Characterization of a Clinically and Biologically Defined Subgroup of Patients with Autism Spectrum Disorder and Identification of a Tailored Combination Treatment.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders (NDDs) with a high unmet medical need. The diagnosis of ASD is currently based on behavior criteria, which overlooks the diversity of genetic, neurophysiological, and clinical manifestations. Failure to acknowledge such heterogeneity has hindered the development of efficient drug treatments for ASD and other NDDs. DEPI® (Databased Endophenotyping Patient Identification) is a systems biology, multi-omics, and machine learning-driven platform enabling the identification of subgroups of patients with NDDs and the development of patient-tailored treatments. In this study, we provide evidence for the validation of a first clinically and biologically defined subgroup of patients with ASD identified by DEPI, ASD Phenotype 1 (ASD-Phen1). Among 313 screened patients with idiopathic ASD, the prevalence of ASD-Phen1 was observed to be ~24% in 84 patients who qualified to be enrolled in the study. Metabolic and transcriptomic alterations differentiating patients with ASD-Phen1 were consistent with an over-activation of NF-κB and NRF2 transcription factors, as predicted by DEPI. Finally, the suitability of STP1 combination treatment to revert such observed molecular alterations in patients with ASD-Phen1 was determined. Overall, our results support the development of precision medicine-based treatments for patients diagnosed with ASD.

Inequalities in access to NHS primary care dental services in Scotland during the COVID-19 pandemic.

Introduction This study aimed to quantify the impact of the COVID-19 pandemic on access and inequalities in primary care dental services among children and adults in Scotland.Methods Access was measured as any NHS Scotland primary care dental contacts derived from administrative data from January 2019 to May 2022, linked to the area-based Scottish Index of Multiple Deprivation for children and adults, and related to population denominator estimates from National Record Scotland. Inequalities for pre-pandemic (January 2019-January 2020) and recent (December 2021-February 2022, and March 2022-May 2022) periods for both children and adults were calculated and compared using the slope index of inequality and relative index of inequality.Results Following the first lockdown (March 2020) there was a dramatic fall to near zero dental contacts, followed by a slow recovery to 64.8% of pre-pandemic levels by May 2022. There was initial widening of relative inequalities in dental contacts in early 2022, which, more recently, had begun to return to pre-pandemic levels.Conclusion COVID-19 had a major impact on access to NHS primary dental care, and while inequalities in access are apparent as services recover from lockdown, these inequalities are not a new phenomenon.

Sleep disturbances in Phelan-McDermid syndrome: Clinical and metabolic profiling of 56 individuals.

Phelan-McDermid Syndrome (PMS) is caused by deletions at chromosome 22q13.3 or pathogenic/likely pathogenic SHANK3 variants. The clinical presentation is extremely variable and includes global developmental delay/intellectual disability (ID), seizures, neonatal hypotonia, and sleep disturbances, among others. This study investigated the prevalence of sleep disturbances, and the genetic and metabolic features associated with them, in a cohort of 56 individuals with PMS. Sleep data were collected via standardized observer/caregiver questionnaires, while genetic data from array-CGH and sequencing of 9 candidate genes within the 22q13.3 region, and metabolic profiling utilized the Biolog Phenotype Mammalian MicroArray plates. Sleep disturbances were present in 64.3% of individuals with PMS, with the most common problem being waking during the night (39%). Sleep disturbances were more prevalent in individuals with a SHANK3 pathogenic variant (89%) compared to subjects with 22q13.3 deletions of any size (59.6%). Distinct metabolic profiles for individuals with PMS with and without sleep disturbances were also identified. These data are helpful information for recognizing and managing sleep disturbances in individuals with PMS, outlining the main candidate gene for this neurological manifestation, and highlighting potential biomarkers for early identification of at-risk subjects and molecular targets for novel treatment approaches.

Becoming Inclusive: Actionable Steps to Diversify the Field of Clinical Ethics.

At the 2022 Clinical Ethics Unconference, the authors perceived a significant lack of racial and ethnic diversity, which was consistent with their experiences in other clinical ethics settings. As a result, they convened a working group to address the pervasive lack of diversity present in the field of clinical ethics and to propose strategies to increase the representation of people from racial and ethnic minority populations. This article identifies the harms associated with the lack of diversity in the healthcare setting and translates these to the field of clinical ethics. The article then proposes a framework that may be used to help diversify the field of clinical ethics. Specifically, the authors identify existing barriers to appropriate diversity, actionable steps to increase diversity, and tools the field can utilize to systematically assess its progress with respect to achieving diversity.

