Excitation/Inhibition Modulators in Autism Spectrum Disorder: Current Clinical Research

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social and communication abnormalities. Heterogeneity in the expression and severity of the core and associated symptoms poses difficulties in classification and the overall clinical approach. Synaptic abnormalities have been observed in preclinical ASD models. They are thought to play a major role in clinical functional abnormalities and might be modified by targeted interventions. An imbalance in excitatory to inhibitory neurotransmission (E/I imbalance), through altered glutamatergic and GABAergic neurotransmission, respectively, is thought to be implicated in the pathogenesis of ASD. Glutamatergic and GABAergic agents have been tested in clinical trials with encouraging results as to efficacy and tolerability. Further studies are needed to confirm the role of E/I modulators in the treatment of ASD and on the safety and efficacy of the current agents. Copyright © 2021 Canitano and Palumbi

Autism with epilepsy: A neurodevelopmental association

Introduction The association between Autism Spectrum Disorders (ASD) and epilepsy has been extensively documented and the estimated prevalence varies, depending upon the selected population and the clinical characteristics. Children with early-onset epilepsy and early brain damage have a higher risk of presenting ASD compared to those without epilepsy. Genetic abnormalities are likely implicated in the association of ASD and epilepsy, although these abnormalities are currently detectable in only a small percentage of patients. Copy number variants (CNVs) with a low rate of occurrence (so-called rare variants) have been found to be implicated in these conditions as well. Furthermore, some genetic and medical conditions are associated with ASD and epilepsy. Currently the co-occurrence of autism and epilepsy is conceptualized as the result of common abnormal neurodevelopmental pathways. Synaptic dysfunction is likely to be involved in both disorders, as observed in preclinical models. There is no specificity of seizure type to be expected in children and adolescents with ASD compared to other neurodevelopmental disorders or epileptic syndromes. Treatment options include developmentally-based early interventions for ASD and medications for epilepsy. The aim of this article is to provide a brief overview of current research on the association of autism with epilepsy, from molecular basis to clinical characteristics. Conclusion Common neurodevelopmental pathways are probably at play in the association of autism with epilepsy. Synaptic abnormalities and genetic variations have been shown to be implicated in this complex condition

Autism Spectrum Disorders and Schizophrenia Spectrum Disorders: Excitation/Inhibition Imbalance and Developmental Trajectories

Autism spectrum disorders (ASD) and schizophrenia spectrum disorders (SSD) share clinical and genetic components that have long been recognized. The two disorders co-occur more frequently than would be predicted by their respective prevalence, suggesting that a complex, multifactor association is involved. However, DSM-5 maintains the distinction between ASD, with core social and communication impairments, and SSD, including schizophrenia (SCZ), with hallucinations, delusions, and thought disorder as essential features. ASD and SSD have common biological underpinnings that may emerge early in development and unfold over time. One of the hypotheses supporting the similarities in the social and cognitive disturbances of ASD and SSD relates to abnormalities in the ratio of excitatory to inhibitory cortical activity (E/I imbalance). E/I imbalance in neurodevelopmental disorders could be the consequence of abnormalities in genes coding for glutamatergic and GABAergic receptors or synaptic proteins followed by system derangements. SSD and ASD have been characterized as polygenic disorders in which to the onset and progression of disease is triggered by interactions among multiple genes. Mammalian target of rapamycin signaling is under intense investigation as a convergent altered pathway in the two spectrum disorders. Current understanding of shared and divergent patterns between ASD and SSD from molecular to clinical aspects is still incomplete and may be implemented by the research domain criteria approach

Role of Genetics in the Etiology of Autistic Spectrum Disorder: Towards a Hierarchical Diagnostic Strategy

Progress in epidemiological, molecular and clinical genetics with the development of new techniques has improved knowledge on genetic syndromes associated with autism spectrum disorder (ASD). The objective of this article is to show the diversity of genetic disorders associated with ASD (based on an extensive review of single-gene disorders, copy number variants, and other chromosomal disorders), and consequently to propose a hierarchical diagnostic strategy with a stepwise evaluation, helping general practitioners/pediatricians and child psychiatrists to collaborate with geneticists and neuropediatricians, in order to search for genetic disorders associated with ASD. The first step is a clinical investigation involving: (i) a child psychiatric and psychological evaluation confirming autism diagnosis from different observational sources and assessing autism severity; (ii) a neuropediatric evaluation examining neurological symptoms and developmental milestones; and (iii) a genetic evaluation searching for dysmorphic features and malformations. The second step involves laboratory and if necessary neuroimaging and EEG studies oriented by clinical results based on clinical genetic and neuropediatric examinations. The identification of genetic disorders associated with ASD has practical implications for diagnostic strategies, early detection or prevention of co-morbidity, specific treatment and follow up, and genetic counselin

A comprehensive approach to understand somatic symptoms and their impact on emotional and psychosocial functioning in children

Introduction Somatic symptoms are frequently reported by children with significant impairment in functioning. Despite studies on adult populations that suggest somatic symptoms often co-occur with difficulties in identifying and describing feelings, little research has been done in childhood. This study aimed to investigate the prevalence and frequency of somatic symptoms as well as to investigate the functional impairment in children with high number of self reported somatic symptoms versus those with fewer somatic symptoms. Additionally the parental perception of their children's somatic symptoms and functioning was explored. Finally, we explored the direct and indirect effects of difficulties in identifying feelings in predicting somatic symptoms and functional disability among school-aged children. Methods 356 Italian school-aged children and their mothers participated in this study. Children (mean age = 11.43; SD = 2.41) completed the Children's Somatization Inventory (CSI-24) to assess somatic symptoms, the Functional Disability Inventory (FDI) to assess physical and psychosocial functioning and the Alexithymia Questionnaire for Children (AQC) to evaluate alexithymic features. Mothers completed the parental forms of the CSI and the FDI. Results Among children, 66.3% did not declare somatic symptoms and 33.7% reported one or more somatic symptoms in the last two weeks. A significant positive correlation emerged between children's and mothers' CSI total scores. Both children's and mothers' FDI total scores were significantly correlated with CSI scores. A significant correlation was observed between somatic symptoms and alexithymic features. Furthermore, the data showed that somatic symptoms mediated the relationship between difficulties in identifying feelings and functional impairment. Finally, it was showed that alexithymia facet of difficulty in identifying feelings contributed in large part to the prediction of the somatic symptomatology (b = 0.978, p < 0.001; R2 = 0.164, F(5, 350) = 10.32, p < 0.001). Conclusions Findings from this study provide evidence that a higher frequency of somatic symptoms is associated with functional disabilities and alexithymic facets in school-aged children. © 2017 Cerutti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Breathing Abnormalities During Sleep and Wakefulness in Rett Syndrome: Clinical Relevance and Paradoxical Relationship With Circulating Pro-oxidant Markers

Background Breathing abnormalities are common in Rett syndrome (RTT), a pervasive neurodevelopmental disorder almost exclusively affecting females. RTT is linked to mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Our aim was to assess the clinical relevance of apneas during sleep-wakefulness cycle in a population with RTT and the possible impact of apneas on circulating oxidative stress markers. MethodsFemale patients with a clinical diagnosis of typical RTT (n = 66), MECP2 gene mutation, and apneas were enrolled (mean age: 12.5 years). Baseline clinical severity, arterial blood gas analysis, and red blood cell count were assessed. Breathing was monitored during the wakefulness and sleep states (average recording time: 13 +/- 0.5 h) with a portable polygraphic screening device. According to prevalence of breath holdings, the population was categorized into the wakefulness apnea (WA) and sleep apnea (SA) groups, and apnea-hypopnea index (AHI) was calculated. The impact of respiratory events on oxidative stress was assessed by plasma and intra-erythrocyte non-protein-bound iron (P-NPBI and IE-NPBI, respectively), and plasma F-2-isoprostane (F-2-IsoP) assays. ResultsSignificant prevalence of obstructive apneas with values of AHI > 15 was present in 69.7% of the population with RTT. The group with SA showed significantly increased AHI values > 15 (p = 0.0032), total breath holding episodes (p = 0.007), and average SpO(2) (p = 0.0001) as well as lower nadir SpO(2) (p = 0.0004) compared with the patients with WAs. The subgroups of patients with WA and SA showed no significant differences in arterial blood gas analysis variables (p > 0.089). Decreased mean cell hemoglobin (MCH) (p = 0.038) was observed in the group with WAs. P-NPBI levels were significantly higher in the group with WA than in that with SAs (p = 0.0001). Stepwise multiple linear regression models showed WA being related to nadir SpO(2), average SpO(2), and P-NPBI (adjusted R-2 = 0.613, multiple correlation coefficient = 0.795 p < 0.0001), and P-NPBI being related to average SpO(2), blood PaCO2, red blood cell mean corpuscular volume (MCV), age, and topiramate treatment (adjusted R-2 = 0.551, multiple correlation coefficient = 0.765, p < 0.0001). ConclusionOur findings indicate that the impact of apneas in RTT is uneven according to the sleep-wakefulness cycle, and that plasma redox active iron represents a potential novel therapeutic target

Economic analysis of early intervention for autistic children: findings from four case studies in England, Ireland, Italy, and Spain

Background. Many autistic children experience difficulties in their communication and language skills development, with consequences for social development into adulthood, often resulting in challenges over the life-course and high economic impacts for individuals, families, and society. The Preschool Autism Communication Trial (PACT) intervention is effective in terms of improved social communication and some secondary outcomes. A previously published within-trial economic analysis found that results at 13 months did not support its costeffectiveness. We modeled cost-effectiveness over 6 years and across four European countries. Methods. Using simulation modeling, we built on economic analyses in the original trial, exploring longer-term cost-effectiveness at 6 years (in England). We adapted our model to undertake an economic analysis of PACT in Ireland, Italy, and Spain. Data on resource use were taken from the original trial and a more recent Irish observational study. Results. PACT is cost-saving over time from a societal perspective, even though we confirmed that, at 13 months post-delivery, PACT is more expensive than usual treatment (across all countries) when given to preschool autistic children. After 6 years, we found that PACT has lower costs than usual treatment in terms of unpaid care provided by parents (in all countries). Also, if we consider only out-of-pocket expenses from an Irish study, PACT costs less than usual treatment. Discussion. PACT may be recommended as a cost-saving early intervention for families with an autistic child