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Anna Guerrini Usubini,1,2 Grazia Terrone,3 Giorgia Varallo,1,2 Roberto Cattivelli,4 Giuseppe Plazzi,5,6 Gianluca Castelnuovo,1,2 Adriano Schimmenti,7 Alessandro Musetti,8 Christian Franceschini9 1Istituto Auxologico Italiano IRCCS, Psychology Research Laboratory, Milan, Italy; 2Department of Psychology, Catholic University of Milan, Milan, Italy; 3Department of History, Cultural Heritage, Education and Society, University of Rome Tor Vergata, Rome, Italy; 4Department of Psychology, University of Bologna, Bologna, 40127, Italy; 5Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy; 6IRCCS Institute of Neurological Sciences of Bologna (ISNB), Bologna, 40139, Italy; 7Faculty of Human and Social Sciences, UKE—Kore University of Enna, Cittadella Universitaria, Enna, Italy; 8Department of Humanities, Social Sciences and Cultural Industries, University of Parma, Parma, Italy; 9Department of Medicine and Surgery, University of Parma, Parma, ItalyCorrespondence: Alessandro Musetti, Department of Humanities, Social Sciences and Cultural Industries, University of Parma, Borgo Carissimi 10, Parma, 43121, Italy, Tel +39 0521 034820, Email alessandro.musetti@unipr.itPurpose: The present study aimed to explore the mediating role of emotion dysregulation and problematic Internet use in the relationship between negative affect and excessive daytime sleepiness.Methods: This cross-sectional study included 664 Italian adults aged between 18 and 70 years (M = 32.13; SD = 11.71). Participants were asked to complete the Depression Anxiety Stress Scale, the Difficulties in Emotion Regulation Scale, the Compulsive Internet Use Scale-7, and the Epworth Sleepiness Scale to assess negative affect, emotion dysregulation, problematic internet use, and excessive daytime sleepiness, respectively.Results: According to our results there are significant associations between negative affect, emotion dysregulation, problematic Internet use, and daytime sleepiness. Moreover, the structural equation model showed good fit indices. Emotion dysregulation and problematic Internet use partially mediated the relationship between negative mood and excessive daytime sleepiness.Conclusion: By exploring the role of emotion dysregulation on the association between excessive daytime sleepiness and its possible predictors, our study might represent an important step toward the implementation of psychological intervention for reducing excessive daytime sleepiness. Emotion dysregulation appears to play a significant role in explaining the relationship between negative affect, problematic Internet use, and excessive daytime sleepiness. Thus, it should be considered a treatment target for reducing excessive daytime sleepiness.Keywords: negative affect, psychological distress, excessive daytime sleepiness, emotion dysregulation, problematic Internet use

Alessandro Musetti,1,* Alessio Gori,2,* Alessia Alessandra,3 Eleonora Topino,4 Grazia Terrone,5 Giuseppe Plazzi,6,7 Marco Cacioppo,4 Christian Franceschini3 1Department of Humanities, Social Sciences and Cultural Industries, University of Parma, Parma, Italy; 2Department of Health Sciences, University of Florence, Florence, Italy; 3Department of Medicine and Surgery, University of Parma, Parma, Italy; 4Department of Human Sciences, Lumsa University of Rome, Rome, Italy; 5Department of History, Cultural Heritage, Education and Society, University of Rome Tor Vergata, Rome, Italy; 6Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; 7IRCCS Institute of Neurological Sciences of Bologna (ISNB), Bologna, Italy*These authors contributed equally to this workCorrespondence: Alessandro MusettiDepartment of Humanities, Social Sciences and Cultural Industries, University of Parma, Borgo Carissimi 10, Parma, 43121, Italy, Tel +39 0521 034820, Email alessandro.musetti@unipr.itPurpose: Although a link between problematic online pornographic use (POPU) and insomnia symptoms has been established, psychological and psychopathological mechanisms underlying this relationship are still not clear. Psychological stress and emotion dysregulation have been pointed out as relevant in the development and maintenance of insomnia. This study aims to explore the associations between POPU, psychological stress, emotion dysregulation and insomnia symptoms and to understand the mediating role of psychological stress and emotion dysregulation in the relationship between POPU and insomnia symptoms.Participants and Methods: A sample of 776 Italian adults aged 19– 48 years (51.4% female; M age = 28.49; SD = 7.33) completed questionnaires regarding demographics, COVID-19-related variables, POPU, psychological stress, emotion dysregulation, and insomnia symptoms.Results: After controlling for demographic covariates and COVID-19-related variables, multiple mediation model showed that higher psychological stress and emotion dysregulation fully mediated the link between POPU and insomnia.Conclusion: The findings underscore the significance of the negative consequences of POPU and underline the importance of working on this and its effects on psychological stress and emotion dysregulation to limit insomnia.Keywords: addictive behaviors, online pornography, problematic online pornographic use, stress, emotion dysregulation, clinical psychology, insomnia

