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Insomnia is a common, impairing, and difficult-to-treat comorbidity in children with neurodevelopmental disorders (NDDs). Behavioral interventions can be challenging because of developmental and behavioral features that interfere with treatment. Medication management also can be difficult due to a high burden of side effects, a high rate of paradoxical responses, and frequent treatment resistance. Therefore, new treatment options for insomnia in children with NDDs are needed. Dual orexin receptor antagonists (DORAs) are a relatively new class of pharmacotherapeutics that induce sleep by inhibiting the orexin signaling pathway. To date, there is little safety or efficacy data on the use of DORAs in children with NDDs. We present four patients with NDDs and insomnia that we treated with the DORA, suvorexant. We found that patients had a wide range of responses, with one patient displaying a robust improvement in sleep onset and maintenance, while another had significant improvement in insomnia symptoms on combination therapy with trazodone. Our final two patients had mild or no benefit from suvorexant therapy. Further research is necessary to establish the safety and efficacy of DORAs in this population and to identify predictive factors, such as specific neurogenetic diagnoses or clinical features, of a positive treatment response.

Individuals with neurodevelopmental disabilities (NDDs) may be at increased risk for catatonia, which can be an especially challenging condition to diagnose and treat. There may be symptom overlap between catatonia and NDD-associated behaviors, such as stereotypies. The diagnosis of catatonia should perhaps be adjusted to address symptom overlap and to include extreme behaviors observed in patients with NDDs, such as severe self-injury. Risk factors for catatonia in individuals with NDDs may include trauma and certain genetic variants, such as those that disrupt SHANK3. Common etiologic features between neurodevelopmental disabilities and catatonia, such as excitatory/inhibitory imbalance and neuroimmune dysfunction, may partially account for comorbidity. New approaches leveraging genetic testing and neuroimmunologic evaluation may allow for more precise diagnoses and effective treatments.

Diagnostic genetic testing is recommended for children with autism spectrum disorder and other neurodevelopmental disorders. One approach to improve access to genetic testing is to offer it on the inpatient child and adolescent psychiatry (CAP) service. We provided medical genetics education to CAP fellows and retrospectively compared the genetic testing rates and diagnostic yield pre- and post-education. We compared demographics to similar patients who received testing on other clinical services and assessed rates of outpatient genetics follow-up post-discharge. The genetic testing rate on the inpatient CAP service was 1.6% before the educational intervention and 10.7% afterward. Genetic risk factors were identified in 4.3% of inpatients. However, 34.8% had variants of unknown significance. 39.1% of patients who received genetic testing while inpatients were underrepresented minorities, compared to 7.7% of inpatients who received genetic testing from other clinical services. 43.5% of patients were lost to outpatient genetics follow-up. We have demonstrated that it is feasible to provide medical genetics education to CAP fellows on an inpatient service, which may improve genetic testing rates. This preliminary evidence also suggests that genetic testing for inpatients may identify variants of unknown significance instead of well-known neurodevelopmental disorder risk variants. Genetic testing on an inpatient CAP service may also improve access to genetic services for underrepresented minorities, but assuring outpatient follow-up can be challenging. LAY SUMMARY: Genetic testing is recommended for children with autism and related developmental conditions. We provided genetic testing to a group of these children who were in a psychiatric hospital by teaching their doctors how it can be helpful. We identified a genetic risk factor in a small percentage of children and a possible genetic risk factor in a large percentage of children. However, many children did not end up receiving their genetic test results once they left the hospital. These results tell us that the psychiatric hospital may be a good place for children with autism and behavioral problems to get genetic testing, but that it is really important that doctors assure follow-up is feasible for all patients to receive their genetic test results once they leave the hospital. Autism Res 2020, 13: 1450-1464. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Cobalamin C disease is the most common complementation class of Cobalamin disorders. Here, we present a case of a 14-year-old male with early-onset cblC disease and autism spectrum disorder (ASD) admitted to our inpatient medical service for behavioral decompensation. We use this case to highlight key aspects of the neurodevelopmental and neuropsychiatric disorders associated with cblC disease. By incorporating a comprehensive review of existing literature, we highlight salient domains of psychological impairment in cblC disease, discuss the full range of neuropsychiatric presentations, and review clinical management implications unique to cblC disease.

