1. Berkel S, Tang W, Trevino M, Vogt M, Obenhaus HA, Gass P, Scherer SW, Sprengel R, Schratt G, Rappold GA. {{Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology}}. {Hum Mol Genet};2011 (Oct 12)
Mutations in the postsynaptic scaffolding gene SHANK2 have recently been identified in individuals with autism spectrum disorder (ASD) and intellectual disability (ID). However, the cellular and physiological consequences of these mutations in neurons remain unknown. We have analyzed the functional impact caused by two inherited and one de novo SHANK2 mutations from ASD individuals (L1008_P1009dup, T1127M, R462X). While all three variants affect spine volume and have smaller SHANK2 cluster sizes, T1127M additionally fails to rescue spine volume in Shank2 knock-down neurons. R462X is not able to rescue spine volume and dendritic branching and lacks postsynaptic clustering, indicating the most severe dysfunction. To demonstrate that R462X when expressed in mouse can be linked to physiological effects, we analyzed synaptic transmission and behavior. Principal neurons of mice expressing rAAV transduced SHANK2-R462X present a specific, long lasting reduction in miniature postsynaptic AMPA receptor currents. This dominant negative effect translates into dose-dependent altered cognitive behavior of SHANK2-R462X expressing mice, with an impact on the penetrance of ASD.
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2. Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI, Jr., Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, Ennis S. {{A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder}}. {Hum Genet};2011 (Oct 14)
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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3. Lessard M, Chouiali A, Drouin R, Sebire G, Corbin F. {{Quantitative measurement of FMRP in blood platelets as a new screening test for fragile X syndrome}}. {Clin Genet};2011 (Oct 12)
The fragile X syndrome usually results from CGG repeats expansion and methylation of the FMR1 gene leading to the absence of expression of its encoded protein, FMRP. Therefore, its diagnosis is traditionally based on the detection of these molecular alterations. As an alternative, FMRP-based screening methods have been proposed over the years. Most of them are based on immunohistochemistry analyses applied to a restricted number of lymphocytes (100) or hair roots (10-20) with limited diagnosis potential. In this study, we describe a truly quantitative approach using a new model, the blood platelet, which can be recovered easily with very high purity (99.9%). FMRP levels in platelets were first measured in a control population (n=124) and reference values were established. FMRP measurements were also performed in confirmed fragile X subjects. ROC curve analysis has shown that our test can easily discriminate fragile X males and females from controls (AUC=0.948). Cognitive functions were also assessed in these individuals using age-specific Wechsler intelligence scales and the Vineland adaptive behavior scales. A proportional relationship between FMRP levels, IQ and adaptive behavior was observed among fragile X individuals, suggesting that our test would be able to detect fragile X cases and may predict cognitive functions.
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4. Nahhas FA, Monroe TJ, Prior TW, Botma PI, Fang J, Snyder PJ, Talbott SL, Feldman GL. {{Evaluation of the Human Fragile X Mental Retardation 1 Polymerase Chain Reaction Reagents to Amplify the FMR1 Gene: Testing in a Clinical Diagnostic Laboratory}}. {Genet Test Mol Biomarkers};2011 (Oct 12)
Fragile X syndrome (FXS) is caused by the absence of a functional fragile X mental retardation protein (FMRP). In most cases, the molecular mutation is an expansion and consequent methylation of the CGG trinucleotide repeat in the 5′ end of the FMR1 gene. Polymerase chain reaction (PCR)-based assays that overcome the limitations of amplifying >100-150 CGG repeats have been designed. One such product, Human FMR1 PCR Reagents, can detect expanded mutation alleles without determining methylation status. We used this assay to amplify 70 clinical samples previously tested in three clinical laboratories, including 28 full mutation alleles, 17 premutation alleles, 6 gray zone alleles, and 21 normal samples (51 normal alleles including 5 homozygous females). The results were concordant with previously reported results. All full and premutation alleles were identifiable: repeat sizes are not assigned when the CGG repeat number is >200 and all full and premutation alleles were scored in the same category using this assay. All normal and gray zone alleles were within 0-1 repeat of their previously reported allele sizes. This method identified a mosaic premutation/full mutation pattern in 12/21 samples previously identified as full mutation only and in 5/7 samples previously reported as mosaic premutation/full mutation. These results demonstrate that this assay provides comparable results to the combination of PCR/Southern blot methodologies. Additional issues such as technologist time, reagent costs, turnaround times, and sample requirements are comparable to the PCR/Southern blotting assays currently utilized; however, methylation status cannot be determined using this assay. It is likely that PCR-only based assays will eventually replace previous methods for FXS and that Southern blotting or another methylation assay will only be utilized when determination of methylation status is necessary. This type of assay may also be utilized for other nucleotide expansion disorders.
