Introduction
Could epilepsy and autism be caused by your genes? Epilepsy is a common disorder that accompanies autism spectrum disorder (ASD), and ASD has been linked with multiple random genetic mutations in the DNA that comprises various genes.1 While genetics is not the only cause of ASD, the question of what mutated genes cause the epileptic seizures in many people with ASD can be asked.
To start off, most epilepsies are a combination of environmental and genetic factors, with genetic epilepsies only making up a small portion of epilepsies. With those that are genetic though, called idiopathic epilepsies, there are various mechanisms that initiate the process by which someone with a normal brain becomes susceptible to developing epilepsy (epileptogenesis). Those mechanisms include ion-channel disorders, the mechanisms underlying progressive myoclonus epilepsies (“myoclonus” meaning causing involuntary muscle spasms), developmental abnormalities, energy metabolism defects, and neuronal migration disorders.2
Table 1. This table displays idiopathic epileptic syndromes, their associated genes, which chromsomes these genes are on, and the mode of inheritance by which these genes are passed on. Oligogen refers to how the trait is influenced by a few genes.2
As you can see in Table 1, there are many epileptic syndromes linked to various genes on different chromosomes, and the way these syndromes are inherited varies. Clearly, genetics plays a role in epilepsy, but how does that correlate to ASD?
ASD Theories
To determine this, we must look at what the impacted genes do within the body and determine parallels between these results and the symptomatic characteristics of ASD. One theory regarding the cause of ASD is the excitatory-inhibitory (E/I) balance disruption theory, which proposes that ASD is due to alterations in the ratio of excitatory to inhibitory neurotransmission. This theory would explain the hyperactivity/hyperexcitability and reduced ability to maintain attention found in ASD patients. Another theory is the altered network connectivity theory, which hypothesizes that changes in neuronal connections within the brain are the main drivers of behaviors observed in ASD.1
Genes Related to Epilepsy & How They Correlate to ASD
Looking at Table 1 again, we see the epileptic syndrome abbreviated as ADNFLE. This is caused by mutations in the CHRNA4 or CHRNB2 genes located on chromosome 20. These genes typically encode for the alpha and beta subunits of nicotinic acetylcholine receptors, which are ion channels. When ADNFLE occurs, the wall of this ion channel is disrupted, disrupting cholinergic system function.2 The system plays a large role in memory, attention, and neuronal connectivity, so this epileptic syndrome, if co-occurring with ASD, could perhaps explain the working memory deficits seen in ASD and ties in well with the altered network connectivity theory of ASD.
Below ADNFLE on Table 1 we see BFNC, which is an ASD-inherited seizure disorder that causes mutations in voltage-gated K+ channel genes KCNQ2 and KCNQ3. In this disorder, the structure of a K+ channel pore is disrupted, reducing potassium current, which as can be seen in Figure 1, is a powerful controller of neuronal firing by controlling repolarization of the neuron.3 If K+ current is reduced, a neuron cannot return to its resting membrane potential, and this causes increased excitability of neurons since there are more easily brought to the threshold potential that causes an action potential to be sent.2 Thus, BFNC ties in nicely with the E/I balance disruption theory of autism and shows how epileptic disorders commonly cause the epileptic symptoms characteristic to ASD.
Figure 1. This diagram shows the flow of ions as an action potential is initiated during depolarization and is subsided during repolarization.3
There are other epileptic syndromes associated with genetic mutations that have similar impacts on ion channels, disrupting neuronal excitability, as well as other mutations related to disruptions of neuronal connectivity. For more examples of these genetic mutations and those that cause the earlier mechanisms characteristic to idiopathic epilepsies, click here.
In conclusion, idiopathic epilepsies are caused by various mechanisms, but the ones that correlate most with ASD are those that disrupt neuronal excitability and/or neuronal connectivity. Therefore, further research should be done to determine if medications that target these processes can improve the symptoms of epileptic phenotypes of ASD.
Footnotes
1Maximilians, Ludwig. “Genetics and epilepsy.” Dialogues Clin Neurosci, vol. 10, no. 1, 2008, pp. 29-36, doi:10.31887/DCNS.2008.10.1/oksteinlein
2DiCarlo, Gabriella E., Wallace, Mark T. “Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates.” Neurosci and Biobehavioral Reviews, vol. 133, 2022, pp. 1-11, https://doi.org/10.1016/j.neubiorev.2021.12.017
3Changes in Sodium and Potassium Conductances. Cellular Physiology. https://neurotext.library.stonybrook.edu/C4/C4_5/C4_5.html
