1. Bach M, Dakin SC. {{Regarding « Eagle-eyed visual acuity: an experimental investigation of enhanced perception in autism}} ». {Biol Psychiatry};2009 (Nov 15);66(10):e19-20; author reply e23-14.
2. Benayed R, Choi J, Matteson PG, Gharani N, Kamdar S, Brzustowicz LM, Millonig JH. {{Autism-associated haplotype affects the regulation of the homeobox gene, ENGRAILED 2}}. {Biol Psychiatry};2009 (Nov 15);66(10):911-917.
BACKGROUND: Association analysis identified the homeobox transcription factor, ENGRAILED 2 (EN2), as a possible autism spectrum disorder (ASD) susceptibility gene (ASD [MIM 608636]; EN2 [MIM 131310]). The common alleles (underlined) of two intronic single nucleotide polymorphisms (SNPs), rs1861972 (A/G) and rs1861973 (C/T), are over-transmitted to affected individuals both singly and as a haplotype in three separate datasets (518 families total, haplotype p = .00000035). METHODS: Further support that EN2 is a possible ASD susceptibility gene requires the identification of a risk allele, a DNA variant that is consistently associated with ASD but is also functional. To identify possible risk alleles, additional association analysis and linkage disequilibrium (LD) mapping were performed. Candidate polymorphisms were then tested for functional differences by luciferase (Luc) reporter transfections and electrophoretic mobility shift assays (EMSAs). RESULTS: Association analysis of additional EN2 polymorphisms and LD mapping with Hapmap SNPs identified the rs1861972-rs1861973 haplotype as the most appropriate candidate to test for functional differences. Luciferase reporters for the two common rs1861972-rs1861973 haplotypes (A-C and G-T) were then transfected into human and rat cell lines as well as primary mouse neuronal cultures. In all cases the A-C haplotype resulted in a significant increase in Luc levels (p < .005). The EMSAs were then performed, and nuclear factors were bound specifically to the A and C alleles of both SNPs. CONCLUSIONS: These data indicate that the A-C haplotype is functional and, together with the association and LD mapping results, supports EN2 as a likely ASD susceptibility gene and the A-C haplotype as a possible risk allele.
3. Crewther DP, Sutherland A. {{The more he looked inside, the more piglet wasn’t there: is autism really blessed with visual hyperacuity?}} {Biol Psychiatry};2009 (Nov 15);66(10):e21-22; author reply e23-24.
4. Daoud H, Bonnet-Brilhault F, Vedrine S, Demattei MV, Vourc’h P, Bayou N, Andres CR, Barthelemy C, Laumonnier F, Briault S. {{Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level}}. {Biol Psychiatry};2009 (Nov 15);66(10):906-910.
BACKGROUND: Pathogenic mutations in the X-linked Neuroligin 4 gene (NLGN4X) in autism spectrum disorders (ASDs) and/or mental retardation (MR) are rare. However, nothing is known regarding a possible altered expression level of NLGN4X that would be caused by mutations in regulatory sequences. We investigated this issue by analyzing these regions in patients with ASDs and no mutation in the NLGN4X coding sequence. METHODS: We studied 96 patients who met all DSM-IV criteria for autism. The entire coding sequence and the regulatory sequences of the NLGN4X gene were analyzed by polymerase chain reaction and direct sequencing. RESULTS: We identified a de novo 1 base pair (-335G>A) substitution located in the promoter region in a patient with autism and nonsyndromic profound MR. Interestingly, this variation is associated with an increased level of the NLGN4X transcript in the patient compared with male control subjects as well as his father. Further in vitro luciferase reporter and electrophoretic mobility shift assays confirmed, respectively, that this mutation increases gene expression and is probably caused by altered binding of transcription factors in the mutated promoter sequence. CONCLUSIONS: This result brings further insight about the phenotypic spectrum of NLGN4X mutations and suggests that the analysis of the expression level of NLGN4X might detect new cases.
5. Frazier TW, Hardan AY. {{A meta-analysis of the corpus callosum in autism}}. {Biol Psychiatry};2009 (Nov 15);66(10):935-941.
