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Background: 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., Methods: 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., Results: 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; α 2 -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., Conclusions: 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., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: MAM, KBB, JB, NDBF, AMN, MLP, RPT, ES, HB, KD have no competing interests. CJK: Biogen/Ionis Pharmaceuticals scientific advisory board member. JMH: Massachusetts Institute of Technology Consultant; American Chemical Society (ACS), ACS Publications, ACS Chemical Neuroscience Editorial Role; Eikonizo Therapeutics Co-Founder, Advisor; Sensorium Therapeutics Co-Founder, Advisor; Psy Therapeutics Consultant; Delix Therapeutics Advisor; Fuzionaire Diagnostics Advisor; Arclight Therapeutics Advisor; Proximity Therapeutics Advisor; Human Health Advisor, Rocket Science Health Advisor; Atai Life Sciences Sponsored research, training grant/gift. CJM: Acadia Pharmaceuticals consultant; Oxford University Press royalties; Springer Publishing royalties., (© 2025. The Author(s).)

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., (© 2024 Wiley Periodicals LLC.)

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., Competing Interests: Competing interests The authors have no competing interests to disclose.

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., (© 2023. The Author(s).)

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., Competing Interests: Declaration of Competing Interest This statement is to declare that the authors have no potential conflicts of interest relevant to this article., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

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., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Genetic variants causing the fast-channel congenital myasthenic syndrome (CMS) have been identified in the α, δ, and ε but not the β 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 β 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 β subunits of different species, but not in other AChR subunits. Measurements of radio-labeled α-bungarotoxin binding show that βP248L reduces AChR expression to 60% of wild-type. Patch clamp recordings of ACh-elicited single channel currents demonstrate that βP248L 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 βP248 with threonine, alanine or glycine reduces the burst duration to 2.3, 1.7, and 1.5 ms, respectively. In non-β subunits, substituting leucine for residues corresponding to βP248 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 βP248 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 βP248L 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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 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.

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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

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.

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.

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., (Copyright © 2018 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

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.

