Genetic Testing History in Adults with Autism Spectrum Disorder.

Background & Objectives: Many genes have been identified in autism spectrum disorder (ASD). Yet little is known about how many adults with ASD receive recommended genetic testing and their outcomes. We investigated the percentage of adults with ASD who received genetic testing using recommended methods in our ASD specialty clinic and the percentage with positive findings. Methods: Potentially eligible adults were identified through search of our health system data repository and ASD diagnoses confirmed using review of relevant medical records by consensus of 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 and demographic data available. Data were collected through manual retrospective review of the electronic health record. Results: Only 41% of the adults with ASD (261/630) had a history of genetic testing documented in the medical record. Genetic testing was declined by patients or families for 11% (72) of records and not recorded in 47% (297). Mean (SD; range) age for the 261 adults with testing documented was 28.5 (5.3; 22-58) years. Sixty-seven (26%) were identified as female, 14 (6%) as Asian, 8 (3%) as Black or African American, 226 (89%) as White, 6 (2%) as other race, and 2 (1%) as Hispanic. 189 (73%) had intellectual disability. Ninety-one percent (236) had the genetic testing method recorded. Only 54% (95% CI: 46%, 61%) of patients had testing using a recommended method (chromosomal array, autism/intellectual disability sequencing panel, or exome sequencing). Few adults had received testing with sequencing technologies. A genetic cause of ASD was found in 28% (95% CI: 19%, 39%) of the 121 adults with results from ASD-related genetic testing recorded. Conclusions: Genetic testing can offer clinical and research insights. Yet it is underutilized in this population of adults with ASD. Nearly half of the adults in our sample lacked documentation of genetic testing. Thus, the percentage of adults with confirmed ASD who had any recommended genetic testing may be even lower than reported. Adults with ASD may benefit from having their genetic testing history reviewed in the clinic and the latest genetic testing performed.

Cervical Cancer Screening and Prevention Uptake in Females with Autism Spectrum Disorder.

This study reports on uptake rates of cervical cancer prevention and screening in a clinically-referred cohort of adolescent and adult females with autism spectrum disorder (ASD). Females with ASD (11-65 years) were invited to participate in an online survey to report on uptake of the human papillomavirus (HPV) vaccination and cervical cancer screening. Participants also provided demographic and clinical information. Chi-square statistical analysis was utilized to examine the relationship between categorical variables and receipt of cervical cancer prevention and screening. Forty-one out of 73 (56%) of adolescent (11-17 years) and 51/108 (47%) of adult (≥ 18 years) females with ASD reported having received at least one dose of the HPV vaccine. Only 30/73 (41%) and 37/108 (34%) of adolescents and adults respectively, were fully vaccinated (≥ 2 doses). Language impairment was the only clinical factor found to be associated with non-receipt of the HPV vaccine. Thirty-one out of 82 (38%) adult females (≥ 21 years) with ASD had received at least one pap smear. Language impairment, intellectual disability, non-independent living, and lower level of education were all associated with not receiving a pap smear. Females with ASD are vulnerable to invasive cervical cancer disease due to low uptake rates of the HPV vaccine and routine pap smear screening.

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

In vivo translocator protein in females with autism spectrum disorder: a pilot study.

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [11C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [11C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [11C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [11C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [11C]PBR28 SUVR across time in both groups. Elevated regional [11C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [11C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.

AACAP Endorses the Inclusion of Methylphenidate in the WHO Model Lists of Essential Medicines.

Despite decades of clinical use and a large body of evidence, the WHO continues to exclude methylphenidate for attention-deficit/hyperactivity disorder (ADHD) from its EML.1 The exclusion of methylphenidate has dire implications for millions of individuals with ADHD worldwide, especially those living in low and low-middle income countries (LMIC), where governmental decisions to make medicines available are contingent on EML listing.

Guanfacine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Down Syndrome: A Retrospective Chart Review.

