More ALS Cases Are Genetic Than Previously Thought

December 23, 2014

Genetics may play a larger role in causing amyotrophic lateral sclerosis (ALS) than previously believed, potentially accounting for more than one third of all cases, according to a new study.

The study, published online in the Annals of Neurology, also showed that patients with defects in two or more ALS-associated genes experience disease onset about 10 years earlier than patients with single-gene mutations.

For the study, researchers from Cedars-Sinai Medical Center, Los Angeles, California, and Washington University, St. Louis, Missouri, used new techniques known as pooled DNA sequencing to comprehensively sequence 17 known ALS genes in 391 patients with ALS from the United States. They estimate that the new techniques used required 83% less DNA per patient and cost just 10% of the cost of traditional sequencing methods, which allowed "the most comprehensively sequenced North American cohort to date."

Results identified 27 novel mutations and an additional 38 that are very rare in control populations.

These potentially pathogenic variants occurred in 64.3% of known patients with familial ALS and in 27.8% of patients previously classified as "sporadic" (ie, not known to have a family history of ALS). The authors point out that this figure of 27.8% "is considerably higher" than rates reported in other studies that used less comprehensive sequencing approaches.

In addition, 3.8% of patients had variants in more than one ALS gene, and these individuals had disease onset 10 years earlier than patients with variants in a single gene.

In most cases with variants found in more than one gene, one of the identified variants was a known mutation with clearly established pathogenicity, but many of the additional variants were of unknown significance. The researchers say that these additional variants could co-occur with pathogenic mutations by chance, but the fact that these patients had disease onset 10 years earlier than other patients "supports a model of ALS where the additive or synergistic effects of multiple defective genes increases risk and influences disease phenotype."

Senior author of the study, Robert H. Baloh, MD, Cedars-Sinai Medical Center, says in a Cedars Sinai press release, "These findings shed new light on the genetic origins of ALS, especially in patients who had no prior family history of the disease."

The press release notes that until now, 90% of ALS cases have been classified as "sporadic," but this study suggests many of these cases do have a genetic basis.

While some ALS cases are thought to be caused by an individual gene defect, this study supports recent findings suggesting that other cases could be brought on by the simultaneous occurrence of two or more lesser genetic defects. In theory, each mutation alone might be tolerated without initiating disease, but in combination they exceed the threshold required for disease development.

The statement reports that the hope for the future is that further genetic defects can be identified and gene-specific therapies can be developed to correct these defects.

It also notes that Cedars-Sinai researchers last year reported a study in which cells from patients with a common pathologic ALS mutation were treated with antisense oligonucleotides targeting the mutation that prevented expression of the defect gene.

The current study was funded by grants from the National Institutes of Health and Genetics Epidemiology Training.

Ann Neurol. Published online November 27, 2014. Abstract

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