Alison R Hwong,1 Stefana Morgan,1 Chelsea Anne Young,2 Aaron D Besterman,3 Michael Jacob,1 Jody Williams,1 Victor I Reus,1 Carol A Mathews,4 Erick Hung,1 Susan Voglmaier1 1Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA; 2Department of Psychiatry, Stanford University, Palo Alto, CA, USA; 3Department of Psychiatry, University of California, San Diego, CA, USA; 4Department of Psychiatry, College of Medicine at the University of Florida, Gainesville, FL, USACorrespondence: Alison R HwongUniversity of California, San Francisco, Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, 401 Parnassus Avenue, Box 0984, San Francisco, CA, 94143-0983, USATel +1 406 414 7185Email alison.hwong@ucsf.eduAbstract: Psychiatry residency programs with robust research training can prepare physician-scientists to make contributions that advance the mental health field. Our psychiatry residency developed a chief resident for research position to help provide mentorship, community building, and advising around scholarly activities for residents. We present the process of implementing this new position in our residency to offer a model for engaging psychiatry residents in research.Keywords: academic psychiatry, residency training, research career

Background The development of advanced genetic technologies has resulted in rapid identification of genetic etiologies of neurodevelopmental disorders (NDDs) and has transformed the classification and diagnosis of various NDDs. However, diagnostic genetics has far outpaced our ability to provide timely medical counseling, guidance, and care for patients with genetically defined NDDs. These patients and their caregivers present with an unmet need for care coordination across multiple domains including medical, developmental, and psychiatric care, and for educational resources and guidance from care professionals. After a genetic diagnosis is made, families also face several barriers in access to informed diagnostic evaluations and medical support. Methods As part of Care and Research in Neurogenetics (CARING), a multidisciplinary clinical program for children and adults with neurogenetic disorders, we conducted qualitative clinical interviews about the diagnostic journey of families. This included the overall timeline to receiving diagnoses, experiences before and after diagnosis, barriers to care, and resources that helped them to navigate the diagnostic process. Results A total of 37 interviews were conducted with parents of children ages 16 months to 33 years. Several key themes were identified: 1) delays between initial caregiver observations of developmental delays and formal developmental or genetic diagnoses; 2) practical barriers to clinical evaluation and care, including long wait times for an appointment, lack of insurance coverage, availability of local evaluations, transportation difficulties, and native language differences; 3) the importance of being part of a patient advocacy group to help navigate the diagnostic journey; and (4) unique challenges faced by adults (18 years or older). Conclusions Families of children with complex neurodevelopmental and genetic disabilities face numerous challenges in finding adequate medical care and services for their child. They experience considerable delays in receiving timely diagnoses and face significant barriers that further delay the process of receiving access to services needed for the child’s continued care. The gaps indicated in this study speak to the need for more comprehensive coordination of care for patients with intellectual and developmental disabilities, as well as the development of systematic, disorder-specific resources both for providers and families in order to improve patient outcomes.

Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in MTOR. The pathogenicity of novel variants in MTOR in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of MTOR variant pathogenicity. We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic MTOR variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of MTOR variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS., Author summary Smith-Kingsmore Syndrome is a rare disease caused by damage in a gene named MTOR that is associated with excessive growth of the head and brain, delays in development and deficits in intellectual functioning. We report 7 patients who have changes in MTOR that have never been reported before. We describe new medical findings in these patients that may be common in Smith-Kingsmore Syndrome more broadly. We then identify how these new gene changes impact the function of the MTOR protein and thus cell function downstream. Lastly, we show that changes in the gene that lie deep inside the 3D structure of the MTOR protein are more likely to cause disease than those changes that lie on the surface of the protein. We may be able to use the 3D properties of MTOR gene changes to predict if future changes we see are likely to cause disease or not.

The International Society of Psychiatric Genetics (ISPG) created a Residency Education Committee with the purpose of identifying key genetic knowledge that should be taught in psychiatric training programs. Thirteen committee members were appointed by the ISPG Board of Directors, based on varied training, expertise, gender, and national origin. The Committee has met quarterly for the past 2 years, with periodic reports to the Board and to the members of the Society. The information summarized includes the existing literature in the field of psychiatric genetics and the output of ongoing large genomics consortia. An outline of clinically relevant areas of genetic knowledge was developed, circulated, and approved. This document was expanded and annotated with appropriate references, and the manuscript was developed. Specific information regarding the contribution of common and rare genetic variants to major psychiatric disorders and treatment response is now available. Current challenges include the following: (1) Genetic testing is recommended in the evaluation of autism and intellectual disability, but its use is limited in current clinical practice. (2) Commercial pharmacogenomic testing is widely available, but its utility has not yet been clearly established. (3) Other methods, such as whole exome and whole genome sequencing, will soon be clinically applicable. The need for informed genetic counseling in psychiatry is greater than ever before, knowledge in the field is rapidly growing, and genetic education should become an integral part of psychiatric training.