Study Design: Retrospective case series. Objectives: The objective of this study was to provide naturalistic data on the use of guanfacine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in a clinically referred sample of youth with Down syndrome (DS). Methods: The medical records of children and adolescents with DS who received guanfacine for the treatment of ADHD from a multidisciplinary neurodevelopmental disorder clinic between September 1, 2011, and September 10, 2021, were reviewed. Demographic and clinical characteristics, guanfacine dose and treatment duration, and adverse effects were recorded. Clinical Global Impression Scale (CGI) scores for ADHD symptom severity (S) and improvement (I) were retrospectively assigned by a child and adolescent psychiatrist based on review of the clinic notes. Response to guanfacine was defined as completion of at least 12 weeks of treatment and a Clinical Global Impression Improvement subscale rating ≤2 (1 = "very much improved" or 2 = "much improved"). Results: Twenty-one patients were eligible for inclusion, of whom 17 (81%) completed at least 12 weeks of guanfacine. Ten of the 21 patients (48%; 95% confidence interval [CI]: 28%-68%) responded to treatment. The median time on guanfacine treatment covered by the clinic notes was 50.4 weeks, with a range of 0.3 weeks to 7.5 years. Thirteen patients (62%) remained on guanfacine at the time of their most recent clinic note. Nine patients had adverse events documented in their clinic notes (43%; 95% CI: 24%-63%), most commonly sleepiness (n = 7) and constipation (n = 2). Conclusion: About half of patients with DS responded to guanfacine for the treatment of ADHD and many tolerated long-term use. Study limitations primarily relate to the retrospective nature of the study and small sample size.

Buspirone for the treatment of anxiety in Williams syndrome: a retrospective chart review study.

BACKGROUND: Williams syndrome (WS) is a rare genetic disorder associated with a high prevalence of anxiety disorders. Evidence-based pharmacologic treatments for anxiety in WS are lacking. The purpose of this study is to provide naturalistic data on the use of buspirone for the treatment of anxiety in WS. RESEARCH DESIGN AND METHODS: Medical records of 24 individuals with Williams syndrome (ages 7-47 years) and anxiety who received treatment with buspirone were reviewed. Treatment response to buspirone was rated by assigning a retrospective Clinical Global Impression Improvement subscale (CGI-I) score. RESULTS: Twenty-three of 24 (96%) patients completed at least a 16-week treatment course with buspirone. Sixteen patients (67%; 95% CI 47%, 82%) were treatment responders (CGI-I ≤ 2). Only 1 (4%) patient discontinued buspirone due to a treatment-emergent side effect (nausea and vomiting). The most common side effect was nausea (13%). Twenty (84%) patients remained on buspirone at the time of their most recent follow-up visit. CONCLUSIONS: In this retrospective study, the majority of patients responded to a 16-week course of buspirone. Prospective studies are warranted to further assess the efficacy and tolerability of buspirone for anxiety in WS.

Psychiatric and behavioral manifestations of Williams syndrome.

PURPOSE OF REVIEW: The purpose of this review is to synthesize recent advances in the psychiatric and behavioral manifestations of Williams syndrome, a rare genetic syndrome. Recent advances have focused on more deeply characterizing the social phenotype and developing social skill interventions, improving the assessment and treatment of anxiety, and exploring eating behaviors. RECENT FINDINGS: The social cognitive phenotype in Williams syndrome, which consists of both high social drive and social cognition deficits, is present cross-culturally and may be related to reduced eye gaze. Social skills training for adults with Williams syndrome has demonstrated promise. Adapted exposure therapy and cognitive behavioral therapy programs for children and adults respectively, have been piloted in Williams syndrome. The majority of adults with Williams syndrome are either underweight or overweight, and problematic food-related behaviors likely contribute to bodyweight status. SUMMARY: Williams syndrome is associated with a number of core social and psychiatric difficulties which have a significant impact on functioning and quality of life. Recent work has begun to utilize a more nuanced understanding of the clinical presentations of these problems to develop interventions tailored to this unique population. However, larger trials, particularly those inclusive of a more diverse Williams syndrome population, are needed.

Diversity of Participants in Williams Syndrome Intervention Studies.

