12:01am Wednesday 18 October 2017

Study highlights role of rare genetic mutations in ALS

Ninety to 95 percent of amyotrophic lateral sclerosis (ALS) cases are “sporadic,” meaning these patients had no clear family history of the condition and therefore no indication that they were at risk. A new study by investigators at University of Utah Health shows that approximately one-fifth of these cases do have signs of a genetic predisposition toward the disease: They carry detrimental mutations associated with the familial form of ALS.

ALS, also called Lou Gehrig’s disease, causes nerve cells in the brain and spinal cord to degenerate. Patients gradually lose the ability to speak, swallow and breathe, typically living for three to five years following symptom onset.

Recently published in Neurology, the findings highlight a new appreciation for the role of genetics in ALS, which could help scientists better understand the causes of disease and bring forth new approaches for caring for this subset of patients.

“Our results highlight that genetic factors play a significant role in the disease, which is important in an era of genetic-focused treatments,” says Summer Gibson, a practicing ALS specialist at the Clinical Neurosciences Center at U of U Health.

Gibson was co-first author on the study together with M.D./Ph.D. student Jonathan Downie. Lynn Jorde, chair of human genetics, and Stefan Pulst, chair of neurology at U of U Health, are co-senior authors.

Previous studies had hinted that genetic factors contributed to anywhere from 11 to 27 percent of sporadic ALS cases. Those estimates were based on the discovery of rare genetic anomalies in some of these patients. But these studies did not investigate whether the DNA changes impacted the function of the genes, information that is necessary for knowing whether the variations are likely responsible for the disease.

Gibson and colleagues addressed the question by analyzing the genomes of 87 patients with sporadic ALS. In particular, they carefully examined 33 genes linked to the disease, looking for variations in DNA sequence that are rarely found in the general population. Advanced software tools predicted whether the changes would break the gene, for example by disrupting the enzymatic function of the protein made by the gene.

Among this ALS patient population, a relatively high proportion, 17 percent (15 individuals) had rare, deleterious genetic defects in genes linked to the disease. By comparison, just 4 percent of healthy controls (13 of 324) carried mutations in this category. The results support the idea that these genetic factors increase the risk for developing ALS, even among patients with the sporadic form of the disease.

“Among patients with no clear family history of ALS, we are finding the same genes are affected as those who do have familial ALS,” says Jorde. “These results blur the line between the two categories of disease.”

Of the 19 rare and deleterious mutations found in the sporadic ALS population, five had never before been described. Experimental work will need to be done to verify the damaging effects of these mutations.

The fact that healthy patients also carry some of these mutations may demonstrate that although the genetic changes likely increase the risk for developing ALS, they do not guarantee that the disease will arise. Though Gibson points out that it is possible that some of these healthy patients could still develop ALS later in life.

“This study contributes to our increasing knowledge that DNA variants in some genes may not cause disease, but greatly increase the risk to develop the disease in concert with other genetic and environmental factors,” explains Pulst.

“We have come a long way in our understanding of ALS but we still have a lot to learn. The causes for the vast majority of ALS cases are still unknown,” Downie adds.

The team is continuing to search for additional genes that increase susceptibility for ALS, and are investigating how environmental factors might contribute to the disease.

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The research was supported by the National Institutes of Health and Target ALS.

“The evolving genetic risk for sporadic ALS” was published online in Neurology on June 21, 2017. In addition to Gibson, Downie, Jorde and Pulst, co-authors are Spyridoula Tsetsou, Julie Feusier, Karla Figueroa, and Mark Bronberg for University of Utah Health.

UNIVERSITY OF UTAH


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