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Abstract Genetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion magnetic resonance imaging [MRI]). A better understanding of pleiotropy across modalities could inform us on the integration of brain function, micro- and macrostructure. Here we show extensive genetic overlap across neuroimaging modalities at a locus and gene level in the UK Biobank (N = 34,029) and ABCD Study (N = 8607). When jointly analysing phenotypes derived from structural, functional and diffusion MRI in a genome-wide association study (GWAS) with the Multivariate Omnibus Statistical Test (MOSTest), we boost the discovery of loci and genes beyond previously identified effects for each modality individually. Cross-modality genes are involved in fundamental biological processes and predominantly expressed during prenatal brain development. We additionally boost prediction of psychiatric disorders by conditioning independent GWAS on our multimodal multivariate GWAS. These findings shed light on the shared genetic mechanisms underlying variation in brain morphology, functional connectivity, and tissue composition.

Introduction Menke-Hennekam syndrome (MHS) is a relatively new genetic condition characterized by intellectual disabilities, autistic behavior, auditory defects, recurrent upper respiratory tract infections, microcephaly and short stature. Facial characteristics include short palpebral fissures, telecanthus, depressed nasal bridge, short nose, anteverted nares, short columella, and long philtrum. The genetic defect is represented by missense variants of CREBBP gene, located on exons 30 or 31. There are only around 30 cases reported by now. Objectives The aim of the paper is to report a new case of MHS. Methods The case is a 3-year-old boy admitted in our department for developmental delay. The clinical examination revealed dysmorphic features; severe speech delay, mild intellectual disability, autistic behaviour.The patient had a personal history of recurrent respiratory infections, visual defect and bilateral sensorineural hearing loss. Other investigations included EEG, abdominal echography, and cerebral MRI all were normal. The genetic studies included array CGH and WES. Results The array CGH was normal. WES identified a pathogenic heterozygote variant c.5600G>A in the exon 31 of CREBBP gene, confirming MHS. Conclusions Overall, the features of our patient are consistent with those reported in the previous reports, including developmental and speech delay, autistic behavior, dysmorphic features, recurrent upper way infections, sensorineural hearing loss, and visual defects. Other common features, such as growth delay and microcephaly were not present in our patient. Our case contributes to the clinical characterisation of the new syndrome. Funding: The research leading to these results has received funding from the EEA Grant 2014-2021, under the project contract No 6/2019. Disclosure No significant relationships.

Introduction Background: Copy-number variants (CNVs) of chromosome 15 have been associated with neurodevelopmental disorders like autism spectrum disorders (ASDs) and developmental delay. Objectives We report 6 patients with autistic features and other neurodevelopmental problems carrying CNVs of chromosome 15. Methods Materials and methods: The probands belong to a group of patients referred to our clinic and laboratory with autism as main feature. A complete clinical evaluation was performed with focus on neurologic, psychiatric, and psychological evaluation with specific autism tests. Array-based comparative genomic hybridization (array-CGH) was performed using 180K platform (Agilent technology). Results six patients investigated by array-CGH had a CNV involving chromosome 15. Four of these patients, previously reported by us (ref 1), had small duplications of 15q13.3 involving CHRNA7 and OTUD7A genes. The other two patients had large deletions of 15q21q22 and 15q24, respectively. A deletion of 15q21.2 - q22.2 was detected in one patient. The deleted region contains 62 genes and has been rarely reported in patients with neurodevelopmental disorders. A deletion of 15q24.1 - q24.2 was detected in the other patient. This region is recurrently deleted in developmentally delayed patients (ref 3). Conclusions Our data highlight that chromosome 15 is a hub for neurodevelopmental disorder and illustrates the utility of array-CGH in the investigation of patients with autism, specifically in the context of complex phenotypes. Acknowledgment: The research leading to these results has received funding from the EEA Grant 2014-2021, under the project contract No 6/2019. References: Genes (Basel). 2021 Jul 1;12(7):1025. https://www.omim.org/entry/618060 Clinical Genome Resource. https://dosage.clinicalgenome.org/clingen_region.cgi?id=ISCA-46296 Disclosure No significant relationships.