Mosaicism of common pathogenic MECP2 variants identified in two males with a clinical diagnosis of Rett syndrome.

Rett (RTT) syndrome, a neurodevelopmental disorder caused by pathogenic variation in the MECP2 gene, is characterized by developmental regression, loss of purposeful hand movements, stereotypic hand movements, abnormal gait, and loss of spoken language. Due to the X-linked inheritance pattern, RTT is typically limited to females. Recent studies revealed somatic mosaicism in MECP2 in male patients with RTT-like phenotypes. While detecting mosaic variation using Sanger sequencing is theoretically possible for mosaicism over ~15%-20%, several variables, including efficiency of PCR, background noise, and/or human error, contribute to a low detection rate using this technology. Mosaic variants in two males were detected by next generation sequencing (NGS; Case 1) and by Sanger re-sequencing (Case 2). Both had targeted digital PCR (dPCR) to confirm the variants. In this report, we present two males with classic RTT syndrome in whom we identified pathogenic variation in the MECP2 gene in the mosaic state (c.730C > T (p.Gln244*) in Patient 1 and c.397C > T (p.Arg133Cys) in Patient 2). In addition, estimates and measures of mosaic variant fraction were surprisingly similar between Sanger sequencing, NGS, and dPCR. The mosaic state of these variants contributed to a lengthy diagnostic odyssey for these patients. While NGS and even Sanger sequencing may be viable methods of detecting mosaic variation in DNA or RNA samples, applying targeted dPCR to supplement these sequencing technologies would provide confirmation of somatic mosaicism and mosaic fraction.

Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281.

Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series.

BACKGROUND: While an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55-200 repeats) of the FMR1 gene may be overlooked. OBJECTIVE: To report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype. METHODS: We collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS. RESULTS: Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity. CONCLUSION: Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

Correlating soil nutrient test lead with bioaccessible lead in highly-contaminated soils receiving lead-immobilizing amendments.

Lead (Pb) is one of the most common metals exceeding human health risk guidelines for soil concentrations worldwide. Pb bioaccessibility is known to vary depending on soil physiochemical characteristics and, as a result, in vitro and in vivo tests exist that are used to estimate bioaccessible Pb in contaminated soils. Although in vitro tests such as the relative bioaccessibility leaching procedure (RBALP) present simpler and more cost-effective risk assessments than in vivo methods, soil tests such as Mehlich-3, Modified Morgan, and ammonium bicarbonate-diethylenetriamine pentaacetate (AB-DTPA) extractions are extremely routine and even more cost-effective. Currently, there are few comparisons examining the viability of common soil nutrient tests for assessing Pb bioaccessibility in soils from contaminated sites with extremely high total Pb concentrations or for sites that have received amendments, such as those containing compost, iron, and/or phosphorus, intended to immobilize Pb. Here, we examine the correlation between RBALP Pb and Pb as determined using three commonly utilized soil tests, Mehlich-3, Modified Morgan, and AB-DTPA, in archived samples from one Pb-contaminated site receiving compost amendment (Seattle, WA, USA) and one extremely Pb-contaminated site receiving mixtures of compost, P, and Fe (Joplin, MO, USA). At both the Seattle and Joplin sites separately, RBALP Pb was significantly correlated with all three soil nutrient test values, regardless of soil amendment. However, RBALP was only significantly correlated with Modified Morgan and total Pb when examining the Joplin and Seattle data together, likely resulting from different factors controlling Pb solubility at the two sites. These findings suggest that a diverse suite of relatively inexpensive and accessible soil nutrient test methods correlate with bioaccessible Pb at a specific site, regardless of whether Pb-immobilizing amendments have been used.

The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders.

Considerable interest has arisen concerning the relationship between hereditary connective tissue disorders such as the Ehlers-Danlos syndromes (EDS)/hypermobility spectrum disorders (HSD) and autism, both in terms of their comorbidity as well as co-occurrence within the same families. This paper reviews our current state of knowledge, as well as highlighting unanswered questions concerning this remarkable patient group, which we hope will attract further scientific interest in coming years. In particular, patients themselves are demanding more research into this growing area of interest, although science has been slow to answer that call. Here, we address the overlap between these two spectrum conditions, including neurobehavioral, psychiatric, and neurological commonalities, shared peripheral neuropathies and neuropathologies, and similar autonomic and immune dysregulation. Together, these data highlight the potential relatedness of these two conditions and suggest that EDS/HSD may represent a subtype of autism.

