1. Ben-Zeev B, Aharoni R, Nissenkorn A, Arnon R. {{Glatiramer acetate (GA, Copolymer-1) an hypothetical treatment option for Rett syndrome}}. {Med Hypotheses} (Oct 14)
Rett syndrome (RTT) is an X-linked dominant postnatal severe and disabling neurodevelopmental disorder which is the second most common cause for genetic mental retardation in girls and the first pervasive disorder with a known genetic basis. The syndrome is primarily caused by mutations in the Methyl CpG binding protein 2 (MECP2) gene on Xq28. Its protein product MeCP2 acts as a transcriptional repressor or activator depending on the target gene associated. Brain derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis and plasticity. It has been identified as a major MeCP2 target through a candidate gene approach and abnormalities in BDNF homeostasis are believed to contribute to the neurologic phenotype and pato-physiology of part of the symptoms in Mecp2 null mice that show progressive deficits in its expression. Based on the presumed role of BDNF in the pathophysiology of Rett syndrome it is reasonable to assume that interventions that will elevate its levels in the brain of RTT patients will be of therapeutic benefit. Glatiramer acetate (GA, Copolymer 1, Copaxone) an immunomodulator with proven safety and efficacy in Multiple Sclerosis has been reported to cause elevated secretion of BDNF both in animal model and in MS patients. Our hypothesis is that continuous treatment of patients with RTT with Glatiramer acetate might lead to an increase in their brain’s BDNF content and an improvement in at least part of the syndrome symptomatology while being safe to use and well tolerated in this population. In a pilot preliminary study we have shown that GA cause elevation of BDNF expression up to the level in naive control mice in several cortical areas in the Mecp2 mutated mouse brain, but as of yet did not examine the behavioral aspects of this elevation.
2. Feyder M, Karlsson RM, Mathur P, Lyman M, Bock R, Momenan R, Munasinghe J, Scattoni ML, Ihne J, Camp M, Graybeal C, Strathdee D, Begg A, Alvarez VA, Kirsch P, Rietschel M, Cichon S, Walter H, Meyer-Lindenberg A, Grant SG, Holmes A. {{Association of Mouse Dlg4 (PSD-95) Gene Deletion and Human DLG4 Gene Variation With Phenotypes Relevant to Autism Spectrum Disorders and Williams’ Syndrome}}. {Am J Psychiatry} (Oct 15)
Objective: Research is increasingly linking autism spectrum disorders and other neurodevelopmental disorders to synaptic abnormalities (« synaptopathies »). PSD-95 (postsynaptic density-95, DLG4) orchestrates protein-protein interactions at excitatory synapses and is a major functional bridge interconnecting a neurexinneuroligin-SHANK pathway implicated in autism spectrum disorders. Method: The authors characterized behavioral, dendritic, and molecular phenotypic abnormalities relevant to autism spectrum disorders in mice with PSD-95 deletion (Dlg4(-/-)). The data from mice led to the identification of single-nucleotide polymorphisms (SNPs) in human DLG4 and the examination of associations Results: Dlg4(-/-) showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses. Dlg4(-/-) had subtle dysmorphology of amygdala dendritic spines and altered forebrain expression of various synaptic genes, including Cyln2, which regulates cytoskeletal dynamics and is a candidate gene for Williams’ syndrome. A signifi-cant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling, both of which characterize Williams’ syndrome. Conclusions: These findings demonstrate that Dlg4 gene disruption in mice produces a complex range of behavioral and molecular abnormalities relevant to autism spectrum disorders and Williams’ syndrome. The study provides an initial link between human DLG4 gene variation and key neural endophenotypes of Williams’ syndrome and perhaps corticoamygdala regulation of emotional and social processes more generally.
3. Hamdan FF, Daoud H, Rochefort D, Piton A, Gauthier J, Langlois M, Foomani G, Dobrzeniecka S, Krebs MO, Joober R, Lafreniere RG, Lacaille JC, Mottron L, Drapeau P, Beauchamp MH, Phillips MS, Fombonne E, Rouleau GA, Michaud JL. {{De Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment}}. {Am J Hum Genet} (Oct 13)
Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.
4. Lynch E. {{Making sense of autism}}. {Nurs Stand} (Sep 15-21);25(2):18-19.
Children with autism are more prone to certain mental health disorders than their counterparts, but services to meet their special needs are lacking.
5. Norbury CF, Griffiths H, Nation K. {{Sound before Meaning: Word Learning in Autistic Disorders}}. {Neuropsychologia} (Oct 14)
Successful word learning depends on the integration of phonological and semantic information with social cues provided by interlocutors. How then, do children with autism spectrum disorders (ASD) learn new words when social impairments pervade? We recorded the eye-movements of verbally-able children with ASD and their typical peers while completing a word learning task in a social context. We assessed learning of semantic and phonological features immediately after learning and again four weeks later. Eye-movement data revealed that both groups could follow social cues, but that typically developing children were more sensitive to the social informativeness of gaze cues. In contrast, children with ASD were more successful than peers at mapping phonological forms to novel referents; however, this advantage was not maintained over time. Typical children showed clear consolidation of learning both semantic and phonological information, children with ASD did not. These results provide unique evidence of qualitative differences in word learning and consolidation and elucidate the different mechanisms underlying the unusual nature of autistic language.
