Many genes have been identified in autism spectrum disorder (ASD). Yet how many adults with ASD receive recommended genetic testing and their outcomes is unknown. We investigated the percentage of adults with ASD with documented genetic testing in our ASD specialty clinic and the percentage with positive findings. Adults were identified through search of our data repository and ASD diagnoses confirmed using record review by psychiatrists specializing in ASD. Patients were included (N = 630) who had at least one visit with a qualifying clinician between 5/1/2010 and 12/15/2020. Data were collected through manual retrospective record review. Only 41

Myhre syndrome is a rare genetic disorder caused by pathogenic variants in SMAD4. The neurocognitive profile may include intellectual disability and developmental delay across a wide spectrum of domains. Four individuals with Myhre syndrome and psychosis and/or schizophrenia have been reported. We discuss three additional individuals (one briefly mentioned in a review of patients with Myhre syndrome) with SMAD4 pathogenic variants at codon Arg496Cys (two cases) and codon Ile500Val (one case). All had social challenges and variable developmental delays. They presented with acute-onset psychosis and were diagnosed with either psychosis, not otherwise specified, or psychosis associated with bipolar disorder. The seven individuals (5 female, 2 male) ranged in age from 13 to 24 years (mean 18.7 years) and had variable responses to pharmacologic and behavioral interventions. The underlying mechanism of psychosis in Myhre syndrome may be due to disruptions in the TGF-β signaling pathway, which involves the interactions of TGF-β family members and SMAD proteins, including SMAD4. Although additional cases are needed to verify our observations, psychosis may be a component of the neurodevelopmental phenotype of Myhre syndrome, highlighting the importance of rapid psychiatric evaluation and intervention.

OBJECTIVE:Eating disorder (ED) symptoms have been studied in adults with other rare genetic conditions but not in Williams syndrome (WS). This study examined the prevalence of ED symptoms in adults with WS and associated clinical and demographic factors. We hypothesized that a proportion would screen positive for an ED, primarily with avoidant/restrictive food intake disorder (ARFID) or binge-eating presentations. METHOD:Adults with WS completed modified versions of the Eating Disorder Assessment for DSM-5 and the Pica, ARFID, and Rumination Disorder Questionnaire, administered as semi-structured interviews by trained research staff. Participants also completed a medical history questionnaire. We used descriptive and between-group analyses to examine clinical and demographic characteristics of ED-positive and ED-negative groups. RESULTS:Of the 86 participants, more than one quarter (n = 24, 28%; 95% CI [20%, 38%]) screened positive for an ED. Adults who screened positive for an ED most commonly had binge-type EDs (n = 15, 63%; 95% CI [43%, 79%]) and ARFID-type EDs (n = 7, 29%; 95% CI [15%, 49%]). Of those who screened positive, 96% reported they had never been previously diagnosed with an ED. DISCUSSION:Our study provides initial evidence of a high frequency of positive ED screens in adults with WS, most commonly ARFID-type and binge-type EDs. Our findings also suggest that, while prevalent in WS, EDs typically go undetected, and that it may be difficult to identify at-risk individuals. There is a need to validate ED screeners for adults with WS to enhance detection and access to care.

PURPOSE:Individuals with Williams syndrome (WS) are disproportionately affected by anxiety. However, gaps remain in our knowledge of the clinical presentation and impact of anxiety in this population. The objectives of this study were to (1) better understand the phenomenology and impact of anxiety in this population without the constraints of standardized mental health diagnostic criteria, and (2) compare caregiver and participants with WS report of anxiety. METHODS:One-hundred caregivers and 79 individuals with WS participated in open-ended, semi-structured interviews designed to learn more about the symptoms, content, and impact of anxiety on individuals with WS. The interviews were analyzed using a six-step thematic analysis approach. McNemar's test was performed to compare the frequency for which each code was reported by caregivers versus WS participants. RESULTS:Thematic analysis revealed five main themes: (1) observable signs of anxiety, (2) anxiety content, (3) interference of anxiety, (4) caregiver accommodation, and (5) response to anxiety. Caregivers were more likely to report all codes than participants with WS, with the exception of physical signs of anxiety. CONCLUSION:This study provides a deeper understanding of common signs and symptoms of anxiety in individuals with WS, as well as the types of symptoms that are best ascertained through caregiver versus self-report.

