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End The Legacy's Genetic ALS & FTD Community Summit

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We are so excited that our first-ever in-person meeting, this June 7th-9th in Chicago, is coming close to reality. With a committed team of activists who have been meeting weekly for four years, joined by those new to the movement and others who are curious, it has the potential to be a life-changing experience. 

With an initial recruitment from our existing team, we have dozens of commitments; soon, a general registration will open for anyone impacted by Genetic ALS & FTD. 

Attendees will have precious time to network and connect with others who understand and have been in their shoes. They will receive the Clinical Research Learning Institute training from NEALS experts like Dr. Terry Heiman-Patterson. They will learn skills needed for our movement to be a success through panels focused on lessons from other patient advocacy movements with pre-symptomatic phases, how to communicate with your relatives about shared risk and research opportunities, and how to share your Genetic ALS & FTD story with differing audiences. 

We are so grateful to our partner, the ALS Hope Foundation, and our local host for the event, the Les Turner ALS Foundation. 

Please stay tuned for our general registration link. If you are interested in sponsoring the event  or have any other questions, reach out to info@endthelegacy.org

One year Out 

We have recently celebrated one year as an organized not-for-profit organization. Here's our self report. 

We are all familiar with the devastation that ALS and/or FTD brings. As the scientific and medical fields developed studying these diseases, the terrible plight of the many suffering with the manifest symptoms of the complete phenotype of the diseases rightly took prominence. The interests of the individuals at significant genetic risk were easy to miss, considering the forgoing. If a person went searching for resources to see their situation reflected in others, very little could be found. If information relating to a person’s genetic risk debuted, an individual at risk may not learn about it at all. If our government, through its legislators, regulators, and government-directed science institutes, considered the stakeholders of these diseases, they would not easily consider the genetically at-risk community as being especially relevant. 

 

All of this and more led Daniel Barvin, myself, and many others to come together a few years ago to get organized. In 2023, it compelled us to debut as a new non-profit Genetic ALS & FTD: End the Legacy. With our founding and our efforts, we have: 

 

  • Spurred intense discussion and debate coinciding with shifts in thinking in the scientific field on the issues important to us - notably ever more consideration for earlier disease trials and the first-ever presymptomatic care conference recently concluded in Pennsylvania. 

 

  • Through the regular work of our team ( weekly meetings for 4 years) and special support-focused meetings, we have documented improved senses of well-being and positivity in relation to our collective risk and provided an avenue for engagement and connection for those searching like we were before our founding. 

 

  • Through our meetings, website, and webinars, we bring the latest scientific news to our community promptly, for example, the first public airing of the recent new analysis of the penetrance of the C9orf72 expansion. And the first patient-facing guide to the c9orf72 expansion. 

 

 

  • When the NIH announced a desire to plan for its ALS work, they explained the stakeholders for the work were “patients and caregivers.” We pointed out immediately that they were missing the largest group of people in whom scientific advances in ALS could be practically implemented - the at-risk genetic community. Within a day, and ever since the NIH has been clear that they now see the genetically at-risk community as part of the stakeholders they serve. 

 

We need to continue pushing on these initiatives and develop them more. We need your support. To join or dialogue with us, email info@endthelegacy.org. To support our growing organization, donate here.  As part of the ALS Hope Foundation, donations are tax deductible. 

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Reflections on the ALS MND Symposium 3 of 3: A Few Concerns for our Community

End the Legacy was so pleased and honored to be able to send both our Executive Director, Jean Swidler, and one of our volunteer Board Members, Cassandra Haddad, to the Basel meetings this year. This was only possible due to our donors and sponsors, and we thank them profusely. 

 

We will provide three blog posts reflecting on the ALS MND Symposium and its lead-in meetings. You can read exciting things we heard and an account of our presence at the symposium on our website. The final post concerns itself with things we observed that warrant concern for the genetic ALS and FTD community. 

 

These notes are our subjective interpretation; we welcome others to share their evaluation of these concerns or the facts as we present them. Drop us a line at info@endthelegacy.org

 

We are offering some critiques here as educated advocates. Still, we must first again celebrate the work, effort, and dedication from the scientific field that has led to so much progress in these diseases, including identifying many of the genes responsible and the forward push into treating and hopefully one day curing these genetic diseases from the root. With that significant caveat, we have just 2 points we would like to focus on. And both could be well addressed simply with more communication between our community and the field.  

1) The forward push into trials for prevention without our community at the table. 

We are confident that our passionate advocacy over the last few years has helped lead to the unmistakable thundering demand for c9orf72 and other prevention trials. Those involved in designing and implementing these trials must include the impacted community in the decision-making process. Without our voice at the table, these trials risk not only not filling. They may not ask the correct research questions without the community’s input, risking the trial’s ability to have a relevant outcome. 