Introduction Brain heterotopia represent a group of rare malformations with a heterogeneous phenotype, ranging from asymptomatic to severe clinical picture (resistant epilepsy, severe developmental delay). The etiology is multifactorial, including both genetic and environmental factors. Objectives In this paper we present our experience regarding behavior problems in patients with heterotopia. Methods A cohort of 16 pediatric patients with brain heterotopia, six females and ten males, with age at last follow-up ranging from 2 months to 24 years were investigated by clinical examination, electroencephalographic studies, brain imaging, and genomic tests. Specific psychological tests and psychiatric evaluation were performed in all children for behavior problems assessment. Results Six individuals presented behavioral problems: autism (three patients) and hyperkinesia with attention deficit (three patients). All of them had intellectual disability or learning problems; five patients had epilepsy, with drug-resistant seizures in four cases. In two cases the behavioral problems occurred before the onset of epileptic seizures. Conclusions Behavior problems are important features in patients with brain heterotopia, making the management of these patients more difficult, especially when they occur in association with drug-resistant epilepsy. Acknowledgements: This work was supported partially by grants of the Romanian National Authority for Scientific Research and Innovation CCCDI – UEFISCDI, Projects COFUND-ERANET E-RARE 3-HETER-OMICS-2 Number 87/2019 and 88/2019 within PNCDI III. Disclosure No significant relationships.

Introduction Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and social interaction across multiple contexts and it is marked by repetitive sensory–motor behaviours and restricted interests or activities. Now recognized to occur in up to 1% of the population, the prevalence of ASD has registered a steady increase in the past two decades. Heterogeneity of presentation is a hallmark with comorbid psychiatric and medical morbidities frequently reported. Comorbidities mask and delay the diagnosis and are the cause of inadequate therapies. Objectives In the present paper, we studied a cohort of patients with ASD, investigating the rates and types of psychiatric and medical comorbidities. Methods A retrospective study of psychiatric and medical comorbidities was carried out on a sample of 120 participants that met ASD criteria according to DSM-V. The patients were examined with a detailed medical history, physical examination, as well as some additional functional, imaging, laboratory and genetic investigations. The associated conditions considered were: attention deficit/hyperactivity disorder (ADHD), epilepsy, intellectual disability, gastrointestinal symptoms, ophtalmologic manifestations, infections. Results Of the 120 ASD subjects referred, 25 (20.8%) received the diagnosis of epilepsy. ADHD was established in 24 cases (20%). IQ score was obtained in half of the patients, 43.3% of them presenting a severe intellectual disability (IQ

Introduction 15q11.2-q13.3 region is prone to genomic rearrangements leading to both deletions and duplications. A wide spectrum of neuropsychiatric conditions, such as developmental delay/intellectual disability (DD/ID), autism, attention-deficit hyperactivity disorder, schizophrenia, epilepsy was reported in association with genomic imbalances of this region. Objectives In this paper we report on 9 children carrying 15q11.2-q13.3 duplications. Methods Seven boys and two girls, aged 15 months to 15 years, were included in the study. Genomic investigations were carried out by array-based comparative genomic hybridization (Agilent Technologies). In all patients the psychomotor development, dysmorphic features, neuroimaging and EEG anomalies were assessed. Psychologic and psychiatric evaluation was performed with specific tests. Results The size of the duplications ranged from 9.65 Mb to 0.38 Mb. All patients presented speech delay. Autistic behavior and muscular hypotonia were detected in 8 out of 9 patients, DD/ID in 6. Two children presented epileptic seizures, in addition 4 other children had EEG anomalies. Facial dysmorphic features were observed in 5 patients. Neuroimaging studies showed anomalies in 4 children. The smallest region of overlap in our patient group harbors CHRNA7 gene, a candidate for the behavioral abnormalities. Conclusions 15q duplications encompassing CHRNA7 gene were associated with different neuropsychiatric features in our patients. Our results further support the association of 15q duplications with neuropsychiatric phenotypes, with clinical heterogeneity and variable severity, which is yet to be explained. Acknowledgment: The research leading to these results has received funding from the EEA RO NO Grant 2014-2021, the project contract No 6/2019. Disclosure No significant relationships.

Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by deficits in social relationships and communication and restrictive, repetitive behaviors and interests. ASDs form a heterogeneous group from a clinical and genetic perspective. Currently, ASDs diagnosis is based on the clinical observation of the individual's behavior. The subjective nature of behavioral diagnoses, in the context of ASDs heterogeneity, contributes to significant variation in the age at ASD diagnosis. Early detection has been proved to be critical in ASDs, as early start of appropriate therapeutic interventions greatly improve the outcome for some children. Structural magnetic resonance imaging (MRI) is widely used in the diagnostic work-up of neurodevelopmental conditions, including ASDs, mostly for brain malformations detection. Recently, the focus of brain imaging shifted towards quantitative MRI parameters, aiming to identify subtle changes that may establish early detection biomarkers. ASDs have a strong genetic component; deletions and duplications of several genomic loci have been strongly associated with ASDs risk. Consequently, a multitude of neuroimaging and genetic findings emerged in ASDs in the recent years. The association of gross or subtle changes in brain morphometry and volumes with different genetic defects has the potential to bring new insights regarding normal development and pathomechanisms of various disorders affecting the brain. Still, the clinical implications of these discoveries and the impact of genetic abnormalities on brain structure and function are unclear. Here we review the literature on brain imaging correlated with the most prevalent genomic imbalances in ASD, and discuss the potential clinical impact., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Background: The Coiled-Coil Domain-Containing Protein 88 A (CCDC88A) gene encodes the actin-binding protein Girdin, which plays important roles in maintaining the actin cytoskeleton and in cell migration and was recently associated with a specific form of epileptic encephalopathy. Biallelic protein-truncating variants of CCDC88A have been considered responsible for progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome. To date, only three consanguineous families with loss-of-function homozygous variants in the CCDC88A gene have been reported. The described patients share many clinical features, such as microcephaly, neonatal hypotonia, seizures, profound developmental delay, face and limb edema, and dysmorphic features, with a similar appearance of the eyes, nose, mouth, and fingers., Case Presentation: We report on a child from a nonconsanguineous family who presented with profound global developmental delay, severe epilepsy, and brain malformations, including subcortical band heterotopia. The patient harbored two heterozygous pathogenic variants in the trans configuration in the CCDC88A gene, which affected the coiled-coil and C-terminal domains., Conclusions: We detail the clinical and cerebral imaging data of our patient in the context of previously reported patients with disease-causing variants in the CCDC88A gene, emphasizing the common phenotypes, including cortical malformations, that warrant screening for sequence variants in this gene., (© 2024. The Author(s).)

Genetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion magnetic resonance imaging [MRI]). A better understanding of pleiotropy across modalities could inform us on the integration of brain function, micro- and macrostructure. Here we show extensive genetic overlap across neuroimaging modalities at a locus and gene level in the UK Biobank (N = 34,029) and ABCD Study (N = 8607). When jointly analysing phenotypes derived from structural, functional and diffusion MRI in a genome-wide association study (GWAS) with the Multivariate Omnibus Statistical Test (MOSTest), we boost the discovery of loci and genes beyond previously identified effects for each modality individually. Cross-modality genes are involved in fundamental biological processes and predominantly expressed during prenatal brain development. We additionally boost prediction of psychiatric disorders by conditioning independent GWAS on our multimodal multivariate GWAS. These findings shed light on the shared genetic mechanisms underlying variation in brain morphology, functional connectivity, and tissue composition., (© 2024. The Author(s).)

