Pubmed du 11/11/10

2010-11-11 12:03:50

1. Avino TA, Hutsler JJ. {{Abnormal cell patterning at the cortical gray-white matter boundary in autism spectrum disorders}}. {Brain Res};2010 (Nov 11);1360:138-146.

Previous research on neuronal spacing and columnar organization indicates the presence of cell patterning alterations within the cerebral cortex of individuals with autism spectrum disorders (ASD). These patterning abnormalities include irregularities at the gray-white matter boundary and may implicate early neurodevelopmental events such as migration in altering cortical organization in ASD. The present study utilized a novel method to quantify the gray-white matter boundary in eight ASD and eight typically developing control subjects. Digital photomicrographs of the gray-white matter boundary were acquired from multiple positions within the superior temporal gyrus (BA21), dorsolateral frontal lobe (BA9), and dorsal parietal lobe (BA7) of each case. A sigmoid curve was fitted to the transition zone between layer VI and underlying white matter (subplate), and the slope of the resulting curve was used as a measure of the spatial extent of the transition zone. For all three cortical regions examined, ASD subjects showed « shallower » sigmoid curves compared to neurotypicals, indicating the presence of an indistinct boundary between cortical layer VI and the underlying white matter. These results may reflect the presence of supernumerary neurons beneath the cortical plate that could be the result of migration deficits or failed apoptosis in the subplate region. Furthermore, these findings raise questions regarding the validity of cortical measures that rely on gray-white matter parcellation, since an indistinct transition zone could lead to a misplaced cortical boundary and errors in both thickness and volume measures.

2. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY. {{Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes}}. {Nature};2010 (Nov 11);468(7321):263-269.

Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (gamma-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

3. Coombs E, Brosnan M, Bryant-Waugh R, Skevington SM. {{An investigation into the relationship between eating disorder psychopathology and autistic symptomatology in a non-clinical sample}}. {Br J Clin Psychol};2010 (Nov 8)

Objective Female adults with a diagnosis of anorexia nervosa (AN) have been found to score higher than healthy controls on a questionnaire that measures characteristics associated with Autism Spectrum Disorders (ASD). This research investigated the relationship between eating disorder (ED) and ASD symptomatology in a non-clinical sample, with an additional focus on prenatal testosterone (pT) levels. Design A cross-sectional research design was used. The selected age group of both males and females allowed for a focus on early onset of ED symptomatology in both sexes. Methods Self-reported questionnaire data from the Eating Attitudes Test (EAT-26) and the Autism Spectrum Quotient (AQ) were collected from 132 schoolchildren (61 boys, 71 girls) aged 11 to 14, with no recorded psychiatric diagnoses. Digit ratio (2D:4D) measures to index levels of pT exposure were also obtained. Results A significant relationship between levels of ED symptomatology and ASD symptomatology was identified. Particularly strong relationships were identified between the EAT-26 and the attention to detail and communication subscales of the AQ. Few relationships were found for digit ratios. Conclusion The results extend previous research from a sample with a diagnosis of AN to a non-clinical population. Those registering higher levels of ED symptomatology also reported higher levels of attention to detail and communication difficulties associated with ASD.

4. Geurts HM, Deprey L, Ozonoff S. {{[Assessment of comorbidity in autism spectrum disorders.]}}. {Tijdschr Psychiatr};2010;52(11):753-761.

summary background It is often difficult to determine whether there is psychiatric comorbidity in addition to an autism spectrum disorder (asd) or whether the observed behavior is described adequately by the asd diagnosis. aim To show when the possibility of comorbidity needs to be seriously considered in children and adults with asd. We will focus on the most common comorbide disorders in children and adults with asd, namely anxiety, depression and adhd. method Discussion of the literature and clinical experiences. results In order to diagnose asd and comorbidities it is important to record a detailed developmental history. This can also serve as a baseline for the client’s behaviour. Changes in the pattern of behaviour with respect to the baseline can often be indicative of the presence of a comorbid disorder. conclusion Since asd is a life long disorder and comorbidity needing treatment or interventions can be present during various phases of life, the diagnostic procedure needs to continue even after asd has been diagnosed.

