1. Brkanac Z, Raskind WH, King BH. {{Pharmacology and genetics of autism: implications for diagnosis and treatment}}. {Per Med};2008 (Nov);5(6):599-607.
Autism has the highest estimated heritability (>90%) among behaviorally defined neuropsychiatric disorders. Rapidly advancing genomic technologies and large international collaborations have increased our understanding of the molecular genetic causes of autism. Pharmacogenomic approaches are currently being applied in two single-gene disorders, fragile X syndrome and Rett syndrome, which capture many aspects of the autistic phenotype. This review describes the current state of the genetics of autism and suggests how to extend pharmacological principles pioneered in fragile X and Rett to the broader group of patients with autism.
2. Casanova MF, El-Baz A, Vanbogaert E, Narahari P, Switala A. A {{Topographic Study of Minicolumnar Core Width by Lamina Comparison between Autistic Subjects and Controls: Possible Minicolumnar Disruption due to an Anatomical Element In-Common to Multiple Laminae}}. {Brain Pathol};2009 (Jul 8)
Abstract Radial cell minicolumns are basic cytoarchitectonic motifs of the mammalian neocortex. Recent studies reveal that autism is associated with a « minicolumnopathy » defined by decreased columnar width and both a diminished and disrupted peripheral neuropil compartment. This study further characterizes this cortical deficit by comparing minicolumnar widths across layers. Brains from seven autistic patients and an equal number of age-matched controls were celloidin embedded, serially sectioned at 200 microm and Nissl stained with gallocyanin. Photomicrograph mosaics of the cortex were analyzed with computerized imaging methods to determine minicolumnar width at nine separate neocortical areas: Brodmann Area’s (BA) 3b, 4, 9, 10, 11, 17, 24, 43 and 44. Each area was assessed at supragranular, granular and infragranular levels. Autistic subjects had smaller minicolumns whose dimensions varied according to neocortical area. The greatest difference between autistic and control groups was observed in area 44. The interaction of diagnosis x cortical area x lamina (F(16,316) = 1.33; P = 0.175) was not significant. Diminished minicolumnar width across deep and superficial neocortical layers most probably reflects involvement of shared constituents among the different layers. In this article we discuss the possible role of double bouquet and pyramidal cells in the translaminar minicolumnar width narrowing observed in autistic subjects.
3. Cohen IL, Gomez TR, Gonzalez MG, Lennon EM, Karmel BZ, Gardner JM. {{Parent PDD Behavior Inventory Profiles of Young Children Classified According to Autism Diagnostic Observation Schedule-Generic and Autism Diagnostic Interview-Revised Criteria}}. {J Autism Dev Disord};2009 (Sep 1)
Quantitative variations in score profiles from the parent version of the PDD Behavior Inventory (PDDBI) were examined in young Autism and PDD-NOS groups defined by ADOS-G and ADI-R criteria, relative to a not spectrum (NS) group of similar age. Both the Autism and the PDD-NOS group profiles markedly differed from the NS group. The most sensitive measures of group differences were those domain and composite scores that assessed social communication competence, as well as the overall Autism Composite score. Sensitivity, specificity and positive and negative predictability measures were quite good for these measures. It was concluded that the PDDBI is useful in assisting in the differential diagnosis of autism spectrum disorder.
4. Grether JK, Li SX, Yoshida CK, Croen LA. {{Antenatal Ultrasound and Risk of Autism Spectrum Disorders}}. {J Autism Dev Disord};2009 (Sep 1)
We evaluated antenatal ultrasound (U/S) exposure as a risk factor for autism spectrum disorders (ASD), comparing affected singleton children and control children born 1995-1999 and enrolled in the Kaiser Permanente health care system. Among children with ASD (n = 362) and controls (n = 393), 13% had no antenatal exposure to U/S examinations; case-control differences in number of exposures during the entire gestation or by trimester were small and not statistically significant. In analyses adjusted for covariates, cases were generally similar to controls with regard to the number of U/S scans throughout gestation and during each trimester. This study indicates that antenatal U/S is unlikely to increase the risk of ASD, although studies examining ASD subgroups remain to be conducted.
5. Kawakubo Y, Kuwabara H, Watanabe K, Minowa M, Someya T, Minowa I, Kono T, Nishida H, Sugiyama T, Kato N, Kasai K. {{Impaired prefrontal hemodynamic maturation in autism and unaffected siblings}}. {PLoS One};2009;4(9):e6881.
BACKGROUND: Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed. METHODOLOGY/PRINCIPAL FINDINGS: Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs. CONCLUSION/SIGNIFICANCE: Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.
6. Lauritsen MB, Jorgensen M, Madsen KM, Lemcke S, Toft S, Grove J, Schendel DE, Thorsen P. {{Validity of Childhood Autism in the Danish Psychiatric Central Register: Findings from a Cohort Sample Born 1990-1999}}. {J Autism Dev Disord};2009 (Sep 1)
The purpose of this study was to assess the validity of the diagnosis of childhood autism in the Danish Psychiatric Central Register (DPCR) by reviewing medical records from 499 of 504 total children with childhood autism born 1990-1999. Based on review of abstracted behaviors recorded in case records from child psychiatric hospitals, case status determination was performed using a standardized coding scheme. In 499 children diagnosed with childhood autism in the DPCR, the diagnosis could be confirmed in 469 children (94%). Of the 30 non-confirmed cases, five were classified by the reviewers as non-autistic cases and the remaining 25 cases were either classified with another ASD diagnosis or the specific diagnosis was not possible to determine.