Background: Boys with autism spectrum disorder (ASD) have lower bone mineral density (BMD) than typically developing controls. Differences in diet and exercise may contribute to low BMD., Objective: Our aim was to examine macro- and micronutrient intakes and self-reported physical activity in boys with ASD compared to TDC and the relationship of these variables with BMD., Design/methods: We conducted a cross-sectional study of 49 boys (25 ASD, 24 typically developing controls) assessed for 3-day food records and physical activity records, and BMD of the whole body less head, hip, and spine using dual-energy x-ray absorptiometry. Fasting levels of 25(OH) vitamin D and calcium were obtained., Participants: Participants were adolescent boys, aged 8 to 17 years, recruited from a clinic population (ASD) or community advertisements (ASD and typically developing controls) matched for age., Results: ASD participants were approximately 9 months younger than typically developing control participants on average. Body mass index and serum vitamin D and calcium levels were similar. Boys with ASD consumed 16% fewer calories, with a larger percentage obtained from carbohydrates, and 37% less animal protein and 20% less fat than typically developing controls. A lower proportion of ASD participants were categorized as "very physically active" (27% vs 79%; P<0.001). BMD z scores were 0.7 to 1.2 standard deviations lower in ASD than typically developing controls at all locations. Higher animal protein, calcium, and phosphorus intakes were associated positively with bone density measures in boys with ASD., Conclusions: Compared to typically developing controls, boys with ASD had lower protein, calcium, and phosphorus intakes, activity levels, and BMD z scores at the lumbar spine, femoral neck, total hip, and whole body less head. Protein, calcium, and phosphorus intakes were associated positively with BMD., (Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Background: Boys with autism spectrum disorder (ASD) have lower areal bone mineral density (aBMD) than typically developing controls (TDC). Studies of volumetric BMD (vBMD) and bone microarchitecture provide information about fracture risk beyond that provided by aBMD but are currently lacking in ASD., Objectives: To assess ultradistal radius and distal tibia vBMD, bone microarchitecture and strength estimates in adolescent boys with ASD compared to TDC., Design/methods: Cross-sectional study of 34 boys (16 ASD, 18 TDC) that assessed (i) aBMD at the whole body (WB), WB less head (WBLH), hip and spine using dual X-ray absorptiometry (DXA), (ii) vBMD and bone microarchitecture at the ultradistal radius and distal tibia using high-resolution peripheral quantitative CT (HRpQCT), and (iii) bone strength estimates (stiffness and failure load) using micro-finite element analysis (FEA). We controlled for age in all groupwise comparisons of HRpQCT and FEA measures. Activity questionnaires, food records, physical exam, and fasting levels of 25(OH) vitamin D and bone markers (C-terminal collagen crosslinks and N-terminal telopeptide (CTX and NTX) for bone resorption, N-terminal propeptide of Type 1 procollagen (P1NP) for bone formation) were obtained., Results: ASD participants were slightly younger than TDC participants (13.6 vs. 14.2years, p=0.44). Tanner stage, height Z-scores and fasting serum bone marker levels did not differ between groups. ASD participants had higher BMI Z-scores, percent body fat, IGF-1 Z-scores, and lower lean mass and aBMD Z-scores than TDC at the WB, WBLH, and femoral neck (P<0.1). At the radius, ASD participants had lower trabecular thickness (0.063 vs. 0.070mm, p=0.004), compressive stiffness (56.7 vs. 69.7kN/mm, p=0.030) and failure load (3.0 vs. 3.7kN, p=0.031) than TDC. ASD participants also had 61% smaller cortical area (6.6 vs. 16.4mm 2 , p=0.051) and thickness (0.08 vs. 0.22mm, p=0.054) compared to TDC. At the tibia, ASD participants had lower compressive stiffness (183 vs. 210kN/mm, p=0.048) and failure load (9.4 vs. 10.8kN, p=0.043) and 23% smaller cortical area (60.3 vs. 81.5mm 2 , p=0.078) compared to TDC. A lower proportion of ASD participants were categorized as "very physically active" (20% vs. 72%, p=0.005). Differences in physical activity, calcium intake and IGF-1 responsiveness may contribute to group differences in stiffness and failure load., Conclusion: Bone microarchitectural parameters are impaired in ASD, with reductions in bone strength estimates (stiffness and failure load) at the ultradistal radius and distal tibia. This may result from lower physical activity and calcium intake, and decreased IGF-1 responsiveness., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Patients with autism spectrum disorder (ASD) are at increased risk for fracture, and peri-pubertal boys with ASD have lower bone mineral density (BMD) than controls. Data are lacking regarding BMD in older adolescents with ASD. We compared BMD using dual-energy X-ray absorptiometry in 9 adolescents/young adults with ASD against 9 typically developing matched controls. Patients with ASD and controls were excluded if they had other underlying conditions that may affect bone. Compared to controls, patients with ASD had (i) lower femoral neck and hip BMD Z-scores, and (ii) lower spine, femoral neck and hip height adjusted BMD Z-scores even after controlling for BMI. Understanding the underlying pathophysiology will be key to developing therapies to improve BMD and reduce fracture risk.

Peripubertal boys with autism spectrum disorder (ASD) have lower bone mineral density (BMD) than typically developing controls. However, it is not clear whether lower BMD in ASD results in an increased fracture rate. This study examined the rate of fractures in children and adults with and without ASD using a national database of emergency room visits (Nationwide Emergency Department Sample). A higher odds ratio for hip fractures in children and young adults (3-22 years) as well as older adults (23-50 years) with ASD than those without ASD, and a higher odds ratio for forearm and spine fractures in women ages 23-50 with ASD were found. Further studies are necessary to better understand the decreased bone density in ASD and its implications for fracture development.

