15 ms·

Hunting Down My Son's Killer

1139 points by synacksynack 14y ago

euroclydon 14y ago
Where is the line drawn between medical research and healthcare for your son? In other words, what on earth does this cost?
- mattmight 14y ago
  Remarkably, the cost of the exomic sequencing is a small fraction of what we spent on individual genetic tests over three years. Exomic sequencing is so efficient that it will likely replace testing for individual genetic disorders one-by-one in the near future. In the pilot study at Duke, they diagnosed 6 of the 12 children, each of whom had an ordeal very much like my son. In the rare disease community, this technique is unparalleled.
  - Stwerp 14y ago
    Your article is amazing. I was moved to tears many times reading through this. (My wife is 6 months pregnant right now.) Just wow. Good luck with it all, and the fact that Victoria does not have the same diagnosis is just amazing! I'm glad Duke could help and your story is beautiful and inspiring. I don't know what to say, just, thank you so much for writing this. I will certainly be passing this on to some friends.
    - mattmight 14y ago
      Thanks for sharing! Becoming a parent is an awesome experience--one I wouldn't trade for anything. I can still remember time freezing the moment each of my kids was born. I wish you, your wife and your little one the best.
  - pimentel 14y ago
    When there's scientific interest in the case, will a university charge for exams and tests? What about research clinics? When does an institution say "from now on, we'll take care of costs"?
  - GFischer 14y ago
    Hopefully, sharing this information and your story will lead to more informed doctors recommending this technique. Thank you for an inspiring story and your exemplary perseverance.
- deleted 14y ago
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lmm 14y ago
I wonder if another jurisdiction would be more willing to let you try the enzyme? The FDA is famously slow in granting approval.
- mattmight 14y ago
  The FDA has a special protocol in place for rare cases like my son. If we get everything done properly, approval could be granted within 30 days. But, before we can apply to the FDA, we have to get Genzyme to agree to make a variant suitable for human use. My wife found studies where it was beneficial to mice that had chlamydia and pneumonia, so we know there's a form out that that's been used on mammals.
  - tincholio 14y ago
    Dude, as a recently minted father, I can't begin to grasp what you guys are going through. I just want to wish you the best of lucks with this. On a completely unrelated - and irrelevant - note, I find your writings fascinating.
moldbug 14y ago
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...
tonetheman 14y ago
Wow this was crazy interesting. My thoughts are with his parents. I learned a ton just reading the article.
jasonlotito 14y ago
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.
- edwinnathaniel 14y ago
  This important lesson can only be detected by parents. People with no children won't ever understand this no matter how hard they try/re-read the articles many times. Once the infant is out of the womb, everything change instantly without any interference by anyone, anybody, or anything else. The child will change your brain, your mind, your heart, your lifestyle, and your future at that moment of birth. The child IS that BIG. I cannot say how much I respect parents, even more for those who have children with special needs. Life is really beautiful isn't it? (^_^).
  - deleted 14y ago
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  - Havoc 14y ago
    >People with no children won't ever understand this no matter how hard they try/re-read the articles many times. Halfway through the article I started re-evaluating whether I still want kids. Not sure I could carry that burden. [] Though that is probably more on a logical level than feeling the raw emotion that a parent would - which is probably what you were getting at. More accurately I know I could out of necessity carry that burden. Its everything else in life which would be more difficult. Kinda like a warrior without family at home has the luxury of adopting a devil-may-care attitude to combat - once others depend on him that isn't possible anymore.
    - edwinnathaniel 14y ago
nicholassmith 14y ago
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?
- mattmight 14y ago
  Thanks for the kind words! My wife updates his progress regularly here: http://overcomingmovementdisorder.blogspot.com/ http://overcomingmovementdisorder.blogspot.com/ The blog is oddly titled now, since we named it back when he was 8 months old.
djb_hackernews 14y ago
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?