Background: Questionnaires for the screening of paternal perinatal psychological distress are based on clinical manifestations expressed by women, showing limitations in capturing the wide array of signs and symptoms exhibited by men. The current study aimed to validate the Perinatal Assessment of Paternal Affectivity, a new self-report tool for the screening of paternal depressive and affective disorder.Method: This study used a cross-sectional design with a 3-month test-retest, involving respectively 385 (T1) and a sub-sample of 111(T2) fathers. Confirmatory factor analysis (CFA) was performed to test structural validity and concurrent validity was assessed by Spearman correlations. We assessed reliability using McDonald's ω and ordinal alpha. Group differences in PAPA scores based on sociodemographic were also tested.Results: The CFA reported a one factor structure as the optimal solution. The PAPA also showed adequate reliability and internal consistency as well as acceptable test-retest indices. Concurrent validity was confirmed by significant correlations between PAPA total score and standardized test scores. Non-Italian fathers and fathers who experienced recent stressful life events reported higher PAPA scores.Limitations: Our sample was not homogeneous in terms of nationality and most of the participants, were from Northern Italy. Some risk factors associated with paternal parental psychological distress (e.g., unplanned pregnancy) have not been considered.Conclusion: This study provides initial evidence of validity and reliability of the PAPA as a brief and sensitive screening tool to detect signs and symptoms of paternal affective disorder during both prenatal and postnatal period. [ABSTRACT FROM AUTHOR]

Background: Prenatal attachment refers to the affective investment that parents develop towards their unborn baby during pregnancy. Studies have identified depressive symptoms, affect dysregulation, and poor marital adjustment as potential risk factors for poor prenatal attachment. However, no research has concurrently examined these factors. This study aims to explore the simultaneous impact of depressive symptomatology, alexithymia, and couple functioning on prenatal attachment to develop a more comprehensive understanding of the factors shaping the emotional bond between expectant mothers and their fetuses., Methods: This cross-sectional study involved 344 women (mean age = 34.1, SD = 4.6) in their last trimester of pregnancy recruited from the National Health System. The participants completed the Edinburgh Postnatal Depression Scale, the Twenty-Item Toronto Alexithymia Scale, the Dyadic Adjustment Scale, and the Maternal Antenatal Attachment Scale., Results: Regression analyses indicated that perinatal depression and alexithymia negatively affected the Quality of Prenatal Attachment, while Dyadic Cohesion served as a protective factor., Conclusions: The results emphasize the need for early identification of perinatal depression and alexithymia, along with targeted interventions aimed at supporting Dyadic Cohesion during pregnancy. These efforts are crucial for fostering positive prenatal attachment and enhancing maternal mental health.

