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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no real disease-modifying therapy. Only until recently did we attribute a small portion of individuals with ALS with a genetic basis. Research from Robert Baloh, MD, PhD, Director of Neuromuscular Medicine at Cedars-Sinai, and colleagues at Washington University in St. Louis, discovered the much larger role of genetics in ALS. Here, I interview Baloh on his findings.
Shaheen Lakhan: Can you provide us with an overview of ALS?
Robert Baloh: ALS, amyotrophic lateral sclerosis, is a neuromuscular disorder: It attacks nerve cells in the brain, brainstem and spinal cord that control muscles. The timing and sequence of progression is unpredictable, but it often begins in the arms or legs and eventually affects the breathing muscles in the chest.
ALS is often considered a very rare disease, but it probably is about as common as other neurodegenerative diseases, such as Parkinson’s disease. The reason ALS seems rare is that few patients survive long – people generally live only three to five years after onset – so unlike other disorders, there is not a growing number of patients living with the disease.
The disorder often is called Lou Gehrig’s disease after the New York Yankees’ first baseman who died of ALS in 1941. Even today, no significant disease-slowing treatments have been found, but we are able to offer therapies that improve patient quality of life. In recent years, there has been a surge in research to find the underlying genetic, molecular and cellular changes that cause the disease. With those discoveries, we expect to begin developing effective interventions.
Research funding increased dramatically when the ALS Ice Bucket Challenge brought much greater attention to finding cures for ALS.
SL: Is ALS inheritable?
RB: Yes, some cases are. Until very recently, we believed that about 10 percent of ALS cases had a genetic origin – there was a family history of the disease. The remaining 90 percent or so were considered “sporadic.”
SL: What is the difference between sporadic and familial ALS?
RB: ALS occurs when one or more changes in certain genes take place. A case is considered familial if a newly diagnosed patient has a previous family history of the disease, but if a new patient is the first family member diagnosed, the case is called sporadic – occurring without a previous genetic explanation.
SL: What has your research group found?
RB: Our study, which involved researchers from Cedars-Sinai and Washington University in St. Louis, found that family history may play a much larger role than previously believed – accounting for more than one-third of all ALS cases rather than only one-tenth. Examining DNA from 391 patients with ALS, we looked at 17 genes already known to be associated with the disease. We found many new or very rare mutations in ALS genes in people with no family history of the disease, suggesting that these supposedly “sporadic” cases may actually have a familial background.
We also found that patients who had mutations in two or more of these ALS genes had disease onset about 10 years earlier than those with defects in only one gene. Often, ALS is caused by well-known defects in single genes, but recent studies suggested that some cases might be brought on by the simultaneous occurrence of two or more “lesser” genetic defects. In theory, each mutation alone might not cause disease, but in combination they exceed the threshold for disease development. Not only does our study support that possibility, it shows that multiple defects can influence the way the disease manifests in individuals – striking 10 years earlier.
SL: What are the potential clinical implications of your research?
RB: We think we are entering a new phase of ALS research and treatment in which we will be able to analyze a patient’s entire genetic makeup and deliver gene-specific therapies to correct detected defects. We recently conducted a disease-in-a-dish study with cells from patients with defects in a gene that commonly causes ALS. Using small segments of genetic material to target the defects, we showed that this type of gene therapy can improve neurons from patients with the disease.
In addition, with the discovery of new and rare genetic mutations in ALS, we may be able to identify at-risk patients earlier because we can follow families previously unknown to have a genetic basis.
SL: Any closing remarks for our Brain Blogger readers?
RB: In our study, we used new technology that quickly and efficiently determines the organizational structure of large numbers of genes, but we focused only on 17 genes already known to be associated with ALS. Even though we identified the involvement of many new and rare mutations in ALS development, the majority of cases are caused by factors we do not yet understand. Therefore, more research using similar technology may help us discover other genes that influence ALS risk, providing more targets for future therapy.
Cady J, Allred P, Bali T, Pestronk A, Goate A, Miller TM, Mitra RD, Ravits J, Harms MB, & Baloh RH (2015). Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Annals of neurology, 77 (1), 100-13 PMID: 25382069
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