Ongoing Research Probes Genetic Basis For Amyotrophic Lateral Sclerosis

Genetic Basis for Amyotrophic Lateral Sclerosis

Dr. William Freeman examines the output from an Illumina HiSeq 2500, a Next Generation Sequencing instrument within the Penn State Hershey Institute for Personalized Medicine (IPM) capable of determining the 3 billion base sequence of a patient’s genome in only 24 hours for less than $5000. By comparison, determination of the first genome sequence 15 years ago required 10 years and $3 billion.

It has been long assumed that the majority of amyotrophic lateral sclerosis (ALS) cases occur sporadically, while only 5 to 10 percent are defined as genetic, in which ALS is inherited via a straightforward autosomal-dominant mechanism. However, researchers at the Penn State Hershey ALS Clinic and Research Center, working in collaboration with the Institute for Personalized Medicine at Penn State Hershey Medical Center, have now found that more cases occur as the result of extremely complex genetic factors than previously thought. Researchers have helped determine that many cases appear to be recessively inherited, which would account for the fact that there is no identifiable history elsewhere in close relatives.

Genetic Basis for Amyotrophic Lateral Sclerosis

A technician prepares genomic DNA samples for subsequent sequence determination. The Covaris uses sound waves to fragment genomic DNA into small pieces suitable for sequencing.

Penn State Hershey scientists collect DNA specimens from their available pool of ALS patients. As one of only 41 ALS centers nationwide with the Certified Center of Excellence designation from the ALS Association, Penn State Hershey clinicians care for more than 80 new patients with ALS annually, and work in collaboration with other centers to examine the DNA sequencing for those patients to determine the genetics of the condition. Zachary Simmons, M.D., director, Neuromuscular Program and ALS Center, states: “Our internal DNA sequencing has permitted us to identify some genes that are potentially causative in ALS, and we continue to move forward to confirm those findings.” A forthcoming partnership with the New York Genome Center aims to further the understanding of the genetic basis of ALS, with the details of the data-sharing process to be finalized over the remainder of the year.

Simmons emphasizes that the key is to view ALS not as a single disease, but as a syndrome, with heterogeneity as wide-ranging as that in cancer. Only by understanding the root causes of the motor neuron deficits that characterize all forms of ALS can researchers begin to examine treatment options. Currently, most clinical trials examine the effects of different treatments on slowing, not reversing, the progress of the disease. In addition, assistive communication systems continue to be rigorously studied, with Penn State Hershey deeply involved in brain-computer interface (BCI) technology. The rapid progress in ALS genetics research offers cause for optimism that more curative ALS therapies will be discovered in the future.1

One major contributing factor to the proliferation of this genetics research is the recent breakthrough that has led to increased affordability of DNA sequencing. Just a few years ago, this procedure was extraordinarily expensive, requiring a major allocation of resources to perform sequencing on just one patient’s genome. The same procedure has now become significantly more cost-efficient, allowing it to be performed on many more patients and family members. Concludes Simmons, “This is what led to a lot of the ongoing collaborations and has pushed this genetics work forward.”

Zachary Simmons, M.D.Zachary Simmons, M.D.
Director, Neuromuscular Program and ALS Center
Professor, Neurology
PHONE: 717-531-1809
FELLOWSHIP: Neuromuscular Diseases, University of Michigan Health System, Ann Arbor, Mich.
RESIDENCY: Neurology, University of Iowa Hospitals and Clinics, Iowa City, Iowa
MEDICAL SCHOOL: University of Florida College of Medicine, Gainesville, Fla.


  1. Peters OM, Ghasemi M, Brown RH Jr. Emerging mechanisms of molecular pathology in ALS. J Clin Invest. 2015 May 1;125(5):1767-79.

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