Background: Epilepsy is a hallmark of IQSEC2-related encephalopathy within a phenotypic variability ranging between early onset epileptic and developmental encephalopathy and X-linked intellectual disability with epilepsy., Patients and Methods: Data including demographic aspects, gene variants, seizure semiology and timing, EEG features, neuroimaging and response to therapy were retrospectively collected in patients with IQSEC2-related epilepsy referring to 8 Italian tertiary centres., Results: The reported cohort included 11 patients (8 males and 3 females). Mean age at the onset of epilepsy was 3.90±2.80 years. No cases were reported in the first year of life. No specific epileptic syndromes were recognized. Predominant seizure-types in the age range 12-36 months included focal onset tonic seizures with impaired awareness, myoclonic seizures, and late onset spasms. Generalized motor seizures were predominant in patients between 3 and 6 years and between 12 and 18 years while focal motor seizures with impaired awareness were the most represented types between 6 and 12 years. No patients experienced status epilepticus. EEG patterns included a delayed maturation of EEG organization, irregular focal or diffuse slow activity, multifocal or diffuse epileptiform abnormalities. No structural epileptogenic lesions were detected at MRI. Valproate, lamotrigine, clobazam, topiramate and levetiracetam were the most used antiseizure medication. Complete seizure freedom was achieved only in 2 patients., Conclusions: Onset of epilepsy after the first year of age, predominance of focal seizures with impaired awareness and generalized motor seizures, no pathognomonic underlying epileptic syndrome and infrequent occurrence of status epilepticus emerged as the main features of IQSEC2-related epilepsy phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The COVID-19 pandemic has exacerbated fears and anxieties, potentially influencing maternal perinatal mental health. This study addresses a gap in the literature on fear of COVID-19 in pregnant women, aiming to identify contributing factors., Method: Participants were 401 primiparous women with an average age of 34 years (SD = 4.56) who were recruited through the National Health System during birth support courses. They completed a series of self-reported instruments via an online survey, providing information on their levels of reflective functioning, dyadic consensus, perinatal maternal affectivity, and fear of COVID-19. Pearson's correlation and mediation analysis via a generalized linear model were implemented to analyze the collected data., Results: The relationship between dyadic consensus and fear of COVID-19 was significant and negative. Furthermore, a significant parallel mediation involving perinatal maternal affectivity and reflective functioning was found to the extent that, when these factors were inserted into the model, the direct association between dyadic consensus and fear of COVID-19 became non-significant (total mediation)., Conclusions: The results highlight the importance of dyadic adjustment in alleviating maternal COVID-19 fear, emphasizing interventions promoting couple functioning, mentalization, and addressing affective difficulties. Such approaches are vital for supporting expecting mothers during challenging times like the COVID-19 pandemic.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date ( PCDH19 -related DEE, CDKL5 -related DEE, MECP2 -related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX , DCX , FLNA ) and DEEs associated with recently recognized genes (e.g., SLC9A6 , SLC35A2 , SYN1 , ARHGEF9 , ATP6AP2 , IQSEC2 , NEXMIF , PIGA , ALG13 , FGF13 , GRIA3 , SMC1A ). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype-phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder characterized by benign tumor growth in multiple organs, including the brain, kidneys, heart, eyes, lungs, and skin. Pathogenesis stems from mutations in either the TSC1 or TSC2 gene, which encode the proteins hamartin and tuberin, respectively. These proteins form a complex that inhibits the mTOR pathway, a critical regulator of cell growth and proliferation. Disruption of the tuberin-hamartin complex leads to overactivation of mTOR signaling and uncontrolled cell growth, resulting in hamartoma formation. Neurological manifestations are common in TSC, with epilepsy developing in up to 90% of patients. Seizures tend to be refractory to medical treatment with anti-seizure medications. Infantile spasms and focal seizures are the predominant seizure types, often arising in early childhood. Drug-resistant epilepsy contributes significantly to morbidity and mortality. This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, clinical manifestations, and treatment approaches for epilepsy and other neurological features of TSC. While narrative reviews on TSC exist, this review uniquely synthesizes key advancements across the areas of TSC neuropathology, conventional and emerging pharmacological therapies, and targeted treatments. The review is narrative in nature, without any date restrictions, and summarizes the most relevant literature on the neurological aspects and management of TSC. By consolidating the current understanding of TSC neurobiology and evidence-based treatment strategies, this review provides an invaluable reference that highlights progress made while also emphasizing areas requiring further research to optimize care and outcomes for TSC patients.

Objective: The COVID-19 pandemic has contributed to the occurrence of psychological disturbances, such as depressive and anxiety symptomatology, thereby significantly impacting individuals' lifestyles by disrupting sleep patterns. This study aimed to elucidate the interconnections between emotion regulation, depression, anxiety, and daytime sleepiness., Method: We recruited 632 community adults who underwent an online survey of self-report questionnaires, including the Depression Anxiety Stress Scale (DASS-21), the Difficulties in Emotion Regulation Scale (DERS), and the Epworth Sleepiness Scale (ESS).A network analysis was performed to examine and visually represent the pattern of relationships between psychological distress, emotion regulation, and daytime sleepiness., Results: The DERS Strategy dimension showed high values across all centrality indices, indicating it as the most influential node in the network. In addition, the DASS Depression and DERS Goals dimensions exhibited high betweenness values, emerging as points of connection between the other nodes within the network structure., Conclusions: Our primary findings underscore the connection between psychological distress and emotion regulation, specifically between depressive symptoms, a lack of emotional clarity, and difficulty in the flexible use of emotional strategies. These specific constructs hold promising potential as valuable targets for both assessment and the development of effective interventions during highly challenging situations such as the COVID-19 pandemic., Competing Interests: Competing interests: None., (© 2023 Giovanni Fioriti Editore s.r.l.)