2)Why are we debating the worth of a whole class of people for their whole lives when the area of interest is a progressive, not fully penetrant, age-dependent set of diseases?  

As an organization of impacted people, we are concerned about statements that were made that classify an entire group of people and their lived human experience as less than others based solely on genes they inherited or families they live in. Labeling people as deficient and their families as “fractured” is not just hurtful but inaccurate as we know the lives of achievement and fulfillment with which many of us and our ancestors have lived. 

 

Like all humans, those at risk of genetic ALS and/or FTD have a rich tapestry of human existence. Like all humans, there are successes and failures intertwined with love and heartbreak. How can a gene or family history be but a single thread of this tapestry when our entire exposome is composed of innumerable factors? The fact that physical brain differences from controls exist in some fashion in presymptomatic C9orf72 is clear and well documented. It seems rational that whatever theory of disease needs proving can be done with these physical readings. Searching for cognitive issues in healthy people included in this analysis based solely on their possession of rare immutable characteristics seems likely to lead to unintended outcomes. 

 

In Basel, the issue first emerged in the Encals satellite meeting: 

 

Trinity College researchers reported a study of 149 relatives of ALS patients, of which 91 were in Familial ALS families, further narrowed to 41 in familial ALS families with C9 (the study did not report on the presence of C9 in the sporadic family members or the control group).  The results were presented as everyone in a C9 family is “not normal.” Unsaid was the clause in the paper that related these deficiencies were subtle and sub-clinical. The presented theory was that the C9 mutation alone was not to blame for the issues, but perhaps many causative genes were shared in the families. 

 

Following this came a talk on the recent C9 penetrance analysis, with the senior author from UMC Utrecht stating definitively that in the absence of knowledge of family history, no personalized risk assessment should be offered. Then, the author of the C9 penetrance paper and the author of the paper showing family member deficiencies began agreeing at the front of the room about the deficiencies present in c9 people and how we have “fractured” families due to this supposed deficit.   We express our gratitude to the prominent UK MND researcher from Oxford who spoke out on behalf of the genetic community in that session to warn against unfairly stigmatizing these families.  We did not comment at that moment. However, we are grateful we were present for this discussion.  If these are the comments made publicly, we can’t help but wonder what is said behind closed doors. And if the desire is to categorize us in this way, surely representatives of us should be in the room for it.

 

Later at the Symposium proper, in the session on surrogate markers, a Foundation Doctor, also from Oxford, candidly shared that while his research showed no cognitive impairment in C9 carriers, it was due to there not being a “quantifiable measure of craziness” available to him. In context, he implied these asymptomatic C9orf72 carriers were indeed crazy, but he could not record it with the validated measures at his disposal. He went on to say it is accepted among the scientific community that asymptomatic C9 carriers are different and overly gregarious in this context, proving in his eye they have cognitive impairment of some kind despite his study not finding it. 

 

How can a difference be accepted by the scientific community without any evidence? Is any inquiry into cognition in healthy members of a genetic minority okay when the supposed deficits they seek to establish are not contrary to successful and happy lives? What would the consent to participate in that kind of research look like, and is it being used now?

 

In a footnote to this, on behalf of the C9 genetic community, a young patient fellow with C9 ALS felt compelled to share his successful career and his happy family life to rebuke the picture painted of C9orf72 carriers by the Foundation Doctor. Why should anyone have to assert their dignity in a meeting supposedly about helping this same person? Our concerns are related to progressive paralysis and progressive dementia, not interrogations and invalidation of our lives and families.

In Closing

In closing, we are determined to ensure the research into our community is centered on the devastating issues that occur with progressive paralysis and dementia. We desire to bring together those studying us for a conversation on how we may untangle some of these knotty issues with the patient and research communities on equal footing. Please contact us at info@endthelegacy.org to start dialoguing with us if you have not already. 

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Reflections on the ALS MND Symposium 2 of 3 : Was there value in having End the Legacy attend?

End the Legacy was so pleased and honored to be able to send both our Executive Director, Jean Swidler, and one of our volunteer Board Members, Cassandra Haddad, to the Basel meetings this year. This was only possible due to our donors and sponsors, and we thank them profusely. A special shout to the Patient Fellows Program and their sponsors for selecting Cassandra for some support in the run-up to the meeting.  

 

We will provide three blog posts reflecting on the ALS MND Symposium and its lead-in meetings. The first blog covered exciting things we heard. This second post concerns itself with our self-evaluation on having 2 ETL patient advocates attend - was it worth it for our movement and our community? 

