Nr2f1 heterozygous knockout mice recapitulate neurological phenotypes of Bosch-Boonstra-Schaaf optic atrophy syndrome and show impaired hippocampal synaptic plasticity.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) has been identified as an autosomal-dominant disorder characterized by a complex neurological phenotype, with high prevalence of intellectual disability and optic nerve atrophy/hypoplasia. The syndrome is caused by loss-of-function mutations in NR2F1, which encodes a highly conserved nuclear receptor that serves as a transcriptional regulator. Previous investigations to understand the protein's role in neurodevelopment have mostly used mouse models with constitutive and tissue-specific homozygous knockout of Nr2f1. In order to represent the human disease more accurately, which is caused by heterozygous NR2F1 mutations, we investigated a heterozygous knockout mouse model and found that this model recapitulates some of the neurological phenotypes of BBSOAS, including altered learning/memory, hearing defects, neonatal hypotonia and decreased hippocampal volume. The mice showed altered fear memory, and further electrophysiological investigation in hippocampal slices revealed significantly reduced long-term potentiation and long-term depression. These results suggest that a deficit or alteration in hippocampal synaptic plasticity may contribute to the intellectual disability frequently seen in BBSOAS. RNA-sequencing (RNA-Seq) analysis revealed significant differential gene expression in the adult Nr2f1+/- hippocampus, including the up-regulation of multiple matrix metalloproteases, which are known to be critical for the development and the plasticity of the nervous system. Taken together, our studies highlight the important role of Nr2f1 in neurodevelopment. The discovery of impaired hippocampal synaptic plasticity in the heterozygous mouse model sheds light on the pathophysiology of altered memory and cognitive function in BBSOAS.

Phenotypic expansion of Bosch-Boonstra-Schaaf optic atrophy syndrome and further evidence for genotype-phenotype correlations.

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is an autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in NR2F1 and characterized by visual impairment, developmental delay, and intellectual disability. Here we report 18 new cases, provide additional clinical information for 9 previously reported individuals, and review an additional 27 published cases to present a total of 54 patients. Among these are 22 individuals with point mutations or in-frame deletions in the DNA-binding domain (DBD), and 32 individuals with other types of variants including whole-gene deletions, nonsense and frameshift variants, and point mutations outside the DBD. We corroborate previously described clinical characteristics including developmental delay, intellectual disability, autism spectrum disorder diagnoses/features thereof, cognitive/behavioral anomalies, hypotonia, feeding difficulties, abnormal brain MRI findings, and seizures. We also confirm a vision phenotype that includes optic nerve hypoplasia, optic atrophy, and cortical visual impairment. Additionally, we expand the vision phenotype to include alacrima and manifest latent nystagmus (fusional maldevelopment), and we broaden the behavioral phenotypic spectrum to include a love of music, an unusually good long-term memory, sleep difficulties, a high pain tolerance, and touch sensitivity. Furthermore, we provide additional evidence for genotype-phenotype correlations, specifically supporting a more severe phenotype associated with DBD variants.

Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies.

PURPOSE: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. METHODS: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. RESULTS: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. CONCLUSION: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome.

BACKGROUND: Nonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties and autism spectrum disorder. Prader-Willi syndrome (PWS) is a genetic disorder characterised by severe infantile hypotonia, hypogonadotrophic hypogonadism, early childhood onset obesity/hyperphagia, developmental delay/intellectual disability and short stature. Scoliosis and growth hormone insufficiency are also prevalent in PWS.There is extensive documentation of the endocrine and metabolic phenotypes for PWS, but not for SYS. This study served to investigate the hormonal, metabolic and body composition phenotype of SYS and its potential overlap with PWS. METHODS: In nine individuals with SYS (5 female/4 male; aged 5-17 years), we measured serum ghrelin, glucose, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3, follicle-stimulating hormone, luteinising hormone, thyroid-stimulating hormone, free T4, uric acid and testosterone, and performed a comprehensive lipid panel. Patients also underwent X-ray and dual-energy X-ray absorptiometry analyses to assess for scoliosis and bone mineral density. RESULTS: Low IGF-1 levels despite normal weight/adequate nutrition were observed in six patients, suggesting growth hormone deficiency similar to PWS. Fasting ghrelin levels were elevated, as seen in individuals with PWS. X-rays revealed scoliosis >10° in three patients, and abnormal bone mineral density in six patients, indicated by Z-scores of below -2 SDs. CONCLUSION: This is the first analysis of the hormonal, metabolic and body composition phenotype of SYS. Our findings suggest that there is marked, but not complete overlap between PWS and SYS.

Sleep spindle activity is associated with state- and trait-based emotion in healthy school-aged children.