PURPOSE: This study describes participant diversity in Williams syndrome (WS) intervention studies. METHODS: A literature search was conducted to identify prospective treatment studies including participants with WS. Data was extracted on the reporting of and information provided on age, sex, cognitive ability, socioeconomic status, race, and ethnicity. RESULTS: Eleven eligible articles were identified. Reporting rates of demographic factors varied considerably, with the highest rates for age and sex (100%) and the lowest reporting rates for race (18%) and ethnicity (9%). Combining demographic data from the two studies that reported on race and/or ethnicity (n = 33), 88% of participants were White. The combined participant mean age was 20.9 years. CONCLUSION: There is a low frequency of reporting on several demographic factors including socioeconomic status, race, and ethnicity in WS intervention studies. There is a need for increased representation of racial and ethnic minority groups, older participants, and more cognitively impaired patients in WS research.

Neuroimaging research in Williams syndrome: Beginning to bridge the gap with clinical care.

Williams syndrome (WS) is a genetic disorder affecting multiple organ systems. Cardinal features include cardiovascular disease, distinct facies, and a unique cognitive profile characterized by intellectual disability, hypersociability, and visuospatial weaknesses. Here, we synthesize neuroimaging research in WS with a focus on how the current literature and future work may be leveraged to improve health and quality of life in WS. More than 80 neuroimaging studies in WS have been conducted, the vast majority of which have focused on identifying morphometric brain differences. Aside from decreased volume of the parieto-occipital region and increased cerebellar volume, morphometric findings have been variable across studies. fMRI studies investigating the visuospatial deficit have identified dorsal stream dysfunction and abnormal activation of the hippocampal formation. Minimal work has been done using PET or MRS. Future approaches that conduct neuroimaging in tandem with clinical phenotyping, utilize novel imaging techniques to visualize brain vasculature or provide biochemical and molecular information, and include more homogenous age groups across the lifespan, have significant potential to advance clinical care.

Clozapine for treatment refractory catatonia in individuals with autism spectrum disorder: a retrospective chart review study.

BACKGROUND: Catatonia is increasingly recognized in individuals with autism spectrum disorder (ASD). Empirical data on treating catatonia in this population are limited. The purpose of this study is to provide naturalistic data on the use of clozapine for the treatment of catatonia in patients with ASD. RESEARCH DESIGN AND METHODS: Medical records of 12 individuals with ASD and catatonia who received treatment with clozapine were reviewed. Treatment response to clozapine was rated by assigning a retrospective Clinical Global Impression Improvement scale (CGI-I) score. RESULTS: Mean (SD) and median (IQR) age at initiation of clozapine treatment were 22.1 (7.7) and 20.4 (9.7) years, with a range of 10-39 years. Eleven of the 12 patients had received treatment with lorazepam prior to initiating clozapine and 9 of the 12 patients received concomitant treatment with lorazepam and clozapine. Eleven of the 12 patients (92%; 95% CI: 65%, 99%) responded to clozapine. All 12 patients remained on clozapine at the time of their most recent clinical note. All 12 patients (100%; 95% CI: 76%, 100%) experienced one or more adverse events, the most common of which was sedation (n = 11, 92%). CONCLUSIONS: Overall, clozapine was associated with a high response rate for the treatment of catatonia in patients with ASD. These naturalistic data support the use of clozapine for the treatment of catatonia in patients with ASD for whom lorazepam is either ineffective or partially effective.

Clinical Challenges and Solutions in Adapting Cognitive Behavioral Therapy for Anxiety in Adults With Intellectual Disability.

While cognitive behavioral therapy (CBT) is a first-line treatment for anxiety, it is not typically offered to those with intellectual disability (ID). In this article, we provide a historical perspective on the treatment of mental health concerns in adults with ID, describe an adapted CBT treatment for anxiety in adults with Williams syndrome (WS) and mild to moderate ID, and discuss general modifications to CBT for adults with ID. Strategies used to successfully adapt CBT for adults with WS that may generalize for adults with ID more broadly include: (a) using child-based CBT manuals as a framework; (b) involving a caregiver as a therapy partner; (c) incorporating a high level of repetition; (d) simplifying language; (e) slowing the pace of instruction; and (f) incorporating specific examples and adaptations for WS.

