Skip to Main Content

 

 

Ask the Doc: Q & A with Edward Kasarskis, MD, PhD

Edward Kasarskis, M.D., Ph.D. is Director of the multidisciplinary ALS Center at the University of Kentucky Neuroscience Center in Lexington, Kentucky, professor in the Department of Neurology at the University of Kentucky, and Chief of Neurology at the VA Medical Center in Lexington KY. 

Dr Kasarskis
Dr. Kasarskis 

Q:  I’ve heard about the research that discovered a genetic mutation that seems to be responsible for frontotemporal dementia and ALS in families. The research stories I’ve read are quite complicated. Can you please boil it down and explain the implications for people with ALS?

A: Yes, the results are complicated for sure. Before diving into my explanation, I must say that this research would never have occurred without patients and their families donating their blood samples and DNA for research. Without that high level of participation, we would never have been able to make such a significant breakthrough in our understanding of ALS.

Recall that there are two general forms of ALS: Familial (FALS, with many blood relatives affected by ALS usually in each generation), and Sporadic (SALS, with no known blood relatives affected). In both forms, there is a spectrum of physical findings, which in some cases involves frontal lobe dysfunction, called frontotemporal dementia or FTD.

The families involved in this research had cases of FTD, typical ALS, or a combination of both in the same patient. In one report, the families resided in Finland and Europe, and in the other, Canada and the United States. Using the isolated DNA from the blood of these families collected over many years, researchers mapped the genetic codes of affected and non-affected individuals through several generations and analyzed the data. It was an arduous task.

A "hot spot" on Chromosome 9 (official location, 9p21) kept popping up in their findings as a region of interest. This is somewhat like saying your house (the mutated gene) is somewhere in ZIP Code 40503 (Chromosome 9, 9p21) -- a true statement but still a long way to go to find the house.

These two independent studies found the identical genetic abnormality in their two populations. That abnormality appears to be the most common cause of FALS with FTD. The researchers, using abundant super computer power (next-generation sequencing technology), discovered a unique mutation: a short DNA sequence that was repeated many more times in people with ALS, FTD, or both as compared to those relatives in the family without the disease.

These research teams found what is called a "GGGGCC hexanucelotide repeat" in a specific gene (abbreviated "C9ORF"). It turns out that this area of DNA is normally repeated only two to 23 times, but in ALS or FTD patients, it is repeated over and over again. At the fundamental genetic level, these results show that ALS and FTD are linked. In addition, this repeat in the C9ORF gene was found in some patients who did not have a family history, and thus would be considered SALS. The research was published in the scientific journal Neuron.

The implications of this research are potentially huge. First, in Finland the abnormalities in the C9ORF gene and the SOD1 gene now account for almost all of the FALS cases in the country. Second, the fact that C9ORF is present in both ALS, and ALS with FTD means that there is likely a common mechanism for neuron dysfunction and death. Third, the C9ORF findings might contribute to the development of ALS in some (but not all) of the sporadic ALS cases. And finally, this discovery expands the number of potential drug targets for future therapy.

So the next time someone invites you to participate in an ALS research project, please roll up your sleeve, give blood, donate a skin biopsy sample, contribute to population-based studies and volunteer for drug trials. I realize that ALS is a devastating diagnosis and that the rigors of daily life take their toll on people with ALS and their families. But please seriously consider volunteering for research into this disease. There really is no other choice if we are to make progress toward a cure.

If you would like to submit questions for a future Q & A, please send your questions to theexchange@alsa-national.org. Please understand that we won’t be able to address all questions and we won’t be able to respond to individuals personally.

 

 



ABOUT SSL CERTIFICATES

All content and works posted on this website are owned and copyrighted by The ALS Association. ©2019
Contact the Webmaster