5. Jou RJ, Minshew NJ, Keshavan MS, Vitale MP, Hardan AY. {{Enlarged right superior temporal gyrus in children and adolescents with autism}}. {Brain Res};2010 (Nov 11);1360:205-212.

The superior temporal gyrus has been implicated in language processing and social perception. Therefore, anatomical abnormalities of this structure may underlie some of the deficits observed in autism, a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. In this study, volumes of the left and right superior temporal gyri were measured using magnetic resonance imaging obtained from 18 boys with high-functioning autism (mean age=13.5+/-3.4years; full-scale IQ=103.6+/-13.4) and 19 healthy controls (mean age=13.7+/-3.0years; full-scale IQ=103.9+/-10.5), group-matched on age, gender, and handedness. When compared to the control group, right superior temporal gyral volumes was significantly increased in the autism group after controlling for age and total brain volume. There was no significant difference in the volume of the left superior temporal gyrus. Post-hoc analysis revealed a significant increase of the right posterior superior temporal gyral volume in the autism group, before and after controlling for age and total brain volume. Examination of the symmetry index for the superior temporal gyral volumes did not yield statistically significant between-group differences. Findings from this preliminary investigation suggest the existence of volumetric alterations in the right superior temporal gyrus in children and adolescents with autism, providing support for a neuroanatomical basis of the social perceptual deficits characterizing this severe neurodevelopmental disorder.

6. Kolevzon A, Cai G, Soorya L, Takahashi N, Grodberg D, Kajiwara Y, Willner JP, Tryfon A, Buxbaum JD. {{Analysis of a purported SHANK3 mutation in a boy with autism: Clinical impact of rare variant research in neurodevelopmental disabilities}}. {Brain Res};2010 (Nov 6)

There is strong evidence for rare, highly penetrant genetic variants playing an etiological role in multiple neurodevelopmental disabilities, including autism spectrum disorders. The rate of discovery of such rare variants is increasing with the advent of larger sample collections, chromosome microarray analyses, and high-throughput sequencing. As the variants that are being discovered can be highly penetrant, they lead immediately to model systems with construct validity, critical for understanding the underlying neurobiology of these conditions, which in turn can provide leads for novel therapeutic targets. Moreover, these discoveries can benefit families with information about recurrence risk, resolve concerns about etiology, provide information about associated medical issues, and engender directed advocacy for specific genetic conditions. For these reasons, diagnostic laboratories are taking advantage of research data as it is produced. In the current report, we present our molecular analysis of a child with a purported disruptive mutation in SHANK3 identified by a commercial genetic testing laboratory and we provide evidence that this was not an etiological variant. The variant was a 1bp insertion in exon 11 of the RefSeq gene, which we then determined was inherited from a healthy mother and found in ~1% of controls. Since the variant would be predicted to disrupt the reference gene, and the penetrance of SHANK3 mutations is very high, we did follow up molecular and bioinformatic analyses and concluded that the presumptive exon containing the variant is not likely to be present in most or all SHANK3 transcripts. The results highlight difficulties that can arise with rapid translation of research findings to clinical practice. Researchers are in a unique position to generate resources with collated and curated information that can inform research, genetic testing, clinicians and families about the best practices as pertains to rare genetic variants in neurodevelopmental disabilities. Of immediate importance would be a well-curated database of gene variation identified in large numbers of typically developing individuals and in individuals affected with neurodevelopmental disabilities. Such a database would reduce false-positive results in clinical settings, would be helpful in structure-function analyses, and would direct translational research to pathways must likely to benefit families.