Orofaciodigital syndrome I (OFD1-MIM #311200) is a rare ciliopathy characterized by facial dysmorphism, oral cavity, digit, and brain malformations, and cognitive deficits. OFD1 syndrome is an X-linked dominant disorder reported mostly in females. The gene responsible for this condition, OFD1 centriole and centriolar satellite protein ( OFD1 ), is involved in primary cilia formation and several cilia-independent biological processes. The functional and structural integrity of the cilia impacts critical brain development processes, explaining the broad range of neurodevelopmental anomalies in ciliopathy patients. As several psychiatric conditions, such as autism spectrum disorders (ASD) and schizophrenia, are neurodevelopmental in nature, their connections with cilia roles are worth exploring. Moreover, several cilia genes have been associated with behavioral disorders, such as autism. We report on a three-year-old girl with a complex phenotype that includes oral malformations, severe speech delay, dysmorphic features, developmental delay, autism, and bilateral periventricular nodular heterotopia, presenting a de novo pathogenic variant in the OFD1 gene. Furthermore, to the best of our knowledge, this is the first report of autistic behavior in a female patient with OFD1 syndrome. We propose that autistic behavior should be considered a potential feature of this syndrome and that active screening for early signs of autism might prove beneficial for OFD1 syndrome patients., Competing Interests: The authors declare no conflicts of interest.

This study aimed to explore the possible moderating role of emotional regulation in the relationship between problem-solving ability, visuomotor precision and visuospatial integration on the one hand and school results on the other in pupils with ADHD. A total of 241 pupils with ADHD (study group) and 207 children without ADHD (control group) were included in our research. Specific tests for the evaluation of the problem-solving ability, visuomotor precision, visuospatial integration, and emotional regulation were applied. The results showed that emotional regulation is a significant moderator of the relationship between school results and problem-solving ability, visuomotor precision, visuospatial integration, and working memory. There are statistically significant differences depending on emotional regulation, visuomotor precision, visuospatial integration, problem-solving ability and working memory in terms of school results of students with ADHD compared to children without this diagnosis. These results can be used in the development of intervention programs.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by communication and social interaction deficits, and by restricted interests and stereotyped, repetitive behavior patterns. ASD has a strong genetic component and a complex architecture characterized by the interplay of rare and common genetic variants. Recently, increasing evidence suggest a significant contribution of immune system dysregulation in ASD. The present paper reviews the latest updates regarding the altered immune landscape of this complex disorder highlighting areas with potential for biomarkers discovery as well as personalization of therapeutic approaches. Cross-talk between the central nervous system and immune system has long been envisaged and recent evidence brings insights into the pathways connecting the brain to the immune system. Disturbance of cytokine levels plays an important role in the establishment of a neuroinflammatory milieu in ASD. Several other immune molecules involved in antigen presentation and inflammatory cellular phenotypes are also at play in ASD. Maternal immune activation, the presence of brain-reactive antibodies and autoimmunity are other potential prenatal and postnatal contributors to ASD pathophysiology. The molecular players involved in oxidative-stress response and mitochondrial system function, are discussed as contributors to the pro-inflammatory pattern. The gastrointestinal inflammation pathways proposed to play a role in ASD are also discussed. Moreover, the body of evidence regarding some of the genetic factors linked to the immune system dysregulation is reviewed and discussed. Last, but not least, the epigenetic traits and their interactions with the immune system are reviewed as an expanding field in ASD research. Understanding the immune-mediated pathways that influence brain development and function, metabolism, and intestinal homeostasis, may lead to the identification of robust diagnostic or predictive biomarkers for ASD individuals. Thus, novel therapeutic approaches could be developed, ultimately aiming to improve their quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MV declared a past co-authorship with one of the authors MN to the handling editor., (Copyright © 2022 Erbescu, Papuc, Budisteanu, Arghir and Neagu.)

Objective: To identify developmental symptoms reported at firsts doctor visits by parents of children later diagnosed with Autism Spectrum Disorder (ASD)., Design: Cohort study., Setting: The study was conducted in the Department of Psychiatry Research of "Prof. Dr. Alexandru Obregia" Clinical Psychiatry Hospital from Bucharest between September 2019 and May 2021., Patients: 105 cases: 82 boys and 23 girls, 100 children with autism, and 5 patients with Asperger's syndrome., Intervention: ASD was diagnosed according to the DSM-5 criteria, ADOS-1 (Autism Diagnostic Observation Schedule, 1st Edition) and/or ADI-R (Autism Diagnostic Interview-Revised) tests scores; features reported by the parents for which they presented to the doctor for a diagnosis were taken into consideration., Main Outcome Measures: The age at first presentation to the doctor; the most common early signs reported by the parents of children with ASD., Results: The age at first presentation to the doctor in our group was between 9 months and 14 years. The most common early signs reported by parents were: delayed language development, deficits in understanding verbal instructions/indications, and hyperactivity and aggressivity. In the case of patients with Asperger's syndrome, the reported features were hyperactivity and aggressivity, learning difficulties, and social interaction problems. Regression and delay in language development occurred more often in boys than in girls., Conclusions: Parents, as well as family doctors or paediatricians, should pay great attention to the children's behaviour, alongside their cognitive and language development. Early detection is essential for early intervention and our results can be used to develop training programs for parents and paediatricians for early recognition of ASD.

