1. Gilbert SJ, Meuwese JD, Towgood KJ, Frith CD, Burgess PW. {{Abnormal functional specialization within medial prefrontal cortex in high-functioning autism: a multi-voxel similarity analysis}}. {Brain};2009 (Apr);132(Pt 4):869-878.
Multi-voxel pattern analyses have proved successful in ‘decoding’ mental states from fMRI data, but have not been used to examine brain differences associated with atypical populations. We investigated a group of 16 (14 males) high-functioning participants with autism spectrum disorder (ASD) and 16 non-autistic control participants (12 males) performing two tasks (spatial/verbal) previously shown to activate medial rostral prefrontal cortex (mrPFC). Each task manipulated: (i) attention towards perceptual versus self-generated information and (ii) reflection on another person’s mental state (‘mentalizing’versus ‘non-mentalizing’) in a 2 x 2 design. Behavioral performance and group-level fMRI results were similar between groups. However, multi-voxel similarity analyses revealed strong differences. In control participants, the spatial distribution of activity generalized significantly between task contexts (spatial/verbal) when examining the same function (attention/mentalizing) but not when comparing different functions. This pattern was disrupted in the ASD group, indicating abnormal functional specialization within mrPFC, and demonstrating the applicability of multi-voxel pattern analysis to investigations of atypical populations.
2. Gong X, Delorme R, Fauchereau F, Durand CM, Chaste P, Betancur C, Goubran-Botros H, Nygren G, Anckarsater H, Rastam M, Gillberg IC, Kopp S, Mouren-Simeoni MC, Gillberg C, Leboyer M, Bourgeron T. {{An investigation of ribosomal protein L10 gene in autism spectrum disorders}}. {BMC Med Genet};2009;10:7.
BACKGROUND: Autism spectrum disorders (ASD) are severe neurodevelopmental disorders with the male:female ratio of 4:1, implying the contribution of X chromosome genetic factors to the susceptibility of ASD. The ribosomal protein L10 (RPL10) gene, located on chromosome Xq28, codes for a key protein in assembling large ribosomal subunit and protein synthesis. Two non-synonymous mutations of RPL10, L206M and H213Q, were identified in four boys with ASD. Moreover, functional studies of mutant RPL10 in yeast exhibited aberrant ribosomal profiles. These results provided a novel aspect of disease mechanisms for autism–aberrant processes of ribosome biosynthesis and translation. To confirm these initial findings, we re-sequenced RPL10 exons and quantified mRNA transcript level of RPL10 in our samples. METHODS: 141 individuals with ASD were recruited in this study. All RPL10 exons and flanking junctions were sequenced. Furthermore, mRNA transcript level of RPL10 was quantified in B lymphoblastoid cell lines (BLCL) of 48 patients and 27 controls using the method of SYBR Green quantitative PCR. Two sets of primer pairs were used to quantify the mRNA expression level of RPL10: RPL10-A and RPL10-B. RESULTS: No non-synonymous mutations were detected in our cohort. Male controls showed similar transcript level of RPL10 compared with female controls (RPL10-A, U = 81, P = 0.7; RPL10-B, U = 61.5, P = 0.2). We did not observe any significant difference in RPL10 transcript levels between cases and controls (RPL10-A, U = 531, P = 0.2; RPL10-B, U = 607.5, P = 0.7). CONCLUSION: Our results suggest that RPL10 has no major effect on the susceptibility to ASD.
3. Guerini FR, Bolognesi E, Manca S, Sotgiu S, Zanzottera M, Agliardi C, Usai S, Clerici M. {{Family-based transmission analysis of HLA genetic markers in Sardinian children with autistic spectrum disorders}}. {Hum Immunol};2009 (Mar);70(3):184-190.
