Drug Shows Promise for Fragile X Syndrome
The excess C, G, G repeats on the FMR1 gene described on p 411 result in the methylation of the promoter (regulatory) portion of the gene and, thus, gene silencing. As a consequence, the glutamate receptor mGluR5 becomes hyperactive, which has led researchers to try mGluR5 blocking drugs to reduce symptoms. In clinical trials with the drug AFQ056, treatment appeared to have no effect overall, but seven Fragile X subjects improved in repetitive behaviors (such as rocking and hand clapping), hyperactivity, inappropriate speech, and social withdrawal. It turned out that these subjects were different from the others: The promoter regions of their FMR1 genes were fully methylated, so their genes were totally silenced and produced no detectable messenger RNA. Why the drug would work only if the gene is fully silenced is a mystery, but the finding suggests that the treatment could be effective with patients who are preselected through genetic screening. Science Translational Medicine, Vol 3, Issue 64, p 64ra1.
More Evidence of Copy Number Variations in ADHD
A characteristic ADHD shares with schizophrenia, autism, and other disorders is rare copy number variations (CNVs)—missing or excessive bits of DNA. In the study described in the text (p 421), subjects with ADHD did not have more CNVs than control subjects, but their CNVs were concentrated in and near genes involved in neural development and functioning. A study published a short time later focused on large CNVs, which are more likely to be deleterious and which occur more frequently in neurodevelopmental disorders such as schizophrenia. In this study, the average number of large CNVs was twice as great in ADHD children and almost six times as great among those with intellectual disabilities. As with the earlier study, CNVs were found particularly often in areas containing genes associated with schizophrenia and autism. Lancet, Vol 376, 1401-1408.
Cognitive Effects of Prenatal Pesticide Exposure
Studies presented in Chapter 13 link organophosphate pesticides to increased risk of autism and ADHD. These pesticides are believed to inactivate acetylcholinesterase, so we would expect them to have broader effects than these two disorders. Three studies, one conducted with children in an agricultural area in California and two with children in New York City, provide evidence this is the case. Pesticide exposure was measured from the mother's urine during pregnancy or from umbilical cord blood at the time of birth; children were assessed at varying ages ranging from 12 months to 9 years. Exposure was associated with a variety of cognitive deficits, including working memory, verbal comprehension, perceptual reasoning, and IQ (as great as 7 points for more highly exposed children). In one of the studies, there was some evidence of a greater effect in children with a specific allele of the PON1 gene which slows metabolism of these toxins. Environmental Health Perspectives, doi:10.1289/ehp.1003185, doi:10.1289/ehp.1003183, doi:10.1289/ehp.1003160.
Aging and the Brain
Dementia, especially Alzheimer's, is accompanied by brain atrophy, which in turn is associated with increased levels of the amino acid homocysteine. In a study of 168 individuals over age 70 with mild cognitive impairment, brain atrophy during 12 months of treatment with folic acid and vitamins B6 and B12 was slowed by 30%. PLoS ONE, Vol 5, e12244. A second study reinforced previous findings about the role of white matter connectivity in the maintenance of functioning during aging. A team of Welsh, Australian, and Chinese scientists assessed white matter density in individuals aged 72-92 years. They found that connectivity throughout the whole brain network was associated with processing speed, visuospatial functions, and executive functioning (planning, behavioral monitoring and control). Connections among specific brain areas were also important; for example, connections between the superior frontal gyrus and the posterior cingulate cortex were asociated with better executive function. Journal of Neuroscience, Vol 31, 1204-1212.
Autism is Marked by Gene Expression Anomalies
In the normal brain, more than 500 genes are activated to different degrees in the frontal lobes compared to the temporal lobes; however, in the autistic brain these differences in gene expression are almost nonexistent. The pattern is similar across autistic brains, which is remarkable because autism is believed to have many causes. Another difference found in the study of deceased brains was reduced expression of genes responsible for neuron function and communication; these genes had previously been associated with autism, so the downregulation observed here apparently plays a causal role in autism. Genes involved in immune function and inflammatory response were upregulated, but the fact that these genes have not been identified with autism suggests that their increased activity was a response to the brain disorder. Nature, Vol 474, 380-384.
Toward a Neurological Diagnosis of Autism
The ability to detect autism with neurological measurementsis detected the more likely intervention will be able to reduce cognitive and social impairment. Two new approaches are showing early promise. The first used diffusion tensor imaging (see p 103) to assess white matter; different patterns of white matter distribution—including reversed hemispheric asymmetry of two measures—distinguished between high functioning autistics (aged 7-28 years) and matched controls with 92% accuracy. Autism Research, Vol 3, 350-358.
A second study used EEG to generate complex measures of neural connectivity and complexity in infants between 6 and 18 months of age. The use of EEG is preferable with infants, because brain scanning procedures require immobility; the infant must be asleep or sedated (which is undesirable when not medically required). The measures distinguished infants at high risk (having an autistic sibling) from control infants with 80% accuracy; accuracy was greater for boys—close to 100% at age 9 months and 70-90% through the age of 18 months; accuracy for girls peaked at 6 months and then declined. The researchers are waiting for the children to reach 2-3 years of age to determine how accurate the measures might be in predicting later diagnosis. CNN Health, February 22, 2011.