 

These notes are our subjective interpretation, we welcome others to share their evaluation of our presence. Pursuing progress can be messy, and we don’t mind being challenged! Drop us a line at info@endthelegacy.org 

Talks Presented

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  • We gave one talk during the ALS MND Alliance meeting. The topic was informing the gathered group of ALS Associations from around the world about End the Legacy’s support efforts. It was well received, and we had many positive conversations following it. The take home is that people in our position of being at genetic risk need support options, and the support ETL has provided has been beneficial. The slides can be viewed here

Posters Presented

  • We presented one poster at the ALS MND Symposium. The title was “Estimating the Size of the Asymptomatic Genetic ALS & FTD Community in the United States,” and it can be viewed here. We had excellent interactions with many, including esteemed clinicians and researchers. The take-home is that there are a lot of people in the US with these genes.  A short social media clip is below. 

Questions and Concerns Raised in formal Q&A 

  • In discussions of C9orf72 prevention trials, the 2022 ALLFTD/ GENFI paper that simulated trial designs for prevention was relied on to discuss the feasibility of such a thing. This paper really is a blockbuster, and we have spent the past two years trying to get the ALS field to grapple with it. Why would ALS researchers bother with an FTD paper? Well, the paper's findings were drawn from pooling the data of hundreds of genetic FTD carriers, mostly presymptomatically. This means the largest group of people in the study were presymptomatic C9orf72 carriers, and no one can tell if they will develop ALS or FTD or neither.  

 

Despite the data in the study coming from longitudinal studies with lots of natural history data, when simulating the trials, the paper does not assume any natural history data would be available. We knew only those who had looked at that paper very closely would know that (it took us reading it a few times to really grasp it). So, in the Q & A, we limited ourselves to querying that if there were patient natural history data leading into the trial, would it would lower the number of people needed? Dr Boxer confirmed this. This is imperative for the field to grapple with, as the practicalities of such approaches require using the smallest ( and least expensive) number of participants.

 

 One tangent on this, especially for NFL: presymptomatically NFL is only of value over time. One-time point results can be noisy and thus would require big groups in a trial if you are basing trial inclusion on that one-time look. NFL that is measured in an individual with a clear trendline over years would show much more concretely where a presymptomatic person is with the disease and what the value of any reduction in NFL that is sustained is. Nothing stops us from gathering NFL in preparation for trials from c9orf72 and other carriers in the many longitudinal studies or even in clinical care.

  • In a talk on clinical care for ALS, prominent Swedish ALS researcher Dr. Caroline Ingre of the Karolinska Institute in Sweden made firm points on the need for genetic testing and the need to diagnose as early as possible. In the Q&A, I paired the two issues together and asked her perspective on the monitoring of at-risk relatives - she enthusiastically agreed and spoke in detail of her vision for that. 

  • A great set of presentations about TDP-43 at the cellular level was a little high level for our non-scientist patient advocate representatives, but it did have a fantastic update to the talk Prof. Jenna Gregory gave for us ( and repeated callouts from her to focus on treating the disease early), some exciting work from Prof. Alicia Coyne of Johns Hopkins in IPSC derived neurons, and a fascinating talk from Prof. Magdalini Polymenidou on her findings also in IPSCs. Professor Polymenidou shared a lot about a protein called NPTX2, which she showed was a driver of TDP-43 pathology. For our patient advocates, NPTX2 rang a bell - just in November, a GENFI paper revealed that NPTX2 was a significant difference in plasma between symptomatic genetic FTD carriers and controls. Interestingly and mysteriously, NPTX2 was higher in the carriers' plasma but lower in the CSF. As the Professor did not mention this, I asked about it in the q and A. The professor shared that she was familiar with the paper, but it did not fit with her findings, and it was still unclear if what they measured was the same as what she was looking at. 

Networking and relationship-building 

  • Our team was running the entire time, deepening connections with those we already knew and forging new ones. Many thanks to all who were so kind with their time to share it with us. 

In Summary

  • The information we gathered at the meetings we are using as patient advocates to inform our community and clarify our asks on the field and of funders. The networking we did as individuals and as an organization was beneficial. The perspectives we shared helped ensure the discussions considered our community. 

  • We think for ourselves, our community, our organization, and for the best chance of cracking these diseases, having genetic ALS and FTD patient advocates generally, and End the Legacy in particular, involved in these meetings is a clear win.

Reflections on the ALS MND Symposium 1 of 3 : Exciting Things we Heard

End the Legacy was so pleased and honored to be able to send both our Executive Director, Jean Swidler, and one of our volunteer Board Members, Cassandra Haddad, to the Basel meetings this year. This was only possible due to our donors and sponsors, and we thank them profusely. 

 

We will provide three blog posts reflecting on the ALS MND Symposium and its lead-in meetings. The first blog sharing exciting things we heard is below.

