Genetics and MND

Reading Time: 5 minutes

This is blog number two in our ‘Symposium Blogathon’ – counting down to the 32nd International Symposium on ALS/MND. Numbers in bold green text correspond to the code in the abstract book. Click on the number to be redirected to the full abstract (the page may take a minute to load).

Approximately 10% of people with MND have a family history of the disease. This is known as familial, or inherited, MND and is caused by a mistake in the genetic code that holds the instructions for making every protein in our bodies. This mistake can be passed down from parent to child.

There are a growing number of genes which have been associated with MND. The most common of these are SOD1, C9ORF72, FUS and TARDBP (commonly known as TDP-43). Other extremely rare causative genes have also been identified. These discoveries represent major breakthroughs because they can provide important clues about how motor neurons are damaged in MND, and may advance our understanding of all types of the disease.

The remaining 90% of cases are said to be sporadic – where there is no known or identifiable cause. Much progress has been made in recent years in our understanding of the genetic basis of MND and it is now believed that up to 10% of sporadic MND cases may be due to mistakes in different genes.

Researchers in Spain sequenced blood samples from 11 people with familial MND, 271 people with sporadic MND and 127 controls to look for variants in 22 genes known to cause MND. After analysis, they found that nearly 8% of people with a diagnosis of sporadic MND carried potentially pathogenic (disease-causing) variants (GEN-01).

For more than a decade it has been known that specific variants in the UNC13A gene increase the risk/severity of MND and frontotemporal dementia (FTD), but the mechanisms underpinning this association have remained unclear. Loss of TDP-43 in the nucleus of a cell is a molecular hallmark of 97% of MND and around 50% of FTD cases. In this study, partly funded by the MND Association, researchers from around the world identify a new component in UNC13A which is greatly increased by loss of TDP-43 in the nucleus. This is present in both people with MND and FTD but is exceptionally high in the nuclei of neurons from people with FTD. In their poster (GEN-05), the researchers discuss further discoveries and the importance of these to the future treatment of all MND and FTD-TDP patients.

Polygenic risk (the collective influence of many genetic variants on the chance of developing a disease) plays a central role in MND risk. Genome-wide Association Studies (GWAS) offer a method to explore this type of risk. A worldwide team of researchers applied polygenic risk score analysis to a genomic data set of 28,500 individuals to distinguish the cellular processes and the cell types relevant to the disease process for MND. Analysis showed the convergence of many genetic etiologies – the cause, set of causes or manner of causation of a disease or condition – onto a smaller number of common pathways, highlighting the power of using genetic data to predict functional outcomes. Potentially, this approach could identify new pathways for therapeutic targets (GEN-20).

Supporting people with inherited MND

Furthering our knowledge of the genetic causes of MND is crucial, but supporting people at high risk from developing MND due to an inherited form of the disease being in their family is equally important.

As our understanding of the genetic basis of MND grows, and the number of clinical trials targeting specific genetic variants increases, there have been suggestions that routine genetic testing may be beneficial to people with MND. This could, however, see more family members living with the knowledge that they are at increased risk of developing MND in the future, which can have a profound impact on people’s lives. A study, funded by the MND Association and carried out by researchers from the Universities of Aberdeen and Edinburgh, focused on the information and support needs of those individuals, and explored critical junctures where people had a particular need for information and support and how those needs might be met (CMS-26).

Genetic testing for all?

In her oral presentation, Katie Stenson reports on the work carried out by researchers in the UK and USA looking at patterns of genetic testing in the USA and Europe, in which 142 neurologists completed questionnaires for 838 people with MND. This figure represents about a third of the patients globally that it was offered to. Genetic testing was offered to 99% of people with familial MND (94% accepted) compared to 47% of people with sporadic MND (63% accepted). Tests were carried out for different genetic variants and, of these, 32 people with familial MND returned a positive result for SOD1, compared to 25 people with sporadic MND.

This analysis shows that only one third of patients were offered and underwent genetic testing and although the proportion of positive results is higher in familial than sporadic patients, these results show the importance of testing all patients, regardless of family history. Although testing was more frequently offered to people with familial MND, SOD1 variants were almost equally identified within sporadic and familial patients, and similar results were seen for other genetic variants (C25).

With more gene therapies that target specific genetic variants in the development pipeline, and entering clinical trials, and an increase in personalised medicine, genetic testing is becoming more important to ensure as many people as possible can access relevant trials and treatments that are right for them.

Stay informed

If you have come across this blog through the Symposium website, or a general search please subscribe (see top right hand corner of page) and you’ll be notified every time we upload a new article.

You can follow our research account on Twitter. We tweet about up to the minute research and will be tweeting throughout the Symposium – #alsmndsymp #drivingmndresearch

Take a look at the schedule of blogs for November as we continue counting down to the 32^nd International Symposium on ALS/MND with our ‘Symposium Blogathon’.

Registered attendees can listen to all presentations live and take part in Q&A sessions. They also have on-demand access to all posters and can meet with poster presenters to discuss their work during the scheduled poster sessions each day.