Fathoming MND

This article was written by our Senior Clinical Fellow Prof Martin Turner, a Consultant Neurologist at John Radcliffe Hospital, Oxford.

“Will it affect my children?” This is one of the questions most commonly asked by people diagnosed with MND. The 20th century answer was a simple “no”, or at least “very unlikely”. With recent scientific advances, however, doctors must give a more complicated answer. At the same time, these advances are cause of excitement about the greater understanding of MND and new hope for treatments for all cases.

It appears that anyone could potentially develop MND. While all diseases have a genetic component, with genes influencing how the body is put together and its resistance to the wear and tear of life, relatively few diseases are determined by a single change in a gene. Such conditions are more easily passed on to the next generation and are often referred to as “hereditary” forms of the disease. The discovery in 1993 of changes in the SOD1 gene as a cause of familial MND, led neurologists to routinely ask whether any other extended family members had had MND when giving someone an MND diagnosis. Such links were clear in the family history of at least 5%, though this was probably an underestimate as there are many reasons why people might not know about their family in sufficient detail. Where a family history of MND was clear however, a longer discussion took place around the option of trying to identify the gene affected. Twenty years ago, such genetic testing in those with a family history of MND had only a 20% chance of finding a positive result, and a lot of uncertainty.

Then in 2011 it was discovered that a previously undetectable change in the gene C9orf72 was not only the commonest cause of hereditary MND (nearly twice as common as SOD1), but also the commonest genetic cause of a related condition: frontotemporal dementia (FTD). Moreover, the two conditions were found to independently affect members of the same family. This now meant needing to extend the family history discussion to include asking about relatives with dementia. When blood samples donated for research by a large group of people living with MND regardless of any family history were screened for the C9orf72 mutation, the test was positive in nearly 10%.

Knowing the cause is important for many people living with a condition like MND, one that often appears to arise suddenly on a background of apparent physical fitness. The discovery that it is a genetic change then brings up the challenge of how best to share the information with siblings and children, who are at 50% risk of being carriers of the same genetic change. Being a carrier does not guarantee developing MND or FTD in one’s lifetime but knowing that this risk is greatly increased can be deeply unsettling. Equally, knowledge can be empowering for some relatives who may wish to use the information to guide their own family planning.

A further development is early promise seen in other neurodegenerative conditions by applying treatments that target genetic changes e.g. babies with spinal muscular atrophy. Similar types of treatment are now being tried in people living with MND caused by SOD1 gene changes, and similar therapies aimed at the much more common C9orf72 gene change are expected in the near future. It is not certain that such treatments will work, and at present they would only be suitable to try in those whose MND has an identifiable genetic code error as the cause. However, even the possibility of therapy trials for at least 10% of all MND means that offering testing to all newly diagnosed cases of MND (and FTD) is starting to become more routine. Genetic testing always requires detailed discussion with doctors familiar with the issues, so that individuals can weigh up the benefits versus any concerns in an informed way before making a decision about being tested.

With such rapid and complex developments and the need for wider education, Families for the Treatment of Hereditary MND (FaTHoM) was conceived. The aim is to create a forum for the issues facing all of those affected by hereditary forms of MND. They include genetic testing and emerging therapeutic trials, but also vital non-therapeutic research such as disease activity (bio)marker development, which will be needed to measure the effectiveness of any future preventative therapies. The MND Association sponsored the first event held Oxford in 2017, which involved a series of talks that can be viewed here.

The insights gained from research on hereditary forms of MND have value for the wider aim of developing treatments for the great majority MND cases, even though they are not hereditary to the same extent. Understanding hereditary MND helps us understand how MND develops more generally, and therefore what types of treatments might work best. I hope to encourage further events around the UK, and to engage many more families affected by hereditary MND in education and research.

2013 martin turner image

Prof Martin R. Turner 
Consultant Neurologist
Medical Research Council & MND Association Lady Edith Wolfson Senior Clinical Fellow
Oxford MND Care Centre Co-Director
John Radcliffe Hospital, Oxford


Find out more about inherited MND in our research information sheets:

Lighthouse Project shines a beacon on HERVs and their role in ALS

There is recent evidence to suggest that Human Endogenous Retroviruses (HERVs) may be involved in amyotrophic lateral sclerosis (ALS). HERV-K has been directly linked to motor neurone damage and has been found in the brain tissue of patients with ALS.

