Minor physical anomalies in autism: a meta-analysis.

Department of Child and Adolescent Psychiatry, University Medical Centre, Utrecht, The Netherlands.
Molecular Psychiatry (Impact Factor: 15.15). 08/2008; 15(3):300-7. DOI: 10.1038/mp.2008.75
Source: PubMed

ABSTRACT Autism is a complex neurodevelopmental disorder in which the interactions of genetic, epigenetic and environmental influences play a causal role. Despite the compelling evidence for a strong heritability, the etiology and molecular mechanisms underlying autism remain unclear. High phenotypic variability and genetic heterogeneity confounds the identification of susceptibility genes. The lack of robust indicators to tackle this complexity in autism has led researchers to seek for novel diagnostic tools to create homogenous subgroups. Several studies have indicated that patients with autism have higher rates of minor physical anomalies (MPAs) and that MPAs may serve as a diagnostic tool; however, the results have been inconsistent. Using the cumulative data from seven studies on MPAs in autism, this meta-analysis seeks to examine whether the aggregate data provide evidence of a large mean effect size and statistical significance for MPAs in autism. It covers the studies using multiple research methods till June 2007. The current results from seven studies suggested a significant association of MPAs in autism with a robust pooled effect size (d=0.84), and thereby provide the strongest evidence to date about the close association between MPAs and autism. Our results emphasize the importance of MPAs in the identification of heterogeneity in autism and suggest that the success of future autism genetics research will be exploited by the use of MPAs. Implications for the design of future studies on MPAs in autism are discussed and suggestions for further investigation of these important markers are proposed. Clarifying this relation might improve understanding of risk factors and molecular mechanisms in autism.


Available from: Joop Hox, Jun 16, 2015
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    ABSTRACT: MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective 'window' to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism. We recruited 91 children aged 7-16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates. Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles. Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to "social brain" dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a "fossil record" of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism.
    PLoS ONE 06/2011; 6(6):e20246. DOI:10.1371/journal.pone.0020246 · 3.53 Impact Factor
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    ABSTRACT: Autism is a highly heritable neurodevelopmental disorder, which greatly reduces reproductive success. The combination of high heritability and low reproductive success raises an evolutionary question: why was autism not eliminated by natural selection? We review different perspectives on the evolution of autism and propose an integration which emphasizes epistatic interactions between the effects of genes during development. It is well-established that autism is a polygenic disorder, and that the genes contributing to autism interact. If a disorder is polygenic, it is likely that the genes underlying the disorder are also involved in traits that are beneficial for the individual. For example, it is possible that genes involved in the development of autism are also involved in the development of intelligence. As intelligence is positively correlated with reproductive success, genes involved in autism can possibly spread in the population. We propose that in most individuals, the interactions between genes result in normal or high intelligence and the absence of autism. However, in some unlucky situations, often in combination with spontaneous negative mutations, the interactions between genes can lead to the development of autism (or other pathologies). Thus, the combination of high heritability and low reproductive success in autism can be explained from an evolutionary developmental perspective that emphasizes the role of epistatic interactions in polygenic disorders.
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