1. Dury AY, El Fatimy R, Tremblay S, Rose TM, Cote J, De Koninck P, Khandjian EW. {{Nuclear Fragile X Mental Retardation Protein Is localized to Cajal Bodies}}. {PLoS Genet};2013 (Oct);9(10):e1003890.
Fragile X syndrome is caused by loss of function of a single gene encoding the Fragile X Mental Retardation Protein (FMRP). This RNA-binding protein, widely expressed in mammalian tissues, is particularly abundant in neurons and is a component of messenger ribonucleoprotein (mRNP) complexes present within the translational apparatus. The absence of FMRP in neurons is believed to cause translation dysregulation and defects in mRNA transport essential for local protein synthesis and for synaptic development and maturation. A prevalent model posits that FMRP is a nucleocytoplasmic shuttling protein that transports its mRNA targets from the nucleus to the translation machinery. However, it is not known which of the multiple FMRP isoforms, resulting from the numerous alternatively spliced FMR1 transcripts variants, would be involved in such a process. Using a new generation of anti-FMRP antibodies and recombinant expression, we show here that the most commonly expressed human FMRP isoforms (ISO1 and 7) do not localize to the nucleus. Instead, specific FMRP isoforms 6 and 12 (ISO6 and 12), containing a novel C-terminal domain, were the only isoforms that localized to the nuclei in cultured human cells. These isoforms localized to specific p80-coilin and SMN positive structures that were identified as Cajal bodies. The Cajal body localization signal was confined to a 17 amino acid stretch in the C-terminus of human ISO6 and is lacking in a mouse Iso6 variant. As FMRP is an RNA-binding protein, its presence in Cajal bodies suggests additional functions in nuclear post-transcriptional RNA metabolism. Supporting this hypothesis, a missense mutation (I304N), known to alter the KH2-mediated RNA binding properties of FMRP, abolishes the localization of human FMRP ISO6 to Cajal bodies. These findings open unexplored avenues in search for new insights into the pathophysiology of Fragile X Syndrome.
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2. Elmose M, Trillingsgaard A, Jorgensen M, Nielsen A, Bruhn SS, Sorensen EU. {{Follow-up at mid-school age (9-13 years) of children assessed for autism spectrum disorder before the age of four}}. {Nord J Psychiatry};2013 (Nov 7)
Background: Studies of diagnosis and outcome in mid-school age children (9-13 years) referred early in life for a suspected autism spectrum disorder (ASD) are scarce. Aims: This study aimed to describe outcome, developmental change and the stability of the early diagnosis in mid-school age. Methods: Children consecutively referred to a specialized autism unit at a regional psychiatric diagnostic centre in Denmark before the age of 4 were contacted in mid-school age (9-13 years). 14 children with ASD and 9 children diagnosed outside the spectrum were included. Current clinical diagnosis, autism characteristics, intellectual abilities and adaptive functioning were assessed at follow-up, and investigated in relation to early measures of intellectual abilities and difficulties in social and communicative situations. Results: The stability of an early ASD diagnosis was confirmed. However, a high degree of change into the autism spectrum was found for children who were initially diagnosed with another developmental disorder. A positive change with regard to IQ level was evident at the individual level. At group level, there was a tendency for lower functioning in the children diagnosed early with ASD. Early measures of intellectual abilities, and of social and communicative difficulties, predicted between 16% and 50% of the variance in intellectual abilities and adaptive functioning. Conclusions: The findings are in line with follow-up studies in preschool and early school age but highlight the need to monitor early diagnostic decisions, and the need for more nuanced baseline and outcome measures that may help increase our prognostic understanding.
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3. Fish EW, Krouse MC, Stringfield SJ, Diberto JF, Robinson JE, Malanga CJ. {{Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile x syndrome}}. {PLoS One};2013;8(10):e77896.
Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y)) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1 (-/Y) mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 (-/Y) mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 (-/Y) than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 (-/Y) mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 (-/Y) mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 (-/Y) mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.
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4. Fujiwara T. {{Socioeconomic Status and the Risk of Suspected Autism Spectrum Disorders Among 18-Month-Old Toddlers in Japan: A Population-Based Study}}. {J Autism Dev Disord};2013 (Nov 8)
The association between family socioeconomic status (SES) and the suspected autism spectrum disorder (ASD) status of 18-month-old toddlers was investigated using a population-based sample in Japan, which has a universal healthcare system and a mandatory health checkup system for toddlers. Questionnaires including SES measurements and modified checklist for autism in toddlers were mailed to all families with 18-month-old toddlers in Chiba, a city near Tokyo (N = 6,061; response rate: 64 %). The results of logistic regression analysis (which were adjusted for potential confounders) indicated that low maternal education, but not paternal education or family income, were associated with having suspected ASD offspring. Lower maternal education was associated with an increased risk of autistic traits in Japan.