William syndrome (WS) is a rare genetic disorder with common features that generally include mild intellectual disability, cardiovascular disease, anxiety, attention-deficit/hyperactivity disorder, hyperacusis, and a highly social and empathic personality. The musical proclivity of individuals with WS has been well studied over the years including brain imaging findings on fMRI that correlate with emotion based areas when music is played. To our knowledge though, there have been no case reports detailing this relationship between WS and music. Here we describe a case of an individual with WS for whom music has been a central aspect of his life. We explore his own personal experience with music ranging from listening to music, to performing in theatre productions whilst overcoming anxiety, and even impacting others with disabilities through his own band.

Objectives: Despite growing knowledge of the underlying neurobiology of autism spectrum disorder (ASD) and related neurogenetic syndromes, treatment discovery has remained elusive. In this review, we provide a blueprint for translational precision medicine in ASD and related neurogenetic syndromes. Methods: The discovery of trofinetide for Rett syndrome (RTT) is described, and the role of nonmammalian, mammalian, and stem cell model systems in the identification of molecular targets and drug screening is discussed. We then provide a framework for translating preclinical findings to human clinical trials, including the role of biomarkers in selecting molecular targets and evaluating target engagement, and discuss how to leverage these findings for future ASD drug development. Results: Multiple preclinical model systems for ASD have been developed, each with tradeoffs with regard to suitability for high-throughput small molecule screening, conservation across species, and behavioral face validity. Future clinical trials should incorporate biomarkers and intermediate phenotypes to demonstrate target engagement. Factors that contributed to the approval of trofinetide for RTT included replicated findings in mouse models, a well-studied natural history of the syndrome, development of RTT-specific outcome measures, and strong engagement of the RTT family community. Conclusions: The translation of our growing understanding of the neurobiology of ASD to human drug discovery will require a precision medicine approach, including the use of multiple model systems for molecular target selection, evaluation of target engagement, and clinical trial design strategies that address heterogeneity, power, and the placebo response.

BACKGROUND:Williams syndrome (WS) is a genetic disorder that results from a microdeletion of 25 to 27 genes on chromosome 7q11.23. Individuals with WS often exhibit comorbid neuropsychiatric symptoms, especially anxiety. To our knowledge, nonsuicidal self-injurious behavior (NSSIB) has not been reported in WS. N -acetylcysteine (NAC) is a safe and readily available drug that may modulate glutamate activity in the brain. NAC is effective for treating various neuropsychiatric symptoms and disorders. There are limited reports in the literature where NAC has been used to treat NSSIB effectively, but none in WS. METHODS:This report describes using NAC to treat NSSIB in 3 adults with WS. FINDINGS:Nonsuicidal self-injurious behavior was successfully treated in 3 adults with WS using NAC in doses ranging from 2400 to 3600 mg a day, resulting in significant improvement in their daily functioning. Additionally, NAC was well tolerated. CONCLUSIONS:NAC was effective for treating NSSIB in 3 adults with WS. By addressing these challenging behaviors, NAC offers a promising pharmacological intervention that can significantly improve the quality of life for patients with WS who engage in NSSIB. Further research and clinical trials are necessary.