Purpose: HNRNPU haploinsufficiency is associated with developmental and epileptic encephalopathy 54. This neurodevelopmental disorder is characterized by developmental delay, intellectual disability, speech impairment, and early-onset epilepsy. We performed genome-wide DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnostic biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder., Methods: DNAm profiles of individuals carrying pathogenic HNRNPU variants, identified through an international multicenter collaboration, were assessed using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses were performed comparing the HNRNPU cohort with 56 previously reported DNAm episignatures., Results: A robust and reproducible DNAm episignature and global DNAm profile were identified. Correlation analysis identified partial overlap and similarity of the global HNRNPU DNAm profile to several other rare disorders., Conclusion: This study demonstrates new evidence of a specific and sensitive DNAm episignature associated with pathogenic heterozygous HNRNPU variants, establishing its utility as a clinical biomarker for the expansion of the EpiSign diagnostic test., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: In epileptic patients with motor disability, it's difficult to disentangle the effects of antiepileptic drugs (AEDs) on bone health from those provoked by impaired mobility. The aim of this study was to evaluate the effects of AEDs on bone mineral status by phalangeal quantitative ultrasound (QUS), a no-radiation and non-invasive method, in pediatric patients with motor impairment and epilepsy., Methods: We enrolled 56 patients (31 females, 25 males) with epilepsy and motor impairment and 24 children with only motor disability (13 females, 11 males). Patients were stratified by Gross Motor Function Classification System Scale (GMFCS) in 4 groups: group A1 with epilepsy and mild motor impairment (GMFCS levels I-II), group A2 with only mild motor impairment, group B1 with epilepsy and severe motor impairment (GMFCS levels III-V), group B2 with only severe motor impairment. The bone mineral status was evaluated by phalangeal QUS and amplitude-dependent speed of sound (AD-SoS) Z-score was calculated for each patient., Results: The four groups showed no significant differences in age, gender and 25-hydroxyvitamin D levels. The group B1 had a statistically lower amplitude-dependent speed of sound Z-score as compared to group A2 (P<0.05). The multivariate analysis of independent factors revealed a significant correlation between amplitude-dependent speed of sound Z-score and Gross Motor Function Classification System levels (P=0.004). The mean Z-score value decreased by 0.53, increasing the motor impairment., Conclusions: The bone mineral status measured as AD-SoS strongly correlates with severity of motor disability evaluated by GMFCS as compared to antiepileptic therapy and 25-hydroxyvitamin D levels.

Abstract: Accumulating evidence suggests that obsessive-compulsive symptoms (OCSs) are positively associated with exposure to traumatic experiences and dissociative symptoms in both clinical and community samples. The current study was aimed at investigating the relationships between traumatic experiences, dissociation, and OCSs. A sample of 333 community adults (56.8% females) aged from 18 to 56 years (mean [SD], 25.64 [6.70] years) completed measures on traumatic experiences, dissociative symptoms, and OCSs. A structural equation modeling (SEM) framework was used to test if dissociative symptoms mediated the relationship between traumatic experiences and OCSs. SEM analyses showed that dissociation fully mediated the predictive association between traumatic experiences of emotional neglect and abuse and OCSs in the sample. Accordingly, some individuals suffering from OCSs might benefit from clinical interventions aimed at processing and integrating traumatic experiences., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes., Methods: we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency., Results: molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy., Conclusions: our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.

