Objectives: Many children with neurodevelopmental disorders (NDD) show complex, multidimensional impairments meeting criteria for multiple NDD, yet remain “diagnostically homeless” as DSM-5 lacks a Multidimensional Impairment (MDI) category. We investigated the prevalence of genetic abnormalities in such complex NDD cases. Methods:Between 2017 and 2019, we diagnosed MDI in 666 patients. Among them, 122 (18 Depending on classification, prevalence ranged from 47

Background Previous pandemics have had negative effects on mental health, but there are few data on children and adolescents who were receiving ongoing psychiatric treatment. Aims To study changes in emotions and clinical state, and their predictors, during the COVID-19 pandemic in France. Method We administered (by interview) the baseline Youth Self-Report version of the CoRonavIruS Health Impact Survey v0.3 (CRISIS, French translation) to 123 adolescent patients and the Parent/Caregiver version to evaluate 99 child patients before and during the first ‘lockdown’. For 139 of these patients who received ongoing treatment in our centre, treating physicians retrospectively completed longitudinal global ratings for five time periods, masked to CRISIS ratings. Results The main outcome measure was the sum of eight mood state items, which formed a single factor in each age group. Overall, this score improved for each age group during the first lockdown. Clinician ratings modestly supported this result in patients without intellectual disability or autism spectrum disorder. Improvement of mood states was significantly associated with perceived improvement in family relationships in both age groups. Conclusions Consistent with previous studies of clinical cohorts, our patients had diverse responses during the pandemic. Several factors may have contributed to the finding of improvement in some individuals during the first lockdown, including the degree of family support or conflict, stress reduction owing to isolation, limitations of the outcome measures and/or possible selection bias. Ongoing treatment may have had a protective effect. Clinically, during crises additional support may be needed by families who experience increased conflict or who care for children with intellectual disability.

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe.

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes 1 . This recent study—and most other large-scale human genetics studies—was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10 −6 ). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes ( SRRM2 and AKAP11 ) were newly implicated as SCZ risk genes, and one gene ( PCLO ) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.

BackgroundIndividuals with Phelan-McDermid syndrome (PMS) present with a wide range of diagnoses: autism spectrum disorder, intellectual disability, or schizophrenia. Differences in the genetic background could explain these different neurodevelopmental trajectories. However, a more parsimonious hypothesis is to consider that they may be the same phenotypic entity. Catatonic disturbances occasionally reported from adolescence onwards in PMS prompts exploration of the hypothesis that this clinical entity may be an early-onset form of catatonia. The largest cohort of children with childhood catatonia was studied by the Wernicke-Kleist-Leonhard school (WKL school), which regards catatonia as a collection of qualitative abnormalities of psychomotricity that predominantly affecting involuntary motricity (reactive and expressive). The aim of this study was to investigate the presence of psychomotor signs in three young adults carrying a mutation or intragenic deletion of the SHANK3 gene through the prism of the WKL school conception of catatonia.MethodsThis study was designed as an exploratory case study. Current and childhood psychomotor phenomena were investigated through semi-structured interviews with the parents, direct interaction with the participants, and the study of documents reporting observations of the participants at school or by other healthcare professionals.ResultsThe findings show catatonic manifestations from childhood that evolved into a chronic form, with possible phases of sub-acute exacerbations starting from adolescence.ConclusionThe presence of catatonic symptoms from childhood associated with autistic traits leads us to consider that this singular entity fundamentally related to SHANK3 mutations could be a form of early-onset catatonia. Further case studies are needed to confirm our observations.

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Abstract Objective Narcolepsy is a rare sleep disorder in which psychotic‐like symptoms can present diagnostic and therapeutic challenges. We aimed to review the association between, and medical management of, narcolepsy and psychosis in children and adults. Methods We reviewed the full text of 100 papers from 187 identified by a PubMed search on narcolepsy plus any of these keywords: psychosis, schizophrenia, delusion, side effects, safety, and bipolar disorder. Results Three relevant groups are described. (i) In typical narcolepsy, psychotic‐like symptoms include predominantly visual hallucinations at the sleep‐wake transition (experienced as “not real”) and dissociation because of intrusion of rapid eye movement (REM) sleep phenomena into wakefulness. (ii) Atypical patients (“the psychotic form of narcolepsy”) experience more severe and vivid, apparently REM‐related hallucinations or dream/reality confusions, which patients may rationalize in a delusion‐like way. (iii) Some patients have a comorbid schizophrenia spectrum disorder with psychotic symptoms unrelated to sleep. Psychostimulants used to treat narcolepsy may trigger psychotic symptoms in all three groups. We analyzed 58 published cases from groups 2 and 3 (n = 17 and 41). Features that were reported significantly more frequently in atypical patients include visual and multimodal hallucinations, sexual and mystical delusions, and false memories. Dual diagnosis patients had more disorganized symptoms and earlier onset of narcolepsy. Conclusion Epidemiological studies tentatively suggest a possible association between narcolepsy and schizophrenia only for very early‐onset cases, which could be related to the partially overlapping neurodevelopmental changes observed in these disorders. We propose a clinical algorithm for the management of cases with psychotic‐like or psychotic features.

