An individual-supported program to enhance placement in a sheltered work environment of autistic individuals mostly with intellectual disability: a prospective observational case series in an Italian community service.

Introduction: Autism spectrum disorder is a lifelong neurodevelopmental disorder. The profile of functioning in autistic people is very heterogeneous, and it is necessary to take into account individual characteristics to better support integration in the workplace. However, unemployment rates are higher for autistic people than for other types of disabilities. We present a prospective case series to explore the feasibility and efficacy of an individual-supported program to enhance placement in a sheltered work environment delivered by an Italian community day care center. Methods: Autistic subjects, aged from 12 to 31 years, participated in an individual-supported program regarding employment in sheltered art workshops, integrated into the regular activity of a semi-residential center three times a week for 1 year. Their feasibility retention rate and time worked per session were registered; moreover, working methods efficacy and self-organization improvement were tracked by the Likert-based rating system. Secondary outcome measures span functional levels, challenge behaviors, and sensory problems. Results: All the individuals presented a good adaptation to the environment, with a significant increase in time worked per session. After 1 year, the intervention allowed an increase in tasks completed in an assigned complex job and an improvement in self-organization within the work schedule in a group of subjects consisting mainly of severe-to-moderate levels of autism severity (86.6%). Finally, we observed a significant increase in independent functioning areas of the TEACCH transitional assessment profile. Challenge behaviors and sensory problems were also recorded. Conclusion: This case series supports the idea that individual-supported programs for placement in sheltered job environments delivered by community day care centers could be feasible and effective for ASD with higher levels of severity and co-occurring intellectual disability. Further targeted studies based on community models and accessible methods need to be planned to define the effectiveness of the intervention and promote improved practice at the community level with a better social impact.

A Machine Learning Approach to the Diagnosis of Autism Spectrum Disorder and Multi-Systemic Developmental Disorder Based on Retrospective Data and ADOS-2 Score.

Early and accurate diagnosis of autism spectrum disorders (ASD) and tailored therapeutic interventions can improve prognosis. ADOS-2 is a standardized test for ASD diagnosis. However, owing to ASD heterogeneity, the presence of false positives remains a challenge for clinicians. In this study, retrospective data from patients with ASD and multi-systemic developmental disorder (MSDD), a term used to describe children under the age of 3 with impaired communication but with strong emotional attachments, were tested by machine learning (ML) models to assess the best predictors of disease development as well as the items that best describe these two autism spectrum disorder presentations. Maternal and infant data as well as ADOS-2 score were included in different ML testing models. Depending on the outcome to be estimated, a best-performing model was selected. RIDGE regression model showed that the best predictors for ADOS social affect score were gut disturbances, EEG retrievals, and sleep problems. Linear Regression Model showed that term pregnancy, psychomotor development status, and gut disturbances were predicting at best for the ADOS Repetitive and Restricted Behavior score. The LASSO regression model showed that EEG retrievals, sleep disturbances, age at diagnosis, term pregnancy, weight at birth, gut disturbances, and neurological findings were the best predictors for the overall ADOS score. The CART classification and regression model showed that age at diagnosis and weight at birth best discriminate between ASD and MSDD.

Diagnostic yield and clinical impact of chromosomal microarray analysis in autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by high heritability estimates and recurrence rates; its genetic underpinnings are very heterogeneous and include variable combinations of common and rare variants. Array-comparative genomic hybridization (aCGH) offers significant sensitivity for the identification of copy number variants (CNVs), which can act as susceptibility or causal factors for ASD. METHODS: The aim of this study was to evaluate both diagnostic yield and clinical impact of aCGH in 329 ASD patients of Italian descent. RESULTS: Pathogenic/likely pathogenic CNVs were identified in 50/329 (15.2%) patients, whereas 89/329 (27.1%) carry variants of uncertain significance. The 10 most enriched gene sets identified by Gene Ontology Enrichment Analysis are primarily involved in neuronal function and synaptic connectivity. In 13/50 (26.0%) patients with pathogenic/likely pathogenic CNVs, the outcome of array-CGH led to the request of 25 additional medical exams which would not have otherwise been prescribed, mainly including brain MRI, EEG, EKG, and/or cardiac ultrasound. A positive outcome was obtained in 12/25 (48.0%) of these additional tests. CONCLUSIONS: This study confirms the satisfactory diagnostic yield of aCGH, underscoring its potential for better, more in-depth care of children with autism when genetic results are analyzed also with a focus on patient management.