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5. Pierpont EI, Richmond EK, Abbeduto L, Kover ST, Brown WT. {{Contributions of phonological and verbal working memory to language development in adolescents with fragile X syndrome}}. {J Neurodev Disord};2011 (Oct 13)
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Although language delays are frequently observed in FXS, neither the longitudinal course of language development nor its cognitive predictors are well understood. The present study investigated whether phonological and working memory skills are predictive of growth in vocabulary and syntax in individuals with FXS during adolescence. Forty-four individuals with FXS (mean age = 12.61 years) completed assessments of phonological memory (nonword repetition and forward digit recall), verbal working memory (backward digit recall), vocabulary, syntax, and nonverbal cognition. Vocabulary and syntax skills were reassessed at a 2-year follow-up. In a series of analyses that controlled for nonverbal cognitive ability and severity of autism symptoms, the relative contributions of phonological and working memory to language change over time were investigated. These relationships were examined separately for boys and girls. In boys with FXS, phonological memory significantly predicted gains in vocabulary and syntax skills. Further, verbal working memory was uniquely associated with vocabulary gains among boys. In girls with FXS, phonological and working memory skills showed no relationship with language change across the 2-year time period. Our findings indicate that, for adolescent boys with FXS, acquisition of vocabulary and syntax may be constrained by the ability to maintain and manipulate phonological representations online. Implications for the identification and treatment of language disorders in this population are discussed. The present study is the first to identify specific cognitive mechanisms contributing to language growth over time in individuals with FXS.
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6. Richmand BJ. {{Hypothesis: Conjugate vaccines may predispose children to autism spectrum disorders}}. {Med Hypotheses};2011 (Oct 10)
The first conjugate vaccine was approved for use in the US in 1988 to protect infants and young children against the capsular bacteria Haemophilus influenzae type b (Hib). Since its introduction in the US, this vaccine has been approved in most developed countries, including Denmark and Israel where the vaccine was added to their national vaccine programs in 1993 and 1994, respectively. There have been marked increases in the reported prevalence of autism spectrum disorders (ASDs) among children in the US beginning with birth cohorts in the late 1980s and in Denmark and Israel starting approximately 4-5years later. Although these increases may partly reflect ascertainment biases, an exogenous trigger could explain a significant portion of the reported increases in ASDs. It is hypothesized here that the introduction of the Hib conjugate vaccine in the US in 1988 and its subsequent introduction in Denmark and Israel could explain a substantial portion of the initial increases in ASDs in those countries. The continuation of the trend toward increased rates of ASDs could be further explained by increased usage of the vaccine, a change in 1990 in the recommended age of vaccination in the US from 15 to 2months, increased immunogenicity of the vaccine through changes in its carrier protein, and the subsequent introduction of the conjugate vaccine for Streptococcus pneumoniae. Although conjugate vaccines have been highly effective in protecting infants and young children from the significant morbidity and mortality caused by Hib and S. pneumoniae, the potential effects of conjugate vaccines on neural development merit close examination. Conjugate vaccines fundamentally change the manner in which the immune systems of infants and young children function by deviating their immune responses to the targeted carbohydrate antigens from a state of hypo-responsiveness to a robust B2 B cell mediated response. This period of hypo-responsiveness to carbohydrate antigens coincides with the intense myelination process in infants and young children, and conjugate vaccines may have disrupted evolutionary forces that favored early brain development over the need to protect infants and young children from capsular bacteria.
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7. Rosenblatt LE, Gorantla S, Torres JA, Yarmush RS, Rao S, Park ER, Denninger JW, Benson H, Fricchione GL, Bernstein B, Levine JB. {{Relaxation Response-Based Yoga Improves Functioning in Young Children with Autism: A Pilot Study}}. {J Altern Complement Med};2011 (Oct 12)
Abstract Objectives: The study objectives were to develop and objectively assess the therapeutic effect of a novel movement-based complementary and alternative medicine approach for children with an autism-spectrum disorder (ASD). Design: A within-subject analysis comparing pre- to post-treatment scores on two standard measures of childhood behavioral problems was used. Settings and location: The intervention and data analysis occurred at a tertiary care, medical school teaching hospital. Subjects: Twenty-four (24) children aged 3-16 years with a diagnosis of an ASD comprised the study group. Intervention: The efficacy of an 8-week multimodal yoga, dance, and music therapy program based on the relaxation response (RR) was developed and examined. Outcome measures: The study outcome was measured using The Behavioral Assessment System for Children, Second Edition (BASC-2) and the Aberrant Behavioral Checklist (ABC). Results: Robust changes were found on the BASC-2, primarily for 5-12-year-old children. Unexpectedly, the post-treatment scores on the Atypicality scale of the BASC-2, which measures some of the core features of autism, changed significantly (p=0.003). Conclusions: A movement-based, modified RR program, involving yoga and dance, showed efficacy in treating behavioral and some core features of autism, particularly for latency-age children.
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8. Sukumaran TU. {{Growth monitoring, developmental assessment and autism modules}}. {Indian Pediatr};2011 (Sep 8);48(9):679-680.