BACKGROUND: While connections between children's sleep and their daytime functioning are well established, less is known about the microstructural features of sleep that support emotional wellbeing. Investigating these relationships in healthy children may provide insight into adaptive emotional development. We therefore examined associations between non-rapid eye movement (N2) sleep spindles and both state- and trait-based measures of emotion. METHODS: A sample of 30 children (7-11 years) without psychiatric disorders completed a baseline assessment, one night of at-home polysomnography (PSG), and an in-lab emotional state assessment the next day including self-reported arousal in response to affective images. Trait-based measures of anxiety and depression as well as savoring, a positive emotion regulatory strategy, were also completed. N2 sleep spindle parameters, including spindle density (number/min) and peak frequency in central regions, were detected using an automated algorithm. RESULTS: Greater spindle density was significantly associated with decreased state-based emotional arousal towards negative affective images, and greater spindle peak frequency was associated with greater trait-based use of savoring. However, neither spindle parameter was associated with child anxiety or depressive symptoms. CONCLUSIONS: Findings align with and expand on prior research to suggest that N2 sleep spindles support adaptive emotional functioning in school-aged children.

Do weighted blankets improve sleep among children with a history of maltreatment? A randomized controlled crossover trial.

STUDY OBJECTIVES: Sleep disruption is prevalent and persistent among children who experience maltreatment/interpersonal trauma. Weighted blankets have gained popularity in recent years as a potential non-pharmacological intervention for improving sleep in various populations, but their efficacy has not been examined among maltreated children. The current study used a randomized, within-subjects, crossover design to examine whether the use of a weighted blanket improves objective and/or subjective indices of sleep among 30 children, ages 6 to 15 years (M = 9.7, SD = 2.9) adopted from foster care. METHODS: Participants used a weighted blanket for two weeks and their usual blanket for two weeks in a counterbalanced order. Sleep outcomes were measured using actigraphy and subjective sleep diaries. RESULTS: No differences in actigraphy-based or subjective estimates of total sleep time, sleep onset latency, wake after sleep onset, or sleep quality ratings were found based on blanket type. Child age, biological sex, timing of participation (school year versus summer months), and maltreatment/trauma history did not impact outcomes. CONCLUSIONS: Although we did not find evidence that weighted blankets improve sleep among children with a history of maltreatment/interpersonal trauma, additional well-controlled studies using larger samples of children are needed.

Increased symptom severity in adults and adolescents admitting to an inpatient psychiatric hospital during the COVID-19 pandemic.

While the negative effects of Coronavirus Disease-2019 (COVID-19) on general mental health are well-established, less is known about the impact on those with severe mental illness. Thus, this study examined symptom severity among psychiatric inpatients admitted prior to versus during the COVID pandemic. Self-reported anxiety (GAD-7), depression (PHQ-9), emotional dysregulation (DERS-SF), sleep quality (PSQI), nightmares (DDNSI), and suicidal ideation (SBQ-R) were examined in 470 adults (n = 235 admitted pre-pandemic) and 142 children and adolescents (n = 65 admitted pre-pandemic) at admission. Adults also completed measures of disability (WHODAS) and substance use (WHOASSIST). Adults admitted during the COVID pandemic reported significantly higher levels of anxiety [p < .001, partial η2=0.18], depression [p < .001, partial η2=0.06], emotion dysregulation [p < .001, partial η2=0.05], nightmares [p = .013, partial η2=0.01], and disability [p < .001, partial η2=0.04] compared to adults admitted pre-COVID. Levels of anxiety [p = .005, partial η2=0.05], depression [p = .005, partial η2=0.06], and sleep quality [p = .011, partial η2=0.05] were significantly higher among adolescents admitted during COVID compared to pre-COVID. The findings help identify areas of prioritization for future mental health prevention/intervention efforts for future disease outbreaks.

Polysomnographic characteristics and sleep-disordered breathing in Schaaf-Yang syndrome.

INTRODUCTION: Schaaf-Yang syndrome (SYS) is a genetic disorder caused by truncating variants in the MAGEL2 gene located in the maternally imprinted Prader-Willi syndrome (PWS) region at 15q11-13. The SYS phenotype shares features with PWS, a syndrome with known high incidence of sleep disorders. However, the spectrum of sleep-disorders in SYS has not been described. METHODS: We performed a retrospective analysis of polysomnograms from 22 patients in an international SYS cohort. Sleep characteristics for individuals with the common c.1996dupC variant (n = 10) were compared to other truncating variants (n = 11). RESULTS: We collected 33 sleep study reports from 22 patients, ages 2 months - 18.5 years (mean 6.5 years). Mean sleep efficiency was 70.5% (range 45%-93%) with arousal index 14.1/h (1.2-45/h). The mean apnea-hypopnea index (AHI) was 19.1/h (0.9-49/h) with mean obstructive AHI (oAHI) of 16.3/h (0.6-49/h). Mean central apnea index was 2.8/h (0-14/h). Mean oxygen desaturation index was 20.8/h (range 0-85/hr). Obstructive sleep apnea (OSA) was diagnosed in 81%, and 62% had moderate or severe OSA. Elevated central apnea index occurred in 9.5%. Comparison by genotype groups and age did not reveal any difference in OSA findings. Periodic limb movement index (PLMI) was elevated in 4/15 (26%). CONCLUSION: OSA is frequently identified on polysomnography in patients with SYS. The mean PLMI is elevated compared to normative data. Patients with SYS should have routine polysomnography screening due to high risk of sleep disorders.