Urinary Untargeted Metabolic Profile Differentiates Children with Autism from Their Unaffected Siblings.

Autism Spectrum Disorder (ASD) encompasses a clinical spectrum of neurodevelopmental conditions that display significant heterogeneity in etiology, symptomatology, and severity. We previously compared 30 young children with idiopathic ASD and 30 unrelated typically-developing controls, detecting an imbalance in several compounds belonging mainly to the metabolism of purines, tryptophan and other amino acids, as well as compounds derived from the intestinal flora, and reduced levels of vitamins B6, B12 and folic acid. The present study describes significant urinary metabolomic differences within 14 pairs, including one child with idiopathic ASD and his/her typically-developing sibling, tightly matched by sex and age to minimize confounding factors, allowing a more reliable identification of the metabolic fingerprint related to ASD. By using a highly sensitive, accurate and unbiased approach, suitable for ensuring broad metabolite detection coverage on human urine, and by applying multivariate statistical analysis, we largely replicate our previous results, demonstrating a significant perturbation of the purine and tryptophan pathways, and further highlight abnormalities in the "phenylalanine, tyrosine and tryptophan" pathway, essentially involving increased phenylalanine and decreased tyrosine levels, as well as enhanced concentrations of bacterial degradation products, including phenylpyruvic acid, phenylacetic acid and 4-ethylphenyl-sulfate. The outcome of these within-family contrasts consolidates and extends our previous results obtained from unrelated individuals, adding further evidence that these metabolic imbalances may be linked to ASD rather than to environmental differences between cases and controls. It further underscores the excess of some gut microbiota-derived compounds in ASD, which could have diagnostic value in a network model differentiating the metabolome of autistic and unaffected siblings. Finally, it points toward the existence of a "metabolic autism spectrum" distributed as an endophenotype, with unaffected siblings possibly displaying a metabolic profile intermediate between their autistic siblings and unrelated typically-developing controls.

Impact of Three Kinds of Early Interventions on Developmental Profile in Toddlers with Autism Spectrum Disorder.

Autism spectrum disorder is a neurodevelopmental disorder with a rising prevalence disorder. This high-cost/high-burden condition needs evidence-based behavioral treatments that are able to reduce the impact of symptoms on children's functioning. This retrospective chart review study compared the impact of different types of early interventions on toddlers diagnosed with an autism spectrum disorder developmental profile. Analyses were conducted on 90 subjects (mean = 27.76 months, range 18−44 months; M:F = 4.29:1), of which 36 children underwent the usual treatment, 13 children underwent an intervention based on early intensive behavioral intervention (EIBI) and 41 children received the Early Start Denver Model, for one year, with the same weekly frequency of about 6 h a week. A significant decrease in the severity of autism symptoms was observed for all children when looking at the Ados-2 severity score (average difference = 3.05, SD = 0.71, p = < 0.001) and the Ados-2 social subscale (average difference = 2.87, SD = 0.59, p < 0.001). Otherwise, for most of the Griffiths subscales, we found a significant improvement only for those children who underwent the Early Start Denver Model intervention (General Quotient average difference = 14.47, SD = 3.22, corrected p < 0.001). Analyzing the influence of age on the investigated scores, we found a significant association with the Eye−hand Coordination Quotient (p = 0.003), Performance Quotient (p = 0.042) and General Quotient (p = 0.006). In all these domains, a mild negative correlation with age was observed, as measured by the Pearson's correlation coefficient (r = −0.32, p = 0.002; r = −0.21, p = 0.044; r = −0.25, p = 0.019, respectively), suggesting less severe developmental skills at the start of treatment for older children. Our results are consistent with the literature that underlines the importance of early intervention, since prompt diagnosis can reduce the severity of autism symptoms; nevertheless, in toddlers, our study demonstrated that an intervention model based on naturalistic developmental behavioral principles such as the Early Start Denver Model is more effective on children's developmental profile. Further studies are required to assess the extent of effectiveness of different early intervention models in community settings.

Efficacy and Safety of Q10 Ubiquinol With Vitamins B and E in Neurodevelopmental Disorders: A Retrospective Chart Review.

