Let’s Start to Eradicate Familial ALS Today

The health care system can start to eradicate familial ALS today. The technology exists.

But is the world ready to accept the technology and utilize it to rid families of this devastating disease?

Debra Quinn first started feeling weakness in her right leg back in 2008. A year later she was formally given a diagnosis of ALS. ALS is not new to Debra; it has plagued her family for as long as she can remember. Her grandmother Dora, aunt Bonnie, father Bill, and sister Rhonda were all diagnosed with and died of ALS. It’s a tragic family history if you look at the genealogy. A genealogy is like a family tree that you can create on Ancestry.com.The Quinn family’s genealogy is no different than any other family with familial ALS—a history of a terminal illness going back many generations.

Unlike most diseases, ALS comes in two flavors.

Sporadic ALS is where the underlying genetic defect or environmental trigger is unclear for the most part, and the disease is not “passed” from generation to generation via mendelian genetic transmission. As much as 90% of ALS cases are sporadic in nature.

The Quinn family unfortunately has Familial ALS (FALS), which is inherited and passed down from generation to generation. For hundreds of years, genealogies have been created that “map” the inheritance of the disease from parent to child/ren. For many families the inheritance is very dominant, meaning one or more children will often inherit the genetic predisposition and eventually be diagnosed with ALS.

Debra Quinn has already suffered the initial horrors that afflict all ALS patients. She is in a wheelchair much of the time and can only walk a very short distance. Her family will soon install a stair lift to eliminate the excruciating task that climbing a flight of stairs has become for Debra. She has difficulty performing day-to-day activities the rest of us take for granted.

The further tragedy is that Debra is a mother with two children. Two young children —her son Dustin is 28 and her daughter Kristin is 29. Both children know about their family history of ALS. They know their family passes down a mutation in a gene called super oxide dismutase (SOD1).

In 2013, Dustin was tested and the results came back positive for the SOD1 mutation in their family. In 2014, Kristin was tested and results came back negative for mutations in the SOD1 gene. It’s an unsettling future for a beautiful family already struggling with the disease that afflicts their mother and one day may afflict Dustin but not Kristin.

It took decades to develop high throughput sequencing technologies that facilitated the sequencing of the first draft of the human genome. During this period, scientists utilized brut force mapping techniques to identify disease-causing genetic modifications. It shouldn’t be surprising that it took almost 200 hundreds years from the first description of Motor Neuron Disease by Charcot, to the mapping and sequencing of the first genetic mutation associated with ALS. A mutation in the gene encoding an enzyme super oxide dismutase 1(SOD1) that was published in Science in 1993,(Rosen) accounts for about 2% of all ALS cases.

As DNA sequencing technologies have developed at the rate of Moore’s Law, reducing the cost to sequence larger cohorts of patients, dozens more ALS-associated genes have been identified such as TDP43, C9ORF72,FUS1, and a host of others.

And as more and more families have been sequenced it has become apparent that for many of these genes there are multiple different mutations that could lead to ALS.

 

SOD1

 

 

 

 

 

 

 

fig1 legend

 

 

In the not too distant future, the scientific community will have identified all genes associated with familial forms of ALS.

Yet even with the accumulation of all this knowledge on the genetics of the disease, the ALS patient community still has no effective treatments for ALS. Not even for the small subset of ALS patients afflicted by mutations in SOD1 families like the Quinns. And their causative set of mutations was identified more than 20 years ago!

Let’s be honest, there are no effective treatments for patients with any of the other known genetic mutations or sporadic ALS either.

Are scientists, clinicians, companies, and other stakeholders working on targeted therapies to treat these specific “genetic subtypes” of ALS?

Of course.

There are multiple strategies in development to target many of these genetic forms of ALS. Some of the approaches rely on decades of progress with gene therapy or antisense RNA technologies.

Others are taking more traditional drug development approaches, by developing protein biologics targeting mutant forms of the proteins encoded by these genetic mutations.

And I am confident we will see proposals to use genetic editing tools (Zinc Finger Nucleases, Talens, and CRISPRs) to “fix” the genetic abnormalities that result in ALS.

