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.

Updated consensus guidelines on the management of Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

Metabolic interventions in Autism Spectrum Disorder.

Metabolic interventions including special diets and supplements are commonly used in Autism Spectrum Disorder (ASD). Yet little is known about how these interventions, typically initiated by caregivers, may affect metabolic function or the core symptoms of ASD. This review examines possible direct and indirect roles for metabolism in the core symptoms of ASD as well as evidence for metabolic dysfunction and nutritional deficiencies. We also discuss some of the most popular diets and supplements used in our patient population and suggest strategies for discussing the utility of these interventions with patients, families, and caregivers.

Bone Accrual in Males with Autism Spectrum Disorder.

OBJECTIVE: To test the hypothesis that bone accrual over a 4-year period is reduced in boys with autism spectrum disorder (ASD) compared with typically developing controls. STUDY DESIGN: Twenty-five boys with ASD and 24 controls were assessed for bone outcomes. Fourteen boys with ASD and 11 controls were assessed both at baseline and after 4 years. The mean subject age was 11.0 ± 1.6 years at study initiation and 14.9 ± 1.6 years at follow-up. Bone mineral density (BMD) was measured at the spine, hip, and whole body using dual-energy X-ray absorptiometry and normalized for age, race, and sex (BMD z-scores). Height adjustments were performed as well. We assessed medical history, physical activity using questionnaires, vitamin D and calcium intake using food records, and serum calcium, phosphorus, 25(OH)-vitamin D, and pubertal hormone levels. RESULTS: Boys with ASD had lower spine, hip, and whole body BMD z-scores compared with controls. In those subjects assessed both at baseline and after 4 years, bone accrual rates did not differ between the 2 groups; however, spine and hip BMD z-scores remained lower in the boys with ASD than in controls at follow-up. Notably, the ASD group was less physically active at both time points. CONCLUSION: Although pubertal bone accrual was similar to that in controls, BMD in children with ASD remained low over a 4-year follow-up period, suggesting that low BMD is a consequence of prepubertal factors, such as low physical activity. Studies are needed to investigate the causes and consequences of decreased BMD, to assess BMD in females and adults with ASD, and to evaluate therapeutic interventions.

Optimizing Care for Autistic Patients in Health Care Settings: A Scoping Review and Call to Action.

OBJECTIVE: We conducted a scoping review of interventions designed to improve the health care experiences of autistic individuals and assessed the methodology and outcomes used to evaluate them. METHODS: Literature from January 2005 to October 2020 was searched using PubMed, Excerpta Medica dataBASE (EMBASE), Cumulated Index to Nursing and Allied Health Literature (CINAHL), PsycINFO as well as hand searching. Studies included described an intervention for autistic individuals in inpatient or outpatient settings and evaluated the intervention using standardized methodology. Results were exported to Covidence software. Ten reviewers completed abstract screening, full text review, and then systematic data extraction of the remaining articles. Two reviewers evaluated each article at each stage, with a third reviewer arbitrating differences. RESULTS: A total of 38 studies, including three randomized controlled trials (RCTs) were included. Twenty-six (68%) took place in dental, psychiatric, or procedural settings. Interventions primarily focused on visit preparation and comprehensive care plans or pathways (N = 29, 76%). The most frequent outcome was procedural compliance (N = 15), followed by intervention acceptability (N = 7) and parent satisfaction (N = 6). Two studies involved autistic individuals and caregivers in study design, and no studies assessed racial/ethnic diversity on intervention impact. CONCLUSIONS: Well-designed evaluations of interventions to support autistic individuals in pediatric health care settings are limited. There is a need to conduct large multi-site intervention implementation studies.

The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects.

BACKGROUND: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. METHODS: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. RESULTS: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein-protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. CONCLUSION: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.

Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach.

