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In autism, brain volumes are enlarged in preschoolers and normalize during adolescence (NEJM JW Psychiatry Aug 21 2002); these findings support studying postmortem childhood cases to capture gene expression. The current investigators studied postmortem brain samples from 11 children who had autism diagnoses (age range, 2–15 years; 8 boys) and 11 unaffected, age- and sex-matched controls. RNA transcripts of 25 genes were measured, including those specific to cell type and cortical layer and those associated with heightened risk for autism. RNA expression was described semiquantitatively (normal, mild abnormality, severe abnormality).
Brain slices from dorsolateral prefrontal cortex showed “patches” of neurons with decreased expression in 10 autistic cases and 1 control. Patches also occurred in temporal lobe (obtained in 2 cases and 3 controls). Occipital lobe (3 cases; 3 controls) and glia were not affected. Location of patches differed between subjects, but occurred mostly in cortical layers 4 and 5. Patches showed a heightened density of neurons, establishing that lower expression was not due to lower neuronal number.
Stoner R et al. Patches of disorganization in the neocortex of children with autism. N Engl J Med 2014 Mar 27; 370:1209. (http://dx.doi.org/10.1056/NEJMoa1307491)
Comment
These RNA expression data from children with autism are consistent with findings of early-life increases in neuronal number (NEJM JW Psychiatry Dec 5 2011) and cerebrospinal fluid (NEJM JW Psychiatry Aug 9 2013). Thus, both neuroimaging and genetics findings increasingly support a prenatal onset of autism pathology. Some studies of high-risk genes (NEJM JW Psychiatry Oct 26 2009) have identified unaffected carriers, which suggests a two-hit etiology — i.e., both genetic and environmental factors.
Prenatal onset implies doing whatever is feasible to decrease risk, but this can be challenging for many nongenetic factors. An example is pharmacotherapy in pregnancy, where immediate clinical needs have to be balanced against the risk for neurodevelopmental aberrations. The existence of early “patches” heightens the need for diagnosis and treatment in the first postnatal year.