Our old genome. When talking about seizures and genes, “malaria” is usually not the first thing that comes to mind. However, malaria-associated seizures are a major cause of neurological disability in Sub-Saharan Africa. Given the frequency of malaria infections on a worldwide scale, Plasmodium falciparum, the parasite causing malaria, is probably one of the most frequent causes of acute seizures. Our genome has adapted to dealing with parasites over evolutionary time and several disease-causing mutations are thought to be relatively frequent, as they also confer resistance to malaria. For malaria-associated seizures, family studies show an increase in epilepsy in relatives, suggesting that these parasite-induced epileptic seizures may also have a genetic predisposition. A recent study in Epilepsia now investigates malaria candidate polymorphisms as genetic risk factors for malaria-associated seizures.

Malaria. Every medical student is burdened by learning about the complicated mechanism behind malaria infections at some point and –like me- forgets about this again right after the exam, as the disease is usually not encountered in Northern Europe. In a nutshell, the pathogenetic mechanism of malaria goes like this: a human is bitten by an Anopheles mosquito that carries Plasmodium falciparum or one of the related protozoa. The parasites migrate as so-called sporozoites to the liver where they replicate and turn in to merozoites. At this stage, the parasites rupture the liver cells and return to the bloodstream to infect the red blood cells (erythrocytes), starting the so-called erythrocytic stage of the life cycle, which eventually leads to the more or less synchronized rupture of erythrocytes, which causes the recurrent fever. Within the erythrocytes, the parasites replicate as trophozoites and schizonts that in turn produce further merozoites that are released into the bloodstream once the red blood cells burst, producing a new generation of merozoites that start a new cycle of red blood cell infection.

The life cycle of the malaria parasite. A mosquito causes infection by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells, where they multiply into merozoites, rupture the liver cells, and return to the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts that in turn produce further merozoites. Sexual forms are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle. Malaria-associated seizures usually occur when the red blood cells rupture. Image and image caption are from Wikipedia and are within the public domain.

Malaria and seizures. Malaria-associated seizures (MAS) can occur within two settings, either as isolated seizures within the setting of fever or in the setting of cerebral malaria. In cerebral malaria, other severe neurological symptoms such as coma and cerebral edema are observed, which are probably due to impaired capillary perfusion. In cerebral malaria, seizures can also occur without fever. Studies have shown that more than 50% of malaria-associated seizures occur due to cerebral malaria. The other group of malaria-associated seizures occur without other neurological symptoms, but the malaria parasites can be confirmed in erythrocytes. These latter seizures may be related to febrile seizures, but the connection is not completely clear. It has been shown that malaria infections are the main contributor to these seizures as opposed to febrile events.

The genetic risk of MAS. Malaria patients with a positive family history of epilepsy or seizures have a ~1.5 times increased risk of seizures in the setting of acute malaria. This led Kariuki and collaborators to investigate possible genetic associations with malaria candidate genes and MAS. Almost 4500 children were included in their study and ~2100 children had seizures. Their results were corrected for multiple testing and several confounding variables. The authors identified several candidate single nucleotide polymorphisms (SNPs) for malaria-associated seizures that confer a modest risk in the range of ~1.5. Particularly, a polymorphism in the IL10 gene (rs3024500) confers both risk to malaria-associated seizures and seizures in the setting of cerebral malaria (referred to as MAS with coma by the authors). Interleukin 10 (IL10) is considered a master regulator of immunity to infection and is known to blunt the excessive immune response that is thought to underlie the symptoms of malaria. Therefore, it is conceivable that genetic variants in IL10 can modify the severity of malaria symptoms including seizures.

From MAS to Febrile Seizures. The study by Kariuki and collaborators is impressive because of the sample size and the stringency of the analysis. The authors already indicate an expansion of this study into a genome-wide association study and it will be interesting to observe whether any of these loci overlap with known epilepsy risk variants. In addition, these studies, even though they have been performed on a different phenotype, might be a first step towards identifying risk variants for Febrile Seizures (FS). Currently, there is no large-scale research performed on FS. The fact that FS are usually mild seizure disorders makes them a
menable to genome-wide association studies. Knowing some candidate genes for studies of related phenotypes such as MAS might help understand the pathogenic mechanisms of FS.

Ingo Helbig

Child Neurology Fellow and epilepsy genetics researcher at the Children’s Hospital of Philadelphia (CHOP), USA and Department of Neuropediatrics, Kiel, Germany