CASE:KM is an 11-year-old autistic boy followed by a developmental-behavioral pediatrician (DBP) practicing within a multidisciplinary autism center. He had been prescribed various attention-deficit hyperactivity disorder (ADHD) medications over the years, most recently dextroamphetamine-amphetamine extended-release capsule 10 mg daily.KM initially presented to the DBP for diagnostic confirmation of autism and ADHD at the age of 7 years. His school had conducted a detailed evaluation the year prior, indicating skills in the borderline range for cognitive, adaptive, and language functioning. Based on his developmental history, physical examination, review of school-based testing, and parent- and school-completed standardized questionnaires, he met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for autism spectrum disorder and ADHD with combined presentation.When KM was between the ages of 8 and 10 years, he trialed several medications, including methylphenidate (which led to emotional lability), dextroamphetamine sulfate oral solution (which caused irritability), and clonidine (which led to destructive behavior). Notably, KM's parents were divorced and had differing opinions and experiences surrounding the efficacy and tolerability of his medications, which made medication trials more complex. He eventually was stabilized on extended-release dextroamphetamine-amphetamine at the age of 9 years, which both parents agreed was helpful for improving attention, despite the medication triggering a new self-injurious behavior of punching himself.At the age of 10 years, after 1 year of stability on dextroamphetamine-amphetamine extended-release capsule 10 mg daily, his parents chose not to refill the medication, to see whether it was still helpful for him. They observed that he seemed much "happier" with improved mood and decreased anxiety when dextroamphetamine-amphetamine was withheld; however, they did note worsened hyperactivity. A few weeks later, he began demonstrating increased symptoms of anxiety such as somatization and externalizing behaviors. This included frustration, aggression, and oppositionality, especially in anticipation of and/or when confronting anxious stimuli.His neuropsychologist and DBP collaborated to create a behavior monitoring plan to help his parents clarify and track his symptoms across households, with the goal of monitoring symptom severity and differentiating ADHD from anxiety-related symptoms. Because of this, his parents identified hyperactivity and impulsivity as KM's most problematic symptoms; therefore, dextroamphetamine-amphetamine extended-release 10 mg daily was restarted. Although this was effective for his hyperactivity, ongoing monitoring suggested that his anxiety symptoms continued to be clinically significant. The DBP consulted a psychiatrist who advised a trial of escitalopram in conjunction with dextroamphetamine-amphetamine. Several weeks after starting escitalopram 5 mg per day, KM exhibited reduced anxious thoughts and decreased aggression, but ongoing symptoms of inattention.Considering KM's complex presentation, how do we approach neuropsychological assessment, behavioral and therapeutic support, and psychopharmacology?

Background: Despite the increased risk for psychopathology in individuals with neurogenetic syndromes, very few psychopharmacology trials have been conducted in these populations. Objectives: The objective of this perspectives article is to describe recruitment challenges and potential solutions for psychopharmacology trials in neurogenetic syndromes. Methods: We describe recruitment challenges and lessons learned from an open-label trial of fluoxetine for the treatment of depression in adults with Down syndrome (DS). These challenges are contrasted with a successful open-label trial of buspirone for the treatment of anxiety in Williams syndrome. Results: Factors that contributed to recruitment challenges include limited research on the clinical presentation of depression in DS and the relatively small target population. This experience highlights the importance of foundational research studies on the phenomenology of target symptoms and burden of disease, as well as disseminating that information to the patient/family community. Partnership with a local family organization with close ties to the patient population can assist in overcoming recruitment barriers. Conclusion: The successes and challenges of early psychopharmacology clinical trials in neurogenetic syndromes should be considered for future trials.

Psychiatric presentations and psychopathology in people with co-occurring gender diversity (GD) and autism spectrum disorder (ASD) are not well understood. The aim of this study is to characterize mental health presentations and history (psychiatric diagnoses, psychotropic medication use, history of suicidal ideation and suicide attempts, and psychiatric hospitalization rates) in patients with co-occurring ASD and GD among those seeking psychiatric care at a tertiary care outpatient neurodevelopmental disorders center. This retrospective chart review included 125 patients who were divided into three study groups: index patients with co-occurring GD and ASD (n = 25), and age-matched comparison males (n = 50) and females (n = 50) with ASD and without indication of GD in their medical records. All subjects were required to have one initial psychiatric note documented in their electronic medical record (EMR), and their records were reviewed for psychiatric diagnoses, psychotropic medication use, history of suicidal ideation and suicide attempts, and psychiatric hospitalizations. All three groups experienced high rates of psychopathology across all characteristics of presentation and history assessed, aside from psychiatric hospitalization which was infrequent across groups. 119/125 (95

