Published in Lancet Neurology on 7 October 2014, Association-funded researcher, Prof Ammar Al-Chalabi based at King’s College London, and an international team of researchers have used a new approach to study the causes of MND.
Under the leadership of Prof Neil Pearce, based at the London School of Hygiene and Tropical Medicine, researchers have used a mathematical approach previously used by cancer researchers to explain why MND is an adult-onset disease, and why it varies (even within families).
The causes of MND
We know that MND is caused by a combination of environmental, lifestyle and subtle genetic factors. A small percentage of cases (5-10%) run in families; this is known as inherited MND.
Although genetics play more of a role in inherited MND, this rare form of the disease is clinically indistinguishable from the non-inherited forms, with similar disease progression. Because, inherited MND is caused by a genetic mistake in an MND-causing gene that has been present from birth, the question ‘why is MND an adult onset disease?’ has been one that has puzzled neurologists.
Led by Prof Al-Chalabi and Prof Pearce, the researchers have used a mathematical model that helps answer this question.
Learning from cancer
Although the mechanism of MND, which involves motor neurones dying, is different to the uncontrolled growth of cells found in cancer, the two diseases share similar characteristics. For example, genetic changes present at birth are only expressed in adult life in both cancer and MND, with the disease progressing rapidly once symptoms appear.
These similarities led the researchers to investigate whether a mathematical model, previously used in cancer, might also apply to MND.
Prof Neil Pearce said: “There are a number of features of MND, which are largely unexplained; Firstly, MND is an adult onset condition, even in those born with a gene mutation, which increases the risk of MND. Despite carrying the mutation from birth, many people remain healthy into old age and never develop MND. Others remain completely well until MND onset apparently begins suddenly, typically at the age of 50 to 70 years, and progresses rapidly.
“It is difficult to explain why a pathological genetic change present from birth is only expressed in adult life, in some but not others, and yet when it is expressed, the pathological process progresses rapidly; cancer has similar characteristics so we decided to assess whether a multistep model which has previously been used for cancer might also apply to MND.”
Some very clever maths
By using a multistep model for MND, the researchers hoped to use a mathematical model to identify how many steps (or factors) are needed to cause MND. The researchers applied their maths to already existing data from good population-based registers for MND: “These are registers which cover a geographical area and which identify all (or almost all) of the new cases occurring in that area; we then used this information to calculate incidence rates (the number of new cases per 100,000 people per year) in each age-group in each area.”
By applying the multistep model to the incidence of MND in each age-group, the researchers found that developing MND involves six different steps. This means that up to six different genetic, lifestyle and environmental factors are needed in order to trigger the disease; this explains the adult-onset nature of the disease and why some people do not go on to develop MND, even if they have inherited an MND-causing gene.
Prof Al-Chalabi commented on their results: “We found that the incidence of MND was proportional to age to the power of 5; this is consistent with the idea that developing MND involves six different steps; so if you inherit a gene which makes you susceptible to MND, that may only account for one step; the other five steps may be caused by (mostly unknown) environmental exposures; if we could work out what these are, we could ultimately work out how to prevent MND, even in people who have genes that make them susceptible.”
What does this research mean?
Prof Al-Chalabi said: “We have found that MND is caused by a sequence of six different events over a lifetime. Each event is a step towards developing MND, until the last one results in disease. Although we cannot yet say what the steps are, at least one is likely to be genetic.
“The next stage is to try to identify the steps, because this will help us understand what causes MND, help us to design treatments, and could help with reducing the risk of developing MND in the first place.”
Dr Brian Dickie, the Association’s Director of Research Development commented: “It is of course possible that the cancer model may not be applicable to MND, but the results are so uncannily consistent across five different European registers, which exist as part of the Euro-MOTOR project to discover new causative and disease-modifying pathways to pave the way for novel therapies for MND. The results provide a convincing case that environmental factors play a crucial role in determining whether and when the disease manifests – and also perhaps how quickly it progresses.