7. McAleer P, Kay JW, Pollick FE, Rutherford MD. {{Intention Perception in High Functioning People with Autism Spectrum Disorders Using Animacy Displays Derived from Human Actions}}. {J Autism Dev Disord};2010 (Nov 11)

The perception of intent in Autism Spectrum Disorders (ASD) often relies on synthetic animacy displays. This study tests intention perception in ASD via animacy stimuli derived from human motion. Using a forced choice task, 28 participants (14 ASDs; 14 age and verbal-I.Q. matched controls) categorized displays of Chasing, Fighting, Flirting, Following, Guarding and Playing, from two viewpoints (side, overhead) in both animacy and full video displays. Detailed analysis revealed no differences between populations in accuracy, or response patterns. Collapsing across groups revealed Following and Video displays to be most accurately perceived. The stimuli and intentions used are compared to those of previous studies, and the implication of our results on the understanding of Theory of Mind in ASD is discussed.

8. Naito K, Matsui Y, Maeda K, Tanaka K. {{Evaluation of the Validity of the Autism Spectrum Quotient (AQ) in Differentiating High-Functioning Autistic Spectrum Disorder from Schizophrenia}}. {Kobe J Med Sci};2010;56(3):E116-124.

The aim of this study is to examine the validity of the Autism Spectrum Quotient (AQ) to differentiate high-functioning autistic spectrum disorder (ASD) from schizophrenia (SCH). The AQ was developed by Baron-Cohen et al. to measure autistic traits. In addition to the original AQ items, we created self-administered questions about psychotic symptoms (S-scale). We administered the modified AQ to 51 ASD patients and 46 SCH patients, and we compared these two groups in terms of total AQ score, AQ subscale scores and S-scale score. We applied receiver operating characteristic (ROC) curves to examine the discriminating power of the AQ. The mean total AQ score of the ASD group (32.6; SD=6.8; range: 8-48) was significantly higher than that of the SCH group (21.8; SD=7.4; range: 10-39) (p<0.001). All AQ subscale scores of the ASD group were significantly higher than those of the SCH group. By using a cut-off score of 29 for the AQ total score, we were able to correctly classify 80% of the subjects. At this cut-off, the positive and negative predictive values were 0.83 and 0.78, respectively. Inclusion of additional questions of the S-scale did not increase the power of differentiation. These results indicate that the usefulness of the AQ in differentiating high-functioning ASD from SCH is limited.

9. Okabe Y, Kusaga A, Takahashi T, Mitsumasu C, Murai Y, Tanaka E, Higashi H, Matsuishi T, Kosai K. {{Neural development of methyl-CpG-binding protein 2 null embryonic stem cells: a system for studying Rett syndrome}}. {Brain Res};2010 (Nov 11);1360:17-27.

Mutations in methyl-CpG-binding protein 2 (MeCP2) gene cause the neurodevelopmental disorder Rett syndrome (RTT). Here, we describe a new experimental system that efficiently elucidates the role of MeCP2 in neural development. MeCP2-null and control ES cells were generated by adenoviral conditional targeting and examined for maintenance of the undifferentiated ES cell state, neurogenesis, and gliogenesis during in vitro differentiation. In addition, dopamine release and electrophysiological features of neurons differentiated from these ES cells were examined. Loss of MeCP2 did not affect undifferentiated ES cell colony morphology and growth, or the timing or efficiency of neural stem cell differentiation into Nestin-, TuJ- or TH-positive neurons. In contrast, gliogenesis was drastically accelerated by MeCP2 deficiency. Dopamine production and release in response to a depolarizing stimulus in MeCP2-null ES-derived dopaminergic neurons was intact. However, MeCP2-null differentiated neurons showed significantly smaller voltage-dependent Na(+) currents and A-type K(+) currents, suggesting incomplete maturation. Thus, MeCP2 is not essential for maintenance of the undifferentiated ES cell state, neurogenesis, or dopaminergic function; rather, it is principally involved in inhibiting gliogenesis. Altered neuronal maturity may indirectly result from abnormal glial development and may underlie the pathogenesis of RTT. These data contribute to a better understanding of the developmental roles of MeCP2 and the pathogenesis of RTT.

10. Saunders JB. {{Overwhelmed by autism: a dramatic increase in diagnoses has lawmakers debating the state’s role}}. {State Legis};2010 (Oct-Nov);36(9):36-39.

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Pubmed du 11/11/10