We determined whether bone mineral density (BMD) is lower in boys with autism spectrum disorders (ASD) than controls, and also assessed variables that may affect BMD in ASD. BMD was measured using dual energy X-ray absorptiometry (DXA) in 18 boys with ASD and 19 controls 8-14 years old. Boys with ASD had lower BMD Z-scores at the spine, hip and femoral neck, and differences at the hip and femoral neck persisted after controlling for maturity and BMI. Vitamin D intake from food and in serum were lower in ASD subjects, as was exercise activity. We conclude that BMD is lower in peripubertal boys with ASD and may be associated with impaired vitamin D status and lower exercise activity.

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., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

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., (Copyright © 2010 American Neurological Association.)

We evaluated myoblast implantation therapy in three subjects with Becker muscular dystrophy who received 60 million myoblasts in one tibialis anterior (TA) muscle 2 months after beginning cyclosporine immunosuppression (5 to 10 mg/kg) that continued for 1 year. Strength of the implanted and control TA muscles was measured before and after treatment using a gauge to record TA contraction force. Our protocol controlled for the effects of cyclosporine and myoblast injections. In this pilot study, myoblast implantation did not improve strength of the implanted TA muscles.

Myotonic dystrophy protein kinase (DMPK) is the protein product of the genetic locus associated with myotonic dystrophy, in which alterations of muscle excitability, cardiac conduction defects, mental retardation, and cognitive deficiencies are inherited as an autosomal dominant trait. DMPK belongs to a novel protein serine/threonine kinase family, but its regulation and physiological functions have not been specified. In a first step toward understanding the functions of DMPK in the central nervous system, we have characterized its localization and developmental pattern of expression in rat brain and spinal cord by using a monospecific rabbit antiserum produced against bacterially expressed DMPK. Expression of DMPK begins after birth and increases gradually to peak at postnatal day 21 with antibody labeling of neuronal cell types in many regions. After postnatal day 21 and proceeding to the adult, the pattern of expression becomes more restricted, with localization to certain regions or cell groups in the central nervous system. Electron microscopy reveals localization within adult spinal motor neurons to the endoplasmic reticulum and dendritic microtubules. The adult localizations suggest that DMPK may function in membrane trafficking and secretion within neurons associated with cognition, memory, and motor control.

Myotonia congenita is an inherited muscle disorder characterized by muscle stiffness and hypertrophy. Its clinical phenotype depends, in part, on whether it is inherited as a dominant or recessive trait, respectively designated Thomsen's disease or Becker's generalized myotonia (BGM). In either case, it is associated with abnormalities in the muscle currents that are linked to the gene (CLCN-1) on human chromosome 7q35 encoding the skeletal muscle chloride channel. Single-strand conformation polymorphism analysis was used to screen two families with the BGM for mutations in the CLCN-1 gene. Two new mutations were found (G 201ins and A317Q). The latter mutation has been previously described in Thomsen's disease.

One of the major limitations of myoblast implantation as a therapy for muscular disease is that multiple injections by intramuscular implantation may be required for widespread delivery of cells. Also, some sites (eg, the diaphragm) are relatively inaccessible to injection. As an alternative, we have undertaken intra-arterial administration of myoblasts. For these experiments, we used donor cell myoblasts from the immortal L6 cell line labeled with lacZ via the beta-gal-at-gal retrovirus. In our model, target rat skeletal muscle (tibialis anterior [TA]) was injured using 0.5 ml of 0.5% bupivacaine and 15 IU of hyaluronidase; saline was injected into the contralateral side as a control. We infused 3 x 10(6) lacZ-positive cells into the abdominal aorta of previously injured, immunosuppressed (cyclosporine A) rats. At 7, 14, and 28 days, TA, liver, heart, lung, and spleen were examined for lacZ staining. In both the injured and control muscles, a few differentiated, lacZ-positive muscle cells were present, both singly and in groups, at each time point. These studies demonstrate that genetically labeled, transformed myoblasts may migrate from the arterial circulation to muscle and fuse there to form differentiated muscle cells. It is conceivable that intra-arterial delivery of myoblasts may have a role in the therapy of selected diseases of skeletal muscle.