However, given that none of these approaches are yet in clinical development for ALS, it could take a decade for an effective treatment to reach ALS patients via any of these approaches. And a different therapy will have to be developed for every gene affected and possibly different therapies for even subtypes of mutations within a gene family. This could take decades.

In my opinion, the loss of the most precious resource on the planet over this period of time is too much to waste. That precious resource is peoples’ lives and the impact it has on the loved ones around them. Families like Debra, Kristin, and Dustin Quinn.

But we can start the eradication of familial ALS today!

How?

Genetic screening coupled with in vitro fertilization (IVF)!

This is not a novel idea. The combination of these two technologies has already been applied in other serious genetic disease indications and has emerged into an entire new medical field called Pre-implantation Genetic Diagnosis (PGD).

PGD involves the in vitro fertilization of an oocyte with the partner’s sperm. Three days post fertilization, at the blastomere stage, a single cell is removed and a polymerase chain reaction is used to amplify the potentially mutated gene, such as SOD1 or TDP43. Only fertilized oocytes which do not contain the potential mutation are planted into the uterus. This results in offspring that no longer carry the genetic mutation associated with familial ALS and no longer risk passing the mutant gene onto their offspring later in life. This ends the cycle of familial ALS in their family lineage. Forever!

Now, before anyone gets too uncomfortable, I want to be clear. I am not talking about any type of genetic engineering. No stems cells. No modification of the genome. No changing of eye color.

In addition, if you think you are a carrier of a mutation who does not want to know, but wants to ensure your children do not have the mutation, you can choose a PGD procedure and ask not to be informed about your status.

Yet as I write this post, if you search in PubMed for IVF or PGD as a co-search term with “amyotrophic,” not a single article comes up!

This was incredibly puzzling to me. Why is there not a very active scientific and clinical strategy to systematically encourage familial ALS families to use PGD? A well-executed plan to implement PGD could cure ALS in 10% of the disease population. This would be a more successful outcome than many FDA-approved drugs.

IVF is a globally common medical procedure practiced to improve the quality of lives for women wanting children in situations where conception has proven challenging. It’s a procedure that exemplifies the incremental advances often required not only in medical procedures, but also in the development of almost all medical treatments.

In England in 1977, Leslie Brown underwent the first IVF procedure and had a healthy baby girl named Louise. Today, it is estimated that more than 60,000 successful IVFs occur in the U.S. annually and more than 5 million successful IVFs have occurred worldwide!

The average cost of IVF today is $15,000-$20,000 with a success rate of higher than 40% before the age of 35.

I should point out that IVF is no walk in the park physically or emotionally, especially for the female. However, we are talking about preventing ALS here. Need I say anything else?

In more than 300 other disease indications, the impact of PGD has been incredible. Take for example Amanda and Bradley Kalinsky. Amanda has the genetic mutation for Gerstmann-Straussler-Scheinker disease (GSS). Thanks to PGD, they have three healthy children free of GSS-causing genetic mutations.

Amanda’s children will live healthy lives and never have to worry about passing on the mutant gene to their own children, even though their mother will eventually suffer through an illness not unlike ALS that may take her life in about five years from symptom onset.

So why is PGD not the hottest topic around the water cooler at annual ALS meetings? It certainly can’t be the cost nor the success rate. A little digging into related indications may shed some light on this puzzling question.

A survey of general practitioners, neurologists, and psychiatrists was conducted asking if they would recommend PGD to a patient with Huntington’s Disease (HD), a patient with Cystic Fibrosis (CF), or a patient seeking a non-lethal elective test to choose the gender of offspring. The results are surprising.

Out of a survey of 163 neurologists and 372 psychiatrists, only 2.9% had discussed PGD with patients carrying genetic disorders. Yet 24.9% of neurologists and 31.9% of psychiatrists had discussed prenatal genetic testing of fetuses with patients carrying genetic disorders (Klitzman,2013; Klitzman, 2014).