BACKGROUND: Previous magnetic resonance imaging (MRI) studies have reported reductions in corpus callosum (CC) total area and CC regions in individuals with autism. However, studies have differed concerning the magnitude and/or region contributing to CC reductions. The present study determined the significance and magnitude of reductions in CC total and regional area measures in autism. METHOD: PubMed and PsycINFO databases were searched to identify MRI studies examining corpus callosum area in autism. Ten studies contributed data from 253 patients with autism (mean age = 14.58, SD = 6.00) and 250 healthy control subjects (mean age = 14.47, SD = 5.31). Of these 10 studies, 8 reported area measurements for corpus callosum regions (anterior, mid/body, and posterior), and 6 reported area for Witelson subdivisions. Meta-analytic procedures were used to quantify differences in total and region CC area measurements. RESULTS: Total CC area was reduced in autism and the magnitude of the reduction was medium (weighted mean d = .48, 95% confidence interval [CI] = .30-.66). All regions showed reductions in size with the magnitude of the effect decreasing caudally (anterior d = .49, mid/body d = .43, posterior d = .37). Witelson subdivision 3 (rostral body) showed the largest effect, indicating greatest reduction in the region containing premotor/supplementary motor neurons. CONCLUSIONS: Corpus callosum reductions are present in autism and support the aberrant connectivity hypothesis. Future diffusion tensor imaging studies examining specific fiber tracts connecting the hemispheres are needed to identify the cortical regions most affected by CC reductions.
6. Geschwind DH. {{Autism: the ups and downs of neuroligin}}. {Biol Psychiatry};2009 (Nov 15);66(10):904-905.
7. McCleery JP, Akshoomoff N, Dobkins KR, Carver LJ. Atypical face versus object processing and hemispheric asymmetries in 10-month-old infants at risk for autism. Biol Psychiatry;2009 (Nov 15);66(10):950-957.
BACKGROUND: Previous studies have documented atypicalities in face/object processing in children and adults with autism spectrum disorders (ASDs). To investigate whether such atypicalities may reflect a genetically mediated risk factor present early in development, we measured face/object processing in 10-month-old high-risk infants who carry some of the genes associated with ASD because they have an older sibling diagnosed with the disorder. METHODS: We employed event-related potentials (ERPs) to measure cortical responses to pictures of faces and objects, the objects being toys. Latencies and amplitudes of four ERP components (P100, N290, P400, and Nc) were compared between 20 high-risk infants and 20 low-risk control subjects (infants with no family history of ASD). RESULTS: Responses to faces versus objects differed between high- and low-risk infants for the latencies of the N290 and P400. Differences were driven by faster responses to faces than objects in low-risk, but not high-risk, infants (P400) and, conversely, faster responses to objects than faces in high-risk, but not low-risk, infants (N290). Object responses were also faster in high-risk than low-risk infants (both N290 and P400). Left versus right hemisphere responses also differed between high- and low-risk infants for the amplitudes of the P100, N290, and P400; collapsed across faces/objects, low-risk, but not high-risk, infants exhibited hemisphere asymmetries. CONCLUSIONS: Genetic risk for ASD is associated with atypical face versus object processing and an atypical lack of hemispheric asymmetry early in life. These atypicalities might contribute to development of the disorder.
8. Saresella M, Marventano I, Guerini FR, Mancuso R, Ceresa L, Zanzottera M, Rusconi B, Maggioni E, Tinelli C, Clerici M. {{An autistic endophenotype results in complex immune dysfunction in healthy siblings of autistic children}}. {Biol Psychiatry};2009 (Nov 15);66(10):978-984.
BACKGROUND: Endophenotypes are simple biological aspects of a disease that can be observed in unaffected relatives at a higher rate than in the general population; an « autism endophenotype » justifies the observation that a mild reduction in ideational fluency and nonverbal generativity might be observed in healthy, unaffected relatives of children with autism. Because it is becoming apparent that autism is associated with given alleles encoding within the human leukocyte antigens region, a region of pivotal importance in immunity, we examined whether the « autism endophenotype » would extend its effects on the immune system. METHODS: Multiple immune parameters were analyzed in autistic children (AC) (n = 20), their siblings (HSAC) (n = 15), and age- and gender-comparable healthy control subjects (HC) (n = 20) without any familiarity for autism. RESULTS: The immune profiles of HSAC were significantly more similar to those of their autistic siblings than to what was observed in HC. Thus, in AC and HSAC compared with HC: 1) proinflammatory and interleukin-10-producing immune cells were augmented (p < .01 in both comparisons); 2) CD8(+) naive (CD45RA(+)/CCR7+) T lymphocytes were increased (p < .0001 and p = .001); and 3) CD8(+) effector memory (CD45RA(-)/CCR7-) (p < .0001 and p = .03) as well as CD4(+) terminally differentiated (CD45RA(-)/CCR7+) (p < .05 in both comparisons) lymphocytes were diminished. Serum autoantibodies (GM1) could be detected in 10% of AC children alone. CONCLUSIONS: Results of this pilot study indicate that a complex immune dysfunction is present both in autistic children and in their non-autistic siblings and show the presence of an « autism endophenotype » that expands its effects on immunologic functions.
9. 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 (Nov 15);66(10):942-949.
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.