AIM: As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy. METHOD: The Social Responsiveness Scale (SRS), a quantitative measure of autistic traits, was distributed to caregivers or companions of patients with TSC, NF1, and childhood-onset epilepsy of unknown cause (EUC), and these results were compared with SRS data from individuals with idiopathic autism spectrum disorders (ASDs) and their unaffected siblings. Scores and trait profiles of autistic features were compared with cognitive outcomes, epilepsy variables, and genotype. RESULTS: A total of 180 SRS questionnaires were completed in the TSC, NF1, and EUC outpatient clinics at the Massachusetts General Hospital (90 females, 90 males; mean age 21 y, range 4-63 y), and SRS data from 210 patients with ASD recruited from an autism research collaboration (167 males, 43 females; mean age 9 y, range 4-22 y) and 130 unaffected siblings were available. Regression models showed a significant association between SRS scores and intelligence outcomes (p<0.001) and various seizure variables (p<0.02), but not with a specific underlying disorder or genotype. The level of autistic features was strongly associated with intelligence outcomes in patients with TSC and epilepsy (p<0.01); in patients with NF1 these relationships were weaker (p=0.25). For all study groups, autistic trait subdomains covaried with neurocognitive comorbidity, with endophenotypes similar to that of idiopathic autism. INTERPRETATION: Our data show that in TSC and childhood-onset epilepsy, the severity and phenotype of autistic features are inextricably linked with intelligence and epilepsy outcomes. Such relationships were weaker for individuals with NF1. Findings suggest that ASDs are not specific in these conditions.

A Practice Pathway for the Treatment of Night Wakings in Children with Autism Spectrum Disorder.

Children with autism spectrum disorder (ASD) report high rates of sleep problems. In 2012, the Autism Treatment Network/ Autism Intervention Research Network on Physical Health (ATN/AIR-P) Sleep Committee developed a pathway to address these concerns. Since its publication, ATN/AIR-P clinicians and parents have identified night wakings as a refractory problem unaddressed by the pathway. We reviewed the existing literature and identified 76 scholarly articles that provided data on night waking in children with ASD. Based on the available literature, we propose an updated practice pathway to identify and treat night wakings in children with ASD.

Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy.

Two mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively-acting mutations and recessively-acting loss-of-function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying large genomic deletions of COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A1and COL6A2is not a disease mechanism for Bethlem myopathy. Our findings have important implications for the genetic evaluation of patients with collagen VI-related myopathies as well as for potential therapeutic interventions for this patient population.

A REDCap-based model for online interventional research: Parent sleep education in autism.

INTRODUCTION: The use of online platforms for pediatric healthcare research is timely, given the current pandemic. These platforms facilitate trial efficiency integration including electronic consent, randomization, collection of patient/family survey data, delivery of an intervention, and basic data analysis. METHODS: We created an online digital platform for a multicenter study that delivered an intervention for sleep disorders to parents of children with autism spectrum disorder (ASD). An advisory parent group provided input. Participants were randomized to receive either a sleep education pamphlet only or the sleep education pamphlet plus three quick-tips sheets and two videos that reinforced the material in the pamphlet (multimedia materials). Three measures - Family Inventory of Sleep Habits (FISH), Children's Sleep Habits Questionnaire modified for ASD (CSHQ-ASD), and Parenting Sense of Competence (PSOC) - were completed before and after 12 weeks of sleep education. RESULTS: Enrollment exceeded recruitment goals. Trial efficiency was improved, especially in data entry and automatic notification of participants related to survey completion. Most families commented favorably on the study. While study measures did not improve with treatment in either group (pamphlet or multimedia materials), parents reporting an improvement of ≥3 points in the FISH score showed a significantly improved change in the total CSHQ (P = 0.038). CONCLUSION: Our study demonstrates the feasibility of using online research delivery platforms to support studies in ASD, and more broadly, pediatric clinical and translational research. Online platforms may increase participant inclusion in enrollment and increase convenience and safety for participants and study personnel.

Vision care among school-aged children with autism spectrum disorder in North America: Findings from the Autism Treatment Network Registry Call-Back Study.