Increased oxidative stress and defective mitochondrial functioning are shared features among many brain disorders. The aim of this study was to verify retrospectively the clinical efficacy and safety of a metabolic support therapy with Q10 ubiquinol, vitamin E and complex-B vitamins in various neurodevelopmental disorders. This retrospective chart review study included 59 patients (mean age 10.1 ± 1.2 y.o., range 2.5-39 years; M:F = 2.47:1), diagnosed with Autism Spectrum Disorder (n = 17), Autism Spectrum Disorder with co-morbid Intellectual Disability (n = 19), Intellectual Disability or Global Developmental Delay (n = 15), Attention-Deficit/Hyperactivity Disorder (n = 3) and Intellectual Disability in Phelan-McDermid syndrome due to chr. 22q13.33 deletion (n = 5). After a minimum of 3 months of therapy, a positive outcome was recorded in 45/59 (76.27%) patients, with Clinical Global Impression-Improvement scores ranging between 1 ("very much improved") and 3 ("minimally improved"). The most widespread improvements were recorded in cognition (n = 26, 44.1%), adaptative functioning (n = 26, 44.1%) and social motivation (n = 19, 32.2%). Improvement rates differed by diagnosis, being observed most consistently in Phelan-McDermid Syndrome (5/5, 100%), followed by Intellectual Disability/Global Developmental Delay (13/15, 86.7%), Autism Spectrum Disorder with co-morbid Intellectual Disability (15/19, 78.9%), Autism Spectrum Disorder (11/17, 64.7%) and ADHD (1/3, 33.3%). No significant adverse event or side effect leading to treatment discontinuation were recorded. Mild side effects were reported in 18 (30.5%) patients, with the most frequent being increased hyperactivity (9/59, 15.3%). This retrospective chart review suggests that metabolic support therapy with Q10 ubiquinol, vitamin E and complex-B vitamins is well tolerated and produces some improvement in the majority of patients with neurodevelopmental disorders, especially in the presence of intellectual disability. Randomized controlled trials for each single neurodevelopmental disorder are now warranted to conclusively demonstrate the efficacy of these mitochondrial bioenergetic and antioxidant agents and to estimate their therapeutic effect size.

Treatment of multiple sclerosis in children: A brief overview.

Multiple sclerosis (MS) is the most common autoimmune, chronic inflammatory demyelinating disorder of the central nervous system. Pediatric-onset MS (POMS), as opposed to adult-onset MS (AOMS), is a rare condition, presenting similar clinical features to AOMS, but a more active course of the disease, with higher relapse rates and greater white and grey matter damage. To date, the therapeutic approaches to treat POMS have been extrapolated from observational studies and data from trials conducted on adults, raising concerns about their efficacy and safety in the pediatric population. Herein, we discuss the most common therapeutic strategies used in POMS management, basing on the individual clinical practice and experience.

Gut mobilization improves behavioral symptoms and modulates urinary p-cresol in chronically constipated autistic children: A prospective study.

Chronic constipation is common among children with ASD and is associated with more severe hyperactivity, anxiety, irritability, and repetitive behaviors. Young autistic children with chronic constipation display higher urinary, and foecal concentrations of p-cresol, an aromatic compound produced by gut bacteria, known to negatively affect brain function. Acute p-cresol administration to BTBR mice enhances anxiety, hyperactivity and stereotypic behaviors, while blunting social interaction. This study was undertaken to prospectively assess the behavioral effects of gut mobilization in young autistic children with chronic constipation, and to verify their possible correlation with urinary p-cresol. To this aim, 21 chronically constipated autistic children 2-8 years old were evaluated before (T0), 1 month (T1), and 6 months (T2) after intestinal mobilization, recording Bristol stool scale scores, urinary p-cresol concentrations, and behavioral scores for social interaction deficits, stereotypic behaviors, anxiety, and hyperactivity. Gut mobilization yielded a progressive and highly significant decrease in all behavioral symptoms over the 6-month study period. Urinary p-cresol levels displayed variable trends not significantly correlated with changes in behavioral parameters, mainly increasing at T1 and decreasing at T2. These results support gut mobilization as a simple strategy to ameliorate ASD symptoms, as well as comorbid anxiety and hyperactivity, in chronically constipated children. Variation in p-cresol absorption seemingly provides limited contributions, if any, to these behavioral changes. Further research will be needed to address the relative role of reduced abdominal discomfort following mobilization, as compared to specific modifications in microbiome composition and in gut bacteria-derived neuroactive compounds.

Role of COMT V158M Polymorphism in the Development of Dystonia after Administration of Antipsychotic Drugs.

