First thoughts reading up on this pretty cool bit of detective work: Since this is a deficiency in production of Pngase F, I'm not sure a simple injection of Pngase F is going to work. I'd guess you'd need to target Pngase F into the ER to kick start the proper clean-up process, and the human form (http://www.uniprot.org/uniprot/Q96IV0) is different to the recombinant form that you can get synthesised (http://www.uniprot.org/uniprot/P21163). I'm not really sure how native Pngase-F is regulated!
That said - I'm about to start work on very similar work now (also in the area of glycobiology). With dirt cheap exome sequencing, we're going to get a whole bunch of really interesting leads from the data. This means that the follow-up research into the mechanism behind the action of the gene can be more likely to yield results.
Right now, I see the bottle neck in this whole process being the actual experimental analysis of these mutations. Once we solve how to scale up this hard work successfully, we can start looking at curing these incredibly rare diseases.
Wow, just wow. A parent will go to any limit for their child but that was one of the most truly detailed descriptions I've ever heard of diagnosing a new genetic condition. Thank you for being willing to share it.
I genuinely hope you find a solution, will you keep updating on the progress?
I've just finished the article and I must say, my feelings are mixed. I'm reading along and it reads like an epic tale where the hero will surely win in the end, it's both mysterious and exciting. I got caught very caught up, wondering what you were going to try next. (Note: It's never Lupus.) But then I would come out of my Dr. House fantasies and realize, this is real. This is your son. And my heart would break for him and your family.
Thank you for sharing, in great detail, the story of your struggle and I hope that in the end it is a story with a wonderful outcome.
Either way, it certainly a story of heroism.
Keep us updated.
Just as a useful data point, exome sequencing is now in the sub-$1000 range.[1] There will definitely be a shortage of skilled people able to interpret the data and find mutations like the one mentioned in this article as the sequencing price point continues to drop.
Thanks so much for the fascinating and emotionally stirring article. I will definitely be passing this on to others I know.
The thing I kept thinking during the article is, "Is there something that I, as a programmer, can do to help people like Bertrand?"
Is there some way that we programmers could use our talent to augment or advance existing technology in this area? I realize that the science involved here is non-trivial, but it seems like a really fascinating subject area to get involved in. Perhaps I just need to bear down and brush up on my biology.
I just saw this thread. If you are a computer scientist interested in making a difference on problems like this, consider joining Counsyl:
https://www.counsyl.com/about/jobs
There are a lot of Hacker News people working here. And while it's sadly not in time for Matt and his son, we are launching a version 2.0 assay soon that should save couples in the future from ever going through something like this again.
As not a parent I will not even pretend to relate with what you are going through. But this is one of the most moving and amazing things I have ever read. A book could not contain the details of just how incredible your story is.
Science does work. The confluence of technologies - search, websites,email, computers, bioinformatics, pharmacology, medical technology (and if hirenj's* advice proves useful then forums, it should be at the top), such that someone can identify, diagnose, commision/customize medication and possibly treat a completely new disease in the span of a few years..The future really is here. An ode to the open source technologies and not so open research that made this possible. Of course it is worth pointing out that the skill required to research, evaluate possible leads, try then untry possible treatments, contact and manage communication with the researchers is also not to be underestimated.
Even though his disease is life-threatening, his seizures are worsening and he continues to lose white matter, we'll need to prove that it's safe.
A good argument could be made, that bureaucratic regulators who get nothing if your son is cured, but could get in trouble if something they allow hurts him even more, are partly responsible for slowly killing him.
For individuals in a dire enough state, a more intelligent set of regulations could be something like if enough well known and respected doctors agree this is worth trying, go for it. But bureaucracies are rarely intelligent.
It's just that most of the time bureaucratic involvement creates frustration, costs money, takes time, kills economic growth, etc.
But when it comes to life threatening disease and potential cures, bureaucratic involvement might actually cost lives. Because it is not optimizing saving lives, it is optimizing "safety" over lives, because it is actually optimizing bureaucratic ass covering.
First i wish to say good luck to your family, i hope you can find something.
Ok here's a guess:
Assuming missing deglycosylation and N-Glycanase's involvement in ERAD (endoplasmic-reticulum-associated protein degradation), perhaps there is amyloid fibril formation due to faulty protein degradation?
If yes, you may want to try out green tea or some kind of extract from it, in particular Epigallocatechin gallate sounds interesting. Besides antioxidant activity (which i guess could help with excessive glycosylation causing an oxidative environment), EGCG is thought to help in various diseases where protein aggregation plays a role. You can find lots of papers on this if you search for "epigallocatechin gallate amyloid" on Google scholar. I'm not a doctor, just a grad student (thanks for the guide!), so you should check with one first if that makes sense.