- mattmight 14y ago
  Sadly, since he's four and a half, "normal" is probably too much to expect. But, if we can stop the seizures, he might be able to start learning. He advanced very rapidly during the two month break from seizures that he got from ACTH. If we stop them soon, there's a good chance he might be able to walk and talk some day. Regardless of how far he develops, he'll be much happier than he is now.
aarondf 14y ago
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.
apaprocki 14y ago
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. [1] https://www.23andme.com/exome/ https://www.23andme.com/exome/
- ykaranfil 14y ago
  Just ordered a kit from 23andme
hirenj 14y ago
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 http://www.uniprot.org/uniprot/Q96IV0) is different to the recombinant form that you can get synthesised (http://www.uniprot.org/uniprot/P21163 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.
- Dn_Ab 14y ago
  In what way is experimental analysis of such mutations a bottleneck?
  - hirenj 14y ago
    Well, once you pinpoint a potential mutation on a gene - that gives you a starting point into the pathway that could be possibly producing this particular disease. From there, it's sort of like clicking outwards from a wikipedia page, except instead of wiki pages, its related genes. Every one you go to, you read and find out what people know about it. You then start to form a picture in your head as to what the mechanisms of action are for this particular gene - what it does and how it is regulated. From there, you build your model for how the gene works, and do some knock-outs / knock-ins, test it in various cell lines, verify the kinetics, try to find out the 3D structure. Really, anything you can do to get a handle on how this actually works in the system. It's quite normal for people to spend their entire PhD studying the mechanism of action for a single gene!
    - 14y ago
sneak 14y ago
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?
- drivebyacct2 14y ago
  >Is it pure egocentrism that keeps high-risk parents from adopting? If it's not, I'd love to know what it is. Aww, downvotes from selfish people. Love doesn't require blood.
  - lostlogin 14y ago
    Cost, complexity, difficulty, perceives trouble bonding, how?, risks, issues with the child's family. There are some.
- mattmight 14y ago
  When we decided to have a second child, we'd ruled out every existing disorder that could possibly explain him. After consultation with our medical team, they concurred that a de novo mutation for Bertrand was a strong possibility. And, in truth, the conditional probability of de novo mutation for Bertrand was much higher than what actually happened--two independent mutations in the same gene colliding with one another. If we had known the probability for Victoria was 1/4, we never would have gotten pregnant. Ignorance was bliss.
- mcmatterson 14y ago
  As a parent of a child who was born with a near-fatal congenital disorder (malignant sacrococcygeal teratoma), I can attest that the decision to try for #2 is a difficult one that we're still wrestling with. On the one hand ours was a one-off event and subsequent kids should be fine. We've always wanted two, and it's been such a wonderful experience that we want more of. So there's that. On the other hand, the months of treatment after diagnosis were the most emotionally draining experience we've ever gone through, and we don't know if we have it in us to go for number two. We're still in the early days (diagnosis + 9 months, all signs pointing to cured) so this may change, but active parenting causes healing and recovery to happen much slower. My wife (and her brother) are also both adopted, so we're well aware of the dynamics involved there. We've said since before we started trying for kids that we weren't going to beat ourselves up if we'd had problems conceiving (we gave ourselves nine months of trying before we'd look at adoption. As it turns out it only took us one). One could probably argue that the truly optimal thing to do would have been to forego trying biologically at all and to jump right into adoption, but that didn't feel right either. All of which is to say that I don't think it's egocentricity per se, but a natural desire to at least try and see your genes successfully expressed in the world. While that's not ideal from a rational perspective, I don't think you can go too far down that line of thinking without verging into eugenics.
vectorpush 14y ago
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.
fghh45sdfhr3 14y ago
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.
- ars 14y ago
  The FDA has a concept of http://en.wikipedia.org/wiki/Compassionate_use http://en.wikipedia.org/wiki/Compassionate_use which would allow them to use the drug even without any proof.
  - Symmetry 14y ago
    Much as I might complain about the FDA sometimes, things have changed for the better since the days when thousands of people were dying for lack of treatments that had been approved in most European states a decade ago.
