1. Ambrosini E, Sicca F, Brignone MS, D’Adamo MC, Napolitano C, Servettini I, Moro F, Ruan Y, Gugliemi L, Pieroni S, Servillo G, Lanciotti A, Valvo G, Catacuzzeno L, Franciolini F, Molinari P, Marchese M, Grottesi A, Guerrini R, Santorelli FM, Priori S, Pessia M. {{Genetically-induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism/epilepsy phenotype}}. {Hum Mol Genet};2014 (May 2)
Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism/epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that: i) enhanced the channel’s surface expression and stability at the plasma membrane; ii) reduced protein ubiquitylation and degradation; iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol-poor domains; iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin-proteasome pathway; in addition it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management.
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2. Amiet C, Couchon E, Carr K, Carayol J, Cohen D. {{Are there cultural differences in parental interest in early diagnosis and genetic risk assessment for autism spectrum disorder?}}. {Front Pediatr};2014;2:32.
Background: There are many societal and cultural differences between healthcare systems and the use of genetic testing in the US and France. These differences may affect the diagnostic process for autism spectrum disorder (ASD) in each country and influence parental opinions regarding the use of genetic screening tools for ASD. Methods: Using an internet-based tool, a survey of parents with at least one child with ASD was conducted. A total of 162 participants from the US completed an English version of the survey and 469 participants from France completed a French version of the survey. Respondents were mainly females (90%) and biological parents (94.3% in the US and 97.2% in France). Results: The mean age of ASD diagnosis reported was not significantly different between France (57.5 +/- 38.4 months) and the US (56.5 +/- 52.7 months) (p = 0.82) despite significant difference in the average age at which a difference in development was first suspected [29.7 months (+/-28.4) vs. 21.4 months (+/-18.1), respectively, p = 7 x 10(-4)]. Only 27.8% of US participants indicated that their child diagnosed with ASD had undergone diagnostic genetic testing, whereas 61.7% of the French participants indicated this was the case (p = 2.7 x 10(-12)). In both countries, the majority of respondents (69.3% and 80% from France and the US, respectively) indicated high interest in the use of a genetic screening test for autism. Conclusion: Parents from France and the US report a persistent delay between the initial suspicion of a difference in development and the diagnosis of ASD. Significantly fewer US participants underwent genetic testing although this result should be regarded as exploratory given the limitations. The significance of these between country differences will be discussed.
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3. Blake JM, Berner J. {{Extenuating circumstances: Autism awareness}}. {S D Med};2014 (Apr);67(4):163, 165.
4. Bluth K, Roberson PN, Billen RM, Sams JM. {{A Stress Model for Couples Parenting Children With Autism Spectrum Disorders and the Introduction of a Mindfulness Intervention}}. {J Fam Theory Rev};2013 (Sep);5(3):194-213.
Parents of children with autism spectrum disorders (ASD) are at an increased risk for acute and chronic stress compared to parents of children with other developmental disabilities and parents of children without disabilities. It is plausible that the stressors of having a child with ASD affect the couple relationship; however, few researchers have focused on this dynamic within these families. In this article, we seek to develop a model for how stress operates in families with children with ASD. In developing this new stress model, we describe the characteristics of ASD, discuss stressors that are pronounced in families of children with ASD as supported by the literature, and highlight the limitations of Perry’s (2004) model in application to this population. Our expanded stress model includes the addition of parenting couple resources and parenting couple outcomes. Finally, we demonstrate how to apply the model using a mindfulness intervention to promote positive outcomes and strengthen the couple relationship.
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5. Cascio MA. {{New Directions in the Social Study of the Autism Spectrum: A Review Essay}}. {Cult Med Psychiatry};2014 (May 4)
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6. Chattopadhyay S, Arora R. {{The ironies of human mind: a case of rett syndrome}}. {Ethiop J Health Sci};2014 (Apr);24(2):171-174.
BACKGROUND: Rett Syndrome (RS) is a chromosome X-linked genetic neurological disorder characterized by developmental regression, particularly in relation to expressive language and use of the hands. It is also associated with profound mental retardation and almost exclusively affects females. CASE DETAILS: A four and a half year old girl reported to our dental OPD for a dental checkup. On complete examination, she was diagnosed to be suffering from Rett Syndrome. Preventive therapies and proper oral hygiene instructions were explained to her mother. CONCLUSION: Early diagnosis of such disorders is extremely important along with treatment of patients’ problems with love and care to prevent them from further pain and stress.
7. Kurtz EG. {{Extenuating circumstances: Effective screening for autism spectrum disorder}}. {S D Med};2014 (Apr);67(4):160-161.