Antenatal depression may be distinct from postpartum depression in terms of prevalence, severity of symptoms, comorbidities, prognosis, and risk factors. Although risk factors for perinatal depression have been identified, it is unclear whether there are differences in the onset of perinatal depression (PND). This study explored the characteristics of women requiring mental health support during pregnancy or postpartum. A sample of 170 women (58% in pregnancy; 42% postpartum) who contacted the SOS-MAMMA outpatient clinic was recruited. Clinical data sheets and self-report questionnaires (EPDS, LTE-Q, BIG FIVE; ECR; BSQ; STICSA) were administered, hypothesizing possible risk factors, such as personality traits, stressful life events, body dissatisfaction, attachment style, and anxiety. Hierarchical regression models were carried out in the pregnancy (F 10;36 = 8.075, p < 0.001, adjR2 = 0.877) and postpartum groups (F 10;38 = 3.082, p < 0.05, adjR2 = 0.809). Recent stressful life events and conscientiousness were associated with depression in both the pregnant (29.3%, 25.5% of variance) and postpartum groups (23.8%, 20.7% of variance). In pregnant women, "openness" (11.6%), body dissatisfaction (10.2%), and anxiety (7.1%) symptoms were predictive of depression. In the postpartum group, "neuroticism" (13.8%) and insecure romantic attachment dimensions (13.4%; 9.2%) were the strongest predictors. Perinatal psychological interventions should consider the differences between mothers with depression during pregnancy and postpartum.

Recently, empirical evidence from perinatal studies has led researchers to pay more attention to fathers. The need to evaluate male suffering led at first to using the same screening tools developed for mothers. However, these instruments present validity concerns with fathers, and today the need to assume a gender-based perspective is clear. The Perinatal Assessment of Paternal Affectivity (PAPA) is a self-reported questionnaire for the screening of a variety of psychological and behavioral dimensions related to affectivity as experienced by fathers during the perinatal period. In the present study, the psychometric properties of the maternal version of the scale (Perinatal Assessment of Maternal Affectivity; PAMA) were examined. The study, based on 225 mothers and their partners ( n = 215), used a cross-sectional design with a single assessment at the third trimester of pregnancy. Results indicated a one-factor structure for a seven-item version of the PAMA, which showed adequate internal consistency reliability and was associated in the expected direction with other clinically relevant variables (depression, psychological distress, perceived stress and dyadic adjustment). The findings suggest the usefulness of developing gender sensitive screening tools for the detection of perinatal affective disorders.

Neuromuscular disease (NMDs) encompass a heterogeneous group of genetic disorders, with respiratory problems of variable intensity and progression described at any pediatric age, from infancy to adolescence, and they are largely associated with significant lifelong morbidity and high mortality. Restriction of breathing, impaired gas exchange, decline of lung function and sleep disordered breathing progressively develop because of muscular weakness and culminate in respiratory failure. Depending on the disease progression, airways manifestations can take weeks to months or even years to evolve, thus depicting two major respiratory phenotypes, characterized by rapid or slow progression to respiratory failure. Assessing type and age at onset of airways problems and their evolution over time can support pediatricians in the diagnostic assessment of NMD. In addition, knowing the characteristics of patients' respiratory phenotype can increase the level of awareness among neonatologists, geneticists, neurologists, pulmonologists, nutritionists, and chest therapists, supporting them in the challenging task of the multidisciplinary medical care of patients. In this review we examine the issues related to the pediatric respiratory phenotypes of NMD and present a novel algorithm that can act as a guide for the diagnostic agenda and the key preventive or therapeutic interventions of airways manifestations. With prolonged survival of children with NMD, the advent of neuromuscular respiratory medicine, including accurate assessment of the respiratory phenotype, will help physicians to determine patients' prognoses and to design studies for the evaluation of new therapies., Competing Interests: Conflict of interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2023 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures. To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology. High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease. In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy., Competing Interests: Declaration of Competing Interest Toshiya Nishi and Shinichi Kondo are employed by Takeda Pharmaceutical Company Limited. Matthew During and Brett Abrahams were/are employed by Ovid Therapeutics., (Copyright © 2022. Published by Elsevier Inc.)