  - asdf25 14y ago
    Thanks for answering the whole issue I came here to complain about, always a nice change to see laws functioning semi-rationally.
- waffle_ss 14y ago
  I find this to be a very interesting idea, although I'm still a little dubious about it. I first heard it from an interview with famous Libertarian [Milton Friedman][1] (whom I adore) in his twilight years. The self-regulating mechanism of a system like this would be tort law, allowing consumers to sue companies if they haven't done adequate research and testing on their drugs before selling them. I have mixed feelings about this because I have a hard time picturing a class action suit being able to adequately take on a large pharmaceutical company with its own dedicated legal department. [1]: http://www.youtube.com/watch?v=KUDV0YII6lk&t=4m10s http://www.youtube.com/watch?v=KUDV0YII6lk&t=4m10s
waffle_ss 14y ago
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.
- mattmight 14y ago
  Computational biology is a field with much room to grow. Finding a mutation is just the start of the journey for someone like Bertrand. Once you find the mutation, you have to figure out what the mutant gene does versus the normal gene. Duke had to work with a lab, culturing cells from my son and poking at them to figure this part out. If we were better at predicting the structure of proteins from the DNA that encodes them, we've taken a big first step toward automating/simulating the "functional work." Protein folding is a nasty research problem at the intersection of chemistry, biology and computer science.
  - borism 14y ago
    Interesting, now that you've mentioned protein folding, even though I've very vague understanding of it, I instantly recalled donating some cycles to http://folding.stanford.edu http://folding.stanford.edu Hope that helped a little.
  - bhickey 14y ago
    I've spent a bit of time waffling about writing this. I hope I'm not crass. There's a major problem with incentives in attracting people to research. Why should supply and demand behave differently at universities? I believe that research is an example of the tragedy of the anti-commons. If I were to jump back to computational biology my lifetime wages would conservatively decrease by $5 million, non-inflation adjusted. Many people are unable to accept lower wages for more interesting work. The wheels of scientific progress will turn slowly as long as it is the sole realm of those able and willing to accept substantial economic sacrifices. I want to help, I'm just not able.
Dn_Ab 14y ago
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. *http://news.ycombinator.com/item?id=4038495 http://news.ycombinator.com/item?id=4038495
postfuturist 14y ago
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.
- mattmight 14y ago
  This comment rings too true. Most doctors quickly realize that they're outgunned when my wife and I start talking about our son. We have a lot more luck with PhDs than MDs.
  - jseliger 14y ago
    Part of the problem is that diagnoses and treatments are expanding faster than the ability of humans to memorize and learn about all of them. IIRC there are close to 14,000 diagnoses—just diagnoses!—that we know about. Combine that with the numerous drugs, treatments, and other changes, and it quickly becomes apparent why people with unusual conditions are better off making themselves experts than in relying solely on the expertise of doctors who aren't specialists in whatever they have. EDIT: Here's the article I was referencing: http://www.newyorker.com/online/blogs/newsdesk/2010/06/gawande-stanford-speech.html http://www.newyorker.com/online/blogs/newsdesk/2010/06/gawan... : Half a century ago, medicine was neither costly nor effective. Since then, however, science has combatted our ignorance. It has enumerated and identified, according to the international disease-classification system, more than 13,600 diagnoses—13,600 different ways our bodies can fail. And for each one we’ve discovered beneficial remedies—remedies that can reduce suffering, extend lives, and sometimes stop a disease altogether. But those remedies now include more than six thousand drugs and four thousand medical and surgical procedures. Our job in medicine is to make sure that all of this capability is deployed, town by town, in the right way at the right time, without harm or waste of resources, for every person alive. And we’re struggling. There is no industry in the world with 13,600 different service lines to deliver. Note that this was published in 2010. By now those numbers have probably grown. I've also had personal experience with the doctor-doesn't-know problem: I had an unusual disease seven years ago, and the first specialist I saw said that she Googled it a few hours prior. Her partner gave me completely wrong information; he didn't even know how to treat what I had. Fortunately my family found a research center where some of the major researchers in the field worked, and the treatment I ultimately got had been published a few months before I started (it had become standard two or so years prior). If you're curious about specifics, send me an e-mail—it's in my profile.