 

These notes are our subjective interpretation of the presentations and posters we were able to see and certainly not reflective of all of the fantastic information presented at the Symposium. Therefore, we welcome others to share their points of excitement or even to question our interpretations. Pursuing progress can be messy, and we don’t mind being challenged! Drop us a line at info@endthelegacy.org to keep the conversation going. 

Exciting Developments for the Genetic ALS & FTD Community 

  • The promise of C9orf72 Repeat Length and Instability as avenues for discerning C9orf72 pathogenesis.

This is an area ripe for more exploration. End the Legacy will be following up with those who study our community (especially longitudinally) to ensure this avenue is not being overlooked. Information from presentations and posters from Dr. Hasse and Evan Udine, as noted below, as well as conversations with researchers, including Phillip McGolddirk, were particularly enlightening.

  • Dr. George Haase from France presented–, Mechanisms of C9orf72 Repeat Instability in Blood and Brain–at the ENCALS Satellite meeting 

  • Evan Udine from Mayo presented a poster, “Targeted long-read sequencing of C9orf72 in multiple human tissues”

  • Dr. Phillip McGolddirk presented a poster on C9orf72. We were also able to discuss his 2018 paper with a documented case of C9orf72 Mosaicism in an asymptomatic carrier who died without developing disease.

  • New Abilities to See TDP-43 Aggregation in more areas of body. 

  • More information on Gregory Lab’s ability to see TDP-43 issues in the nucleus of the cell and in more areas of the body than just the brain.

  • With the compelling theory that the cascade starts outside the brain, this area of research could allow for possible early detection and treatment of disease.

  • Professor Gregory gave a talk for us with earlier data a few months ago, so we were excited to see more information in this evolving area.

  • The highlighting of the ALS and FTD Overlap with a special Track

  • We celebrate the research community’s embracing the closeness of these two diseases (which has become boilerplate background for any journal article on the disease) with shared presentations from experts in both fields. 

  • A particularly noteworthy item was the drilling down on the use of models in some FTD field papers portraying a gradual rise in neurofilament in presymptomatic C9orf72 carriers. The sharing of charts showing individual marks that tracked the model hopefully tempers some of the criticisms going forward.

  • Ever finer detailing of various biomarker methods beyond NFL, including Lipid panels and neuroimaging.  

  • We appreciate the many efforts going on all over the world on this! 

  • Further defining the prodromal stages of ALS / FTD. 

  • The more formal definition of prodromal ALS/FTD from Dr. Benatar, with an acceptance it will be a composite of many domains. There were some especially thrilling simple statements as part of this for a firm threshold for full ALS conversion that would revolutionize care for those at risk. I will not name those bright lines here, but trust they will make their way to public discourse soon.

  • The highlighting of the importance of Genetic Testing and New Resources

  • The importance of genetics to forward progress in ALS was clear. 

  • We were happy to see not only the hard work of many being rightly celebrated and shared but also to witness the acknowledgment of not only our participation but also that of generations of our families in studies, including the ultimate sacrifice of brain donations.

  • Other significant developments shared in Basel included the new Genetic Testing Guidelines, services from the Les Turner ALS Foundation, and the new Light the Way project through Sano Genetics.

  • The Closing Plenary in its entirety

  • The importance of genetics and biomarkers to the field was fully displayed with the acknowledgment of the development of the FUS ASO therapy and the herculean effort to bring Neurofilaments to the bedside by many across the field. We share in thanks and wonder at the work of these teams. 

  • As advocates, we must constantly stress areas for improvement, and in FUS, it is clear with the knowledge that those with a strong family history of FUS ALS are not getting diagnosed in time to make it into the FUS trial more could be done to support those families.

  • The talk from Dr Harms on the further application of genetics in treatment and from Dr. Westeneng on ever-finer prediction models were excellent reminders of all that is possible now. 

We are Thankful for Wanda Smith, a Finalist For the 2023 RareVoice Awards

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Wanda Smith is a fierce advocate for the Genetic FTD and ALS community. We are filled with gratitude to have her on the team! She has been pushing for better for decades, working with many groups and, when needed, independently. She is a fantastic storyteller and organizer. We are glad the Everylife Foundation for Rare Diseases agreed, placing her in a select group of nominees for the 2023 State Advocacy Award.  Read more and see all the nominees here. 

This week, she was also recently profiled in her hometown paper in a great story to introduce more people to Genetic FTD. 

Just this month, she traveled to Washington,  meeting with the NIH, Congress, and the Milken Institute all in one trip! 

And we can't celebrate Wanda without remembering her powerful testimony to the FDA in our January Patient Listening Session

Cheers to you, Wanda! 

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