LAY ABSTRACT: Children with autism are at high risk for vision problems, which may compound core social and behavioral symptoms if untreated. Despite recommendations for school-aged children with autism to receive routine vision testing by an eye care practitioner (ophthalmologist or optometrist), little is known about their vision care. This study, therefore, examined vision care among 351 children with autism ages 6-17 years in the United States or Canada who were enrolled in the Autism Treatment Network Registry. Parents were surveyed using the following vision care measures: (1) child's vision was tested with pictures, shapes, or letters in the past 2 years; (2) child's vision was tested by an eye care practitioner in the past 2 years; (3) child was prescribed corrective eyeglasses; and (4) child wore eyeglasses as recommended. Sociodemographic characteristics such as parent education level, child functioning characteristics such as child communication abilities, and family functioning characteristics such as caregiver strain were also assessed in relationship to vision care. Although 78% of children with autism had their vision tested, only 57% had an eye care practitioner test their vision in the past 2 years. Among the 30% of children with autism prescribed corrective eyeglasses, 78% wore their eyeglasses as recommended. Differences in vision care were additionally found among children with autism by parent education, household income, communication abilities, intellectual functioning, and caregiver strain. Overall, study results suggest many school-aged children with autism do not receive recommended vision care and highlight potentially modifiable disparities in vision care.

Assessment of Walking Routes as a Possible Approach for Promoting Physical Activity in Children with Autism Spectrum Disorder: Brief Report.

Children with autism spectrum disorder (ASD) are at increased risk for being overweight/obese and face a variety of challenges with achieving the recommended levels of physical activity. Physical activity level has additionally been linked to motor skills, sleep, cognitive function and academic performance, and mental health in children with ASD. We pilot tested the feasibility and preliminary efficacy of walking routes as a novel approach to increasing physical activity among children with ASD. Physical activity was measured by accelerometry in 21 children ages 6-10 years. Participants received feedback on their physical activity and were counseled on using their surrounding neighborhoods to increase their physical activity. Non-completion (n = 9) reasons included equipment discomfort, family challenges, and diagnosis misattribution. While small changes in physical activity level and sedentary time were observed, neither was statistically significant. Further controlled studies on walking route interventions should continue to explore the potential benefits among this high-risk population.

A novel fast-channel myasthenia caused by mutation in ß subunit of AChR reveals subunit-specific contribution of the intracellular M1-M2 linker to channel gating.

Genetic variants causing the fast-channel congenital myasthenic syndrome (CMS) have been identified in the α, δ, and ε but not the ß subunit of acetylcholine receptor (AChR). A 16-year-old girl with severe myasthenia had low-amplitude and fast-decaying miniature endplate potentials. Mutation analysis revealed two heteroallelic variants in CHRNB1 encoding the AChR ß subunit: a novel c.812C>T (p.P248L) variant in M1-M2 linker (p.P271L in HGVS nomenclature), and a ~430 bp deletion causing loss of exon 8 leading to frame-shift and a premature stop codon (p.G251Dfs*21). P248 is conserved in all ß subunits of different species, but not in other AChR subunits. Measurements of radio-labeled α-bungarotoxin binding show that ßP248L reduces AChR expression to 60% of wild-type. Patch clamp recordings of ACh-elicited single channel currents demonstrate that ßP248L shortens channel opening bursts from 3.3 ms to 1.2 ms, and kinetic analyses predict that the decay of the synaptic response is accelerated 2.4-fold due to reduced probability of channel reopening. Substituting ßP248 with threonine, alanine or glycine reduces the burst duration to 2.3, 1.7, and 1.5 ms, respectively. In non-ß subunits, substituting leucine for residues corresponding to ßP248 prolongs the burst duration to 4.5 ms in the α subunit, shortens it to 2.2 ms in the δ subunit, and has no effect in the ε subunit. Conversely, substituting proline for residues corresponding to ßP248 prolongs the burst duration to 8.7 ms in the α subunit, to 4.6 ms in the δ subunit, but has no effect in the ε subunit. Thus, this fast channel CMS is caused by the dual defects of ßP248L in reducing expression of the mutant receptor and accelerating the decay of the synaptic response. The results also reveal subunit-specific contributions of the M1-M2 linker to the durations of channel opening bursts.

Paroxysmal oculogyric dystonia associated with a de novo 3q29 microdeletion.