The prevalence of autism spectrum disorder (ASD) has surged, with an estimated 1 in 36 eight-year-olds in the United States meeting criteria for ASD in 2020. Autistic individuals face elevated rates of co-occurring medical, psychiatric, and behavioral conditions compared to non-autistic individuals. The rising ASD-patient demand is increasingly outpacing the capacity of ASD-specialty clinics, resulting in urgent need for autism-competent providers in general practice settings. This work aims to empower healthcare providers, especially primary care providers (PCPs), with guidelines for the recognition and safe pharmacologic management of common co-occurring psychiatric and behavioral conditions in ASD. Lurie Center for Autism medical providers, who have extensive experience in ASD care, delineated approaches for recognition and pharmacological treatment of sleep disturbances, attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, and irritability tailored to ASD patients. Pharmacological guidelines were iteratively refined until consensus was reached. Treatment differences relative to standard of care (SOC) of non-autistic individuals are noted. Key literature and clinical trial results were reviewed to supplement clinical experience. The pharmacological treatment pathways reflect how appropriate medication options for ASD patients can depend on many factors unique to the patient and can differ from established non-autistic SOC. Key takeaways include: For sleep disturbances in ASD, initial strategies align with non-autistic SOC, emphasizing sleep hygiene and melatonin use. First-line recommendations for treating ADHD, anxiety, and depression in ASD differ from non-autistic SOC; α2-adrenergic agonists are more suitable than stimulants for some ASD-ADHD patients, buspirone and mirtazapine are preferred to selective serotonin reuptake inhibitors (SSRIs) for anxiety, and duloxetine, mirtazapine, bupropion, and vortioxetine are recommended ahead of SSRIs for depression. Addressing irritability in ASD requires interdisciplinary evaluation of contributing factors, and guanfacine, risperidone, or aripiprazole may be appropriate, depending on severity. Recognition and treatment of co-occurring psychiatric and behavioral conditions in autistic patients must account for differences in clinical presentation and medication effectiveness and tolerability. Drawing on evidence-based clinical insights, these guidelines seek to support PCPs in making informed decisions when prescribing medications for ASD patients with co-occurring psychiatric and behavioral conditions, ultimately enhancing access to timely, comprehensive care for all individuals with ASD.

INTRODUCTION:Diagnosing autism spectrum disorder (ASD) in adults is challenging due to its heterogeneity and symptom overlap with other conditions. Making an accurate diagnosis can be difficult and overwhelming but is vital for proper accommodations and interventions while avoiding unproductive or harmful treatments. AREAS COVERED:The authors have based their review on a comprehensive literature search using PubMed, PsycINFO, and Google Scholar to identify relevant recommendations, diagnostic tools, and common differential diagnoses for adults with ASD. A clinical framework is provided based on the DSM-5 criteria, starting with an evaluation of childhood symptom onset and persistent manifestations of the core criteria - social and communication impairment, along with restricted, repetitive behaviors. Conditions with overlapping presentations, including personality disorders, anxiety, depression, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, and schizophrenia, are discussed, as well as challenges in differentiating these from ASD. EXPERT OPINION:Many factors complicate diagnosing ASD in adults - such as skewed public perception or misinformation spread on social media. Existing tools frequently miss subtle or atypical presentations, particularly in underdiagnosed groups like women and older adults. Promising advances in machine learning and artificial intelligence will hopefully improve diagnostic precision in the future. Up-to-date clinician training and large-scale research remain paramount for refining adult ASD diagnosis.