I wonder if another jurisdiction would be more willing to let you try the enzyme? The FDA is famously slow in granting approval.
"Unfortunately, we can't just order a batch and inject Bertrand.
We need to get FDA approval, and we'll need Genzyme's cooperation.
Even though his disease is life-threatening, his seizures are worsening and he continues to lose white matter, we'll need to prove that it's safe."
It's shit like this that makes me hate the FDA.
Every time I watch an episode of House or read a story like this I think "Why isn't there an expert system for diagnostics". The notion of a person being able to manage such vasts amount of knowledge seems ridiculous and cost-ineffective.
If you could enter a bunch of positive and negative statements together with various medical records, and have the computer being able to ask additional queries, it seems a good system would be able to narrow down a list substantially. It would also side-step a lot of cognitive problems we humans face.
Now, I'm sure there are systems like this but they probably just aren't sophisticated , widespread enough or don't have large enough database. Or have they simply not yet reached widespread use because they cost too much, what's holding them back?
* Found this article on the topic: http://www.informationweek.com/news/healthcare/clinical-syst...
Here is wonderful explanation of "DNA seen through the eyes of a coder". It makes Intercal seem sane.
Inspiring and amazing.
A few impressions:
Although the author removes much of the emotion of the story, I still sense the undercurrent.
The future is going to be strange. Way more complicated than science fiction, our guidestar for so long, led us to believe.
I hope that when the time comes, I will be able to measure up to the author as a person, as a parent, etc.
When a mutation occurs, there are four possibilities for
the mutant...
You could say there's three types of mutations: genes that do not affect evolutionary fitness, genes that increase fitness (faster running, better eyesight, etc) and genes that decrease fitness. (chromosomal trisomy, which either instantly kills the host, or greatly reduce its fitness)
And, of course, fitness is relative. Heterozygous HbgS makes you resistant to malaria, homozygous HbgS gives you sickle cell anemia. Being tall adds fitness in a calorie-rich environment, but reduces it when food is comparatively expensive. Etc etc etc.
But you probably won't want to double the length of the article, by going into even greater depth on genetics.
Where is the line drawn between medical research and healthcare for your son? In other words, what on earth does this cost?
Kudos to the mother and father for not giving up and to figure out the medical mystery, it read like a House episode with the various diagnoses then you realize that it's real life, not a TV plot. I truly believe that future technological advancements have an obligation to serve humankind for the better and that real progress is made though breakthrough medical and scientific breakthroughs.
That was an awesome article. I couldn't finish it as it was too long, but the technical detail in it was really awesome. Just the biology and relating it to computer nomenclature was really interesting. I think what's really amazing about blogging about the topic is you've created a brain dump of your most of your knowledge on the subject. Everyone who reads that is now much more versed than most medical staff anyone might run into, but because it exists they can educate themselves on your child's history as well. You've created a piece of fairly rare scientific information that exists in the public free for comment. That's not something we'd have done even 10 years ago.
I have a question for Matt, if you are still here. How did you get in touch with Genzyme? What do they have to gain by helping you? Developing a recombinant therapeutic drug is an exceedingly expensive and technically-difficult undertaking. Why are they developing a treatment for a condition for which the potential market size is one single patient?
This is extremely interesting.
Whats the best case scenario for your son? Suppose everything works out perfectly with the treatment/therapy, is it expected he'll start to develop normally?
Fantastic read and story. Thanks for writing it and best wishes to you all.
One of my best friends recently had a son with a rare bowel disorder, requiring a full bowel transplant, and he's been saying that every day they are educating the doctors on what to do, up at all hours calling all different countries. They've been by his side in hospital since his birth, but it's incredible to see the pics of that baby laughing like a champion!
Thank you for posting this, Matt.
It's amazing that you were able to learn so much about his condition. It gives me hope for the future of medicine, because I sometimes feel like we are still in the dark ages.
I hope you have success with the treatments.
I honestly appreciated this read. To me this is "Genes for Dummies". Exactly what I need. I tried reading about genetics on wikipedia once but I got lost in all the details and thus failed to see the bigger picture.
This is incredibly long and seems like it will probably never tell me the info that interests me. As I understand it, in most genetic disorders, all of the problems are rooted in a miscoded protein. I am wondering if it has been determined which protein is miscoded and what it does?