Alpha-thalassemia X-linked intellectual disability syndrome (ATRX) is a rare genetic condition caused by mutations in the ATRX gene characterized by distinctive dysmorphic features, alpha thalassemia, mild-to-profound intellectual disability, and epilepsy, reported in nearly 30% of the patients. To date, different types of seizures are reported in patients with ATRX syndrome including either clonic, tonic, myoclonic seizures or myoclonic absences. However, an accurate analysis of electroencephalographic features is lacking in literature. We report on the epileptic and electroencephalographic phenotype of seven unpublished patients with ATRX syndrome, highlighting the presence of a peculiar EEG pattern characterized by diffuse background slowing with superimposed low voltage fast activity. Likewise, we also review the available literature on this topic., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

X-linked lissencephaly with abnormal genitalia (XLAG) and developmental epileptic encephalopathy-1 (DEE1) are caused by mutations in the Aristaless-related homeobox (ARX) gene, which encodes a transcription factor responsible for brain development. It has been unknown whether the phenotypically diverse XLAG and DEE1 phenotypes may converge on shared pathways. To address this question, a label-free quantitative proteomic approach was applied to the neonatal brain of Arx knockout (ArxKO/Y) and knock-in polyalanine (Arx(GCG)7/Y) mice that are respectively models for XLAG and DEE1. Gene ontology and protein-protein interaction analysis revealed that cytoskeleton, protein synthesis and splicing control are deregulated in an allelic-dependent manner. Decreased α-tubulin content was observed both in Arx mice and Arx/alr-1(KO) Caenorhabditis elegans ,and a disorganized neurite network in murine primary neurons was consistent with an allelic-dependent secondary tubulinopathy. As distinct features of Arx(GCG)7/Y mice, we detected eIF4A2 overexpression and translational suppression in cortex and primary neurons. Allelic-dependent differences were also established in alternative splicing (AS) regulated by PUF60 and SAM68. Abnormal AS repertoires in Neurexin-1, a gene encoding multiple pre-synaptic organizers implicated in synaptic remodelling, were detected in Arx/alr-1(KO) animals and in Arx(GCG)7/Y epileptogenic brain areas and depolarized cortical neurons. Consistent with a conserved role of ARX in modulating AS, we propose that the allelic-dependent secondary synaptopathy results from an aberrant Neurexin-1 repertoire. Overall, our data reveal alterations mirroring the overlapping and variant effects caused by null and polyalanine expanded mutations in ARX. The identification of these effects can aid in the design of pathway-guided therapy for ARX endophenotypes and NDDs with overlapping comorbidities., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

GRIN2A encodes for the 2A subunit of N-methyl-D-aspartate receptors. Pathogenic variants in GRIN2A have been associated with a wide spectrum of neurodevelopmental disorders ranging from speech disorders and/or self-limiting epilepsy (childhood epilepsy with centrotemporal spikes) to severe and disabling phenotypes (atypical childhood epilepsy with centrotemporal spikes, epileptic encephalopathy with continuous spike-wave during sleep, Landau-Kleffner syndrome and infantile-onset epileptic encephalopathy). Here we describe a family with two affected sisters with atypical childhood epilepsy with centrotemporal spikes and their mildly affected mother carrying a novel N-terminal null variant in GRIN2A gene. These familial cases corroborate previous studies showing that loss-of-function GRIN2A variants are associated with milder phenotypes, possibly due to haploinsufficiency., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: The detrimental role of childhood emotional neglect (CEN) on long-term affective and social development has received increasing attention in the literature. Individuals who were emotionally neglected during their childhood are more prone to feeling isolated and excluded by their parent during adolescence. However, little is known about the mediating processes underlying this association., Objective: This study investigated whether self-other differentiation (SOD) and emotional detachment from parents mediate the link between CEN and parent-related loneliness., Method and Participants: A sample of 535 high school students aged 13-18 years (63.6% female; M age  = 16.21; SD = 1.40) completed questionnaires regarding demographics, CEN, SOD, emotional detachment, and parent-related loneliness., Results: After controlling for demographic covariates, structural equation modeling (SEM) showed that (a) CEN was positively associated with parent-related loneliness (β = 0.64, p < .001), (b) SOD did not mediate the relationship between CEN and parent-related loneliness (β = -0.01, p = .142), (c) emotional detachment partially mediated the relationship between CEN and parent-related loneliness (β = 0.16, p < .001), and (d) SOD and emotional detachment partially and sequentially mediated the link between CEN and parent-related loneliness, albeit with a small effect size (β = 0.02, p = .027)., Conclusions: The findings underscore the significance of the link between CEN and parent-related loneliness in adolescence. Moreover, our results suggest that some adolescents with a history of CEN have difficulties in establishing clear boundaries between "self" and "other" and tend to engage in emotionally detached relationships with their parents, which may lead them to feel more parent-related loneliness. Clinical implications and directions for future research are discussed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In the field of perinatal clinical psychology, most studies focus on mothers' psychological states during pregnancy, neglecting the role of their partners. This study used an Actor-Partner Interdependence Mediation Model to evaluate the mediating role of dyadic satisfaction on the relationship between perceived stress and prenatal depressive symptomatology in both members of male-female-mixed-gender couples who were expecting their first child. One hundred thirty-eight couples in their third trimester of pregnancy were asked to complete questionnaires about perceived stress, dyadic adjustment, and depression. The model revealed that there was an intrapersonal indirect effect of fathers' perceived stress on prenatal paternal depression through their marital satisfaction. Moreover, an interpersonal indirect effect was found with mothers' perceived stress being associated with prenatal paternal depression through fathers' dyadic satisfaction. Maternal indirect effects were all non-significant, suggesting that their dyadic satisfaction and that of their partner did not mediate the relation between their perceived stress and that of their partner and their prenatal depression. Findings support the importance of assessing the dyadic satisfaction of couples during pregnancy, especially in expectant fathers, and targeting it in the psychological support offered to couples as a way of improving their prenatal distress, and consequently, their mental health., (© 2021 John Wiley & Sons Ltd.)

