1. Esposito G, Ruggiero R, Savarese G, Savarese M, Tremolaterra MR, Salvatore F, Carsana A. {{A 15-year case-mix experience for Fragile X syndrome molecular diagnosis and comparison between conventional and alternative techniques leading to a novel diagnostic procedure}}. {Clin Chim Acta}. 2012 Dec 29.
Fragile X syndrome (FXS) is the main cause of heritable mental retardation. In most patients, it is associated with an increased number of CGG repeats (>200) within the 5′-untranslated region of the FMR1 gene, and with methylation of the expanded repeats and of the promoter. FXS female carriers and transmitting males have expansions of between 55 and 200 repeats (premutated alleles). Alleles with premutations are unstable in female meioses. Normal and premutated repeats are unmethylated in males and subject to lyonization in females. Here, we report the postnatal and prenatal molecular diagnoses of FXS made with conventional PCR and Southern blotting in a cohort of Italian patients and their families over a period of 15 years. Moreover, we tested two novel high-performance PCR procedures (PCR with a chimeric primer, and the AmplideX(TM) FMR1 kit) in our patients and compared the results with our previous observations. We concluded that the high-performance PCR assays complement the results obtained by conventional methods, but they cannot replace the Southern blot procedure. Consequently, also based on cost-benefit considerations, our FXS diagnostic flowchart now consists of conventional PCR and Southern blotting plus the chimeric primer PCR procedure, whereas the AmplideX(TM) procedure is reserved for doubtful cases.
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2. Greco B, Manago F, Tucci V, Kao HT, Valtorta F, Benfenati F. {{Autism-related behavioral abnormalities in synapsin knockout mice}}. {Behavioural brain research}. 2012 Dec 29.
Several synaptic genes predisposing to autism-spectrum disorder (ASD) have been identified. Nonsense and missense mutations in the SYN1 gene encoding for Synapsin I have been identified in families segregating for idiopathic epilepsy and ASD and genetic mapping analyses have identified variations in the SYN2 gene as significantly contributing to epilepsy predisposition. Synapsins (Syn I/II/III) are a multigene family of synaptic vesicle-associated phosphoproteins playing multiple roles in synaptic development, transmission and plasticity. Lack of SynI and/or SynII triggers a strong epileptic phenotype in mice associated with mild cognitive impairments that are also present in the non-epileptic SynIII(-/-) mice. SynII(-/-) and SynIII(-/-) mice also display schizophrenia-like traits, suggesting that Syns could be involved in the regulation of social behavior. Here, we studied social interaction and novelty, social recognition and social dominance, social transmission of food preference and social memory in groups of male SynI(-/-), SynII(-/-) and SynIII(-/-) mice before and after the appearance of the epileptic phenotype and compared their performances with control mice. We found that deletion of Syn isoforms widely impairs social behaviors and repetitive behaviors, resulting in ASD-related phenotypes. SynI or SynIII deletion altered social behavior, whereas SynII deletion extensively impaired various aspects of social behavior and memory, altered exploration of a novel environment increased self-grooming. Social impairments of SynI(-/-) and SynII(-/-) mice were evident also before the onset of seizures. The results demonstrate an involvement of Syns in generation of the behavioral traits of ASD and identify Syn knockout mice as a useful experimental model of ASD and epilepsy.
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3. Knight O, Bebbington A, Siafarikas A, Woodhead H, Girdler S, Leonard H. {{Pubertal trajectory in females with Rett syndrome: A population-based study}}. {Brain & development}. 2012 Dec 24.
Background: Rett syndrome is a severe genetic neurodevelopmental disorder mainly affecting females. The aim of this study was to describe pubertal development in a population-based cohort of females with Rett syndrome. Methods: To assess pubertal trajectory we used six waves of data provided by parents of girls and women, recruited through the Australian population-based Rett Syndrome Database. The age at which adrenarche, thelarche or menarche occurred was used as the parameter for time to event (survival) analysis. The relationships between BMI, mutation type and the trajectories were investigated, using Cox proportional hazards. Results: One quarter of girls reached adrenarche by 9.6years, half by 11years and three quarters by 12.6years. Half reached menarche by 14years (range 8-23). Being underweight was associated with later age at adrenarche, thelarche and menarche, while higher BMI (overweight) was associated with earlier onset. In general, girls with C-terminal deletions and early truncating mutations reached pubertal stages earlier and those with the p.R168X mutation reached them later. Conclusion: The pubertal course in Rett syndrome may be abnormal, sometimes with early adrenarche but delayed menarche. These features may be genotype dependent and may have varying relationships with growth and bone acquisition.
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4. McMorris CA, Brown SM, Bebko JM. {{An Examination of Iconic Memory in Children with Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2012 Dec 29.