3q29 deletion syndrome is caused by a heterozygous 1.6 Mb deletion on chromosome 3, which occurs in about 1 in 30 000 births. Phenotypic features of this syndrome include mild-to-moderate intellectual disability, autism spectrum disorder, slightly dysmorphic facial features, ataxic gait, and chest-wall deformity. Gastrointestinal disorders, dental abnormalities, feeding problems during infancy, recurrent ear infections, and heart defects have also been observed. Since the incidence of the deletion is rare, the phenotype has not been fully described, particularly in adults. This report describes a young adult female with 3q29 deletion syndrome, autism spectrum disorder, intellectual disability, and anxiety who experienced a sustained, non-medication induced paroxysmal oculogyric dystonia which responded to anticholinergic and antihistaminic medications. This is the first report of paroxysmal oculogyric dystonia associated with this deletion, possibly expanding the phenotypic features of this microdeletion syndrome.

Physical activity rates in children and adolescents with autism spectrum disorder compared to the general population.

Physical activity may improve symptoms and skill deficits associated with autism spectrum disorder (ASD). The objective of this study was to compare the reported frequency of physical activity and covariates in a large sample of children with ASD with children of similar age from the general population. The sample with ASD was derived from the Autism Treatment Network Registry Call Back Assessment (n = 611), and the general population data were derived from the National Survey of Children's Health (NSCH) (n = 71,811). In addition, demographic, child, and family (parent) factors were examined in relation to frequency of recent physical activity in children with ASD. Among males in the 6-11 year-old age group, those with ASD participated in physical activity less often (p <0.001) than those in the NSCH general population. Specifically, 33 % of boys 6-11 years old in the NSCH group vs. only 17 % in the RCBA group 6-11 years old engaged in some physical activity every day, while 4 % of boys in the NSCH group vs. 18 % in the RCBA group engaged in no physical activity whatsoever. A similar effect was seen across other age groups and in females but was not statistically significant. The demographic, child, and family characteristics associated with physical activity in children and adolescents with ASD included ethnicity in females, DSM-IV ASD diagnosis, IQ, and PAM-13 total score in females. Parents and caregivers are encouraged to find suitable physical activity programs for children with ASD. This may be especially important for 6-11 year-old boys with ASD who engage in significantly less physical activity than their peers in the general population.

Course and Predictors of Sleep and Co-occurring Problems in Children with Autism Spectrum Disorder.

The chronicity of sleep disturbance and its relation to co-occurring symptoms in children with autism spectrum disorder (ASD) are not well understood. The current study examined longitudinal relations among sleep and co-occurring symptoms in a large well-characterized sample of 437 children with ASD assessed at baseline and follow-up (M = 3.8 years later). Twenty-three percent experienced worsening sleep problems over time, while 31.5% showed improvement. Path analysis indicated that sleep problems at baseline predicted later development of ADHD symptoms in younger children and somatic complaints in older children. For younger children, sensory over-responsivity predicted future sleep problems. Findings suggest that sensory over-reactivity may contribute to sleep problems in some children with ASD, and that sleep problems may result in poor daytime functioning.

Identifying Associations Among Co-Occurring Medical Conditions in Children With Autism Spectrum Disorders.

OBJECTIVE: Children with autism spectrum disorder (ASD) have a high prevalence of co-occurring medical conditions, including speech, sleep, and gastrointestinal disorders (constipation and feeding difficulties); developmental delay; attention deficit/hyperactivity disorder; hypotonia; epilepsy; anxiety; disruptive behavior; pica; and eczema. Less is known about whether these commonly coexist in the same children. We sought to determine clinically meaningful, statistically significant associations among co-occurring medical conditions in children with ASD that could lead to better understanding, identification, and treatment of these disorders. METHODS: We studied 2114 children with ASD aged 17 months to 5years and 1221 children aged 6 to 17years at 15 Autism Speaks Autism Treatment Network Registry sites. Clinician-reported diagnoses and problems were grouped into 12 core conditions. We determined the observed prevalence (O) of co-occurring conditions and the estimated expected prevalence (E) across the network, adjusting for sitevariability in the prevalence of individual conditions. Pvalues were calculated using a Cochran-Mantel-Haenszel test stratified by site. We identified pairs of conditions co-occurring more frequently than expected (O/E >1) and less frequently than expected (O/E <1) and highlighted statisticallysignificant differences. RESULTS: Among the 66 condition pairs for each age group, we confirmed previously identified associations, such as sleep disorders and anxiety symptoms, in older children. We found some associations not previously described, including feeding with sleep disorders (younger children only), constipation with sleep disorders, feeding with speech disorders, and constipation with speech disorders. CONCLUSIONS: We have identified new associations among co-occurring medical conditions in children with ASD, offering the potential to examine common pathways.