We describe a patient with focal epilepsy characterized by ictal asystole episodes and low-grade tumour over the left temporal neocortex. Non-invasive pre-surgical evaluation showed an epileptogenic zone extended beyond the low-grade tumour. This extension was confirmed by intraoperative electrocorticography. One-stage surgery with anterior temporal lobe resection was performed. The patient was seizure-free after one year of follow-up. Detailed electroclinical and therapeutic reasoning with hypotheses defining epileptogenic and symptomatogenic networks are discussed.

Background: White-Sutton (WHSUS) is a recently recognized syndrome caused by mutations of the POGZ gene. Approximately 70 patients have been reported to date. Intellectual disability, hypotonia, behavioral abnormalities, autism, and typical facial dysmorphisms are recognized as WHSUS features; however, still few patients receive a comprehensive psychometric, behavioral and neurological examination. In this report, we describe the pediatric, dysmorphological, neurological, psychometric and behavioral phenotype in a new WHSUS patient due to a novel heterozygous POGZ mutation, highlighting the distinctive epileptic phenotype and the cognitive pattern., Case Presentation: The patient, an 8 years-old girl, presented history of hypotonia, motor and speech delay, and distinctive facial features. The diagnosis of WHSUS followed the identification of the de novo variant p.Asp828GlyfsTer36 (c.2482dupG) in the POGZ gene. The patient showed a distinctive neurological phenotype with the occurrence of both paroxysmal not-epileptic events in the first 6 months of age and EEG abnormalities without evidence of clinical seizures after the first year of age. Psychological and behavioral testing highlighted moderate intellectual and communication deficit, mild autism spectrum and visual-motor integration deficit., Conclusions: This is the first described case of WHSUS with a co-existence of paroxysmal not-epileptic events and abnormal EEG without seizures in the same patient. Together with the available literature data, this observation suggests that paroxysmal not-epileptic events could be more frequent than expected and that this feature belongs to the WHSUS phenotypic spectrum. Autism is a known comorbidity of WHSUS but is still poorly investigated. Specific clinical testing could help detect also mild autistic phenotypes and better define autism prevalence in POGZ-related syndrome. Special attention should be given to symptoms such as stereotypies, social withdrawal, and hyperactivity that, when present, should be considered as possible signs of autism symptoms. The dissection of the neurological and behavioral phenotype is crucial for individualized therapies tailored to patient's needs.