However, when asked specifically if they would suggest PGD to patients with Huntington’s Disease, Cystic Fibrosis, or those seeking selective gender testing, the majority of physicians responded that “Yes” they would discuss PGD with their patients positive for HD and CF, but the procedure was not as well accepted for gender selection. These data suggest that physicians who are specialists have a higher likelihood of being familiar with PGD and are willing to discuss it with their patients who may benefit and consider PGD.

HD data

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

hd legend

Based on these data, it’s not a huge leap of faith to conclude that ALS neurologists or ALS patients are either uncomfortable or unclear on the possible application of PGD for familial ALS patients in their clinic, and more importantly are unfamiliar with the demonstrated success rates in diseases like HD.

The success of the process in HD is actually incredible even without widespread knowledge and discussion of its potential application in devastating neurological diseases.

Data from a multicenter European consortium in HD cites:

“In total, 257 couples had started workup and 174 couples (70% direct testing, 30% exclusion testing) completed at least one PGD cycle. In total, 389 cycles continued to oocyte retrieval (OR). The delivery rates per OR were 19.8%, and per embryo transfer 24.8%, resulting in 77 deliveries and the birth of 90 children.” (Rij, 2012)

The next generation of these families will be rid of HD forever. Can one imagine the impact this could have on ALS families? To rid familial ALS in only a handful of families would be the biggest outcome in ALS since discovering the SOD1 gene mutation in 1993.

Based on a recent report published by The Muscular Dystrophy Association, the annual cost to care for ALS patients in the U.S. is almost $1.1 billion dollars (Larkindale, 2014). If PGD could prevent even a fraction of familial ALS cases it would save the economy billions of dollars in the next few generations.

But is the world ready?

Obviously I am thinking about the ethical concerns regarding PGD. There have been dozens of studies and follow-up reports on the discussion and use of PGD with patients. These studies have tried to address the justification in settings that include highly penetrant childhood diseases, highly penetrant adult onset diseases, diseases where the genetic susceptibility is not as clear, as well as the selection of traits not associated with disease.

Based on these studies it is clear that the use of PGD for selection of non-disease associated traits is not viewed as ethical by the medical community or almost any other community for that matter.

For diseases where the genetic trait may never result in disease (low penetrance), it is very debatable on when to recommend or discuss PGD with a patient.

But for highly penetrant childhood and adult disease where there is no effective treatment, it is highly accepted by the medical community.

One such report from the Ethics Committee of the American Society for Reproductive Medicine concludes:

  • “Preimplantation genetic diagnosis (PGD) for adult-onset conditions is ethically justifiable when the conditions are serious and when there are no known interventions for the conditions or the available interventions are either inadequately effective or significantly burdensome. “

If this isn’t the definition of ALS I don’t know what is.

The ethical and religious discussions on the appropriate implementation of PGD are clearly beyond the scope of this discussion and there is probably no clear cut answer. It will be up to each individual parent, family, and their beliefs on the lesser of two evils:

Passing a devastating disease with no effective treatment to your children or the moral obligation to not destroy a fertilized egg with a known genetic mutation.

A possible billion-dollar question you may ask at this point:“Steve, if you or your wife had ALS, would you use PGD?”

It’s a challenging question since we don’t have ALS in my family. But I did have four uncles on my father’ side die in their 40s of myocardial infarctions due to arterial blockage. My father is a healthy 82 year-old. However, in 2010 I had a massive arterial blockage with no signs before the event. I almost died. I would have died if it hadn’t been for another “early morning” TDI scientist who was in the lab at 7 a.m. that June morning in 2010. His immediate CPR and being only 5 minutes from Mass General Hospital saved my life. I have two young, beautiful daughters. I don’t know if I passed my families’ susceptibility to cardiovascular disease to my children. But I obviously pray not. If I could have screened for this susceptibility by PGD testing I would have done it in a microsecond. No second thought required.

I encourage every neurologist to educate familial ALS families about PGD as an option. I encourage every ALS organization to help fund this strategy. We could all share in the commitment to end familial ALS while we continue the process of finding effective treatments for all ALS patients.