Analyses of a 6-Mb region spanning the human leukocyte antigen (HLA) region from the HLA-DR to the HFE gene were performed in 37 families of Sardinian ancestry, all of whom had at least one autistic child, to identify genetic markers associated with autism spectrum disorders (ASD) development. In particular, four microsatellites (MIB, D6S265, MOGc, and D6S2239) and three single-nucleotide polymorphisms (SNPs; two in positions -308 and -238 in the promoter of the TNF-alpha and SNP rs2857766 [V142L] in exon 3 of the MOG gene) were analyzed. An intrafamilial case-control method (affected family-based controls) and transmission disequilibrium test analysis were used to evaluate the association of microsatellite and SNP markers with ASD-affected children. Results indicated positive associations with ASD for D6S265*220 (p < 0.01) and MOGc*131 (p < 0.05) and negative associations for MOGc*117 and MIB*346 alleles (p < 0.01) in ASD children. Polymorphism haplotype analysis indicated that D6S265 allele *220 and MOGc allele *131 were significantly more likely to be transmitted together, as a whole haplotype, to ASD children (p < 0.05). Conversely, the D6S265*224-MOGc*117-rs2857766(G) haplotype was significantly less frequently transmitted to ASD children (p < 0.01). The results present novel gene markers, reinforcing the hypothesis that genetic factors play a pivotal role in the pathogenesis of ASD.
4. Henningsson S, Jonsson L, Ljunggren E, Westberg L, Gillberg C, Rastam M, Anckarsater H, Nygren G, Landen M, Thuresson K, Betancur C, Leboyer M, Gillberg C, Eriksson E, Melke J. {{Possible association between the androgen receptor gene and autism spectrum disorder}}. {Psychoneuroendocrinology};2009 (Jun);34(5):752-761.
Autism is a highly heritable disorder but the specific genes involved remain largely unknown. The higher prevalence of autism in men than in women, in conjunction with a number of other observations, has led to the suggestion that prenatal brain exposure to androgens may be of importance for the development of this condition. Prompted by this hypothesis, we investigated the potential influence of variation in the androgen receptor (AR) gene on the susceptibility for autism. To this end, 267 subjects with autism spectrum disorder and 617 controls were genotyped for three polymorphisms in exon 1 of the AR gene: the CAG repeat, the GGN repeat and the rs6152 SNP. In addition, parents and affected siblings were genotyped for 118 and 32 of the cases, respectively. Case-control comparisons revealed higher prevalence of short CAG alleles as well as of the A allele of the rs6152 SNP in female cases than in controls, but revealed no significant differences with respect to the GGN repeat. Analysis of the 118 families using transmission disequilibrium test, on the other hand, suggested an association with the GGN polymorphism, the rare 20-repeat allele being undertransmitted to male cases and the 23-repeat allele being overtransmitted to female cases. Sequencing of the AR gene in 46 patients revealed no mutations or rare variants. The results lend some support for an influence of the studied polymorphisms on the susceptibility for autism, but argue against the possibility that mutations in the AR gene are common in subjects with this condition.
5. Kenworthy L, Black DO, Harrison B, Della Rosa A, Wallace GL. {{Are Executive Control Functions Related to Autism Symptoms in High-Functioning Children?}}. {Child Neuropsychol};2009 (Jan 27):1-16.
Background: Linking autism symptoms to cognitive abilities can expand phenotypic descriptions and facilitate investigations into the etiology and treatment of this multiplex disorder. Executive dysfunction is one of several potential cognitive phenotypes in autism. Method: Archival clinical data on 89 children diagnosed with Autism Spectrum Disorders and administered a large neuropsychological battery were evaluated for relationships between executive functioning and autism symptoms. Results: Significant relationships between both laboratory tasks and behavior rating scales of executive functions and autism symptoms were identified. Multiple regression analyses revealed that measures of semantic fluency, divided auditory attention, and behavioral regulation were significantly correlated with autism symptoms, even after accounting for the variance from correlated « nuisance variables, » such as vocabulary and age. Conclusions: Executive dysfunction is related to all three clusters of behavioral symptoms in Autism Spectrum Disorders.
6. Malow BA, Crowe C, Henderson L, McGrew SG, Wang L, Song Y, Stone WL. {{A sleep habits questionnaire for children with autism spectrum disorders}}. {J Child Neurol};2009 (Jan);24(1):19-24.
