What causes autism in children with prenatal exposure to anti-epileptic drugs?
Aim and background of project
The project set out to test whether variations in certain genes might be contributing to the development of autistic spectrum disorders in a group of children whose mothers were taking anti-epileptic drugs during pregnancy.
Autistic spectrum disorders, are classifi ed according to the widely used DSM-4 system into Autistic Disorder, Asperger’s syndrome and Pervasive Developmental Disorder Not Otherwise Specified. These disorders are characterised by diffi culties with social interaction and communication of varying degrees, and thought to have many diff erent causes. It is known that genetic factors contribute, but the precise genetic causes of the common forms of autistic spectrum have yet to be identified.
In a previous study of children born to mothers taking anti-epileptic drugs in pregnancy, we noticed a much higher frequency of autistic spectrum disorders than expected. This could be because the same genetic factors cause epilepsy in the mother and autistic spectrum disorder in the child, or because the drugs taken to prevent epilepsy, aff ect the child’s development.
We were not able to investigate the first possibility in this study, and the second is unlikely, as we and others have previously shown no eff ect of the mother’s epilepsy control in pregnancy on the health of her children. Antiepileptic drugs are thought to interact with certain genes in the developing embryo, so it is possible that variations in these genes might aff ect the susceptibility of a child to autistic spectrum disorder when exposed to antiepileptic drugs before birth. This project was designed to investigate this possibility.
The highest risk of autistic spectrum disorder was associated with the mother taking the drug sodium valproate in our previous study. This drug is known to affect the way genes are expressed generally by stopping a special group of regulator genes (histone deacetylases or HDACs) from working properly. It also reduces the working of another gene, a protein kinase, which is an effect used to treat bipolar disorder, a form of depression.
Methods with results discussed
In the first part of the study, we investigated whether there were any changes in the genetic code for the part of the HDAC1 gene which sodium volproate is thought to attach to. This involved reading the genetic code for this region, (called the L1 binding pocket region), in DNA samples taken from children with autistic spectrum disorder who were exposed to sodium valproate. In some cases, the mother took only sodium valproate, in others, sodium valproate plus other anti-epileptic drugs. No significant variations in the gene sequence were detected: two variants were detected, but they were in regions of the gene thought to have no functional significance, and one was in a patient and the other in a control sample. We did not sequence the whole of the HDAC1 gene, as there was insufficient time and budget to undertake this. It remains that variation elsewhere in the HDAC1 gene could affect the risk of autistic spectrum disorder.
To investigate this further, we also undertook a study where we checked DNA samples from affected and unaffected children for known variations of the HDAC1 genetic code (SNPs or Single Nucleotide Polymorphisms), to see if any of these were more common in affected than in unaffected children. For 6 of the 7 SNPs checked, none of the cases or normal controls were found to have SNP, suggesting that HDAC1 variation is not the cause of susceptibility to autistic spectrum disorder in these children.
HDAC1 interacts with another gene, SAP18, in controlling the expression of developmental genes in the embryo. We looked to see if there were any known variants of SAP18 in the various human genome bases, and identified one that we could readily test for. Unfortunately, none of our cases or controls had this variant, so this experiment provided no evidence for or against a role for SAP18 in susceptibility to autistic spectrum disorder in the children studied.
Lastly, we looked at 3 variants, (SNPs), in the protein kinase C subunit B1 gene (PRKCB1), in our cases and controls. These variants in this gene have recently been reported to be associated with autistic spectrum disorder in another study of children not exposed to sodium valproate. It is also known that sodium valproate reduces the activity of this gene, and that reduced activity of the gene may also affect susceptibility to spina bifida (solium valproate is also known to cause spina bifida in some cases). No difference in the frequencies of any of these variants was detected between our cases exposed to antiepileptic drugs, who have autistic spectrum disorder and our control group, who were exposed to the drugs but did not develop autistic spectrum disorder. We also compared the frequency of these variants in a group of healthy blood donor controls but no differences were seen. We went on to test some further children who had fetal valproate syndrome, (that is, they had malformations or developmental delay thought to be due to valproate exposure, but only some had autistic spectrum disorder), and some further children exposed to sodium valproate and other anti-epileptic drugs, but who were healthy. This analysis suggested that the frequency of one of the variants was different in unaffected exposed children compared with healthy blood controls. This could suggest that this variant helps protect against the adverse effects of exposure to anti-epileptic drugs before birth. When you do multiple tests on a particular population, it is generally accepted that a correction should be applied to the statistical interpretation, to take account of the fact that the chances of finding a spurious association rise, the more tests that you do. When we undertook this correction, the apparent difference in frequencies was no longer statistically significant.
Conclusion
We have not found any conclusive evidence that genetic variation in the HDAC1, SAP18 or PRKCB1 genes is associated with susceptibility to autistic spectrum disorders or other aspects of fetal anticonvulsant syndrome in children whose mother took anti-epileptic drugs before birth. The testing of SAP18 was uninformative (no variants were detected in cases or controls). There was a suggestion that one variant in PKBC1 may protect against adverse consequences of anti-epileptic drug exposure before birth. It is also possible that variations in regions of the genes distant from the regions we studied, might have an effect. Investigation of these issues would require a larger study.
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