Repetitive Thoughts and Behaviors in Autism Spectrum Disorder: A Symptom-Based Framework for Novel Therapeutics.

While the core symptoms of autism spectrum disorder include repetitive thoughts and repetitive behaviors, repetitive phenomena also occur in many other psychiatric disorders. Types of repetitive thoughts include preoccupations, ruminations, obsessions, overvalued ideas, and delusions. Types of repetitive behaviors include tics, stereotypies, compulsions, extrapyramidal symptoms, and automatisms. We provide a description of how to recognize and classify different types of repetitive thoughts and behaviors in autism spectrum disorder, providing clarity on which phenomena should be considered a core feature of autism spectrum disorder and which phenomena are indicative of a comorbid psychiatric disorder. Clinical features that can be used to differentiate types of repetitive thoughts include whether they are distressing and the degree of insight the individual has, while repetitive behaviors can be classified based on whether they are voluntary, goal-directed/purposeful, and rhythmic. We present the psychiatric differential diagnosis of repetitive phenomena within the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) framework. Careful clinical consideration of these transdiagnostic features of repetitive thoughts and behaviors can improve diagnostic accuracy and treatment outcomes, and influence future research.

The occurrence of delirium diagnosis among youth hospitalizations in the United States: A Kids' Inpatient Database analysis.

OBJECTIVES: Delirium is an acute neuropsychiatric condition associated with increased morbidity and mortality. There is increasing recognition of delirium as a substantial health burden in younger patients, although few studies have characterized its occurrence. This study analyzes the occurrence of delirium diagnosis, its comorbidities, and cost among youth hospitalized in the United States. METHODS: The Kids' Inpatient Database, a national all-payers sample of pediatric hospitalizations in general hospitals, was examined for the year 2019. Hospitalizations with a discharge diagnosis of delirium among patients aged 1-20 years were included in the analysis. RESULTS: Delirium was diagnosed in 43,138 hospitalizations (95% CI: 41,170-45,106), or 2.3% of studied hospitalizations. Delirium was diagnosed in a broad range of illnesses, with suicide and self-inflicted injury as the most common primary discharge diagnosis among patients with delirium. In-hospital mortality was seven times greater in hospitalizations caring a delirium diagnosis. The diagnosis of delirium was associated with an adjusted increased hospital cost of $8648 per hospitalization, or $373 million in aggregate cost. CONCLUSIONS: Based on a large national claims database, delirium was diagnosed in youth at a lower rate than expected based on prospective studies. The relative absence of delirium diagnosis in claims data may reflect underdiagnosis, a failure to code, and/or a lower rate of delirium in general hospitals compared with other settings. Further research is needed to better characterize the incidence and prevalence of delirium in young people in the hospital setting.

Prevalence and factors associated with overweight, obesity, and hypertension in a large clinical sample of adults with autism spectrum disorder.

Adults with autism spectrum disorder (ASD) are at risk for excess bodyweight and hypertension, yet the prevalence of and clinical predictors for these health conditions remain unknown. The objective of this study was to assess the prevalence of overweight, obesity, and hypertension in a large clinical sample of adults with a confirmed diagnosis of ASD and to examine potential clinical predictors. This retrospective chart review study included adult subjects (≥ 20 years) with ASD who had been seen within the past 5 years at a multidisciplinary developmental disorders clinic. Data collected from the electronic health record included age, sex, race and ethnicity, cognitive ability, language ability, body mass index (BMI), hypertension, and use of second generation antipsychotic medications (SGAs). Of 622 adults with a confirmed diagnosis of ASD potentially eligible for the study, 483 (78%) had one or more notes in their records from the past 5 years. Those with recent notes were 23% female, 89% White, and had a mean (SD) age of 28.1 (7.1) years. Overall prevalence estimates for adults represented by this predominantly male, White, and young clinical sample were 28% (95% CI 24%, 32%) for overweight (BMI 25-29.9 kg/m2), 35% (95% CI 31%, 40%) for obesity (≥ 30 kg/m2), and 11% (95% CI 9%, 15%) for hypertension. Controlling for age and sex, intellectual disability (ID) was significantly associated with BMI (p = 0.003) but not hypertension (p = 0.69); those with moderate or more severe ID had a mean BMI that was 2.26 kg/m2 (95% CI 0.96, 3.57) lower than those with no ID. Controlling for age and sex, neither language ability, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) subtype of autism, nor past or current use of SGAs were significantly associated with BMI or hypertension. The study identified a high prevalence of overweight and obesity in adults with ASD consistent with the prevalence of these medical comorbidities in the U.S. population.