Antipsychotics (APDs) represent the main pharmacological strategy in the treatment of schizophrenia; however, their administration often may result in severe adverse effects, such as extrapyramidal symptoms. Typically, dystonic movements are considered the result of impaired function and/or abnormalities of dopaminergic neurotransmission/signaling in the basal ganglia. The catechol O-methyltransferase (COMT) gene is located within the 22q11.2 region, and its product is an enzyme involved in transferring a methyl group from S-adenosylmethionine to catecholamines, including dopamine. Studies showed that COMT Val158Met polymorphism modifies enzymatic activity and, consequently, synaptic dopamine concentration in specific brain areas. We identified a patient with 22q11.2 deletion syndrome presenting with cervical and trunk dystonia after paliperidone administration, which persisted even after drug discontinuation. Given the patient's genetic condition, we hypothesized that the dopaminergic dysfunction had been aggravated by COMT involvement, thus causing dystonia. In line with this hypothesis, we carried out a study on psychiatric patients in chronic treatment with APD to evaluate the distribution of the COMT Val158Met polymorphism and its role in the onset of adverse extrapyramidal symptoms. The study included four patients with dystonia after administration of APDs compared to 17 patients who never presented adverse drug reactions. Our data suggest that the Val/Val and Met/Met polymorphisms of the COMT gene are associated with a protective effect for the development of collateral extrapyramidal symptoms in patients treated with APDs, while the Val/Met genotype could be considered a risk factor for the development of dystonia after APDs administration.

The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part I: The past and the present.

Autism Spectrum Disorder (ASD) is a severe and lifelong neurodevelopmental disorder, with high social costs and a dramatic burden on the quality of life of patients and family members. Despite its high prevalence, reaching 1/54 children and 1/45 adults in the United States, no pharmacological treatment is still directed to core symptoms of ASD, encompassing social and communication deficits, repetitive behaviors, restricted interests, and abnormal sensory processing. The purpose of this review is to provide an overview of the state-of-the-art of psychopharmacological therapy available today for ASD in children and adolescents, in order to foster best practices and to organize new strategies for future research. To date, atypical antipsychotics such as risperidone and aripiprazole represent the first line of intervention for hyperactivity, impulsivity, agitation, temper outbursts or aggression towards self or others. Tricyclic antidepressants are less prescribed because of uncertain efficacy and important side effects. SSRIs, especially fluoxetine and sertraline, may be effective in treating repetitive behaviors (anxiety and obsessive-compulsive symptoms) and irritability/agitation, while mirtazapine is more helpful with sleep problems. Low doses of buspirone have shown some efficacy on restrictive and repetitive behaviors in combination with behavioral interventions. Stimulants, and to a lesser extent atomoxetine, are effective in reducing hyperactivity, inattention and impulsivity also in comorbid ASD-ADHD, although with somewhat lower efficacy and greater incidence of side effects compared to idiopathic ADHD. Clonidine and guanfacine display some efficacy on hyperactivity and stereotypic behaviors. For several other drugs, case reports and open-label studies suggest possible efficacy, but no randomized controlled trial has yet been performed. Research in the pediatric psychopharmacology of ASD is still faced with at least two major hurdles: (a) Great interindividual variability in clinical response and side effect sensitivity is observed in the ASD population. This low level of predictability would benefit from symptom-specific treatment algorithms and from biomarkers to support drug choice; (b) To this date, no psychoactive drug appears to directly ameliorate core autism symptoms, although some indirect improvement has been reported with several drugs, once the comorbid target symptom is abated.

Arrhythmic event prediction in patients with heart failure and reduced ejection fraction.

AIMS: Implantable cardioverter defibrillator (ICD) is an effective treatment to reduce mortality in patients with symptomatic heart failure and left ventricular ejection fraction (LVEF) 35% or less. LVEF presents a low sensitivity for predicting arrhythmic events. Aim of this study was to identify predictors of sustained ventricular arrhythmias (SVAs), overall and according to the cause of heart failure. METHODS: Single-center, retrospective, cohort study of 193 patients (51 nonischemic and 142 ischemic) with chronic heart failure and LVEF less than 35% who had received ICD for primary prevention of sudden cardiac death. We collected clinical data, echocardiographic parameters and SVAs detected by the ICD. RESULTS: During a median follow-up of 1440 days, 32 (16.2%) patients had SVAs. SVAs incidence was similar in patients with nonischemic (15.6%) and ischemic cause of heart failure (16.9%). Hypertension, diabetes, chronic renal failure, atrial fibrillation, chronic obstructive pulmonary disease, New York Heart Association class at least III were predictors at univariate analysis of SVAs. A clinical score, assigning one point to each of these variables, was associated with a significantly increased risk of SVAs [odds ratio for each point increase = 1.92, 95% confidence interval 1.40-2.65, P < 0.0001, area under the curve (AUC) 0.73], with 72% sensitivity and 60% specificity for a cutoff at least three and remained significant in nonischemic (AUC 0.84) and ischemic (AUC 0.68) patients. CONCLUSION: Our study shows the benefit of ICD implantation in primary prevention and its independency of cause. A simple clinical score, based on comorbidities, identifies patients with more benefits from ICD implantation.

