1. Becerra TA, Wilhelm M, Olsen J, Cockburn M, Ritz B. {{Ambient Air Pollution and Autism in Los Angeles County, California}}. {Environ Health Perspect}. 2012.
BACKGROUND: The prevalence of Autistic Disorder (AD), a serious developmental condition, has risen dramatically over the past two decades but high-quality population-based research addressing etiology is limited. OBJECTIVES: We studied the influence of exposures to traffic-related air pollution during pregnancy on the development of autism using data from air monitoring stations and a land use regression (LUR) model to estimate exposures. METHODS: Children of mothers who gave birth in Los Angeles who were diagnosed with a primary AD diagnosis at ages 3-5 years during 1998-2009 were identified through the California Department of Developmental Services and linked to 1995-2006 California birth certificates. For 7,603 children with autism and 10 controls per case matched by sex, birth year, and minimum gestational age, birth addresses were mapped and linked to the nearest air monitoring station and a LUR model. We used conditional logistic regression, adjusting for maternal and perinatal characteristics including indicators of SES. RESULTS: Per interquartile range (IQR) increase, we estimated a 12-15% relative increase in odds of autism for O3 (OR = 1.12, 95% CI: 1.06, 1.19; per 11.54 ppb increase) and PM2.5 (OR = 1.15, 95% CI: 1.06, 1.24; per 4.68 mug/m3 increase) when mutually adjusting for both pollutants. Furthermore, we estimated 3-9% relative increases in odds per IQR increase for LUR-based NO and NO2 exposure estimates. LUR-based associations were strongest for children of mothers with less than a high school education. CONCLUSION: Measured and estimated exposures from ambient pollutant monitors and LUR model suggest associations between autism and prenatal air pollution exposure, mostly related to traffic sources.
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2. Cabras V, Milia A, Montaldo C, Nucaro A. {{Cryptic Chromosome Rearrangements in Five Patients, with Normal and/or Abnormal Karyotypes, Associated with Mental Retardation, Autism and/or Epilepsy, Detected by BAC Genome Array-CGH}}. {Prague Med Rep}. 2012; 113(4): 279-88.
This report describes the usefulness of the BAC genome array-CGH platform in the detection of cryptic rearrangements. We examined ten patients with normal and/or abnormal karyotypes and dysmorphic features, associated with mental retardation, autism and/or epilepsy. This approach led us to discover further cryptic chromosomal rearrangements, not previously detected by conventional cytogenetic procedures, and allowed us to better delineate genotype/phenotype correlation. Our experience shows the validity of the BAC platform as a reliable method for genome-wide screening of chromosomal aberrations in patient with idiopathic mental retardation and/or in association with autism and epilepsy.
3. Fujita-Jimbo E, Yu ZL, Li H, Yamagata T, Mori M, Momoi T, Momoi MY. {{Mutation in Parkinson Disease-Associated, G-Protein-Coupled Receptor 37 (GPR37/PaelR) Is Related to Autism Spectrum Disorder}}. {PLoS One}. 2012; 7(12): e51155.
Little is known about the molecular pathogenesis of Autism spectrum disorder (ASD), a neurodevelopmental disorder. Here we identified two mutations in the G-protein-coupled receptor 37 gene (GPR37) localized on chromosome 7q31-33, called the AUTS1 region, of ASD patients; 1585-1587 ttc del (Del312F) in one Japanese patient and G2324A (R558Q) in one Caucasian patient. The Del312F was located in the conserved transmembrane domain, and the R558Q was located in a conserved region just distal to the last transmembrane domain. In addition, a potential ASD-related GPR37 variant, T589M, was found in 7 affected Caucasian men from five different families. Our results suggested that some alleles in GPR37 were related to the deleterious effect of ASD. GPR37 is associated with the dopamine transporter to modulate dopamine uptake, and regulates behavioral responses to dopaminergic drugs. Thus, dopaminergic neurons may be involved in the ASD. However, we also detected the Del321F mutation in the patient’s unaffected father and R558Q in not only an affected brother but also an unaffected mother. The identification of unaffected parents that carried the mutated alleles suggested that the manifestation of ASD was also influenced by factors other than these mutations, including endoplasmic reticulum stress of the mutated proteins or gender. Our study will provide the new insight into the molecular pathogenesis of ASD.
