This is the homepage for eEF1A2 information hosted by Cathy Abbott’s lab at the IGMM, University of Edinburgh. The gene encoding eEF1A2 has been found to be mutated in a small number of individuals with severe intellectual difficulties, intractable epilepsy and autism. We want this to be a useful resource for scientists, clinicians and families. You can follow us on Twitter @CathyAbbottLab . Below are the answers to some frequently asked questions; more information is available on other pages.
What is EEF1A2?
At first sight the name is seemingly random letters and numbers, conveying almost nothing. The letters do in fact stand for something (eukaryotic elongation factor 1 alpha 2) but that’s not much help.
The EEF1A2 gene is the code for a protein called eEF1A2. This is, in turn, responsible for making all other proteins in nerve cells and muscle. The process of making new proteins is called translation, and all cells completely depend on this process. When eEF1A2 goes wrong, it will affect how well the nerve cell and muscles can work.
We now know of ~100 individuals worldwide who have a mutation (i.e. a change in the DNA) in EEF1A2. Most of these are children or young people, but there are some adults. The only reason for there being so many more children is because the huge leaps forward with genetic diagnosis over the last few years have mostly been implemented in paediatric settings. It doesn’t mean that having a mutation in EEF1A2 affects survival. There are undoubtedly many adults with EEF1A2 related disorders out there, they just haven’t had the appropriate genetic tests.
Each of the mutations in EEF1A2 that cause epilepsy and/or developmental delay change just one of the amino acids (“ building blocks”) out of nearly 500 amino acids that go to make up the eEF1A2 protein. Each of these building blocks seems to be really important for the normal function of eEF1A2 in nerve cells. More information can by found on the page eEF1A2: a Primer
Why is there so much variability in how people are affected by EEF1A2 mutations?
There is a big range in development and seizure incidence amongst people with mutations in EEF1A2, and at the moment it is very hard to predict how any one person will experience the disorder. Why is this? Well, the most obvious answer is that there are many different mutations in EEF1A2. Different mutations affect the resulting protein in subtly different ways, some worse than others. There is more on this below. As there are so many different mutations, over 40 so far, any given mutation (e.g. E124K) has often only been found in a few children, making it hard to generalise.
Another potential cause of variability is that almost all the mutations we know of in EEF1A2 are what is called “de novo”. This means that they weren’t inherited from either parent but are the result of a random event. This could have happened very early in development, so that every cell has the mutation. However, if the mutation happens after the embryo has started to form, an individual could have a patchwork of nerve cells, some with the mutation and some without. This would likely mean that they were less badly affected than someone with a mutation in every nerve cell.
How might different mutations in EEF1A2 result in different degrees of severity?
As we all know, we need eEF1A2 protein to keep us healthy, and we all have two copies of the gene that makes it. Let’s imagine that instead of genes, we each have to take two doses of eEF1A2 each day to stop us from getting epilepsy- picture two of those drug capsules with little beads inside (see the picture below). In this case, the little beads are all the molecules of eEF1A2.
Now imagine what happens if you have a mutation in one copy of EEF1A2. You still have one capsule a day that works well (the “normal” copy of the gene that gives lots of normal eEF1A2 molecules), but the other capsule is not quite right. There are lots of different ways in which the other capsule can be not quite right (the different mutations), and the end effect will be different.
Some people might have a mutation which means that the second capsule is just not quite full enough (what we would call a “loss of function” mutation). This means that they don’t have quite enough eEF1A2 to prevent seizures, but do alright otherwise.
Other people have a mutation which means that the second capsule is full of eEF1A2, but it’s a version of eEF1A2 which is not quite the right drug. In this case, not only does the eEF1A2 not work well enough to stop seizures, but it is actually a bit toxic and can harm nerve and muscle cells. These people might have additional problems like intellectual disability and hypotonia.
There are lots of possible variations of this scenario, with different combinations of loss and gain of function. Some people will even have mutations in some of their nerve cells but not all, and this could affect whether they develop epilepsy, too. EEF1A2 disorder is a challenging to understand, but research is moving us forward all the time.
Where can I get support?
Any families who would like to be on contact with others who have children with mutations in eEF1A2 are welcome to join a Facebook group set up by Kari Haldeman. Kari has a child with the condition- you can find her at karihaldeman23 at verizon dot net.
How can I help with research?
Thanks to Invitae we have been able to set up a patient registry for EEF1A2. More surveys will be added over time. You can find the registry here at the Invitae Patients Information Network.
Registries are really important for research, so that we can begin to look at the different mutations and collect information on their effects. In this way we will be better able to predict which mutations are likely to be milder and which more severe. With your help, we will be able to track outcomes, pull together information about which drugs help and which don’t, and ultimately design better therapeutic strategies and develop new drugs. Registries are also used as a way of recruiting patients for clinical trials.
Why does Google give links to eEF1A2 and cancer?
This is a quick note for anyone new to eEF1A2, and especially anyone with a newly diagnosed child. If you do a google or other search for eEF1A2 you will find lots of papers talking about the role of eEF1A2 in cancer. This is not connected in any way with the mutations that cause epilepsy and ID and/or autism. The role of eEF1A2 in cancer relates to it being turned on inappropriately in cells other than neurons; this is essentially the opposite mechanism to that seen with the missense mutations.