Huntingtin gene CAG repeat size affects autism risk: Family-based and case-control association study.

The Huntingtin (HTT) gene contains a CAG repeat in exon 1, whose expansion beyond 39 repeats consistently leads to Huntington's disease (HD), whereas normal-to-intermediate alleles seemingly modulate brain structure, function and behavior. The role of the CAG repeat in Autism Spectrum Disorder (ASD) was investigated applying both family-based and case-control association designs, with the SCA3 repeat as a negative control. Significant overtransmission of "long" CAG alleles (≥17 repeats) to autistic children and of "short" alleles (≤16 repeats) to their unaffected siblings (all p < 10-5 ) was observed in 612 ASD families (548 simplex and 64 multiplex). Surprisingly, both 193 population controls and 1,188 neurological non-HD controls have significantly lower frequencies of "short" CAG alleles compared to 185 unaffected siblings and higher rates of "long" alleles compared to 548 ASD patients from the same families (p < .05-.001). The SCA3 CAG repeat displays no association. "Short" HTT alleles seemingly exert a protective effect from clinically overt autism in families carrying a genetic predisposition for ASD, while "long" alleles may enhance autism risk. Differential penetrance of autism-inducing genetic/epigenetic variants may imply atypical developmental trajectories linked to HTT functions, including excitation/inhibition imbalance, cortical neurogenesis and apoptosis, neuronal migration, synapse formation, connectivity and homeostasis.

FARP-1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family.

BACKGROUND: Children with autism spectrum disorder (ASD) display impressive clinical heterogeneity, also involving treatment response. Genetic variants can contribute to explain this large interindividual phenotypic variability. METHODS: Array-CGH (a-CGH) and whole genome sequencing (WGS) were performed on a multiplex family with two small children diagnosed with ASD at 17 and 18 months of age. Both brothers received the same naturalistic intervention for one year according to the Early Start Denver Model (ESDM), applied by the same therapists, yielding dramatically different treatment outcomes. RESULTS: The older sibling came out of the autism spectrum, while the younger sibling displayed very little, in any, improvement. This boy was subsequently treated applying a structured Early Intensive Behavioral Intervention paired with Augmentative Alternative Communication, which yielded a partial response within another year. The ESDM nonresponsive child carries a novel maternally inherited 65 Kb deletion at chr. 13q32.2 spanning FARP1. Farp1 is a synaptic scaffolding protein, which plays a significant role in neural plasticity. CONCLUSION: These results represent a paradigmatic example of the heuristic potential of genetic markers in predicting treatment response and possibly in supporting the targeted prescription of specific early intervention approaches.

P-cresol Alters Brain Dopamine Metabolism and Exacerbates Autism-Like Behaviors in the BTBR Mouse.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction/communication, stereotypic behaviors, restricted interests, and abnormal sensory-processing. Several studies have reported significantly elevated urinary and foecal levels of p-cresol in ASD children, an aromatic compound either of environmental origin or produced by specific gut bacterial strains. Methods: Since p-cresol is a known uremic toxin, able to negatively affect multiple brain functions, the present study was undertaken to assess the effects of a single acute injection of low- or high-dose (1 or 10 mg/kg i.v. respectively) of p-cresol in behavioral and neurochemical phenotypes of BTBR mice, a reliable animal model of human ASD. Results: P-cresol significantly increased anxiety-like behaviors and hyperactivity in the open field, in addition to producing stereotypic behaviors and loss of social preference in BTBR mice. Tissue levels of monoaminergic neurotransmitters and their metabolites unveiled significantly activated dopamine turnover in amygdala as well as in dorsal and ventral striatum after p-cresol administration; no effect was recorded in medial-prefrontal cortex and hippocampus. Conclusion: Our study supports a gene x environment interaction model, whereby p-cresol, acting upon a susceptible genetic background, can acutely induce autism-like behaviors and produce abnormal dopamine metabolism in the reward circuitry.