ABSTRACT
The efficacy of bumetanide (oral liquid formulation 0.5 mg bid) as a treatment for the core symptoms of autism spectrum disorders in children and adolescents aged 7-17 years is being investigated in an international, randomised, double-blind, placebo-controlled phase III study. The primary endpoint is the change in Childhood Autism Rating Scale 2 (CARS2) total raw score after 6 months of treatment. At baseline, the 211 participants analysed are broadly representative of autistic subjects in this age range: mean (SD) age, 10.4 (3.0) years; 82.5% male; 47.7% with intelligence quotient ≥ 70. Mean CARS2 score was 40.1 (4.9) and mean Social Responsiveness Scale score was 116.7 (23.4). Final study results will provide data on efficacy and safety of bumetanide in autistic children and adolescents.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Humans , Child , Male , Adolescent , Female , Autism Spectrum Disorder/drug therapy , Bumetanide/adverse effects , Autistic Disorder/diagnosis , Double-Blind Method , Treatment OutcomeABSTRACT
There are currently no approved pharmacological treatments to improve social reciprocity and limit repetitive and rigid behaviors in autism spectrum disorder (ASD). We describe the design of two Phase III studies evaluating the efficacy/safety of bumetanide oral liquid formulation in ASD. These are international, multicenter, randomized, double-blind, placebo-controlled studies in children and adolescents with ASD aged 7 to 17 years (n = 200; study 1), or younger children with ASD aged 2 to 6 years (n = 200; study 2). The primary endpoint of each is change in Childhood Autism Rating Scale 2 total raw score after 6 months. These studies could contribute to the first pharmacological treatment to improve social reciprocity and limit repetitive and rigid behaviors in children and adolescents with ASD.
Subject(s)
Autism Spectrum Disorder/drug therapy , Bumetanide/therapeutic use , Research Design , Social Behavior , Adolescent , Bumetanide/administration & dosage , Child , Child, Preschool , Double-Blind Method , Humans , Male , Treatment OutcomeABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component whose knowledge evolves quickly. Next-generation sequencing is the only effective technology to deal with the high genetic heterogeneity of ASD in a clinical setting. However, rigorous criteria to classify rare genetic variants conferring ASD susceptibility are currently lacking. We have performed whole-exome sequencing to identify both nucleotide variants and copy number variants (CNVs) in 253 ASD patients, including 68 patients with intellectual disability (ID) and 90 diagnosed as Asperger syndrome. Using explicit criteria to classify both susceptibility genes and susceptibility variants we prioritized 217 genes belonging to the following categories: syndromic genes, genes with an excess of de novo protein truncating variants and genes targeted by rare CNVs. We obtained a susceptibility variant detection rate of 19.7% (95% CI: [15-25.2%]). The rate for CNVs was 7.1% (95% CI: [4.3-11%]) and 12.6% (95% CI: [8.8-17.4%]) for nucleotide variants. The highest rate (30.1%, 95% CI: [20.2-43.2%]) was obtained in the ASD + ID subgroup. A strong contributor for at risk nucleotide variants was the recently identified set of genes (n = 81) harboring an excess of de novo protein truncating variants. Since there is currently no evidence that the genes targeted here are necessary and sufficient to cause ASD, we recommend to avoid the term "causative of ASD" when delivering the information about a variant to a family and to use instead the term "genetic susceptibility factor contributing to ASD".