Sleep difficulties in children with autism spectrum disorders are common, with poor sleep hygiene a contributing factor. We developed the Family Inventory of Sleep Habits to measure sleep hygiene in this population. Its validity and reliability in 2 groups of children aged 4 to 10 years, those with a clinical diagnosis of autism spectrum disorders, and those who are typically developing are described. In both groups, total and modified (reflecting insomnia subscales) scores on the Children’s Sleep Habits Questionnaire showed significant negative correlations with the total score. The Peabody Picture Vocabulary Test-III was significantly correlated with total score in the autism spectrum group but not in the typically developing group. Age and socioeconomic status were not correlated with total score in either group. This preliminary work suggests that the Family Inventory of Sleep Habits is a valid and reliable measure of sleep hygiene in autism spectrum disorders.
7. Prasad HC, Steiner JA, Sutcliffe JS, Blakely RD. {{Enhanced activity of human serotonin transporter variants associated with autism}}. {Philos Trans R Soc Lond B Biol Sci};2009 (Jan 27);364(1514):163-173.
Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling. Here, we document functional perturbations of three of these variants: Ile425Leu; Phe465Leu; and Leu550Val. In transiently transfected HeLa cells, the three variants confer a gain of 5-HT transport phenotype. Specifically, enhanced SERT activity was also observed in lymphoblastoid lines derived from mutation carriers. In contrast to previously characterized Gly56Ala, where increased transport activity derives from catalytic activation, the three novel variants exhibit elevated surface density as revealed through both surface antagonist-binding and biotinylation studies. Unlike Gly56Ala, mutants Ile425Leu, Phe465Leu and Leu550Val retain a capacity for acute PKG and p38 MAPK regulation. However, both Gly56Ala and Ile425Leu demonstrate markedly reduced sensitivity to PP2A antagonists, suggesting that deficits in trafficking and catalytic modulation may derive from a common basis in perturbed phosphatase regulation. When expressed stably from the same genomic locus in CHO cells, both Gly56Ala and Ile425Leu display catalytic activation, accompanied by a striking loss of SERT protein.
8. Santos M, Temudo T, Kay T, Carrilho I, Medeira A, Cabral H, Gomes R, Lourenco MT, Venancio M, Calado E, Moreira A, Oliveira G, Maciel P. {{Mutations in the MECP2 gene are not a major cause of Rett syndrome-like or related neurodevelopmental phenotype in male patients}}. {J Child Neurol};2009 (Jan);24(1):49-55.
Rett syndrome is a genetic neurodevelopmental disorder that affects mainly girls, but mutations in the causative MECP2 gene have also been identified in boys with classic Rett syndrome and Rett syndrome-like phenotypes. We have studied a group of 28 boys with a neurodevelopmental disorder, 13 of which with a Rett syndrome-like phenotype; the patients had diverse clinical presentations that included perturbations of the autistic spectrum, microcephaly, mental retardation, manual stereotypies, and epilepsy. We analyzed the complete coding region of the MECP2 gene, including the detection of large rearrangements, and we did not detect any pathogenic mutations in the MECP2 gene in these patients, in whom the genetic basis of disease remained unidentified. Thus, additional genes should be screened in this group of patients.
9. Turk J, Bax M, Williams C, Amin P, Eriksson M, Gillberg C. {{Autism spectrum disorder in children with and without epilepsy: impact on social functioning and communication}}. {Acta Paediatr};2009 (Apr);98(4):675-681.
AIM: To compare developmental and psychological functioning in two groups of children with autism spectrum disorder (asd), one with epilepsy and one without. METHODS: Sixty 7-17-year-old children in each group were recruited through a range of services in order to screen as representative a sample as possible. Parents were interviewed using the diagnostic interview for social and communication disorders (DISCO-11), and children were clinically examined and their medical histories assessed. RESULTS: The asd and epilepsy (asd+e) group demonstrated a substantially more even gender ratio, with a greater proportion of girls. They were more likely to have received later asd diagnoses and additional medical diagnoses. They also showed more motor difficulties, developmental delays and challenging behaviours, but were no more likely to be aloof and passive. The asd-only group experienced more abnormal fascinations with objects and used brief glances as a means of eye contact more than the asd+e group. CONCLUSION: Results support important between-group differences with diagnostic and therapeutic implications. asds often present atypically in children with seizures. However, both groups showed widely varying social and linguistic presentations.