Ni, Guiyan; Gratten, Jacob; Wray, Naomi R; Lee, Sang Hong; Schizophrenia Working Group of the Psychiatric Genomics Consorti; (2018) Age at first birth in women is genetically associated with increased risk of schizophrenia. Scientific reports, 8 (1). 10168-. DOI: https://doi.org/10.1038/s41598018-28160-z Downloaded from: http://researchonline.lshtm.ac.uk/id/eprint/4652865/ DOI: https://doi.org/10.1038/s41598-018-28160-z

H a rold, De nis e, Con nolly, Siobh a n, Riley, Brie n P., Kendler, Kenn e t h S., McC a r t hy, S h a n e E., McCo m bie, Willia m R., Rich a r d s , Alex, Ow e n, Mich a el J. ORCID: h t t p s://o rcid.o rg/00 0 0-0 0 0 3-4 7 9 8-0 8 6 2, O'Donova n, Mich a el C. ORCID: h t t p s://o rcid.o rg/00 0 0-0 0 0 1-7 0 7 3-2 3 7 9, Walt e r s, Jam e s ORCID: h t t p s://o rcid.o rg/00 0 0-0 0 0 2-6 9 8 0-4 0 5 3, Donohoe, Ga ry, Gill, Mich a el, Co rvin, Aiden, Mo r ris, De r ek W. a n d H o pkins, Lucind a 2 0 1 9. Pop ula tion-b a s e d ide n ti ty-by-d e s c e n t m a p pin g co m bin e d wi t h exo m e s e q u e ncing to d e t e c t r a r e ri sk va ri a n t s for sc hizop h r e nia. Ame ric a n Jou r n al of M e dical Gen e tics Pa r t B: N e u ro psychia t ric Ge n e tics 1 8 0 (3) , p p . 2 2 3-2 3 1. 1 0.10 0 2/ajm g.b.327 1 6 file

La esquizofrenia de principio precoz (SDP) es una entidad nosografica reciente en pedopsiquiatria, actualmente definida como un trastorno multifactorial de desarrollo cerebral. Su etiopatogenia sigue siendo dificil de modelizar, intrincandose factores de riesgo geneticos, prenatales y unas desviaciones en juego en el desarrollo. La SDP presenta particularidades clinicas con relacion a la forma adulta, con tipicamente un desarrollo precoz alterado. Ademas, determinadas caracteristicas sintomaticas deben empujar el clinico a buscar formas secundarias, de origen somatico. La atencion debe ser integrativa e incluir un tratamiento antipsicotico, vigilandose con regularidad la aparicion de efectos indeseables.

La schizophrenie a debut precoce (SDP) est une entite nosographique recente en pedopsychiatrie, definie actuellement comme un trouble multifactoriel du developpement cerebral. Son etiopathogenie reste difficile a modeliser, intriquant des facteurs de risque genetiques, prenataux et des deviations neurodeveloppementales. La SDP presente des particularites cliniques par rapport a la forme adulte, avec typiquement un developpement precoce altere. De plus, certaines caracteristiques symptomatiques doivent pousser le clinicien a rechercher des formes secondaires, d’origine somatique. La prise en charge doit etre integrative et inclure un traitement antipsychotique, en surveillant regulierement l’apparition d’effets indesirables.[Resume d'editeur]