Iconic memory is the ability to accurately recall a number of items after a very brief visual exposure. Previous research has examined these capabilities in typically developing (TD) children and individuals with intellectual disabilities (ID); however, there is limited research on these abilities in children with Autism Spectrum Disorders (ASD). Twenty-one TD and eighteen ASD children were presented with circular visual arrays of letters for 100 ms and were asked to recall as many letters as possible or a single letter that was cued for recall. Groups did not differ in the number of items recalled, the rate of information decay, or speed of information processing. These findings suggest that iconic memory is an intact skill for children with ASD, a result that has implications for subsequent information processing.
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5. Naigles LR, Tovar AT. {{Portable Intermodal Preferential Looking (IPL): Investigating Language Comprehension in Typically Developing Toddlers and Young Children with Autism}}. {Journal of visualized experiments : JoVE}. 2012(70).
One of the defining characteristics of autism spectrum disorder (ASD) is difficulty with language and communication.(1) Children with ASD’s onset of speaking is usually delayed, and many children with ASD consistently produce language less frequently and of lower lexical and grammatical complexity than their typically developing (TD) peers.(6,8,12,23) However, children with ASD also exhibit a significant social deficit, and researchers and clinicians continue to debate the extent to which the deficits in social interaction account for or contribute to the deficits in language production.(5,14,19,25) Standardized assessments of language in children with ASD usually do include a comprehension component; however, many such comprehension tasks assess just one aspect of language (e.g., vocabulary),(5) or include a significant motor component (e.g., pointing, act-out), and/or require children to deliberately choose between a number of alternatives. These last two behaviors are known to also be challenging to children with ASD.(7,12,13,16) We present a method which can assess the language comprehension of young typically developing children (9-36 months) and children with autism.(2,4,9,11,22) This method, Portable Intermodal Preferential Looking (P-IPL), projects side-by-side video images from a laptop onto a portable screen. The video images are paired first with a ‘baseline’ (nondirecting) audio, and then presented again paired with a ‘test’ linguistic audio that matches only one of the video images. Children’s eye movements while watching the video are filmed and later coded. Children who understand the linguistic audio will look more quickly to, and longer at, the video that matches the linguistic audio.(2,4,11,18,22,26) This paradigm includes a number of components that have recently been miniaturized (projector, camcorder, digitizer) to enable portability and easy setup in children’s homes. This is a crucial point for assessing young children with ASD, who are frequently uncomfortable in new (e.g., laboratory) settings. Videos can be created to assess a wide range of specific components of linguistic knowledge, such as Subject-Verb-Object word order, wh-questions, and tense/aspect suffixes on verbs; videos can also assess principles of word learning such as a noun bias, a shape bias, and syntactic bootstrapping.(10,14,17,21,24) Videos include characters and speech that are visually and acoustically salient and well tolerated by children with ASD.
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6. Scattoni ML, Martire A, Cartocci G, Ferrante A, Ricceri L. {{Reduced social interaction, behavioural flexibility and BDNF signalling in the BTBR T+tf/J strain, a mouse model of autism}}. {Behavioural brain research}. 2012 Dec 25.
Autism is a neurodevelopmental disorder characterized by social and communication impairments and repetitive behaviours. The inbred BTBR T+tf/J (BTBR) strain, a putative mouse model of autism, exhibits lower social interactions, higher repetitive self-grooming levels and unusual pattern of vocalizations as compared to C57BL/6J strain. First aim of the present study was to evaluate at adolescence (postnatal days 30-35) male BTBR and C57BL/6J performances in two different tasks involving either investigation of social cues (same strain partners) or non social ones (inanimate objects). In the social interaction test, BTBR mice showed a reduction of investigation of the social partner, due to a selective reduction of head sniffing, associated with a decrease in ultrasonic vocalizations. By contrast, no strain differences were detected in object investigations. Second aim of the study was to evaluate adult male BTBR and C57BL/6J performances in a fear conditioning task. Strain differences were evident during contextual retest: these strain differences primarily suggested a lack of behavioural flexibility in BTBR mice (i.e. realizing the occurrence of changes in the experimental paradigm). Subsequent electrophysiological analysis in hippocampal slices from adult BTBR and C57BL/6J mice revealed a significant reduction of Brain Derived Neurotrophic Factor (BDNF)-induced potentiation of synaptic transmission in BTBR mice. BDNF and tyrosine kinase B (TrkB) protein levels measured in the hippocampal region were also lower in BTBR as compared to C57BL/6J mice. These data confirm the presence of low levels of direct interaction with social stimuli in BTBR mice at adolescence, in the absence of any strain difference as for investigation of physical objects. At adulthood in BTBR mice clear signs of behavioural inflexibility were evident whereas both biochemical and electrophysiological data point to decreased BDNF signalling (likely due to a reduction in TrkB levels) in the hippocampus of this mouse strain.