ObjectiveFor psychiatry research resident career development, there is a recognized need for improved cross-institutional mentoring and networking opportunities. One method to address this need is via regional conferences, open to current and recently graduated research residents and their mentors. With this in mind, we developed the biennial California Psychiatry Research Resident Retreat (CPRRR) and collected feedback from participants to 1) Assess resident satisfaction, 2) Determine the utility of the retreat as a networking and mentorship tool, and 3) Identify areas for improvement.MethodsWe gathered survey data from resident attendees at the two first CPRRRs. We analyzed the data to look for trends in satisfaction as well as areas that need improvement.ResultsThirty-two residents from five California training programs attended the CPRRR in 2013 while 33 attended from six programs in 2015. The residents were from all years of training, but concentrated in their second and third years. Approximately 41% and 49% of the attendees were female and 53% and 39% had an MD/PhD in 2013 and 2015, respectively. Twenty-four and 32 residents provided anonymous feedback in 2013 and 2015, respectively. Mean feedback scores were very high (> 4/5) for overall satisfaction, peer- and faculty-networking, the keynote speaker and the flash talks for both years. Mean feedback scores for the ethics debates and mentoring sessions were somewhat lower (≤ 4/5), however, both showed significant improvement from 2013 to 2015.ConclusionThe CPRRRs appear to be an effective mechanism for providing psychiatry research residents with a meaningful cross-institutional opportunity for networking and mentorship. Feedback-driven changes to the CPRRRs improved participant satisfaction for several components of the conference. Future efforts will be aimed at broadening mentorship and networking opportunities, optimizing teaching approaches for research ethics, and considering different feedback-gathering approaches to allow for improved longitudinal follow-up and subgroup analysis.

Fragile X-associated disorders are a group of disorders caused by expansion of noncoding CGG repeat elements in the fragile X (FMR1) gene. One of these disorders, fragile X syndrome, is the most common heritable cause of intellectual disability, and is caused by large CGG repeat expansions (>200) resulting in silencing of the FMR1 gene. An increasingly recognized number of neuropsychiatric fragile X-associated disorders have recently been identified that are caused by ‘premutation’ range expansions (55–200). These disorders are characterized by a spectrum of neuropsychiatric manifestations ranging from an increased risk of neurodevelopmental, mood and anxiety disorders to neurodegenerative phenotypes, such as the fragile X-associated tremor ataxia syndrome. This article reviews the advances in the clinical understanding of neuropsychiatric disorders in premutation carriers across the lifespan and offers guidance for the detection of such disorders by practicing psychiatrists and neurologists.

Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 25, Number x, 2015 a Mary Ann Liebert, Inc. Pp. 1–2 DOI: 10.1089/cap.2015.0107 Letter to the Editor Psychopharmacological Management of Problem Behaviors in Mowat–Wilson Syndrome Aaron D. Besterman, MD, 1 and Robert L. Hendren, DO 1,2 To The Editor: ZEB2 gene, which is predicted to disrupt the canonical splice site between exons 2 and 3. Psychotropic management was initiated by a child neurologist for seizure control and problem behaviors such as irritability, tan- trums, aggression, and nighttime awakenings. In summary, levetir- acetam was found to be helpful for seizure control, but was ultimately discontinued because of worsening aggression and nighttime awak- enings. Ethosuximide, clobazam, and divalproex sodium were also found to be helpful in seizure control, but did not have significant effects on behavior. Risperidone was found to be moderately helpful in reducing the frequency and intensity of tantrums, but overall be- havior remained significantly problematic. Melatonin and clonidine were trialed as sleep aids, without benefit. Amphetamine/dextro- amphetamine salts were trialed for 3 weeks to target attention, but then were stopped because of exacerbation of irritability and tan- trums. At the time of referral for ongoing behavioral management, the patient was on a regimen of risperidone 1.5 mg twice daily, ethosuximide 7 mL b.i.d., and clonidine 0.05 mg at bedtime. On initial presentation, the patient’s father reported that she fre- quently hit caretakers, but would then kiss them ‘‘as if to apologize.’’ She had chronic irritability with sporadic tantrums for up to an hour, with unclear triggers. She awoke several times per night, with in- termittent sleep terrors. We hypothesized that part of her irritability might be the result of difficulty keeping focus on external tasks; therefore, we started dexmethylphenidate 2.5 mg daily. She devel- oped worse aggression and new biting behavior, and was sent home from school for being ‘‘out of control,’’ ultimately leading to a brief hospitalization. We started the patient on olanzapine ODT 2.5 mg at night and divalproex sodium 125 mg b.i.d., up to 250 mg b.i.d, and slowly tapered her off of dexmethylphenidate and risperidone. Im- provements in behavior and sleep were observed; therefore, olan- zapine ODT was gradually increased to 2.5 mg in morning and 10 mg at night. On this new regimen, the patient’s sleep greatly improved with fewer nighttime awakenings, almost-resolved night terrors, improved behavior and learning in school, and less intense and fre- quent tantrums. However, her behavior continued to fluctuate with environmental factors, such as seasonal allergies, and she has gained significant weight since initiating olanzapine ODT. M owat–Wilson Syndrome (MWS) is a neurodevelop- mental disorder characterized by intellectual disability (ID), Hirschsprung disease, agenesis of the corpus collosum, seizures, expressive language deficits, a distinct facial gestalt, congenital heart defects, and behavioral dysregulation, with a happy and social demeanor (Adam et al. 2006). It is caused by de novo heterozygous mutations in the ZEB2 gene, which is produced at high levels in postmitotic neocortical neurons and may play a role in determining neuronal cell fate in corticogenesis (Seuntjens et al. 2009). The be- havioral phenotype associated with MWS was recently characterized in a systematic evaluation of 61 MWS patients (Evans et al. 2012). The MWS behavioral profile was then compared with contrast par- ticipants with ID of various etiologies. Individuals with MWS were found to have higher rates of several behaviors, such as being un- realistically happy or elated and underreacting to pain. However, overall rates of clinically significant psychopathology were similar to the general ID population at *30% (Evans et al. 2012). Evidence-based psychopharmacological approaches can be used to target behavioral and emotional symptoms in individuals with MWS. However, the evidence base is built on studies of individuals with ID of many etiologies (Handen and Gilchrist 2006). Reporting of anecdotal clinical successes and failures in the MWS population specifically is a first step to improving future treatment outcomes. To our knowledge, there are currently no reports in the literature on the psychopharmacological management of problem behaviors in pa- tients with MWS. Therefore, we report our experience with a single patient in hopes that it may act as a starting point toward more precise behavioral management strategies for individuals with MWS. Case Report The patient was a 5-year-old nonverbal girl with ID, seizures, behavioral dysregulation, hypoalgesia, and gastrointestinal motility difficulties. Pregnancy and birth occurred without complication. The patient rolled over at 4 months, walked at 16 months, and babbled at 6 months, but then lost her verbal language abilities until she started babbling again at 4 years of age. Her language com- prehension was intact, but she is learning sign language to ex- press herself. Her developmental course had been complicated by seizures, with early-onset absence seizures and later-onset myo- clonic and atonic seizures. Serial head MRIs revealed trace thin- ning of periatrial white matter without progression. Exome sequencing revealed a c.73 + 1G > T pathogenic variant in the Discussion For many MWS patients with both behavioral problems and seizures, the two can be interrelated, and patients can undergo behavioral decompensation in a post-ictal period or put themselves at increased risk for seizures by becoming agitated and stressed. Department of Psychiatry and 2 Division of Child and Adolescent Psychiatry University of California, San Francisco, California. Funding: This work was supported by the National Institute of Mental Health grant R25MH060482.