Edit: I have managed to read the whole thing and, no, it doesn't answer my question. The closest I get is that some enzyme is not being produced. For me, that is insufficient info. Moving on to the blog but would still be happy to get an answer here. Thanks!
Wow this was crazy interesting. My thoughts are with his parents. I learned a ton just reading the article.
I stongly urge you to look into Ataluren (also referred to as PTC124, in the literature). It has a number of advantages over gentamicin and may be a better long term solution. It is currently in clinical trials for a number of premature termination codon (PTC) diseases. Check out this paper: http://ajrccm.atsjournals.org/content/182/10/1262.long
I have a son that was born prematurely at 7 months and the doctors weren't too optimistic about his chances of survival or about his long-term health. And we've had problems with him, like manifestations of Lyle's syndrome. He's fine and healthy now, but I'm afraid the battle ain't over.
I know what the author goes through and it's hearth breaking to see your own child suffer. It's the worst kind of pain imaginable.
This was a fascinating and inspiring read. It's astounding to consider the granularity with which we can debug the software of human biology, even if it requires incredible resources. That protein visualization is dumbfounding, but it feels comforting to know that human source code isn't completely intractable.
>>Laughter
The morning after Bertrand was weaned from ACTH and the ketogenic diet, we heard something we hadn't heard before: laughter.
Still bloated and near death, in his hospital bed, he was laughing.
Everytime the laugh track came on the hospital TV, he chipped in.
It was the most direct sign of Bertrand's humanity we had ever seen.
Cristina was in tears.
As some one who is not married, has no friends, doesn't understand women and kids, Spends whole day in front of a computer. I hope someday I will have a family to truly understand what you are going through.
I hope and pray your boy recovers. The conviction and faith in which you write has me convinced that being parent is a sublime emotion which every human being must experience.
I have two healthy children (0 and 3) and can't even begin to relate with what you've gone through and are going through. It sounds like the worst kind of hell mixed with small moments of the very best life has to offer.
This reminds me so much of the story of Lorenzo's Oil.
Your story brought tears in my eyes. Thanks for sharing with us all. Surely someone or the other will benefit from your findings. Also, salute to your patience, and the hope that kept you on. I have never been outside India, but if I ever came to US, I will surely meet you.
Thanks Matt. You are amazing. period.
why not just perform euthanasia and focus your energy into raising the healthy child?
Hi matt, I used to work on MPS 3a and did some studies on non-viral gene therapy to treat it in the central nervous system.
Do you know if the enzyme crosses the blood brain barrier?
It was a few years ago, but feel free to ask questions.
Reminds me of the Odone story as dramatize in the film "Lorenzo's Oil"
If one's condition is a usual one then the doctor is the best approach. Similar symptoms can appear in meningitits or west nile virus (arbitrary example) but the doctor knows how many people he treated in the area recently and can quickly come up with an answer. Others can't have sense of analogy and size. It's the same thing as reading posts regarding NOSQL databases where the best way to learn the caveats is to wait a little for the "why it was a bad idea for us" posts. If you have some rare condition and you have reached to the conclusion that you can't find what it is, a solution is to try and improve on the symptoms by using simple statistics or machine learning. Here is a simple tutorial of machine learning with WEKA where the guy uses data from his heart condition: http://www.youtube.com/watch?v=m7kpIBGEdkI If you have a rare condition and you found what it is, then be prepared yourself. Unfortunately reproducibility in scientific experiments has problems http://blog.scienceexchange.com/2012/04/the-need-for-reprodu... so it is better to use books that come from established groups or organizations. What if research was absolutely trustworthy? For more daily things you can read forever (try putting "cognitive" and "daily" to pubmed http://www.ncbi.nlm.nih.gov/pubmed to see thousands of post relating to cognitive function). It's too much work, so stick to what's important for you. If you have some rare condition and you have reached to the conclusion that you can't find what it is, a solution is to try and improve on the symptoms by using simple statistics or machine learning. Here is a simple tutorial of machine learning with WEKA where the guy uses data from his heart condition: http://www.youtube.com/watch?v=m7kpIBGEdkI If you have a rare condition and you found what it is, then be prepared yourself. Unfortunately reproducibility in scientific experiments has problems http://blog.scienceexchange.com/2012/04/the-need-for-reprodu... so it is better to use books that come from established groups or organizations. What if research was absolutely trustworthy? For more daily things you can read forever (try putting "cognitive" and "daily" to pubmed http://www.ncbi.nlm.nih.gov/pubmed to see thousands of post relating to brain function). It's too much work, so stick to what's important for you.