6. O’Brien FM, Page L, O’Gorman RL, Bolton P, Sharma A, Baird G, Daly E, Hallahan B, Conroy RM, Foy C, Curran S, Robertson D, Murphy KC, Murphy DG. {{Maturation of limbic regions in Asperger syndrome: A preliminary study using proton magnetic resonance spectroscopy and structural magnetic resonance imaging}}. {Psychiatry Res} (Oct 15)
People with autistic spectrum disorders (ASD, including Asperger syndrome) may have developmental abnormalities in the amygdala-hippocampal complex (AHC). However, in vivo, age-related comparisons of both volume and neuronal integrity of the AHC have not yet been carried out in people with Asperger syndrome (AS) versus controls. We compared structure and metabolic activity of the right AHC of 22 individuals with AS and 22 healthy controls aged 10-50years and examined the effects of age between groups. We used structural magnetic resonace imaging (sMRI) to measure the volume of the AHC, and magnetic resonance spectroscopy ((1)H-MRS) to measure concentrations of N-acetyl aspartate (NAA), creatine+phosphocreatine (Cr+PCr), myo-inositol (mI) and choline (Cho). The bulk volume of the amygdala and the hippocampus did not differ significantly between groups, but there was a significant difference in the effect of age on the hippocampus in controls. Compared with controls, young (but not older) people with AS had a significantly higher AHC concentration of NAA and a significantly higher NAA/Cr ratio. People with AS, but not controls, had a significant age-related reduction in NAA and the NAA/Cr ratio. Also, in people with AS, but not controls, there was a significant relationship between concentrations of choline and age so that choline concentrations reduced with age. We therefore suggest that people with AS have significant differences in neuronal and lipid membrane integrity and maturation of the AHC.
7. Qiu Z, Cheng J. {{The Role of Calcium-Dependent Gene Expression in Autism Spectrum Disorders: Lessons from MeCP2, Ube3a and Beyond}}. {Neurosignals} (Oct 19)
During the last decade, autism spectrum disorders (ASD) have become the center of attention where several branches of modern biology unexpectedly meet, such as neural development, molecular biology, epigenetics, neurophysiology and psychiatry. This review will focus on the molecular mechanism by which calcium-dependent gene expression regulates brain development and how ASD may occur if this process is compromised. Specifically, the studies of the calcium-dependent transcriptional repressor MeCP2 gave us much insight about how abnormal development may lead to ASD. Most recently, studies about Ube3a, a critical component of the ubiquitination system enzyme, shed light on how neural activity regulates synapse function through the protein degradation pathway. Taken together, these studies suggest that ASD may be caused by the incapability of neurons to generate adaptive responses via regulating gene expression upon incoming activity.
8. Russo NM, Hornickel J, Nicol T, Zecker S, Kraus N. {{Biological changes in auditory function following training in children with autism spectrum disorders}}. {Behav Brain Funct} (Oct 16);6(1):60.
ABSTRACT: BACKGROUND: Children with pervasive developmental disorders (PDD), such as children with autism spectrum disorders (ASD), often show auditory processing deficits related to their overarching language impairment. Auditory training programs such as Fast ForWord Language may potentially alleviate these deficits through training-induced improvements in auditory processing. METHODS: To assess the impact of auditory training on auditory function in children with ASD, brainstem and cortical responses to speech sounds presented in quiet and noise were collected from five children with ASD who completed Fast ForWord training. RESULTS: Relative to six control children with ASD who did not complete Fast ForWord, training-related changes were found in brainstem response timing (three children) and pitch-tracking (one child), and cortical response timing (all five children) after Fast ForWord use. CONCLUSIONS: These results provide an objective indication of the benefit of training on auditory function for some children with ASD.
9. Shen C, Zhao XL, Ju W, Zou XB, Huo LR, Yan W, Zou JH, Yan GD, Jenkins EC, Brown WT, Zhong N. {{A Proteomic Investigation of B Lymphocytes in an Autistic Family: A Pilot Study of Exposure to Natural Rubber Latex (NRL) May Lead to Autism}}. {J Mol Neurosci} (Oct 19)
Autism is a multi-factorial neurodevelopmental disorder. We have investigated the molecular mechanism involved in a Chinese family with autism by a proteomic approach. Antibody chips containing 500 spots of human protein antibodies were used to screen for differentially expressed proteins in the peripheral B lymphocytes between autistic and non-autistic siblings in this family. Four proteins relevant to immuno-pathway, including IKKalpha that was up-regulated and Tyk2, EIF4G1 and PRKCI that were down-regulated, were identified differentially expressed in autistic versus non-autistic siblings. Western blot analysis and reverse transcription quantitative polymerase chain reaction validated the differential expression of these four proteins. Based on the function of these differentially expressed proteins, relevant studies on immunoglobulin E (IgE) level, nuclear factor kappa B signaling activation and cell cycle were conducted in both autistic and non-autistic children of this family. Considering the fact that the family members were in close contact with natural rubber latex (NRL) and that IgE-mediated cross-reactions could be triggered by Hevea brasiliensis (Hev-b) proteins in NRL, we hypothesize that immune reactions triggered by close contact with NRL might influence the functions of B lymphocytes by altering expression of certain proteins identified in our experiments thus contributing to the occurrence of autism.
