A new gene for ALS: What sharing your genetics could mean for research
In today’s issue of the journal Science two papers describe the discovery of a new gene for ALS (you can read the abstracts here and here). Around 90% of ALS cases are sporadic, i.e. we don’t know what causes them, but for 5-10% of patients the disease runs in their family (known as familial ALS, FALS). Until today, there was only one major causative gene that we knew about, called SOD1, which accounted for 20% of familial cases. Today’s new discovery of the gene FUS (also known as ALS6) accounts for an additional 3-5% of familial cases and was the result of an international collaboration between scientists in Boston, London, and Sydney. This is very exciting for research because the more we know about what causes ALS, the better our chances of finding an effective treatment through better understanding of the pathways involved in motor neuron degeneration.
Here at PatientsLikeMe, we’ve recently upgraded our ALS platform to capture data on familial ALS patients’ known genetic mutations. The goal is to help familial ALS patients find another patient like them, and to enhance understanding of the phenotype of each mutation, e.g. if different types of mutation cause a faster or slower disease progression. Ultimately our aim is to try and establish whether there might be any treatments that have a differential effect on patients with different disease-causing mutations. There are examples of this already known in other diseases; for instance the presence of absence of the Philadelphia chromosome in chronic myelogenous leukemia (CML) predicts whether the patient will respond to the drug Gleevec. Although there is currently only a single effective treatment for ALS (Rilutek), there are a number of trials underway investigating the potential of drugs for patients with specific gene mutations.
The unique outcome data captured on the PatientsLikeMe platform also allows us to learn more about the nature of the disease for FALS patients with different genetic mutations. In the graph above you can see the average rate of progression for patients with three different FALS mutations; the common and aggressive A4V mutation (sadly average survival is ~18 months), the rarer recessive D90A mutation (much longer average survival of ~13 years), and a very rare and recently identified mutation of VAPB, referred to as ALS8. Collecting genetic data and combining it with high-quality patient-reported outcomes helps a patient to answer the question “Given my status, what is the best outcome I can expect to achieve, and how do I get there?”.
Note: If you have familial ALS and know your genetic mutation status please consider joining our ALS community and sharing your genetic information through your diagnosis history.
hi,
i was on a meeting about genetic als. as rilutek is the only known medecine, and its effect is better when started early. why not start feeding family members 5 years before diagnose age in that family?
comments please…
cheers antti
Comment by aaamies — March 18, 2009 @ 2:21 pm
Dear Antti,
A very good point! There is a group of “people at risk of familial ALS” (PARFALS) that should be studied in more detail. To our knowledge there are only two small studies on this population. The first looked at brain changes of SOD1 D90A mutation patients and found that healthy people *with* the mutation had some subtle, but detectable changes relative to healthy people without the mutation (see Turner MR et al 2005, Distinct cerebral lesions in sporadic and ‘D90A’ SOD1 ALS: studies with [11C]flumazenil PET, Brain 128(6):1323-1329). The second looked at the brains of healthy people carrying the SOD1 mutation was compared to controls; they found that the brains of SOD1 carriers who went on to develop ALS symptoms became more electrically excitable just before the onset of ALS. (see Vucic S et al 2008, Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis, Brain 131(6):1540-1550).
In the animal studies that are conducted on ALS mice, researchers start giving treatments before the onset of symptoms, so it would certainly be an interesting study. The problem though is one of logistics: most research grants only last 3-5 years and require a statistically significant “critical mass” of participants to be meaningful. If we were to study whether giving PARFALS Riluzole preventatively (as a “prophylactic”) we would need an multicenter 10-20 year study with PARFALS randomized to either get Riluzole or not. You’d probably want to do it in the more aggressive A4V SOD1 mutation patients because that way you could see the difference faster (D90A patients progress too slowly anyway to see a difference).
During the course of Paul’s PhD he met about two dozen FALS patients and their families, including children who are PARFALS. The hope is that there will be a cure by the time they would start expressing symptoms but this is a real threat hanging over many people. To make this type of research a reality will require lobbying and advocacy by informed people such as yourself, we wish you luck and are happy to help in any way we can.
Sincerely,
Paul Wicks & Catherine Brownstein
Comment by Paul Wicks — March 20, 2009 @ 9:40 am
This month 3/09 in our “Star” Newspaper was a story about a dog who researchers link its malady to human ALS. The findings appeared last month in the “Proceedings of the National Academy of Sciences. The researchers at the University of Missouri College of Veterinary Medicine were exploring a genetic cause for degenerative myelopathy or DM in dogs. I have not heard one word about this break-through about the ALS connection to humans, could you check this breakthrough out? It is to late for my son, Jim he passed last month one year after being diagnosed Feb. 14, 2009 he was 52.
Comment by Lois Reimers — March 28, 2009 @ 3:18 pm
Dear Ms. Reimers,
Thank you so much for your comment!
Degenerative myelopathy (DM) has been documented in certain kinds of dogs (such as German Shepards and Brittany Spaniels) since 1973. However, when the disease began showing up in more and more dog breeds, researchers took notice. In February it was reported that DM affected dogs have a mutation in the SOD1 gene, similar to the ALS-causing mutation sometimes seen in humans. Analysis of DNA samples from 38 DM-affected Pembroke Welsh corgis revealed a SOD1 E40K missense mutation not seen in the 17 related unaffected controls.
The SOD1 mutation discovery is great news for the ALS community, since possible future therapies will be tested on these dogs. There is hope that this dog model of ALS will be better tool for research than the mouse model of ALS; it was recently found that minocycline, which had been reported to slow the disease in SOD1 mice, actually accelerates the disease in humans with ALS (though whether this was due to inappropriate dosing remains under debate).
In other words, the discovery of the SOD1 mutation in canines is a great thing for ALS research, and we look forward to what therapies this discovery may bring!
Sincerely,
Catherine
Catherine Brownstein MPH, PhD
Comment by cbrownstein — March 30, 2009 @ 12:58 pm
My mother and aunt, though 7 years apart in age were diagnosed with Bulbar ALS within 6 month of each other. Does that sound like something they were exposed to at the same time or could it be that their children were born around the same time. I worry about myself and my siblings and cousins. No genetic link was found in my mothers case. Can I do something to fight off getting it?
Comment by Donna Guevremont — August 7, 2009 @ 5:18 am