An umbrella review on the use of antipsychotics in anxiety disorders: A registered report protocol.

Anxiety disorders, including panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), agoraphobia, and specific phobia, are among the most common psychiatric disorders. Although the traditional pharmacologic treatments for anxiety included barbiturates and then benzodiazepines, the introduction of tricyclic antidepressants, followed by the selective serotonin reuptake inhibitors (SSRIs), marked a tidal shift in the treatment of anxiety. Although not approved for treatment of anxiety disorders (with the exception of trifluoperazine) there is ongoing off-label, unapproved use of both first-generation "typical" antipsychotics (FGAs) and second-generation or "atypical" antipsychotics (SGAs) for anxiety. Although there have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of these reviews focused on SGAs, primarily the use of quetiapine in GAD. Given that there is little known about the potential benefits and short-and long-term risks of using antipsychotics in anxiety, there is a need for an umbrella review of systematic reviews and meta-analyses of the use of both FGAs and SGAs in anxiety disorders. The specific aims of this study are as follows: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs) and other non-antipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects; and (3) Evaluate the short- and long-term risks and side effects of prescribing antipsychotics in anxiety disorders. The review is registered on PROSPERO (CRD42021237436). Since data extraction has not begun, there is not preliminary data to share.

Stimulant intolerance in children with Angelman syndrome with hyperactivity: a case series.

OBJECTIVES: Angelman syndrome is a neurogenetic disorder resulting from the loss of expression of the ubiquitin-protein ligase E3A gene on chromosome 15. Problematic behaviors including attention-deficit/hyperactivity disorder (ADHD) symptoms of hyperactivity, impulsivity and inattention are highly prevalent in Angelman syndrome. The efficacy, safety and tolerability of stimulant medications in children with Angelman syndrome for the treatment of ADHD symptoms have not been previously reported. METHODS: We describe three boys with Angelman syndrome who were treated with open-label stimulant medications for ADHD symptoms. RESULTS: Stimulant medications were highly intolerable, and treatment had to be discontinued after limited dosing in all three cases due to marked increases in hyperactivity and impulsivity along with worsened distractibility. CONCLUSION: The findings of this study suggest that stimulant medications may be ineffective and poorly tolerated in children with Angelman syndrome.

A randomized double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in children and adolescents with autism spectrum disorder.

This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5-45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated "much improved" (CGI-I = 2) or "very much improved" (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine's safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Clinical trial registration information: Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders; https://clinicaltrials.gov ; NCT01302964.

Functional Neurological Symptom Disorder in Williams Syndrome: Case Series and Review of Relevant Literature.

BACKGROUND: Williams syndrome (WS) is a neurodevelopmental disorder associated with several medical and psychiatric comorbidities. OBJECTIVE: To describe the clinical presentation and treatment course of functional neurological symptom disorder (FNSD) in 3 adult patients with WS. METHODS: This report describes the clinical presentation and long-term follow-up of 3 individuals with WS and FNSD who experienced a range of clinical presentations and responses to treatment. The literature on the clinical assessment and treatment of FNSD as it applies to patients with neurodevelopmental disorders is reviewed. RESULTS: FNSD treatment strategies used in the general population were successfully adapted for these 3 patients. Literature on the diagnosis and treatment of FNSD in patients with neurodevelopmental disorders is lacking. CONCLUSIONS: FNSD may be more common in individuals with WS than previously appreciated, and future studies describing the prevalence, clinical presentation, risk factors, and treatment of FNSD in WS are needed.