Brain heterotopia is a group of rare malformations with a heterogeneous phenotype, ranging from asymptomatic to a severe clinical picture (drug-resistant epilepsy, severe developmental delay). The etiology is multifactorial, including both genetic and environmental factors. In the present study, a cohort of 15 pediatric patients with brain heterotopia were investigated by clinical examination, electroencephalographic studies, brain imaging, and genomic tests. Most of the patients had epileptic seizures, often difficult to control with one antiepileptic drug; another frequent characteristic in the cohort was developmental delay or intellectual disability, in some cases associated with behavioral problems. The genomic studies revealed an interstitial 22q11.2 microduplication, an anomaly not reported previously in heterotopia patients. Comparing the cohort of the present study with that of a previous series of heterotopia patients, both adult and pediatric, similar aspects, such as the high frequency of drug-resistant epilepsy were observed as well as some differences, such as no systemic malformations and no cases with fatal evolution. The current findings add new data to existing knowledge on a rare heterogeneous disorder. The detailed clinical description, including the epilepsy phenotypes, and genomic profiles bring new insights into a group of disorders, yet to be fully understood., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Budisteanu et al.)

Schizophrenia is a severe mental illness with a significant impact on the life of both the patient and the patient's family. Magnetic resonance imaging has proven a useful tool for studying structural changes of the brain in schizophrenia. However, interpreting the published literature presents several challenges. Despite thorough research in recent years, which has included anatomopathological, imaging, electrophysiological, and genetic studies, the intimate pathophysiological mechanisms of this disease are not yet fully elucidated. The present study included patients with schizophrenia diagnosed in the psychiatric clinics from the 'Prof. Dr. Alexandru Obregia' Clinical Psychiatry Hospital between September 2019 and December 2020. Three Tesla magnetic resonance neuroimaging studies were performed. In a significant number of cases, the neuroimaging studies showed association of cerebral modifications such as enlargement of the Virchow spaces, lesions of the white matter with demyelinating appearance, and inflammatory sinus reactions. Cortical atrophy and hemosiderotic spots were present in a statistically significant proportion in the patient group with an age range of 29-61 years. MRI is indicated as a useful technique in the follow-up process of schizophrenia patients. However, whether the anomalies revealed in this disorder can be utilised as diagnostic biomarkers is still being debated., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Iliuta et al.)

Life expectancy has increased worldwide and, along with it, a greater prevalence of age-dependent disorders, chronic illnesses and comorbidities can be observed. In 2019, in both Europe and the Americas, dementias ranked 3rd among the top 10 causes of death. Parkinson's disease (PD) is the second most frequent type of neurodegenerative disease. In the last decades, globally, the number of people suffering from PD has more than doubled to over 6 million. Of all the neurological disorders, PD increased with the fastest rate. This troubling trend highlights the stringent need for accurate diagnostic biomarkers, especially in the early stages of the disease and to evaluate treatment response. To gain a broad and complex understanding of the recent advances in the '-omics' research fields, electronic databases such as PubMed, Google Academic, and Science Direct were searched for publications regarding metabolomic studies on PD to identify specific biomarkers for PD, and especially PD with associated psychiatric symptomatology. Discoveries in the fields of metagenomics, transcriptomics and proteomics, may lead to an improved comprehension of the metabolic pathways involved in disease etiology and progression and contribute to the discovery of novel therapeutic targets for effective treatment options., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Ciobanu et al.)