Beyond the brain: A multi-system inflammatory subtype of autism spectrum disorder.

An immune-mediated subtype of autism spectrum disorder (ASD) has long been hypothesized. This article reviews evidence from family history studies of autoimmunity, immunogenetics, maternal immune activation, neuroinflammation, and systemic inflammation, which suggests immune dysfunction in ASD. Individuals with ASD have higher rates of co-morbid medical illness than the general population. Major medical co-morbidities associated with ASD are discussed by body system. Mechanisms by which FDA-approved and emerging treatments for ASD act upon the immune system are then reviewed. We conclude by proposing the hypothesis of an immune-mediated subtype of ASD which is characterized by systemic, multi-organ inflammation or immune dysregulation with shared mechanisms that drive both the behavioral and physical illnesses associated with ASD. Although gaps in evidence supporting this hypothesis remain, benefits of this conceptualization include framing future research questions that will help define a clinically meaningful subset of patients and focusing clinical interactions on early detection and treatment of high-risk medical illnesses as well as interfering behavioral signs and symptoms across the lifespan.

Investigating Potential Biomarkers in Autism Spectrum Disorder.

BACKGROUND: Early identification and treatment of individuals with autism spectrum disorder (ASD) improves outcomes, but specific evidence needed to individualize treatment recommendations is lacking. Biomarkers that could be routinely measured within the clinical setting could potentially transform clinical care for patients with ASD. This demonstration project employed collection of biomarker data during regular autism specialty clinical visits and explored the relationship of biomarkers with clinical ASD symptoms. METHODS: Eighty-three children with ASD, aged 5-10 years, completed a multi-site feasibility study integrating the collection of biochemical (blood serotonin, urine melatonin sulfate excretion) and clinical (head circumference, dysmorphology exam, digit ratio, cognitive and behavioral function) biomarkers during routine ASD clinic visits. Parents completed a demographic survey and the Aberrant Behavior Checklist-Community. Cognitive function was determined by record review. Data analysis utilized Wilcoxon two-sample tests and Spearman correlations. RESULTS: Participants were 82% male, 63% White, 19% Hispanic, with a broad range of functioning. Group means indicated hyperserotonemia. In a single regression analysis adjusting for race and median household income, higher income was associated with higher levels of blood serotonin and urine melatonin sulfate excretion levels (p = 0.004 and p = 0.04, respectively). Melatonin correlated negatively with age (p = 0.048) and reported neurologic problems (p = 0.02). Dysmorphic status correlated with higher reported stereotyped behavior (p = 0.02) and inappropriate speech (p = 0.04). CONCLUSION: This demonstration project employed collection of multiple biomarkers, allowed for examination of associations between biochemical and clinical measures, and identified several findings that suggest direction for future studies. This clinical research model has promise for integrative biomarker research in individuals with complex, heterogeneous neurodevelopmental disorders such as ASD.

Expanding the Capacity of Primary Care to Treat Co-morbidities in Children with Autism Spectrum Disorder.

We examined barriers and facilitators to expanding primary care's capacity to manage conditions associated with autism spectrum disorder (ASD). We conducted semi-structured interviews with specialists, primary care providers (PCPs), primary care staff, and parents of children with ASD, discussing health/behavior problems encountered, co-management, and patient/family experience. Participants endorsed primary care as the right place for ASD-associated conditions. Specialists advising PCPs, in lieu of referrals, efficiently uses their expertise. PCPs' ability to manage ASD-associated conditions hinged on how behavioral aspects of ASD affected care delivery. Practices lacked ASD-specific policies but made individual-level accommodations and broader improvements benefitting children with ASD. Enhancing access to specialty expertise, particularly around ASD-associated behaviors, and building on current quality improvements appear important to expanding primary care.