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4. Heil KM, Schaaf CP. {{The genetics of autism spectrum disorders – a guide for clinicians}}. {Curr Psychiatry Rep}. 2013; 15(1): 334.
Recent advances in genetic testing technology have made chromosome microarray analysis (CMA) a first-tier clinical diagnostic test for Autism Spectrum Disorders (ASDs). Two main types of microarrays are available, single nucleotide polymorphism (SNP) arrays and array comparative genomic hybridization (aCGH), each with its own advantages and disadvantages in ASDs testing. Rare genetic variants, and copy number variants (CNVs) in particular, have been shown to play a major role in ASDs. More than 200 autism susceptibility genes have been identified to date, and complex patterns of inheritance, such as oligogenic heterozygosity, appear to contribute to the etiopathogenesis of ASDs. Incomplete penetrance and variable expressivity represent particular challenges in the interpretation of CMA testing of autistic individuals. This review aims to provide an overview of autism genetics for the practicing physician and gives hands-on advice on how to follow-up on abnormal CMA findings in individuals with neuropsychiatric disorders.
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5. Hinton R, Budimirovic DB, Marschik PB, Talisa VB, Einspieler C, Gipson T, Johnston MV. {{Parental reports on early language and motor milestones in fragile X syndrome with and without autism spectrum disorders}}. {Dev Neurorehabil}. 2013; 16(1): 58-66.
Objective: This study examined features of early language and motor milestones in children with fragile X syndrome (FXS) and contrasted these features with a diagnosis of Autism Spectrum Disorder (ASD) later in life in these children. Methods: We retrospectively examined parental report of age of onset for walking and first words for primarily boys with FXS, both with ASD (FXS + ASD) and FXS-only. The diagnosis of ASD was established by DSM-IV criteria, which were complemented by the ADOS. The age of onset was analyzed as a continuous and categorical variable, which were compared to the upper limit of typically developing children. Results: Individuals with FXS-only are more delayed in the onset of first words than first walks. The finding represents a pattern suggesting a continuum as robustly demonstrated in individuals with FXS + ASD vs. FXS-only. Conclusion: Our results support validity of FXS + ASD co-morbidity as a distinct phenotype in individuals with FXS.
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6. Iliff AJ, Renoux AJ, Krans A, Usdin K, Sutton MA, Todd PK. {{Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice}}. {Hum Mol Genet}. 2012.
Fragile X premutation-associated disorders, including Fragile X-associated Tremor Ataxia Syndrome, result from unmethylated CGG repeat expansions in the 5-untranslated region of the FMR1 gene. Premutation sized repeats increase FMR1 transcription but impair rapid translation of the fragile X protein, FMRP, which is absent in Fragile X Syndrome. Normally, FMRP binds to RNA and regulates metabotropic glutamate receptor (mGluR) mediated synaptic translation, allowing for dendritic synthesis of several proteins. FMRP itself is also synthesized at synapses in response to mGluR activation. However, the role of activity-dependent translation of FMRP in synaptic plasticity and Fragile X-premutation associated disorders is unknown. To investigate this question, we utilized a CGG knock-in mouse model of the Fragile X premutation with 120-150 CGG repeats in the mouse Fmr1 5-UTR. These mice exhibit increased Fmr1 mRNA production but impaired FMRP translational efficiency, leading to a modest reduction in basal FMRP expression. Cultured hippocampal neurons and synaptoneurosomes derived from CGG KI mice demonstrate impaired FMRP translation in response to the group I mGluR agonist DHPG. Electrophysiological analysis reveals enhanced mGluR mediated long term depression (mGluR-LTD) at CA3-CA1 synapses in acute hippocampal slices prepared from CGG KI mice relative to wild-type littermates, similar to Fmr1 knockout mice. However, unlike mGluR-LTD in mice completely lacking FMRP, mGluR-LTD in CGG knock-in mice remains dependent on new protein synthesis. These studies demonstrate partially overlapping synaptic plasticity phenotypes in mouse models of FXS and Fragile X premutation disorders and support a role for activity-dependent synthesis of FMRP in enduring forms of synaptic plasticity.
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7. Jayaseelan S, Tenenbaum SA. {{Neurodevelopmental disorders: Signalling pathways of fragile X syndrome}}. {Nature}. 2012; 492(7429): 359-60.
