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Arbitrary age limits on ALS genetic testing means many patients go missed

Written by Lauren Robertson, Science Writer.

A new study in the journal Brain has found that as many as 98% of people with clinically actionable amyotrophic lateral sclerosis (ALS) may be missed by current genetic testing guidelines – purely because onset of the disease began after they turned 40.

It’s in the genes

ALS – otherwise known as motor neurone disease or Lou Gehrig’s disease – is a progressive neurodegenerative disease that eventually leads to paralysis of the muscles. Despite the devastating consequences of this deterioration, there is currently no cure.

In up to 20% of ALS cases, there is an observable family history. Those with ALS that runs in the family are often offered genetic testing. For others – described as having “sporadic” ALS – Mendelian disease gene variants have been identified, but testing is restricted to patients with an age at onset under 40.

To better understand how and when genetic testing should be carried out, researchers from the Institute of Psychiatry, Psychology & Neuroscience at King’s College London decided to use global ALS datasets to analyse four common ALS genes and 26 other genes associated with the disease.

The team sequenced blood-derived DNA for the ALS genes and determined the probability of a clinically actionable genetic test result. Though the analysis was carried out on international data, the UK was used as an example to estimate how many people might be missed by restricting testing by age of onset – as according to the UK’s National Genomic Test Directory.

They found that by limiting testing availability in those without a family history to people with symptom onset before the age of 40, 115 out of 117 positive tests were missed. Because genetic testing guidelines are similar across the globe, this means that potentially thousands of people worldwide do not know they have a genetic component to their ALS.

Impact on treatment

Why is this important in terms of treating ALS? If no genetic link is identified, these patients will not be offered appropriate genetic counselling and will not be able to access many of the potentially life-changing gene-based therapies in development and those currently in clinical trials.

“ALS is a condition that destroys lives,” said lead author Ammar Al-Chalabi, Professor of Neurology and Complex Disease Genetics at King’s IoPPN. “Genetic testing means that people and their families can be given correct advice and access to genetic counselling and be supported with family planning. Our study found that there are large numbers of people who are unable to access this care and support because of the arbitrary age limits and rules currently in place.”

Moving forward, the authors highlight that genetic testing should be available to all, not just a select few who have affected family members or exhibit early onset. Though expanding test availability to all ages might be resource intensive, they argue the potential pay-off could be enormous.

Dr Puja Mehta, the study’s first author, said “Our study shows the importance of being able to offer people with ALS of all ages a blood test to identify a possible genetic cause. In addition to accessing appropriate genetic counselling and support, with the exciting prospect of specific gene-based therapies on the horizon, and with clinical trials underway, it will become all the more important for people with ALS to know if they have an identifiable genetic cause.”