Pediatric Ethics Consultation: Practical Considerations for the Clinical Ethics Consultant.

Clinical ethics consultants face a wide range of ethical dilemmas that require broad knowledge and skills. Although there is considerable overlap with the approach to adult consultation, ethics consultants must be aware of differences when they work with infant, pediatric, and adolescent cases. This article addresses unique considerations in the pediatric setting, reviews foundational theories on parental authority, suggests practical approaches to pediatric consultation, and outlines current available resources for clinical ethics consultants who wish to deepen their skills in this area.

Hand stereotypies: Lessons from the Rett Syndrome Natural History Study.

OBJECTIVE: To characterize hand stereotypies (HS) in a large cohort of participants with Rett syndrome (RTT). METHODS: Data from 1,123 girls and women enrolled in the RTT Natural History Study were gathered. Standard tests for continuous and categorical variables were used at baseline. For longitudinal data, we used repeated-measures linear and logistic regression models and nonparametric tests. RESULTS: HS were reported in 922 participants with classic RTT (100%), 73 with atypical severe RTT (97.3%), 74 with atypical mild RTT (96.1%), and 17 females with MECP2 mutations without RTT (34.7%). Individuals with RTT who had classic presentation or severe MECP2 mutations had higher frequency and earlier onset of HS. Heterogeneity of HS types was confirmed, but variety decreased over time. At baseline, almost half of the participants with RTT had hand mouthing, which like clapping/tapping, decreased over time. These 2 HS types were more frequently reported than wringing/washing. Increased HS severity (prevalence and frequency) was associated with worsened measures of hand function. Number and type of HS were not related to hand function. Overall clinical severity was worse with decreased hand function but only weakly related to any HS characteristic. While hand function decreased over time, prevalence and frequency of HS remained relatively unchanged and high. CONCLUSIONS: Nearly all individuals with RTT have severe and multiple types of HS, with mouthing and clapping/tapping decreasing over time. Interaction between HS frequency and hand function is complex. Understanding the natural history of HS in RTT could assist in clinical care and evaluation of new interventions.

Behavioral profiles in Rett syndrome: Data from the natural history study.

INTRODUCTION: Rett syndrome (RTT) is a complex neurodevelopmental disorder with known behavioral abnormalities, both internalizing (e.g., anxiety, social withdrawal) and externalizing (e.g., aggression, self-abuse). However, a broad evaluation of behavioral abnormalities in a large cohort is lacking. OBJECTIVE: In this report, we describe profiles of internalizing and externalizing behaviors in individuals evaluated in the multi-center U.S. Rett Natural History Study. METHODS: Cross-sectional and longitudinal data were collected from 861 females with RTT and from 48 females who have MECP2 mutations without meeting criteria for RTT. Standard statistical methods including linear regression evaluated internalizing behavioral components from the Child Health Questionnaire (CHQ-PF50) and externalizing components from the Motor Behavioral Assessment (MBA). RESULTS: We found mildly to moderately severe internalizing behaviors in nearly all individuals with RTT, while externalizing behaviors were mild and uncommon. Internalizing behavior in RTT was comparable to groups with psychiatric disorders. Participants with mixed (internalizing and externalizing) behaviors were younger and less affected overall, but showed prominent self-injury and worsening internalizing behaviors over time. CONCLUSIONS: This study revealed that internalizing behaviors are common at a clinically significant level in RTT. Understanding clinical features associated with behavioral profiles could guide treatment strategies.

Training the Motor Aspects of Pre-driving Skills of Young Adults With and Without Autism Spectrum Disorder.

The purpose of this study was to investigate the utility of using a driving simulator to address the motor aspects of pre-driving skills with young adults with Autism Spectrum Disorder (ASD). A group of neurotypical control participants and ten participants with ASD completed 18 interactive steering and pedal exercises with the goal to achieve error-free performance. Most participants were able to achieve this goal within five trials for all exercises except for the two most difficult ones. Minimal performance differences were observed between the two groups. Participants with ASD needed more time to complete the tasks. Overall, the interactive exercises and the process used worked well to address motor related aspects of pre-driving skills in young adults with ASD.