Seriously, one of the best stories I have read on the web. Thank you for sharing this with us all...and hoping for better news in the future!
I used to follow Matt's blog. Reading the title of this post really upset me.
Matt,
I hope you are able to take at least some comfort from actually knowing the cause of your son's illness. Some people aren't so lucky.
I had my own medical struggle while in the middle of grad school. Mid October a few years ago, I contracted a rather nasty respiratory infection. Among other things, I was severely fatigued and needed to sleep for extended amounts of time (think 12+ hours a day). The excessive sleeping didn't worry me while I was busy hacking and coughing, but when the respiratory symptoms had gone away a couple weeks later, I was still left with the extreme fatigue and hypersomnia.
Normally, I'm not one to run to a doctor at the slightest sign of any illness, but I began to get worried a week or so after the acute infection passed and I was still sleeping a minimum of 12+ hours a day. (I should emphasize, too, this really was a minimum, not an average -- I'd typically wake up around 8 am, go to class and do other things until around 2 or 3, come home and fall asleep around 4 PM and wake up and do it again the next day. One weekend, I think I was awake for a total of about 8 hours over the two days.)
I went through the usual struggle anyone who has anything that's at least mildly rare goes through, and, after visiting a sleep neurologist, I got my diagnosis: post-infectious idiopathic hypersomnia. I then knew this was a problem that was going to take months or years to resolve, and, for a while, I thought my life was effectively over.
But, the real kick in the teeth was that word, "idiopathic." There's a great line on an episode of House where one of the fellows suggests a diagnosis of idiopathic something-or-other, and House responds "'idiopathic,' from the Latin meaning we're idiots because we can't figure it out." So, there I was, with a diagnosis that amounted to "you sleep a lot and we don't know why," and the only treatment available was basically stimulants to treat the symptoms (which didn't work well at all -- I slept less, but I was walking around like a zombie by early afternoon every day).
Looking back, I consider myself lucky that it happened while I was in school, since I could have easily found myself unemployed and broke if I were in less flexible circumstances at the time. I'm also quite lucky that it resolved itself within about 9 months. I effectively lost a semester of grad school that I had to make up later, but I recovered, and it should never recur.
I don't know if what I had is what would be considered a "rare" disease by the strict definition, but it's rare enough that your average primary care physician might not ever see a case in his or her life, and a sleep specialist might see a handful. It's rare enough that there don't seem to be any studies or research available on the condition, on top of the obvious difficulties of studying people who effectively have to sleep 1/2-3/4 of the day.
So, back to my original point: my best wishes to you and your son, of course, but please take comfort in the fact you know exactly what is wrong.
Why on Earth would you conceive another child with the risks involved here?
There are thousands of unwanted children that would benefit from having such a thoughtful and dedicated set of parents.
Is it pure egocentrism that keeps high-risk parents from adopting?
As a father with a son with severe autism (not to suggest it's equivalent to Bertrand's condition), there is an important lesson here that might not be apparent at first read.
Before you have children, understand that it's for the rest of your life. Really understand the impact. Your concerns are second, beyond anything you've ever understood. Marriage is about compromise. Children, however, afford no such privilege.
Make no mistake, it's worth it. Looking into those eyes, seeing that smile. Getting your first smile, laugh, hug, or kiss. Nothing compares.
Wow. BTW, any couple planning a pregnancy soon should get tested for Mendelian carriers - eg using the Counsyl or Natera test. These tests won't catch a de novo mutation, of course. But they'll catch a lot of other horrible, horrible crap...
So there was a paternity test, right? I'm assuming there was and it just wasn't mentioned in the write up.
The author states with authority that he is the father, but doesn't mention the tests confirming it whereas every other finding is linked to the tests involved.
Please don't tell me, in an article praising science, that this was left to faith or trust or whatever.
That guy knows how to get attention... Science shows that human DNA is degenerating. We are not getting "better and better" as some priests would say.
Colloidal silver will probably help as well.
It pays to become an expert in your own (or your family members') medical conditions, because you'll quickly become more of an expert than 99% of the doctors you will rely on for care. It helps when they all ask the same dumb questions, which they will do. If your condition is mildly rare, you'll notice when you see a new doctor, that their knowledge will be limited to what you found out in the first hour of internet research on the condition, unless they are a specialist on that particular condition.
I have a slightly rare genetic condition, and I've only met 2 doctors who know more than I do, and that's because they do active research on the exact condition and have authored or co-authored multiple research articles on it.