8. Lugo JN, Smith GD, Arbuckle EP, White J, Holley AJ, Floruta CM, Ahmed N, Gomez MC, Okonkwo O. {{Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins}}. {Front Mol Neurosci};2014;7:27.
Many genes have been implicated in the underlying cause of autism but each gene accounts for only a small fraction of those diagnosed with autism. There is increasing evidence that activity-dependent changes in neuronal signaling could act as a convergent mechanism for many of the changes in synaptic proteins. One candidate signaling pathway that may have a critical role in autism is the PI3K/AKT/mTOR pathway. A major regulator of this pathway is the negative repressor phosphatase and tensin homolog (PTEN). In the current study we examined the behavioral and molecular consequences in mice with neuron subset-specific deletion of PTEN. The knockout (KO) mice showed deficits in social chamber and social partition test. KO mice demonstrated alterations in repetitive behavior, as measured in the marble burying test and hole-board test. They showed no changes in ultrasonic vocalizations emitted on postnatal day 10 or 12 compared to wildtype (WT) mice. They exhibited less anxiety in the elevated-plus maze test and were more active in the open field test compared to WT mice. In addition to the behavioral alterations, KO mice had elevation of phosphorylated AKT, phosphorylated S6, and an increase in S6K. KO mice had a decrease in mGluR but an increase in total and phosphorylated fragile X mental retardation protein. The disruptions in intracellular signaling may be why the KO mice had a decrease in the dendritic potassium channel Kv4.2 and a decrease in the synaptic scaffolding proteins PSD-95 and SAP102. These findings demonstrate that deletion of PTEN results in long-term alterations in social behavior, repetitive behavior, activity, and anxiety. In addition, deletion of PTEN significantly alters mGluR signaling and many synaptic proteins in the hippocampus. Our data demonstrates that deletion of PTEN can result in many of the behavioral features of autism and may provide insights into the regulation of intracellular signaling on synaptic proteins.
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9. Mathews TL, King ML, Kupzyk KA, Lake CM. {{Findings and Implications of Developmental Screening for High-Risk Children Referred to a Tertiary Developmental Disability Center}}. {J Pediatr Health Care};2014 (May 1)
INTRODUCTION: The primary goal of this article is to describe an intake process and results of screening for developmental and autism spectrum disorders in children referred to a tertiary center. A secondary analysis of abnormal screening results, demographic variables, and parental concerns of autism was conducted, along with a correlation analysis between developmental and autism-specific screening tools. METHODS: A total of 379 children younger than 6 years were « prescreened » with the Ages and Stages Questionnaire-3 and the Modified Checklist for Autism in Toddlers or the Social Communication Questionnaire. Medical records were reviewed to identify demographic variables and parental primary concerns. RESULTS: In approximately 11% of participants who screened positive for autism, no parental concerns of autism were present. Medium effect size correlations were found between the failed autism screening tools and delays in two domains on the Ages and Stages Questionnaire-3. DISCUSSION: Clinical implications are addressed concerning diligent use of developmental and autism-specific rating scales to identify children at risk.
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10. McGavin CL. {{More than « a case of fragile x »}}. {JAMA};2014 (May 7);311(17):1735.
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11. Rossignol DA, Frye RE. {{Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism}}. {Front Physiol};2014;5:150.
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are defined solely on the basis of behavioral observations. Therefore, ASD has traditionally been framed as a behavioral disorder. However, evidence is accumulating that ASD is characterized by certain physiological abnormalities, including oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation. While these abnormalities have been reported in studies that have examined peripheral biomarkers such as blood and urine, more recent studies have also reported these abnormalities in brain tissue derived from individuals diagnosed with ASD as compared to brain tissue derived from control individuals. A majority of these brain tissue studies have been published since 2010. The brain regions found to contain these physiological abnormalities in individuals with ASD are involved in speech and auditory processing, social behavior, memory, and sensory and motor coordination. This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders. This understanding may lead to new testing and treatment strategies in individuals with ASD.
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12. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. {{The familial risk of autism}}. {JAMA};2014 (May 7);311(17):1770-1777.
IMPORTANCE Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved. OBJECTIVE To provide estimates of familial aggregation and heritability of ASD. DESIGN, SETTING, AND PARTICIPANTS A population-based cohort including 2 049 973 Swedish children born 1982 through 2006. We identified 37 570 twin pairs, 2 642 064 full sibling pairs, 432 281 maternal and 445 531 paternal half sibling pairs, and 5 799 875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained. MAIN OUTCOMES AND MEASURES The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors. RESULTS In the sample, 14 516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100 000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64). CONCLUSIONS AND RELEVANCE Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.
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13. Schendel DE, Gronborg TK, Parner ET. {{The genetic and environmental contributions to autism: looking beyond twins}}. {JAMA};2014 (May 7);311(17):1738-1739.