Schizophrenia, one of the most common psychiatric disorders, with a worldwide annual incidence rate of approximately 0.3-0.7%, known to affect the population below 25 years of age, is persistent throughout lifetime and includes people from all layers of society. With recent technological progress that allows better imaging techniques, such as the ones provided by computed tomography and particularly magnetic resonance imaging (MRI), research on schizophrenia imaging has grown considerably. The purpose of this review is to establish the importance of using imaging techniques in the early detection of brain abnormalities in patients diagnosed with schizophrenia. We reviewed all articles which reported on MRI imaging in schizophrenia. In order to do this, we used the PubMed database, using as search words 'MRI' and 'schizophrenia'. MRI studies of first episode patients and chronic patients, suggest reduction of the whole brain volume. Enlargement of lateral ventricles was described as positive in 15 studies out of 19 and was similar to findings in chronic patients. Moreover, for the first episode patients, all data collected point to important changes in medial temporal lobe structures, diminished hippocampal volume, the whole frontal lobe, asymmetry in prefrontal cortex, diminished volume in cingulate, corpus callosum, and cavum septum pellucidum reported abnormalities. MRI is recommended as an important tool in the follow-up process of patients with schizophrenia. Yet, it is still under debate whether the abnormalities described in this condition are able to be used as diagnostic biomarkers., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Iliuta et al.)

Chromosome 15q13.3 microduplications are associated with a wide spectrum of clinical presentations ranging from normal to different neuropsychiatric conditions, such as developmental delay (DD), intellectual disability (ID), epilepsy, hypotonia, autism spectrum disorders (ASD), attention-deficit hyperactivity disorder, and schizophrenia. The smallest region of overlap for 15q13.3 duplications encompasses the Cholinergic Receptor Nicotinic Alpha 7 Subunit ( CHRNA7 ) gene, a strong candidate for the behavioral abnormalities. We report on a series of five patients with 15q13.3 duplications detected by chromosomal microarray. The size of the duplications ranged from 378 to 537 kb, and involved the CHRNA7 gene in all patients. The most common clinical features, present in all patients, were speech delay, autistic behavior, and muscle hypotonia; DD/ID was present in three patients. One patient presented epileptic seizures; EEG anomalies were observed in three patients. No consistent dysmorphic features were noted. Neuroimaging studies revealed anomalies in two patients: Dandy-Walker malformation and a right temporal cyst. 15q13.3 duplications are associated with various neuropsychiatric features, including speech delay, hypotonia, ASD, and ID, also present in our patient group. Our study brings detailed clinical and molecular data from five ASD patients with 15q13.3 microduplications involving the CHRNA7 gene, contributing to the existing knowledge about the association of 15q13.3 duplications with neuropsychiatric phenotypes.

Pallister-Killian syndrome (PKS) is a rare, sporadic disorder defined by a characteristic dysmorphic face, pigmentary skin anomalies, intellectual disability, hypotonia, and seizures caused by 12p tetrasomy due to an extra isochromosome 12p. We present three cases of PKS and two cases of trisomy 12p to illustrate and discuss features rarely cited in the literature, present certain particularities that not yet been cited, and analyze the differences between entities. Moreover, we present alternative methods of diagnosis that could be easily used in daily practice. Features not yet or rarely reported in PKS literature include marked excess of hair on the forehead and ears in the first months of life, a particular eye disorder (abnormal iris color with pointed pupil), connective tissue defects, repeated episodes of infection and autonomic dysfunction, endocrine malfunction as a possible cause of postnatal growth deficit, more complex sensory impairments, and mild early myoclonic jerks. After performing different combinations of tests, we conclude that MLPA (follow-up kit P230-B1) or array CGH using DNA extracted from a buccal swab is a reliable method of diagnosis in PKS and we recommend either one as a first intention diagnostic test. In cases without major defects associated (suspicion trisomy 12p), subtelomeric MLPA should be performed first.