Today, let’s start work to end Familial ALS! No, seriously, today…

The community can help educate and offer support and guidance for families with SOD1, TDP43, C9ORF72, and any other known familial mutations.

Eradication doesn’t happen overnight for any disease, so let’s get started on ending familial ALS right now.

 

Steve

12 thoughts on “Let’s Start to Eradicate Familial ALS Today

  1. Thank you for the post. You forgot to mention that even though PGD is an important and helpful procedure, it is often not covered by health insurance, while IVF is. For many people, the cost associated with PGD is prohibitive. Moreover, would you expect that there is still a risk for the disease due to error or maybe unknown mutations that could be missed?

  2. Hi eeke
    Both good points. The coverage for PGD varies from state to state and insurance plan to insurance plan. The cost is not insurmountable at $20,000-$25,000 but I get your point. If the familial ALS patients out there felt strongly that they wanted to start this process I am sure “we” the ALS community could find an economic solution for those who can;t afford to pursue PGD. For your second point we all have a chance of “inserting” predispositions to various disease indications from cancer, to cardiovascular disease, to yes ALS. However for a family where we know the genetic mutation that causes ALS in that family we can at least utilize PGD to correct that mutation in their offspring and that should end ALS in that family lineage.

    Steve

  3. I am Debra Quinn’s mother and I and happy to see that you, Steve, are helping to stop familiar ALS, as I have witnessed and taken care of the 5 family members that have died of ALS. Thank you and keep finding a cure.

  4. What about FALS of an unidentified gene? My mother, aunt and grandmother all passed away from ALS. My aunt had genetic testing which came back negative but she still developed ALS and passed away.

    Also, what can be done, besides raising funds and attending events, to help find a cure?

    1. Hi Debra
      For families with familiar ALS where the gene has not been discovered we need to work harder to identify the mutation associated with your family. Have you and multiple family member given DNA samples for analysis at an ALS clinic to identify the gene?
      Outside of raising awareness and funds make sure you and your extended family follow up on my comment above. We need the DNA samples to find the gene.
      Steve

    2. Thats the million dollar question. Being new to the ALS neighborhood, I was shocked to read that the NIH only spends $34 million a year on ALS research/grants.

      Additionally, I would think ALS needs its own lobby, more than what exists now. Look how AIDS went from a little known disease attributed to a small subset of the population to a massive lobbying campaign that garners more money than larger diseases like Alzheimers (as part of gov spending/research).

      ALS also needs lowered barriers to product entry. If we are looking to industry to help in the fight, they should have a chance to contribute to the fight without spending $30 mil for one stage of a multi stage trial. (Imagine what could happen if a small company had a legit product/approach that could be applied without selling their soul to a Venture Capital group!!)

      In short, there is a need for more resources, more researchers, more opportunties for companies to help the fight. I would imagine lobbying the gov to spend on research would be great first step.

      Just my two cents.

  5. Steve,
    My mother was a patient at the UCSF ALS clinic. She passed away 13 1/2 years ago but it seems they would have that dna sample.

    As far as myself and two siblings none of us so far are showing symptoms so would we still want to give a sample? I want to do whatever it takes to help in the research area. Thank you for your time! Debra

  6. Now you have heard of a case of PGD for familial ALS!
    My mother died of ALS in 2007 and now my sister is suffering from it. In September 2013 I tested positive for c9orf72 and on February 1 I gave birth to beautiful twin girls through PGD.
    To the point of the cost, I did it at Shaarei Tzedek Hospital in Jerusalem where they have a fund that covers almost the entire cost of PGD!
    We are very grateful!

    1. Hi Hindy,
      Thank you so much for responding to Steve’s article. I have recently found out our family is positive for the SOD1 gene. I have a daughter who very much wants children along with a niece the same. My question is did you have to travel to Jerusalem or were the samples sent there??

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  8. My husbands family refuses to get tested. My brother in law who just passed away refused to get tested. I hate them all. I hate them for their ignorance. My husband has a 50% chance and he refuses to get tested. My children at risk and I can’t do anything. I get depressed everyday!! Help!!!! 206-637-9717 Jen

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