suicide: A Narrative Review.

Specific risk factors for self-harm and suicide in children and adolescents with neurodevelopmental disorders (NDD) may differ from those in the general population within this age range. In the present review paper, we conducted a narrative analysis of the literature, aiming to establish a connection between suicide and affective disorders in children and adolescents with NDD. Emotion dysregulation (ED) as an individual factor and adverse childhood experiences (ACE) as environmental factors are discussed as risk factors for suicidality in all individuals with NDD. We propose a theoretical model in which ED and ACE can directly lead to self-harm or suicide, directly or indirectly by interacting with depressive spectrum disorders. Additionally, we suggest that specific risk factors are more frequently associated with each of the neurodevelopmental disorders listed in the DSM-V. This review underlines the key points useful to improve the knowledge of the trajectory leading to suicide risk in NDDs with the purpose to facilitate the early identification of the suicide risk.

PLEKHG1: New Potential Candidate Gene for Periventricular White Matter Abnormalities.

Hypoxic-ischemic brain damage presents a significant neurological challenge, often manifesting during the perinatal period. Specifically, periventricular leukomalacia (PVL) is emerging as a notable contributor to cerebral palsy and intellectual disabilities. It compromises cerebral microcirculation, resulting in insufficient oxygen or blood flow to the periventricular region of the brain. As widely documented, these pathological conditions can be caused by several factors encompassing preterm birth (4-5% of the total cases), as well single cotwin abortion and genetic variants such as those associated with GTPase pathways. Whole exome sequencing (WES) analysis identified a de novo causative variant within the pleckstrin homology domain-containing family G member 1 (PLEKHG1) gene in a patient presenting with PVL. The PLEKHG1 gene is ubiquitously expressed, showing high expression patterns in brain tissues. PLEKHG1 is part of a family of Rho guanine nucleotide exchange factors, and the protein is essential for cell division control protein 42 (CDC42) activation in the GTPase pathway. CDC42 is a key small GTPase of the Rho-subfamily, regulating various cellular functions such as cell morphology, migration, endocytosis, and cell cycle progression. The molecular mechanism involving PLEKHG1 and CDC42 has an intriguing role in the reorientation of cells in the vascular endothelium, thus suggesting that disruption responses to mechanical stress in endothelial cells may be involved in the formation of white matter lesions. Significantly, CDC42 association with white matter abnormalities is underscored by its MIM phenotype number. In contrast, although PLEKHG1 has been recently associated with patients showing white matter hyperintensities, it currently lacks a MIM phenotype number. Additionally, in silico analyses classified the identified variant as pathogenic. Although the patient was born prematurely and subsequently to dichorionic gestation, during which its cotwin died, we suggest that the variant described can strongly contribute to PVL. The aim of the current study is to establish a plausible association between the PLEKHG1 gene and PVL.

On the Waves of the COVID-19 Pandemic.

The COVID-19 pandemic has been a tsunami that has deeply changed the lives of the people all over the planet [...].

Use and Abuse of Digital Devices: Influencing Factors of Child and Adolescent Neuropsychology.

The impact of technology on human life is significant, touching various aspects such as communication, economy, education, medicine, industry, and even ecosystems [...].

The Complex Association between Sleep Quality, Psychological Wellbeing, and Neurodevelopmental Disorders in Childhood.

During child development, the psychophysiological state is influenced by factors such as family routine, school experiences, stressful life events, or, in general, the environmental context in which the child grows up [...].

Epilepsy: A Multifaced Spectrum Disorder.

Epilepsy is one of the most widespread chronic conditions, affecting about 50 million people worldwide [...].

Poor School Academic Performance and Benign Epilepsy with Centro-Temporal Spikes.

BACKGROUND: Poor academic performance of students with epilepsy seems to be a multifactorial problem related to difficulties in reading, writing, math, and logic skills. Poor school and academic performances refer to learning problems in a specific academic area due to learning disorders and learning difficulties not excluding the ability to learn in a different manner during school and academic life. Sometimes, school, academic difficulties, and Rolandic epilepsy can coexist together, and there may be comorbidities. Consequently, the risk of impaired academic performance in people with epilepsy is high. METHODS: This review analyzed the relationship between Benign Epilepsy with Centro-Temporal Spikes (BECTS) and poor school and academic performance (PSAP) in children and adolescents (aged 6 to 19), and in adults (aged 20 to no age limit). The PRISMA guideline was used to guide our review strategy. RESULTS: This research shows that Benign Epilepsy with Centro-Temporal Spikes (BECTS) and poor school and academic performances are strongly correlated. An early onset age, as well as a long persistence of seizures, correlate more closely with PSAP. On the other hand, it appears that good pharmacological control of seizures and remission from the acute phase of the pathology support better school performance. CONCLUSIONS: This review highlights how neuropsychological aspects are also involved in patients with BECTS and PSAP, both in the greater predisposition to the establishment of other neuropsychiatric conditions and in the possibility that stigma conditions and poor academic results may have repercussions on the adaptation and functioning of these subjects. Global management of the subject with BECTS and PSAP is essential, which also pays attention to the aspects of social and scholastic inclusion, both to achieve age-appropriate educational and behavioral objectives, to give the necessary tools for the growth of the individual, and to allow a serene transition to adulthood, favoring autonomous learning and better outcomes.

Diet-Related Attitudes, Beliefs, and Well-Being in Adolescents with a Vegetarian Lifestyle.

Vegetarianism can meet healthy, ethical, or ecological values (such as equality and protection of animals or the environment). At the same time, it can represent a response to the need for self-determination in adolescence. Furthermore, some studies show vegetarians have greater depressive risk and a lower sense of body satisfaction. Considering the spread of non-meat diets in the Western world, researchers have investigated the benefits and risks to physical and psychological health. Despite this, few studies have been conducted on factors influencing adolescent's vegetarian diet-related attitudes. Through self-administered loosely structured interviews, this research investigated factors potentially associated with vegetarian choices in adolescence. It checked (a) gender differences in vegetarian choices; (b) religious, familial, ethical, or health factors implied in vegetarian choices; and (c) indicators of well-being among young vegetarians. The findings suggest that for our sample, non-vegetarians have lower scores on health-related questions than others, while for vegetarian adolescents, the benefits of vegetarianism mainly depend on their ethical stances, beliefs, and values. Conversely, it is unrelated to factors such as the desire to lose weight, dissatisfaction about one's body shape, or depressive feelings.