Data regarding the associations of anemia (hemoglobin level <13.0 g/dl in men and <12.0 g/dl in women) with clinical outcomes in patients with atrial fibrillation (AF) remains scarce. This study sought to investigate the associations of anemia with the incidences of stroke or systemic embolism, major bleeding, heart failure (HF) hospitalization, and all-cause mortality including its causes, using the data from a Japanese community-based survey, the Fushimi AF Registry. A total of 4,169 AF patients were divided into the 3 groups, based on the baseline hemoglobin level: no (n = 2,622), mild (11.0 to <13.0 g/dl for men and <12.0 g/dl for women; n = 880), and moderate/severe anemia (<11.0 g/dl; n = 667). During a median follow-up of 1,464 days, the incidences of major bleeding, HF hospitalization, and mortality increased with higher rates of cardiac death, in accordance with anemic severity. On multivariate analyses, the higher risk of moderate/severe anemia, relative to no anemia, for major bleeding remained statistically significant (hazard ratio [HR]: 2.00, 95% confidential interval [CI]: 1.48 to 2.72). The risks of those with anemia, relative to no anemia, for HF hospitalization (mild; HR: 1.87, 95% CI: 1.51 to 2.31, and moderate/severe; HR: 2.02, 95% CI: 1.59 to 2.57) as well as for mortality (mild; HR: 1.80, 95% CI: 1.50 to 2.16, and moderate/severe; HR: 2.95, 95% CI: 2.45 to 3.55) were also higher, but not for stroke/systemic embolism. These relations were consistent, regardless of the use of oral anticoagulants. In conclusion, anemia was associated with higher risks of HF hospitalization, mortality, and major bleeding in AF patients.

Psychotic disorders in children are more heterogeneous than is captured by categorical diagnoses. In a new cohort of children and adolescents, we evaluated the relationships among age at onset (AAO), clinical symptoms and developmental impairments. Patients with schizophrenia and other "spectrum" psychotic diagnoses (N = 88; AAO 6-17, mean 12.6) were evaluated with diagnostic interviews, a new clinical scale (Lifetime Dimensions of Psychosis Scale-Child and Adolescent), and neuropsychological and medical evaluations. Key findings were replicated in an adult cohort of 2420 cases, including 127 with retrospective AAO<13. Factor and cluster analyses were carried out to identify clinical profiles. Five clinical factors were identified in each cohort: Positive, Bizarre Positive, Negative/Formal Thought Disorder, Depression and Mania. Earlier AAO predicted severity of bizarre positive symptoms in children and of bizarre and other symptoms in adults. Four clinical clusters in the child cohort were characterized by: more severe bizarre positive symptoms (N = 31); negative symptoms (N = 15); premorbid autism spectrum features and developmental delay (N = 12); and depressive symptoms with heterogeneous diagnoses and mild positive/negative symptoms (N = 25). Previous factor-analytic studies of childhood psychosis did not specifically consider bizarre positive symptoms. Here, bizarre positive symptoms emerged as clinical markers of severe, childhood-onset psychosis similar to adult schizophrenia. The four clusters are clinically meaningful and useful for treatment planning and potentially for biological research. Childhood-onset cases are rare and thus difficult to study, but additional, larger cohorts may be useful in dissecting the biological and developmental heterogeneity of psychotic disorders.

Pediatric catatonia is a rare and severe neuropsychiatric syndrome. We previously reported, in 58 children and adolescents with catatonia, a high prevalence (up to 20%) of medical conditions, some of which have specific treatments.1 Here we extend the cohort inclusion and report the first systematic molecular genetic data for this syndrome. Among the 89 patients consecutively admitted for catatonia (according to the pediatric catatonia rating scale)2 between 1993 and 2014, we identify 51 patients (57.3%) who had genetic laboratory testing, of whom 37 had single nucleotide polymorphism (SNP) microarray tests for CNVs and 14 had routine genetic explorations (karyotyping and searches for specific chromosomal abnormalities by fluorescence in situ hybridization [FISH]) or a specific diagnosis test based on clinical history. To assess the causality of observed genetic findings in each patient, we used a causality assessment score (CAUS)3 including 5 causality-support criteria on a 3-point scale (0 = absent; 1 = moderate; 2 = high): the existence of similar cases in the literature; the presence of a clinical contributing factor; the presence of a biological contributing factor; the presence of other paraclinical symptoms; and response to a specific treatment related to the suspected genetic or medical condition.