“Of course, the major challenge will be identifying what these factors might be, as epidemiological studies to date have not delivered many convincing environmental candidates. Larger scale international studies, such as the JPND-funded pan-European STRENGTH project will be crucial to the search for answers, but researchers may also need to come up with entirely new methods for performing research studies into the interaction of genes and environment.”
For further information about the causes of MND see our website.
Reference: Al-Chalabi et al. 2014 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197338/
Please can you add the link to the academic paper as I’d like to read it as I work in a univ (not a researcher) – don’t know if it open access though.
Here’s the link to the abstract for the paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197338/
Research Information Co-ordinator
MND Association, UK
My family have a number of ideas of potential triggers which may have been the last 1 or 2 of the 6 triggers required. Would it be possible to tap into these theories and those of other families to see if there are any correlations?
We funded an epidemiology study (led by Prof Al-Chalabi) in the UK, which is investigating what the other potential triggers may be and one of our researchers has also identified that physical activity may be a contributory factor in those who are already genetically predisposed. If you’d like to send us your ideas, we can happily look into these and see if any research has already been conducted?
If you email email@example.com we will happily get back to you on this.
MND Association, UK
It is “green” open access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197338/
Thank you so much for all that you’re doing to end this nightmare called MND. For what it’s worth . . . of the gentlemen I’ve had the honour of knowing . . . 1) male; 2) more physically active than others their age; 3) altruistic personalities; 4) above average intelligence. 🙂
This is an interesting way to look at it. My theory has 3 factors – genetic, lifestyle and environment. Within lifestyle and environment there are various factors. For environment there are certain chemicals that my Dad would have been exposed to as a gardener. I’d be interested to read “Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013;9:617–628” – is it available to the public to read?
You can view the abstract for the paper you’ve mentioned in your comment but the full text of this article is not available open access. However the paper mentioned in this blog post can be viewed in full online here .
Alternatively, Prof Al-Chalabi gave a plenary talk on the causes of MND for the 23rd International Symposium on ALS/MND, which you may find interesting? We wrote a blog on this, which you can view here.
on behalf of the Research Development team, MND Association, UK
If you or anyone else would like a copy of a paper that is not available in full you can email the corresponding author who is often able to send a copy. Please ask Sam to forward your details to me and I will send you a copy of the Nature Reviews Neurology paper you mention.
As a person with upper ALS and now in my mid 70s. I have looked back over my life for possible triggers. I would agree with all the triggers before mentioned. But will also strongly suggest that stress, either environmental or self imposed as a trigger. For 21 years (my 30s and 40s). I subjected myself to, and work under significant pressure until I was quite burnt out.
I bottled this up and the company I work for never really knew it. The experience resulted in me leaving the company where I had a good position. I never felt I ever really recovered.
A significant point was that I had to write, by hand in the 70s, pressing hard onto plastic paper. I would do this for the whole day for weeks at a time would leave my arms aching. Now I have had week arms or at least 10 or 15 years, although only diagnosed in March 72.
Apologies for spelling and grammatical errors as I’m still getting used to Dragon naturally speaking.
I tend to agree with Roger about the stress issue. A biological family member has just passed away from MND. Diagnosed late in the disease and passed away unexpectedly within a year. The member was extremely stressed and nervous most of their life due to an abusive environment.
Very interesting reading these comments. My mother passed away aged 73 from ALS. Physicially very fit, slim, active and a keen gardener for 50 years; since retiring from a fairly stressful office job in her late 50s, took up conservation work in Dorset, alongside her own gardening. Born in second world war was tiny child, throughout adult life very varied and healthly diet. I am convinced her ALS was triggered through environment factors, ie soil, chemicals from gardening/conservation work etc. As she did not want to prolong her illness she refused any feeding intervention and died within 8 months of being diagnosed. Due to her being so fit, even not taking any food, she lasted 8 weeks with limited fluid.
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