Subject(s)
Autism Spectrum Disorder , Autism Spectrum Disorder/genetics , DNA Copy Number Variations , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Exome SequencingABSTRACT
BACKGROUND: Executive functions (EF) are often impaired in autism spectrum disorder (ASD). Such dysfunctions are associated with anxiety, depression, and a lack of autonomy. Transcranial direct current stimulation (tDCS) has been shown to enhance EF in healthy adults and clinical populations and to improve working memory - a component of the EF - in adults with high-functioning ASD (HF-ASD). We hypothesized that tDCS could improve the EF of HF-ASD patients. Such enhancement could improve their adaptive behaviors. METHOD: Eight patients with HF-ASD received 10 consecutive cathodal tDCS sessions (2 mA) over the left dorsolateral prefrontal cortex (F3) for 15 min each in an open trial. EF (with the Stroop test, Trail Making Test [TMT] A and B, Modified Wisconsin Card Sorting Test [mWCST], and Verbal Fluency Test) and behavioral dysexecutive syndrome (with the Behavioral Dysexecutive Syndrome Inventory and the Repetitive and Restricted Behaviour scale) were assessed before and 10 days after treatment. RESULTS: This study showed significant improvement in initiation (TMT-A time: p = 0.018) and cognitive flexibility (TMT-B time: p = 0.009; letter Verbal Fluency Test: p = 0.017; mWCST total errors: p = 0.028) after tDCS. Regarding behavior, the hypoactivity of the patients improved, as well as their repetitive and restrictive behaviors. In addition, this noninvasive neurostimulation technique was well tolerated. CONCLUSIONS: Flexibility and initiation are the most impaired EF in autism. These are promising results which justify a randomized and placebo-controlled study in a wider population. If these results were confirmed by a randomized controlled trial, tDCS could be an easy and well-tolerated adjunctive treatment aiming to improve the quality of life and the autonomy of ASD patients.
Subject(s)
Autism Spectrum Disorder/therapy , Executive Function/physiology , Prefrontal Cortex/physiopathology , Adult , Autism Spectrum Disorder/physiopathology , Autism Spectrum Disorder/psychology , Female , Humans , Male , Neuropsychological Tests , Pilot Projects , Transcranial Direct Current Stimulation , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Autism spectrum disorders (ASDs) are neurodevelopmental disorders that comprise wide graduated clinical expressions but similar core symptoms (repetitive, stereotyped behavior, and social communication disabilities). Many patients with ASD have disruptive behaviors like aggressiveness, temper tantrums, or self-injury that interfere with their socializations, their learning abilities, and their quality of life. These behaviors represent a common target for pharmacology. Beherec et al (J Clin Psychopharmacol. 2011;31:341-344) (first cohort), showed the efficacy of clozapine on disruptive behaviors in 6 patients with autism who were older than 16 years. The aim of this study was to assess the efficacy and tolerance of clozapine in a new cohort and the long-term effect in our first cohort. PROCEDURES: Concerning the replication study, we conducted a retrospective study of the changes of aggressive behaviors for all patients with ASD who were treated with clozapine from 2011 to 2017. Disruptive behaviors were monitored from 1 to 6 months before and after the initiation of the clozapine. RESULTS: All the patients of the first cohort were still on clozapine after an average of 11 + 2.6 years, with the same efficacy and no serious adverse effect was noted. For the replication study, 13 patients were included. Clozapine resulted in a significant decrease in the number of the days with aggression (65.2% + 32.6%). Once again, no serious adverse effect was notified. All the patients had a better quality of life. CONCLUSIONS: Our study confirms that clozapine could be an efficacious and well-tolerated treatment for ASD patients with disruptive behaviors who do not respond to other antipsychotics on the long term.
Subject(s)
Aggression/drug effects , Antipsychotic Agents/pharmacology , Autism Spectrum Disorder/drug therapy , Autism Spectrum Disorder/physiopathology , Clozapine/pharmacology , Outcome Assessment, Health Care , Adolescent , Adult , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Clozapine/administration & dosage , Clozapine/adverse effects , Female , Follow-Up Studies , Humans , Male , Retrospective Studies , Young AdultABSTRACT
Semaphorins are a large family of secreted and membrane-associated proteins necessary for wiring of the brain. Semaphorin 5A (SEMA5A) acts as a bifunctional guidance cue, exerting both attractive and inhibitory effects on developing axons. Previous studies have suggested that SEMA5A could be a susceptibility gene for autism spectrum disorders (ASDs). We first identified a de novo translocation t(5;22)(p15.3;q11.21) in a patient with ASD and intellectual disability (ID). At the translocation breakpoint on chromosome 5, we observed a 861-kb deletion encompassing the end of the SEMA5A gene. We delineated the breakpoint by NGS and observed that no gene was disrupted on chromosome 22. We then used Sanger sequencing to search for deleterious variants affecting SEMA5A in 142 patients with ASD. We also identified two independent heterozygous variants located in a conserved functional domain of the protein. Both variants were maternally inherited and predicted as deleterious. Our genetic screens identified the first case of a de novo SEMA5A microdeletion in a patient with ASD and ID. Although our study alone cannot formally associate SEMA5A with susceptibility to ASD, it provides additional evidence that Semaphorin dysfunction could lead to ASD and ID. Further studies on Semaphorins are warranted to better understand the role of this family of genes in susceptibility to neurodevelopmental disorders.
Subject(s)
Autism Spectrum Disorder/genetics , Chromosome Deletion , Intellectual Disability/genetics , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Autism Spectrum Disorder/complications , Autism Spectrum Disorder/diagnosis , Child , Chromosome Breakpoints , Chromosomes, Human, Pair 22/genetics , Chromosomes, Human, Pair 5/genetics , Humans , Intellectual Disability/complications , Intellectual Disability/diagnosis , Male , Paternal Inheritance , Semaphorins , Translocation, GeneticABSTRACT
Autism spectrum disorder (ASD) is a serious childhood-onset disorder in which social and language development are primarily affected, with associated repetitive behavior and, in some patients, behavioral symptoms including aggression and self-injury. In ASD, risperidone and aripiprazole are the only second-generation antipsychotic drugs that have shown to decrease disruptive behaviors in large-scale, controlled, double-blind studies. However, in some patients, these medications are not effective. Clozapine, a second-generation antipsychotic drug known to be effective in the treatment of aggression associated with schizophrenia, has received little attention in ASD.We conducted a retrospective analysis of the changes in disruptive behaviors for all patients with ASD treated with clozapine from 2002 to 2010. Disruptive behaviors were monitored during the 4 to 6 months before and after the initiation of clozapine. Long-term tolerance (10 months to 7 years) was also assessed. The relationship between disruptive behaviors and period of treatment (before and after clozapine) was studied with a generalized linear marginal model. Clozapine resulted in a significant 2-fold decrease in the number of the days with aggression, a decrease in the number of psychotropic drugs, and a decrease in the dose of the antipsychotic drugs. The long-term tolerance of clozapine (white blood cell count and extrapyramidal effects) was good, with the exception of significant weight gain (14.3 ± 10.9 kg), the occurrence of metabolic syndrome in 1 patient, and tachycardia in another patient.These results suggest that clozapine should be considered for the management of disruptive behaviors in patients with ASD not improved by first-line antipsychotic drugs.
Subject(s)
Antipsychotic Agents/therapeutic use , Attention Deficit and Disruptive Behavior Disorders/drug therapy , Child Development Disorders, Pervasive/drug therapy , Clozapine/therapeutic use , Adult , Antipsychotic Agents/adverse effects , Attention Deficit and Disruptive Behavior Disorders/complications , Child Development Disorders, Pervasive/complications , Child, Preschool , Clozapine/adverse effects , Female , Humans , Male , Psychiatric Status Rating Scales , Retrospective StudiesSubject(s)
Aggression/drug effects , Antipsychotic Agents/therapeutic use , Autistic Disorder/drug therapy , Clozapine/therapeutic use , Adolescent , Aggression/psychology , Antipsychotic Agents/administration & dosage , Autistic Disorder/diagnosis , Autistic Disorder/psychology , Clozapine/administration & dosage , Female , Humans , Treatment OutcomeABSTRACT
CONTEXT: Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia. OBJECTIVES: To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category. DESIGN: Case-control study. SETTING: Academic research. PARTICIPANTS: We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls. MAIN OUTCOME MEASURES: Collective and individual frequencies of the analyzed CNVs in cases compared with controls. RESULTS: Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes. CONCLUSIONS: Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.