Objective: Psychotic disorders in childhood and early adolescence often progress to chronic schizophrenia, but in many cases there are diagnosable medical and genetic causes or risk factors. We reviewed our clinical experience and the relevant literature to identify these factors and to define their clinical features, appropriate work-up and treatment. Method: We reviewed the results of comprehensive medical evaluations of 160 psychotic children and adolescents in our center. We also searched the Medline database (January 1994 to December 2015) with the following keywords and combinations: early onset schizophrenia, childhood onset schizophrenia, early onset psychosis, first episode psychosis, inborn errors of metabolism (IEM), genetic syndrome, copy number variants, autoimmune disorders, endocrine diseases, nutritional deficiencies, central nervous systeminfections, movement disorders, and epilepsy. Results: In our center, 12.5% of cases hadmedical disorders likely to be contributing to psychosis. Based on 66 relevant papers and our experience, we describe the clinical features ofmultiple genetic syndromes, IEM, and autoimmune, neurological, endocrinological and nutritional disorders that increase the risk of psychotic disorders in childhood and adolescence. We propose an algorithm for systematic laboratory evaluation, informed by clinical examination, emphasizing common and/or treatable factors. Conclusions: In children and early adolescentswith psychotic disorders, systematic medical work-up iswarranted to identify medical and genetic factors. Not every rare cause can beworked up, thus careful clinical examinations are required to detect medical, neurological and genetic signs. Comprehensive medical evaluation can detect treatable diseases among cases of early-onset psychosis. (c) 2017 Elsevier B.V. All rights reserved.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia. Several publications have shown that some polymorphisms are associated with COS. Identification of rare variants is just beginning, with regard to copy number variation (CNV) and de novo mutations.

Microduplication of chromosome 1q21.1 is observed in ~0.03% of adults. It has a highly variable, incompletely penetrant phenotype that can include intellectual disability, global developmental delay, specific learning disabilities, autism, schizophrenia, heart anomalies and dysmorphic features. We evaluated a 10-year-old-male with a 1q21.1 duplication by CGH microarray. He presented with major attention deficits, phonological dysphasia, poor fine motor skills, dysmorphia and mild autistic features, but not the typical macrocephaly. Neuropsychiatric evaluation demonstrated a novel phenotype: an unusually large discrepancy between non-verbal capacities (borderline-impaired WISC-IV index scores of 70 for Working Memory and 68 for Processing Speed) vs. strong verbal skills – scores of 126 for Verbal Comprehension (superior) and 111 for Perceptual Reasoning (normal). HYDIN2 has been hypothesized to underlie macrocephaly and perhaps cognitive deficits in this syndrome, but assessment of HYDIN2 copy number by microarray is difficult because of extensive segmental duplications. We performed whole-genome sequencing which supported HYDIN2 duplication (chr1:146,370,001-148,590,000, 2.22 Mb, hg38). To evaluate copy number more rigorously we developed droplet digital PCR assays of HYDIN2 (targeting unique 1 kb and 6 kb insertions) and its paralog HYDIN (targeting a unique 154 bp segment outside the HYDIN2 overlap). In an independent cohort, ddPCR was concordant with previous microarray data. Duplication of HYDIN2 was confirmed in the patient by ddPCR. This case demonstrates that a large discrepancy of verbal and non-verbal abilities can occur in 1q21.1 duplication syndrome, but it remains unclear whether this has a specific genomic basis. These ddPCR assays may be useful for future research on HYDIN2 copy number.

Background: Agenesis of the internal carotid artery (ICA) is a rare anatomic variation of the cerebral circulation.A malfunction during the embryonic period is at stake.It is very often asymptomatic and therefore discovered incidentally.Association with ischemic stroke is exceptional.Physiopathology is uncertain; the hypothesis of a blood flow reversal is reported in the literature.The diagnosis is based on the absence of a carotid canal as revealed by CT scans at skull base level with bone settings.Other non-invasive techniques, including echo-Doppler of the neck vessels, can now make the diagnosis.Objective: Discuss the association between occurrence of an ischemic stroke in the left posterior sylvian territory and discovery of ipsilateral carotid agenesis.Case report: A 24-year-old female patient was prospectively recruited at DAX hospital center (France).Vascular risk factors involved active smoking of 8 pack-years and a combined estrogen/progestin contraceptive.Her family history included an uncle with heterozygote Factor V Leiden mutation.She presented a left upper limb sensorimotor deficit.Nuclear Magnetic Resonance Angiography (MRA) revealed a right superficial sylvian ischemic stroke associated with agenesis of the right internal carotid artery.CT scan at skull base level with bone settings showed absence of a right carotid canal, thus confirming agenesis.An opinion was then requested for an arteriography which showed an operative polygon of Willis, a sylvian artery or middle cerebral artery (MCA) irrigated by a very large right posterior communicating artery (PCOM) and the left anterior cerebral artery (ACA) supplied by the anterior communicating artery (ACOM), through the left carotid system.The right sylvian territory where stroke occurred was therefore supplied by the functional vertebrobasilar system.ECG and four-day meticulous monitoring detected no cardiac rhythm disorders.Transesophageal echocardio-

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium–potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.