rogerbinns 14y ago
Here is wonderful explanation of "DNA seen through the eyes of a coder". It makes Intercal seem sane. http://ds9a.nl/amazing-dna/ http://ds9a.nl/amazing-dna/
- jcmoscon 14y ago
  It's crazy when people think we evolved from something. The DNA is our source code and God is the programmer!
kanghaz 14y ago
Reminds me of the Odone story as dramatize in the film "Lorenzo's Oil"
hexagonal 14y ago
When a mutation occurs, there are four possibilities for the mutant... I'd nitpick this slightly, since there's a slight anthropocentric bias here. 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.
engtech 14y ago
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.
ne0codex 14y ago
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.
orbenn 14y ago
"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.
- meepmorp 14y ago
  > It's shit like this that makes me hate the FDA. So, what? You'd prefer no enforcement of basic drug safety testing? There are reasons why we have the controls we do in medical trials, other than just to provide busy work to career bureaucrats and generally make trouble for sick people. There is a process for getting patients access to investigational drugs, but you still typically need to do some paperwork in order to provide the drug to the patient. Given this is a new use of an existing, approved drug, this should go fairly quickly.
  - CamperBob2 14y ago
    You'd prefer no enforcement of basic drug safety testing? If only there was a middle ground of some kind.
  - ef4 14y ago
    I don't think this is an approved drug. It's sold as a reagent to laboratories, but not used for anything medical.
    - meepmorp 14y ago
      I think you're right. I just checked a manufacturer product page, and it looks like its just used in labs currently.
- deleted 14y ago
  [deleted]
sgt 14y ago
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.
- valencourt 14y ago
  Wikipedia also has an article called Introduction to Genetics. There are more and more of these lately, introduction articles which try to break down topics that are naturally technical: https://secure.wikimedia.org/wikipedia/en/wiki/Introduction_to_genetics https://secure.wikimedia.org/wikipedia/en/wiki/Introduction_...
hobbyist 14y ago
Thanks Matt. You are amazing. period.
sevenstar 14y ago
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.
sevenstar 14y ago
Colloidal silver will probably help as well.
- Mz 14y ago
  Yes, if you want irreversible metal poisoning. If you want to try poisoning yourself with an old fashioned treatment, then mercury -- at one time a treatment for syphillis -- is probably a better bet if only because there are well established chelation protocols for getting it out of your system. In contrast, I can find no well established, proven means to remove silver. And I have tried, repeatedly, since colloidal silver is a popular alternative treatment in the CF community and I wish I had something better to offer them than the bad news they are likely making their situation worse in the long run.
  - sevenstar 14y ago
    Ha.. Mercury? Really? You are right, mercury is poison. But... there are too many people who have had spectacular results with colloidal silver, including myself, who would disagree with your post. Hospitals still use it in the eyes of newborns today to combat infections. Did you know that arsenic is not poison in the body if it is in organic form?
    - Mz 14y ago
      People also got "spectacular" results from antibiotics. Initially, optimists announced that we were ushering in an age free from disease. Fast forward a few decades and we now have frightening antibiotic resistant infections to contend with. I am not claiming there are zero short term benefits to be had. I am only claiming there is a long term cost and I deem it to be too high since there is no known means to reverse silver poisoning. My genetic disorder is deemed to be degenerative and fatal. I have reversed a lot of the symptoms, gotten off eight prescription drugs and gotten my life back. I recommend against colloidal silver any time anyone asks me. I am clear the build up of poisons in the body is why my condition is degenerative.
- GigabyteCoin 14y ago
chubbard 14y ago
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.
joshu 14y ago
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.
Mz 14y ago
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!
- Scaevolus 14y ago
  "Cristina and I each carried a different mutant NGLY1 gene." NGLY1 is also the name of the enzyme.