The MND Association recently awarded a small grant to fund part of the ‘Lighthouse Project’ which is investigating the safety and any beneficial effects of an antiretroviral drug on ALS symptoms. Continue reading

Networking to progress in the world of science: Mini-Symposium on MND

Conferences and symposia are a crucial part of the research world – not only for the amount of knowledge that is communicated to large audiences but also for the exchange of ideas on a more inter-personal level. Novel ideas are created there as well establishment of collaborations that might lead to new research projects and clinical trials – all in all, putting a bunch of researchers in a venue with a projector, coffee and biscuits can only lead to good things!

One of the recent events that I had the pleasure to attend was a small-scale conference – the Mini-Symposium on generic disease mechanisms in MND and other neurodegenerative disorders. Held at the Brighton and Sussex Medical School in late June, this event was a precursor to the inauguration of a new MND Care and Research Centre for Sussex, directed by Prof Nigel Leigh. Continue reading

Investigating the role of the cell’s waste disposal systems in TDP-linked MND

In April 2016, Dr Jackie Mitchell gave a talk at the Regional Conference in Gatwick to explain the aims of her three year MND Association funded research project. We have now received her second year report. In this blog we explain a little bit more about what she’s been doing. She has already made some good progress.

A little bit of background
One known genetic cause of MND is a defect in the TARDBP gene, which makes the protein TDP-43, that can be found in the nucleus of a healthy cell. The nucleus is the part of the cell that contains all our DNA. Healthy cells also have two major ‘waste disposal systems’ which break down and remove unwanted proteins from cells. More information on the role of TDP-43 in MND can be found on our blog. Continue reading

More information for families affected by inherited MND available online

In April this year MND clinician-researchers Professors Martin Turner and Kevin Talbot at the University of Oxford organised an information day about the rare, inherited form of MND called ‘Families for the Treatment of Hereditary MND’ (FATHoM). The day was filmed and podcasts of the talks have recently become available. This article gives an overview of each talk and a link to the video. Continue reading

11th Lady Edith Wolfson Clinical Fellowship awarded

We are delighted to announce that Dr Arpan Mehta has been appointed as our latest Lady Edith Wolfson Fellow, jointly funded by the MND Association and Medical Research Council.  This clinical research training fellowship will help to launch his career as an aspiring academic neurologist, providing comprehensive training in cellular, molecular and bioinformatics technologies in a world-class environment. Continue reading

New ALS review article available

ammar2.jpgLast week, The New England Journal of Medicine (NEJM) published a review article by Professors Ammar Al-Chalabi and Robert Brown, in which they looked at the up to date evidence on the incidence of ALS, pathological mechanisms of the disease, as well as genetics and therapeutic strategies.

We would very much like to thank the NEJM who kindly allowed us to share full text of this article on our website – this is now available to view here.

Closing the door on toxic proteins – new clues in understanding a genetic form of MND

The defects in the C9orf72 gene are known to cause motor neurone disease, but researchers don’t understand why. Defective copies of this gene are passed down in some families affected by the rare, inherited form of MND. This week MND Association grantees Drs Guillaume Hautbergue, Lydia Castelli and colleagues, based at the Sheffield Institute of Translational Neuroscience have published their research study providing some important clues about the toxicity of C9orf72. Their research is published in the prestigious journal Nature Communications. Continue reading

ANXA11 – another gene closer to understanding ALS

A new research paper has been published today in the Science Translational Medicine journal, describing a new gene implicated in developing MND. What is this gene and why is it important for our fight against MND?

Although they are not the sole cause of MND, genes play a big role in someone’s probability of developing the disease. A number of such genes that make a person susceptible to developing MND have already been identified, with most of them causing the rarer, inherited form of the disease.

A new addition to a list of genes that are related to development of ALS, the most common form of MND, has been discovered by researchers from King’s College London. Dr Bradley Smith and colleagues screened genetic data of an unusually high number of people of European origin: 751 with inherited – familial – ALS (fALS) and 180 with non-inherited – sporadic – ALS (sALS). Detailed analysis of this data found that specific mutations in the ANXA11 gene are associated with around 1% of all fALS and 1.7% of all sALS cases. Continue reading

What goes wrong with electrical signalling in MND?

Last year, we introduced a PhD Studentship that we are funding at the University of St Andrews. Under the supervision of Dr Gareth Miles and Prof Siddharthan Chandran, the student working on this project, Amit Chouhan, is investigating why electrical signalling goes wrong in MND.

As the project enters its second year, Amit and the team have made some important discoveries… Continue reading