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/