ALS Often Has Genetic Basis Even Without Family History

July 03, 2017

A new study has shed more light on the genetic basis of amyotrophic lateral sclerosis (ALS), confirming that gene mutations may still be responsible for many cases of sporadic ALS, where there is no family history.

But the study also suggests that not all mutations in genes associated with ALS in patients with the sporadic form of the disease actually cause disease, so fewer cases of sporadic ALS are thought to have a known genetic base than have previously been estimated.   

The study, published online in Neurology on June 22, was conducted by a team led by Summer B. Gibson, MD, and Jonathan M. Downie, PhD, University of Utah School of Medicine, Salt Lake City.

They explain that ALS — a progressive neurodegenerative disease of the upper and lower motor neurons, which eventually leads to death within an average of 3 to 5 years after symptom onset — is classified as familial when a clear family history of ALS exists (about 10% of cases) and sporadic when it does not (about 90% of cases).

Genetic research on ALS has largely been focused on familial ALS, but it is increasingly seen that sporadic ALS cases often have a genetic basis too.

The researchers note that most familial ALS is inherited in an autosomal-dominant fashion. However, this transmission pattern can be complicated by the early death of unrecognized affected family members due to non-ALS causes, misdiagnoses in older affected individuals, small family sizes, incomplete penetrance of genetic risk factors, and the development of disorders associated with ALS, such as frontotemporal dementia.

Thus, sporadic and familial forms of ALS can be difficult to distinguish, and much remains unknown about the roles of genetic factors in ALS and especially in sporadic ALS.

"It is a much-debated subject as to what percentage of cases of sporadic ALS actually have a genetic basis," Dr Downie commented to Medscape Medical News. "We know that genetic factors pay a role in sporadic ALS, and we wanted to figure out just how important they are. We used the latest generation of sequencing techniques and computer programs to ascertain which mutations are likely to cause disease."

"We focused on genes already known to be associated with ALS, and we found some new mutations, but we didn't look at genes not currently known to be associated with ALS in his study," he added. "There will be many of these, but this is for future research."

The researchers performed a genomic analysis of 87 patients of European origin with sporadic ALS. They found 28 rare variants in 33 ALS genes, including 18 variants that have not been described previously in patients with ALS.

"Previous studies have quantified the percentage of ALS cases with any mutations in genes known to be associated with ALS, but many of these mutations may not be pathogenic," Dr Downie noted. "So we used computational methods, which consider the type and position of a mutation to predict which ones were likely to be pathogenic."

He explained: "There tend to be trends — some amino acid mutations are more likely to cause disease than others. And the position of a mutation within the genome is also relevant — stretches of DNA that are highly conserved in multiple species are likely to be functionally more important, so mutations in these areas are more likely to be harmful."

The results confirmed that known ALS genes are important to sporadic ALS but, compared to other recent estimates, there were fewer mutations that were likely to be pathogenic.

"We estimate from this study that around 17% of sporadic ALS cases can be attributed to known ALS genes whereas previous estimates have been around 25% to 30%," Dr Downie said. "The previous estimates have probably overestimated the genetic basis for sporadic ALS as they have included mutations that probably wouldn't be pathogenic."

He gave an example as the senataxin gene (SETX). "This gene is associated with ALS and there are many mutations in this gene, but our results suggest they are not nearly as pathogenic as we thought they would be."    

Dr Downie elaborated that the ALS cases that have been classed as sporadic but do in fact appear to have a genetic basis can come about in several ways.

"There may a germline mutation — a mutation in the sperm or egg DNA — which was not expressed in the parent. Or mutations may skip a generation, and if a patient looks far enough back in their family history they might discover someone who had ALS."

"So many sporadic ALS cases actually do have a genetic basis, and the classification as familial/sporadic is not so useful," he added. 

Genetic Testing?

He says this research will become more clinically relevant once genetic-based treatments for ALS come through. "There are several antisense-based drugs targeted towards specific mutations currently in clinical trials. If these are successful and become clinically available, then I would recommend all ALS patients to undergo genetic testing.

"But at present I think if a patient has ALS which has been classified as sporadic, I think it is still worth a conversation about genetic testing.  It would not be unwarranted, particularly because of concerns about passing the gene on to children."

Dr Downie points out that the percentage of sporadic ALS with a genetic basis will probably turn out to be higher than those known about at present.  

"There are likely to be many more genetic mutations associated with the disease that we haven't yet discovered," he said. "Noncoding mutations — those that don't actually code for specific genes but determine how much or where that gene is expressed — are much harder to understand, but I would be shocked if these were not implicated in ALS to some degree."

In an associated editorial, Peter M. Andersen, MD, Umeå University, Sweden, emphasizes that the approach of using pathogenicity prediction computer models is the real novelty of the present study.

"The relative effect of ALS-associated genes is stronger when variant pathogenicity is considered instead of only variant rarity," he writes. "This is a critical observation in this study, but of course relies on the sensitivity and specificity of the used prediction models to determine pathogenicity."

He adds that while only a fifth of the sporadic ALS group had an identifiable probable genetic cause among the studied 33 genes, this should not be taken as evidence that genetics do not play a predisposing role for most sporadic ALS cases, "just that we are not yet able to reveal it despite using sophisticated second-generation sequencing technologies."

Neurology.  Published online June 22, 2017. Abstract, Editorial

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