Received July 8, 2014; revised August 9, 2014; accepted August 11, 2014. FromSchool ofMedicine, University of California San Francisco, San Francisco, CA (WBF); Department of Psychiatry, University of California San Francisco, San Francisco, CA (ADB, JJD, JAB); Department of Radiology andBiomedical Imaging, University of California San Francisco, San Francisco, CA (J-PJY). Send correspondence and reprint requests to William B. Feldman, D.Phil., School of Medicine, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143; e-mail: william.feldman@ucsf.edu & 2015 The Academy of PsychosomaticMedicine. Published by Elsevier Inc. All rights reserved. Introduction

Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a complex genetic etiology. Little is known about the role of inherited common variants in the development of ASD and it’s persistent, and perhaps increased, frequency in our population, despite decreased fecundity in ASD individuals. One possible explanation for this phenomenon is assortative mating. Individuals with elevated, but sub-diagnostic ASD behaviors may be more likely than chance to mate, and thus increase the likelihood of their offspring of inheriting an underlying genetic load that pushes them over the ASD diagnostic threshold. In parents of children with ASD, we investigate 1) If genetic risk for ASD, schizophrenia (SCZ) or height can predict ASD-like behaviors 2) If they are more similar than chance in their ASD-like behaviors and their genetic risk for ASD, SCZ or height and 3) If there is a correlation between ASD behavioral and genetic similarity. Methods Analyses were performed on 2727 Caucasian parental pairs of children with ASD in the Simons Simplex Collection. All parents completed the Broad Autism Phenotype Questionnaire (BAPQ) and were genotyped via microarray. After standard quality control measures, Polygenic Risk Scores (PRS) were calculated in PLINK using summary data from published GWAS for SCZ, ASD, and height. Linear regression was performed in R to predict individual PRS based on individual BAPQ scores for all phenotypes. Degree of correlation between mothers and fathers was calculated for both BAPQ scores and PRS for SCZ, ASD, and height. Finally, the degree of correlation was calculated between the squared difference of mother and father BAPQ scores and the squared difference between mother and father PRS for all phenotypes. Results For parents of children with ASD, individual PRS for ASD, SCZ or height did not predict individual BAPQ total or subscale scores (b = -0.06 – 0.3 , p > 0.01). Total BAPQ score and BAPQ pragmatic subscale scores were strongly correlated between parents (r = 0.14 , p = 1.4e-12 ; r = 0.11 , p = 2.4e-8). PRS for both ASD and SCZ were also strongly correlated between parents (r = 0.16, p = 1.1e-9; r = 0.19, p = 3.9e-14). Height PRS were more weakly correlated (r = 0.08, p = 0.003). Squared difference of parental PRS scores for all phenotypes were not predictive of the squared difference of parental total BAPQ scores or any subscales (b = -0.07 – 0.02, p ≥ 0.01). Discussion Assortative mating is an established phenomenon in individuals with ASD. Here, we show that parents of individuals with ASD are also more likely than chance to highly correlate on broad autism phenotype measures, primarily on pragmatic language measures. Pragmatic language measures are, for example, when someone says inappropriate or unrelated things during conversations or has little variety in language use. Further, we found that parents of children with ASD have highly correlated PRS for both ASD and SCZ, but not height (our non-psychiatric control phenotype). Therefore, we hypothesized that the degree of correlation between ASD and SCZ genetic risk may predict correlation on total BAPQ measures or on the BAPQ pragmatic language subscale. However, the results of this analysis found that there was no significant correlation between these measures. This suggests that the genetic similarity we captured through PRS may reflect assortative mating in parents of ASD individuals due to factors other than autistic-like behaviors and that there are yet unknown factors underlying BAPQ similarities between parents of ASD individuals.

Background: The prevalence of multiple sclerosis (MS) in the Middle East has been reported to be low to medium. Methods: To verify this assertion we conducted a review of published data on the occurrence of MS in the Middle East.Results: Fourteen studies reporting on the prevalence of MS in the Middle East were initially identified, 5 of which were excluded due to inadequate data or serious methodological limitations. The data from the 9 included studies suggested that the prevalence of MS may vary widely within the Middle East, from low to high. However, these 9 studies were inconsistent in case ascertainment, inclusion criteria and methods of prevalence calculation, and most did not include age/sex standardization. Conclusion: Methodological inconsistencies among studies make it difficult to be confident in drawing conclusions about the prevalence of MS in the Middle East. Nevertheless, there is little evidence to support the assertion that the prevalence of MS in the Middle East is low to medium. Rather, the prevalence of MS in the Middle East may range from low to high, depending on the specific population and environment of study. However, to confirm these findings, further epidemiological research is needed.