New knowledge about the genetic architecture underlying febrile seizures in young children

An international team of scientists under the leadership of senior researcher Bjarke Feenstra from the Danish Statens Serum Institut (SSI) has taken a serious first step towards mapping the genetic background of febrile seizures in young children.

This is the world’s biggest scientific study of febrile seizures to date. Febrile seizures affect around 4% of young children – typically between the ages of six months and five years.

The study was recently published in the scientific journal Brain.

The project is based on extensive analyses of the DNA profiles of more than 90,000 individuals, and the mapping work and analyses were mainly carried out by researchers from Denmark and Australia.

The data on febrile seizures collected from these individuals come primarily from the Danish National Patient Registry.

‘Every single sample was tested for the seven million genetic variants that may be relevant to febrile seizures in young children. The analyses have given us new knowledge about the genetic architecture underlying febrile seizures. What’s more, we gained new knowledge about genetic factors that seem to affect both febrile seizures and epilepsy,’ says Bjarke Feenstra, whose research is funded by a Lundbeck Foundation Ascending Investigators grant.

A parent’s nightmare

Any parent who has seen their young child have a febrile seizure will tell you it is something they will never forget – these seizures are quite alarming to observe.

The preliminary stage is almost banal: the child is in bed with a common fever, probably fairly lethargic and with a relatively high temperature but otherwise with apparently no specific symptoms.

However, as many parents know, things can change dramatically in the space of no time.

The child’s body goes stiff – rigid and almost locked. Breathing becomes heavy, the skin becomes pale or even bluish, the head lolls backwards and the arms and legs twitch. And it can be difficult to communicate with the child.

Swift action is essential, and the child must be taken to hospital for further examination without delay! Although it may look dramatic and extremely serious while the seizure is ongoing, in the great majority of cases, the story ends happily – and the child makes a full recovery.

There are many unanswered questions when it comes to febrile seizures in young children, one of the obvious ones being: why do around 4% of children in Denmark and a great many other countries suffer from febrile seizures, while 96% remain unaffected?

And why do around 7% of the affected children develop epilepsy in later life?

Genetic links

By studying the many DNA profiles, the research team have so far identified seven loci in human DNA in which genetic variants possibly linked to febrile seizures may occur. Bjarke Feenstra explains:

‘We’d already identified four of these loci, so we’re now up to 11. We can say that – in all probability – they play a part in the development of febrile seizures. But we’re not yet sure how it’s all connected. This is one of the things we’ll now be studying.’

According to Bjarke Feenstra, if we take a closer look at the 11 loci, a picture begins to emerge of a certain genetic link between febrile seizures and epilepsy.

‘We can see that three of the 11 loci also contain well-known epilepsy genes. So febrile seizures and epilepsy seem to have a common genetic denominator – and we’ll also be investigating this in more depth.’

One of the things they will do will be to study the genetics of a large number of adults who suffered from febrile seizures while growing up.

‘Some of these people will have developed epilepsy in later life; others won’t have experienced the disorder at all. The question is whether we can identify genetic differences between the two groups which would help explain why this is the case.’

The researchers will also be studying a genetic variant which seems to play a role in causing fever in humans and other mammals in general. Bjarke Feenstra explains:

‘This variant is found close to the PTGER3 gene which, in experiments on mice, has proven to be key to the ability to develop a fever. The researchers who conducted the experiment were able to see this when they used genetic engineering to switch off this gene in the mice. When they then exposed them to infection, these mice were unable to develop a fever. We now want to look more closely at PTGER3 to gain a better understanding of the way in which small genetic differences in humans may help control the body’s fever response.’