7. Schumann CM, Barnes CC, Lord C, Courchesne E. {{Amygdala Enlargement in Toddlers with Autism Related to Severity of Social and Communication Impairments}}. {Biol Psychiatry};2009 (Sep 1)
BACKGROUND: Autism is a heterogeneous neurodevelopmental disorder of unknown etiology. The amygdala has long been a site of intense interest in the search for neuropathology in autism, given its role in emotional and social behavior. An interesting hypothesis has emerged that the amygdala undergoes an abnormal developmental trajectory with a period of early overgrowth in autism; however this finding has not been well established at young ages nor analyzed with boys and girls independently. METHODS: We measured amygdala volumes on magnetic resonance imaging scans from 89 toddlers at 1-5 years of age (mean = 3 years). Each child returned at approximately 5 years of age for final clinical evaluation. RESULTS: Toddlers who later received a confirmed autism diagnosis (32 boys, 9 girls) had a larger right (p < .01) and left (p < .05) amygdala compared with typically developing toddlers (28 boys, 11 girls) with and without covarying for total cerebral volume. Amygdala size in toddlers with autism spectrum disorder correlated with the severity of their social and communication impairments as measured on the Autism Diagnostic Interview and Vineland scale. Strikingly, girls differed more robustly from typical in amygdala volume, whereas boys accounted for the significant relationship of amygdala size with severity of clinical impairment. CONCLUSIONS: This study provides evidence that the amygdala is enlarged in young children with autism; the overgrowth must begin before 3 years of age and is associated with the severity of clinical impairments. However, neuroanatomic phenotypic profiles differ between males and females, which critically affects future studies on the genetics and etiology of autism.
8. Zhang C, Milunsky JM, Newton S, Ko J, Zhao G, Maher TA, Tager-Flusberg H, Bolliger MF, Carter AS, Boucard AA, Powell CM, Sudhof TC. {{A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export}}. {J Neurosci};2009 (Sep 2);29(35):10843-10854.
Neuroligins (NLs) are postsynaptic cell-adhesion molecules essential for normal synapse function. Mutations in neuroligin-4 (NL4) (gene symbol: NLGN4) have been reported in some patients with autism spectrum disorder (ASD) and other neurodevelopmental impairments. However, the low frequency of NL4 mutations and the limited information about the affected patients and the functional consequences of their mutations cast doubt on the causal role of NL4 mutations in these disorders. Here, we describe two brothers with classical ASD who carry a single amino-acid substitution in NL4 (R87W). This substitution was absent from the brothers’ asymptomatic parents, suggesting that it arose in the maternal germ line. R87 is conserved in all NL isoforms, and the R87W substitution is not observed in control individuals. At the protein level, the R87W substitution impaired glycosylation processing of NL4 expressed in HEK293 and COS cells, destabilized NL4, caused NL4 retention in the endoplasmic reticulum in non-neuronal cells and neurons, and blocked NL4 transport to the cell surface. As a result, the R87W substitution inactivated the synapse-formation activity of NL4 and abolished the functional effect of NL4 on synapse strength. Viewed together, these observations suggest that a point mutation in NL4 can cause ASD by a loss-of-function mechanism.
9. Zhang GQ, Gong Q, Zhang FL, Chen SM, Hu LQ, Liu F, Cui RH, He L. {{[Effects of auditory integrative training on autistic children.]}}. {Beijing Da Xue Xue Bao};2009 (Aug 18);41(4):426-431.
OBJECTIVE:To explore the short-term treatment effect of the auditory integrative training on autistic children and provide them with clinical support for rehabilitative treatment. METHODS: A total of 81 cases of autistic children were selected through the standard of DSM-4 and clinical case study was used. They were divided randomly into experimental group and control one, and respectively received auditory integrative training and no training based on the multiple therapies. The patients were investigated using clinical manifestation and Autism Behavior Checklist (ABC) and intelligence quotient (IQ) before and after six months of treatment. The effect was evaluated through the changes of clinical manifestations and scores of ABC and IQ. The changes of scores of IQ were determined with Gesell and WPPSI or WISC-R. RESULTS: Compared with 40 patients of the control group after the six months of the auditory integrative training, 41 of the experimental group had greatly improved in many aspects, such as the disorders of their language, social interactions and typical behavior symptoms while they had not changed in their abnormal behaviors. The scores of IQ or DQ had increased and scores of ABC had dropped. The differences between the two groups were greatly significant in statistics (P<0.01). The decreasing level of both ABC scores and the increasing level of the IQ scores were negatively correlated with age, and the decreasing level of ABC scores was in line regression(positive correlation) with base IQ. CONCLUSION: The treatment of auditory integrative training(AIT) could greatly improve on language disorders, the difficulties of social interactions, typical behavior symptoms and developmental levels,therefore it is positive to the autistic children in its short-term treatment effect.