Background: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance., Methods: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A -related disorders., Results: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain., Conclusion: The present study further enlarges the clinical and mutational spectrum of KIF1A -related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction : Several studies have supported the evidence that attachment styles are a central factor in adolescent gambling problems. On this theoretical basis, the aim of the present study is to analyze a hypothesized mediation model exploring both the direct and indirect effects of insecure attachment on gambling disorder by investigating the role of the developmental perspective, theory of mind (friend) and adaptive response in that relationship. Method : The sample consists of 178 adolescents who underwent the Measures: South Oaks Gambling Screen-Revised for Adolescents and Friends and Family Interview . Result : The mediation analysis was conducted following Hayes' (2018) procedure, using Model 6. The results showed a significant association between insecure attachment and gambling disorder ( β = 0.669; p < 0.001). The findings also highlighted a significant chained mediation model in which insecure attachment negatively influenced the developmental perspective ( β = -0.742; p < 0.001), which affected the theory of mind toward one's own best friend ( β = 0.352; p < 0.001). Conclusions : The results highlighted a significant role of insecure attachment in predicting the symptomatic expression of gambling among adolescents, specifically impacting the development perspective, theory of mind toward one's best friend and adaptive response to stress, which were linked to each other by a sequential influence. Therefore, our results showed that a poor developmental self-vision predicted a dysfunctional theory of mind toward the best friend. This could hinder the formation of positive peer relationships, which are crucial for the development of one's identity.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy., Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature., Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants., Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis., (© 2020 International League Against Epilepsy.)

Mutations in SPTAN1 gene are responsible for a wide spectrum of neurodevelopmental disorders including early-onset epileptic encephalopathy with progressive brain atrophy, severe intellectual disability with cerebellar malformations, and relatively milder phenotypes with or without epilepsy. Herein, we report three affected individuals including two siblings of 13 and 8 years and their 39-year-old mother, carrying a novel pathogenic variant in SPTAN1 gene. The phenotype of the index cases and their mother was remarkable for the variable expressivity, including benign convulsions with mild gastroenteritis, intellectual disability and developmental encephalopathy with epilepsy. Our clinical observation suggests for the first time that variants in SPTAN1 gene might be involved in the aetiology of benign convulsions correlated with mild gastroenteritis., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Maladaptive daydreaming (MD) is an extensive fantasy activity that replaces human interaction and interferes with work and interpersonal functioning. In this study, we investigated the nomological network of the MD construct and examined the psychometric properties of the Maladaptive Daydreaming Scale (MDS-16) in an Italian sample. The MDS-16 is a self-report measure composed of 16 items designed to assess MD. Participants in this study were 468 individuals (333 volunteers, 56.8% female; 135 self-diagnosed maladaptive daydreamers, 78.5% female) between 18 and 56 years of age. MDS-16 scores showed good internal reliability. An exploratory factor analysis suggested a 2-factor solution (interference with life and sensory-motor retreat); this solution was consistent with theory, and all items loaded in the expected direction. MDS-16 scores were associated with global psychopathology, traumatic experiences, maladaptive personality features, alexithymia, dissociation, shame feelings, and anxious attachment styles. Furthermore, MDS-16 scores showed satisfactory incremental validity, and a receiver operating characteristic curve analysis suggested that a cutoff value of 51 best discriminates between cases and noncases of self-diagnosed MD. Results suggest that the scale is a suitable measure for assessing MD in Italian samples.

Background: Many researchers who evaluated psychological distress during the transition to parenthood agree in identifying pregnancy as the most sensitive period for the onset of psychiatric symptomatology for both parents. Furthermore, research highlights a correlation between symptoms experienced by fathers in relation to those experienced by mothers., Objective: The aim of this study was to investigate whether dyadic functioning influences the level of psychiatric symptomatology in couples expecting their first child. Participants were 137 couples expecting their first child; they were recruited at the San Filippo Neri and the Santo Spirito hospitals in Rome (ASLROMA1). We used an Actor-Partner Interdependence Model (APIM) to test the interdependence of both partners and the effect of dyadic relationships on psychiatric symptoms in the couple., Results: The overall test of distinguishability yielded a chi square value of 122.167 (23 df; p < .001). The actor-partner interdependence model showed significant paths between couple coping and psychiatric symptomatology. Specifically, we found that the quality of couple coping perceived by the mother negatively predicted maternal psychiatric symptomatology, and the quality of couple coping perceived by the father negatively predicted paternal psychiatric symptomatology. Furthermore, the quality of couple coping perceived by the father negatively predicted maternal psychiatric symptomatology., Conclusions: The results of this study confirm that dyadic adjustment is an important element for the development of effective interpersonal relationships. These data highlight the importance of promoting psycho-educational and clinical courses and programs for the development of social support with future parents., Competing Interests: Declaration of Competing Interest All authors have no conflicts of interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest.