A Combined Study on the Use of the Child Behavior Checklist 1½–5 for Identifying Autism Spectrum Disorders at 18 Months

The capacity of the Child Behavior Checklist 1½–5 (CBCL 1½–5) to identify children with autism spectrum disorder (ASD) at 18 months was tested on 37 children clinically referred for ASD and 46 children at elevated likelihood of developing ASD due to having an affected brother/sister. At 30 months the clinically referred children all received a confirmatory diagnosis, and 10 out of 46 siblings received a diagnosis of ASD. CBCL 1½-5 profiles were compared with a group of matched children with typical development (effect of cognitive level controlled for). The capacity of the CBCL 1½-5 DSM Oriented-Pervasive Developmental Problems scale to differentiate correctly between children diagnosed with ASD and children with typical development appeared dependent on group ascertainment methodology

Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues

Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS

Nonverbal Cognitive Abilities and Auditory Performance in Children Fitted with Auditory Brainstem Implants: Preliminary Report

OBJECTIVES/HYPOTHESIS:: Auditory brainstem implants (ABIs) can provide excellent open set speech recognition in adults without auditory tumors. These favorable results prompted us to extend ABI indications to children with profound hearing loss (HL) who are not candidates for a cochlear implant (CI). This article reports on the auditory performance and cognitive development measured in children with ABIs. STUDY DESIGN:: This study quantifies the development of auditory perceptual and nonverbal cognitive abilities of children with profound HL undergoing ABI. From 2000 to 2006, 17 children aged 14 months to 16 years received an ABI for different tumor and nontumor diseases in our department in Verona, and nine children were operated in other countries. Six of the children had been previously fitted elsewhere with a CI with no auditory results. Fourteen children had multiple associated psychomotor handicaps. METHODS:: The retrosigmoid approach was used in all children. Intraoperative and postoperative electrically evoked auditory brainstem responses were performed in all children. Perceptual auditory abilities were evaluated with the Evaluation of Auditory Responses to Speech battery and the Category of Auditory Performance test. Cognitive evaluation was performed on 10 children using the Leiter International Performance Scale-Revised test. RESULTS:: All children consistently use their devices for 8 h/d at average and have environmental sound awareness and utterance of words and simple sentences. Their category of auditory performance test scores increased significantly with ABI use. Scores on two of the four subtests considered for cognitive evaluation in this study increased significantly (P < .05) during the first year of ABI use. Postimplant cognitive outcomes were positively related to the auditory results. CONCLUSIONS:: The present investigation clearly indicates that children who are not candidates for CI fitted with ABI obtain significant development of their hearing ability and a significant improvement in some cognitive parameters. The outcomes of the present study suggest that children with cochlear or cochlear nerve abnormalities with associated cognitive deficits should not be excluded from ABI implantation

nonverbal cognitive abilities and auditory performance in children fitted with auditory brainstem implants: preliminary report

The present investigation clearly indi- cates that children who are not candidates for CI fitted with ABI obtain significant development of their hearing ability and a significant improvement in some cognitive parameters. The outcomes of the present study suggest that children with cochlear or cochlear nerve abnormali- ties with associated cognitive deficits should not be ex- cluded from ABI implantation

[Energy metabolism at rest and the respiratory quotient in obese and normal-weight prepubertal children]

The resting metabolic rate (RMR) was measured in obese (n. 14) and normo-weight (n. 14) pre-pubertal children using indirect calorimetry: correlations between RMR and anthropometric and metabolic parameters were also assessed in order to identify the existence of a causal relationship between the reduction of the RMR and the onset of obesity in children. RMR was expressed as an absolute value and appeared to be higher in obese subjects in comparison to controls (5138 +/- 498 kJ/d vs 4443 +/- 481, p less than 0.0001). If corrected for Kg of fat free mass (FFM), the anthropometric variable which accounts for the major (75%) variations of RMR, resting metabolism in obese subjects was lower than that in normal weight controls (173.2 +/- 20.1 kJ/kg FFM/d vs 189.9 +/- 17.6, p less than 0.05). The lower percentage of metabolic active organs which make up the lean body mass in FFM (brain, heart, liver and kidneys) and the absence of a defect in resting thermogenesis in the obese child could nevertheless explain the reduction of RMR/kg FFM observed in the study

The effectiveness of lurasidone add-on for residual aggressive behavior and obsessive symptoms in antipsychotic-treated children and adolescents with tourette syndrome: Preliminary evidence from a case series

Children and adolescents with Tourette syndrome may suffer from comorbid psychological and behavioral difficulties, primarily Attention-Deficit Hyperactivity Disorder-related manifestations including impulsive, aggressive, and disruptive behavior, and Obsessive-Compulsive Disorder-related disturbances. Often, such additional problems represent the major cause of disability, re-quiring their prioritization above the tic symptomatology. Here, we present six cases of children and adolescents with treatment-resistant Tourette syndrome aged 11–17 years, whose symptoms, especially the non-tic symptoms such as aggressive behavior and obsessive symptoms, failed to respond adequately to at least two different antipsychotics and, where deemed appropriate, to a combination with a medication with a different therapeutic indication or chemical class (e.g., antide-pressant or anticonvulsant). Such symptomatic manifestations were significantly reduced by the time of the subsequent control visit planned 30 days later, by using lurasidone as an add-on therapy to risperidone or aripiprazole (all p ≤ 0.009). No significant neuromotor or metabolic side effects were reported in all cases in a follow-up period ranging from 4 months to 6 months, supporting the stability of the observed clinical improvement. While still investigational, the preliminary evidence presented here gives reason to hope that lurasidone could possibly be an effective option in Tourette syndrome, warranting further investigation of its potential benefits in neurodevelopmental conditions

Palmitoylethanolamide and its biobehavioral correlates in autism spectrum disorder: A systematic review of human and animal evidence

Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading to the investigation of molecules targeting the immune-glutamatergic system in ASD treatment. Palmitoylethanolamide (PEA) is a naturally occurring saturated N-acylethanolamine that has proven to be effective in controlling inflammation, depression, epilepsy, and pain, possibly through a neuroprotective role against glutamate toxicity. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in ASD. Studies indicate altered serum/brain levels of PEA and other endocannabinoids (ECBs)/acylethanolamines (AEs) in ASD. Altered PEA signaling response to social exposure and altered expression/activity of enzymes responsible for the synthesis and catalysis of ECBs/AEs, as well as downregulation of the peroxisome proliferator activated receptor-α (PPAR-α) and cannabinoid receptor target GPR55 mRNA brain expression, have been reported. Stress and exposure to exogenous cannabinoids may modulate ECBs/AEs levels and expression of candidate genes for neuropsychiatric disorders, with implications for ASD. Limited research suggests that PEA supplementation reduces overall autism severity by improving language and social and nonsocial behaviors. Potential neurobiological underpinnings include modulation of immune response, neuroinflammation, neurotrophy, apoptosis, neurogenesis, neuroplasticity, neurodegeneration, mitochondrial function, and microbiota activity, possibly through peroxisome proliferator-activated receptor-α (PPAR-α) activation