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5. Miller L, McGonigle-Chalmers M. {{Erratum to: Exploring Perceptual Skills in Children with Autism Spectrum Disorders: From Target Detection to Dynamic Perceptual Discrimination}}. {J Autism Dev Disord};2013 (Nov 10)
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6. Mohammadi MR, Yadegari N, Hassanzadeh E, Farokhnia M, Yekehtaz H, Mirshafiee O, Akhondzadeh S. {{Double-Blind, Placebo-Controlled Trial of Risperidone Plus Amantadine in Children With Autism: A 10-Week Randomized Study}}. {Clin Neuropharmacol};2013 (Nov 5)
OBJECTIVE: This study aimed to investigate the effect of adding amantadine to risperidone for treatment of autism. METHODS: Forty outpatients aged 4 to12 years, who were diagnosed with autism spectrum disorders based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, were assigned to this double-blind clinical trial. The subjects were divided randomly into 2 groups. One group received risperidone plus amantadine, and the other group received risperidone plus placebo. The dose of risperidone was titrated between 1 and 2.0 mg/d, and the dose of amantadine was 100 or 150 mg/d for patients less than 30 kg or more than 30 kg, respectively. The patients were assessed using the Aberrant Behavioral Checklist-Community (ABC-C) and adverse effects checklist as well as clinical global impression-improvement (CGI-I) at 2 checkpoints of 5-week intervals after the baseline. Informed consent was obtained from the parents of each participant. RESULTS: Among ABC-C subscales, Hyperactivity and Irritability showed significantly greater reduction in the amantadine group than the placebo group. There was no significant difference in adverse effects between the 2 groups. The CGI-I scores show significant improvement in the amantadine group compared to the placebo group. CONCLUSIONS: The present study suggests that amantadine may be a potential adjunctive treatment strategy for autism and it was generally well tolerated.
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7. Percy A. {{The American History of Rett Syndrome}}. {Pediatr Neurol};2013 (Nov 4)
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8. Rivest JB, Jemel B, Bertone A, McKerral M, Mottron L. {{Luminance- and texture-defined information processing in school-aged children with autism}}. {PLoS One};2013;8(10):e78978.
According to the complexity-specific hypothesis, the efficacy with which individuals with autism spectrum disorder (ASD) process visual information varies according to the extensiveness of the neural network required to process stimuli. Specifically, adults with ASD are less sensitive to texture-defined (or second-order) information, which necessitates the implication of several cortical visual areas. Conversely, the sensitivity to simple, luminance-defined (or first-order) information, which mainly relies on primary visual cortex (V1) activity, has been found to be either superior (static material) or intact (dynamic material) in ASD. It is currently unknown if these autistic perceptual alterations are present in childhood. In the present study, behavioural (threshold) and electrophysiological measures were obtained for static luminance- and texture-defined gratings presented to school-aged children with ASD and compared to those of typically developing children. Our behavioural and electrophysiological (P140) results indicate that luminance processing is likely unremarkable in autistic children. With respect to texture processing, there was no significant threshold difference between groups. However, unlike typical children, autistic children did not show reliable enhancements of brain activity (N230 and P340) in response to texture-defined gratings relative to luminance-defined gratings. This suggests reduced efficiency of neuro-integrative mechanisms operating at a perceptual level in autism. These results are in line with the idea that visual atypicalities mediated by intermediate-scale neural networks emerge before or during the school-age period in autism.
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9. Schaaf RC, Benevides T, Mailloux Z, Faller P, Hunt J, van Hooydonk E, Freeman R, Leiby B, Sendecki J, Kelly D. {{An Intervention for Sensory Difficulties in Children with Autism: A Randomized Trial}}. {J Autism Dev Disord};2013 (Nov 10)
This study evaluated a manualized intervention for sensory difficulties for children with autism, ages 4-8 years, using a randomized trial design. Diagnosis of autism was confirmed using gold standard measures. Results show that the children in the treatment group (n = 17) who received 30 sessions of the occupational therapy intervention scored significantly higher (p = 0.003, d = 1.2) on Goal Attainment Scales (primary outcome), and also scored significantly better on measures of caregiver assistance in self-care (p = 0.008 d = 0.9) and socialization (p = 0.04, d = 0.7) than the Usual Care control group (n = 15). The study shows high rigor in its measurement of treatment fidelity and use of a manualized protocol, and provides support for the use of this intervention for children with autism. Findings are discussed in terms of their implications for practice and future research.
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10. Schmunk G, Gargus JJ. {{Channelopathy pathogenesis in autism spectrum disorders}}. {Front Genet};2013;4:222.
Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.
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11. Smith LN, Cowan CW. {{Striking a balance in fragile X}}. {Nat Med};2013 (Nov);19(11):1370-1371.
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12. Tsang KM, Croen LA, Torres AR, Kharrazi M, Delorenze GN, Windham GC, Yoshida CK, Zerbo O, Weiss LA. {{A genome-wide survey of transgenerational genetic effects in autism}}. {PLoS One};2013;8(10):e76978.
Effects of parental genotype or parent-offspring genetic interaction are well established in model organisms for a variety of traits. However, these transgenerational genetic models are rarely studied in humans. We have utilized an autism case-control study with 735 mother-child pairs to perform genome-wide screening for maternal genetic effects and maternal-offspring genetic interaction. We used simple models of single locus parent-child interaction and identified suggestive results (P<10(-4)) that cannot be explained by main effects, but no genome-wide significant signals. Some of these maternal and maternal-child associations were in or adjacent to autism candidate genes including: PCDH9, FOXP1, GABRB3, NRXN1, RELN, MACROD2, FHIT, RORA, CNTN4, CNTNAP2, FAM135B, LAMA1, NFIA, NLGN4X, RAPGEF4, and SDK1. We attempted validation of potential autism association under maternal-specific models using maternal-paternal comparison in family-based GWAS datasets. Our results suggest that further study of parental genetic effects and parent-child interaction in autism is warranted.