Schizophrenia is a neurodevelopmental disorder, characterized by impairment in reasoning, affectivity and social relationships. Although the diagnosis of schizophrenia in children and adolescents has been challenged for many years, at present childhood-onset schizophrenia is considered and accepted as a clinical and biological continuum with the adult-onset disorder. The present study aimed to evaluate the influence of biological (psychiatric family history, perinatal factors), and socio-demographic factors (area of residence, gender) on the age at onset and severity of symptomatology in children and adolescent with schizophrenia. The data were collected from 2016 to 2019 and included 148 children and adolescents with schizophrenia. Data were analysed with statistical software (IBM SPSS 22, JASP and JAMOVI, Linear Regression Model, χ² tests, t-test, U-test). A positive familial history for psychiatric diseases was an important risk factor both for an early onset and for the severity of symptoms. Urbanicity was another studied risk factor, 61% of patients being from urban areas; no statistically significant correlations between urbanicity and age at onset and severity of symptoms were identified. There was no statistically significant gender difference in terms of age at onset and severity of symptoms. Moreover, no statistically significant correlations were found between perinatal factors and age at onset and severity of symptoms. Positive psychiatric family history showed a statistically significant influence on age at onset and symptoms severity in children and adolescent schizophrenia; no statistical significant impact on the aforementioned schizophrenia aspects was observed for urbanicity, gender or perinatal factors., (Copyright © 2020, Spandidos Publications.)

Chromosomal diseases are heterogeneous conditions with complex phenotypes, which include also epileptic seizures. Each chromosomal syndrome has a range of specific characteristics regarding the type of seizures, EEG findings and specific response to antiepileptic drugs, significant in the context of the respective genetic etiology. Therefore, it is very important to know these particularities, in order to avoid an exacerbation of seizures or some side effects. In this paper we will present a review of the epileptic seizures and antiepileptic treatment in some of the most common chromosomal syndromes., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2020 Magdalena Budisteanu et al. published by De Gruyter.)

Introduction: Multiple sclerosis (MS) has an increasing incidence and affects a young s egment of t he population, having a major impact on patients and consequently on society. The multifactorial aetiology and pathogenesis of this disease are incompletely known at present, but autoimmune aggression has a documented mechanism., State of the Art: Since the 1990s, immunomodulatory drugs of high efficacy and a good safety profile have been launched. But the concept of NEDA (No Evidence of Disease Activity) remains the target to achieve. Thus, the new revolutionary class of monoclonal antibodies (moAbs) used in multiple medical fields, from this perspective represents a challenge even for multiple sclerosis, including the primary progressive form, for which there has been no treatment until recently., Clinical Implications: In this article, we will review monoclonal antibodies' use for MS, presenting their advantages and disadvantages, based on data accumulated since 2004 when the first monoclonal antibody was approved for active forms of the disease., Future Directions: There is still a need for personalised medicines, with a specific target, which should have fewer adverse effects and drug interactions.

Floating-Harbor syndrome (FHS) is a rare autosomal dominant syndrome characterized by short stature with delayed bone age, retarded speech development, intellectual disability and dysmorphic facial features. Recently, dominant mutations almost exclusively clustered in the final exon of the Snf2-related CREBBP activator protein ( SRCAP ) gene were identified to cause FHS. Here, we report a boy with short stature, speech delay, mild intellectual disability, dysmorphic features, and with genetically confirmed FHS. To the best of our knowledge, this is the first molecularly confirmed case with this syndrome reported in Romania. An intensive program of cognitive and speech stimulation, as well as yearly neurological, psychological, ophthalmological, otorhinolaryngological, pediatric and endocrinological monitoring for our patient were designed. We propose a checklist of clinical features suggestive of FHS, based on the main clinical features, in order to facilitate the diagnosis and clinical management of this rare condition.

Background: Mutations in forkhead box protein P1 ( FOXP1 ) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far., Methods: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting., Results: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability., Conclusions: FOXP1 -related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Little is known about use of early interventions for autism spectrum disorder in Europe. Parents of children with autism spectrum disorder aged 7 years or younger (N = 1680) were recruited through parent organisations in 18 European countries and completed an online survey about the interventions their child received. There was considerable variation in use of interventions, and in some countries more than 20% of children received no intervention at all. The most frequently reported interventions were speech and language therapy (64%) and behavioural, developmental and relationship-based interventions (55%). In some parts of Europe, use of behavioural, developmental and relationship-based interventions was associated with higher parental educational level and time passed since diagnosis, rather than with child characteristics. These findings highlight the need to monitor use of intervention for children with autism spectrum disorder in Europe in order to contrast inequalities., (© The Author(s) 2015.)

MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG2-deficiency was detected - in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG1-levels were detected in 11/21 patients and supra-normal IgG3-levels were seen in 8/21 patients - in 6 of the patients as combined elevation of IgG1 and IgG3. Three of the four patients with IgA/IgG2-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG2-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG2 may benefit from prophylactic substitution of sIgA and IgG.

Unlabelled: Down Syndrome (DS) is the most common genetic cause of mental retardation, with a reported frequency of epilepsy between 1.4-17% (1). There is a paucity of data in the literature regarding epilepsy in Down syndrome and its relation to intellectual disability., Objectives: The purpose of this article is to analyze the association of epilepsy in children with DS - frequency and type of seizures, treatment, outcome and to compare cognitive impairment of children with DS and epilepsy and DS without epilepsy from our cohort., Methods: A four years systematic retrospective analysis of the database of the Pediatric Neurology Clinic (January 2010 - December 2013) identified a cohort of 39 pediatric cases with DS and neurological symptoms, 9 of them (23%) associating epileptic seizures. Following data were analysed: clinical and neurological examination, type/s of seizures, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), psychological examination, psychiatric evaluation in selected cases, electrocardiography (ECG), cardiac ultrasonography, ophthalmologic examination., Results: 23% (9 patients) of the children with DS of our cohort presented epilepsy. Five patients had epileptic spasms (56%), one of these further developed astatic seizures. Focal seizures were observed in three patients (33%) and absence with eyelid myoclonias in one patient (11%). Two of the nine patients with DS and epilepsy had generalized seizures, both with very good response to levetiracetam (LEV). EEG was abnormal at seizure onset, and was improved after treatment. Of the nine children with DS and epilepsy, two (22%) presented mild mental retardation and seven (78%) had moderate to severe cognitive delay. Of the 30 children with DS and without epilepsy, 21 (70%) had mild mental retardation and 9 (30%) had moderate to severe cognitive impairment., Conclusions: The most frequent epileptic syndrome associated with DS is West syndrome, with good response to specific antiepileptics. All children with DS from our cohort have intelectual disability, more severe in those with epilepsy. Slight improvement of intelectual and language capabilities were seen after seizures control.

Background: Angelman syndrome (AS) is a genetic condition, characterized by severe mental retardation, ataxic gait, severe speech delay, dysmorphic features, abnormal behaviour, movement disorder. It is caused by a variety of genetic mechanisms which all interfere with expression of the UBE3A gene on chromosome 15q11-13., Objectives: To present our experience regarding diagnosis of children with Angelman syndrome., Material and Methods: 15 children were clinically and genetically diagnosed with AS in the Department of Pediatric Neurology of the "Prof. Dr. Alex. Obregia" Clinical Hospital. In all cases, diagnosis of AS was made by the clinical criteria. The clinical evaluation focused on the patient history, a general examination, dysmorphological evaluation, a neurological examination, psychological evaluation, and paraclinical tests., Results: All patients from this study presented the characteristic facial features and the characteristic behavior phenotype. Psychomotor development was delayed in all children, most of cases (73%) presenting with sever mental retardation. Epileptic seizures were observed in all patients with microdeletion, the partial seizures being the most frequent type. EEG in all children showed the characteristic pattern for AS., Conclusions: Angelman syndrome is a rare and severe neurodevelopmental disorder, with a complex clinical picture. There are some characteristic facial features, which, in association with hypopigmentation, happy disposition, jerky movements, and ataxia in a child with psychomotor delay should raise the strong suspicion of AS.

We present a case of oculocutaneous albinism in a child associating multiple malformations (preaxial polydactyly, small penis, cardiac malformation) and psychomotor retardation. To our knowledge, this association has not been previously described.