  - Mz 14y ago
    Um, it's possible I am just stupid and I am still trying to look up info on this. But that doesn't help me adequately understand it. This piece is interesting to me because I have a form of cystic fibrosis, which is a genetic disorder. Long QT waves -- the heart problem the child had from an antibiotic -- can be caused by a magnesium deficiency. Magnesium supplementation helps a lot of people with CF. Also, they mention a possible treatment for this condition that is currently used for some people with CF. So I am wondering how it relates to my condition, basically. But I have gotten well by framing the question different from the medical community and others with my condition. In cystic fibrosis, the miscoded protein is the CFTR, which handles traffic into and out of the cell for certain specific molecules. Understanding which molecules are impacted was enormously useful info. People with CF are routinely put on digestive enzymes, which I no longer require. So I am trying to understand what is going on with this child in terms which make sense from my mental framework regarding my genetic disorder and "enzyme deficiency" doesn't sound to me like it is really the root problem (but maybe I am an idiot -- it would hardly be a first). That may not be possible to achieve but I will work on it anyway. Thank you for replying.
    - pmiller2 14y ago
      Enzymes are proteins that function as catalysts. That seems to be the key bit you're missing.
luminaobscura 14y ago
why not just perform euthanasia and focus your energy into raising the healthy child?
- perlgeek 14y ago
  Because parents love their children, even if they aren't healthy.
- diaphoros 14y ago
  ^ this. How is keeping this profoundly sick & disabled child alive not abuse?
- snowwrestler 14y ago
  Ethical objections aside, clearly he doesn't want to do that.
  - sgtgrumbles 14y ago
    I believe luminaobscura is referring to the following position: http://www.slate.com/articles/health_and_science/human_nature/2012/03/after_birth_abortion_the_pro_choice_case_for_infanticide_.html http://www.slate.com/articles/health_and_science/human_natur...
- perlgeek 14y ago
  It took me a while to realize what exactly it was that disturbed me about your question. I don't have any problems with talking about euthanasia, but the casualness with which you mention it shocks me. Would you "just" kill your son if he wasn't healthy enough?
  - luminaobscura 14y ago
    "just" refers to easiness of the alternative route, nothing more. i didn't mean it should be an easy decision.(I am not a native English speaker.) I realize that this is a very painful situation for the family. regarding your question, there are two different scenarios: 1- my son reaches the necessary neural development stage so that he is conscious, self-aware, interacts with other humans etc. then we can't kill him unless he requests it. 2- he has never reached that stage so he has not any personality, memory etc. then we can kill him. because there is not really a "son" here, not yet. in fact, we humans continously kill pigs, dolphins and other animals that are more intelligent and conscious than a newborn.
shpoonj 14y ago
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.
- dangoldin 14y ago
  Other than the fact that this is offensive and shouldn't have been posted - did you read the article? The conclusion was that they both had a recessive trait that manifested itself in their son.
  - shpoonj 14y ago
    Who are you to decide what is offensive and what should and should not be posted? And yes I read the article and no I am not so foolish as to believe that there is only one possible cause for every result.
- Havoc 14y ago
  I thought about this too - but concluded that even without a test, its reasonable. A caring parent wouldn't keep such a thing secret when its causing (continued) suffering for their child. I'm sure there are psychopaths out there where this is not true, but given that they are married, a judgement call is acceptable in my view - even if not ideal.
  - shpoonj 14y ago
    I would argue that the same callous personality evidenced in a person capable of infidelity would also come into play when considering whether or not to reveal said infidelity. Wouldn't you agree?
    - breadbox 14y ago
      Uh, not really. I think you'll find that quite a lot of people are willing to consider engaging in infidelity, but would not be okay with torturing their own offspring on a daily basis in order to keep that fact hidden.
rickyconnolly 14y 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?
- mattmight 14y ago
  We're contacting Genzyme via friends of friends. Your question is valid. I wouldn't expect Genzyme to do much unless there's profit (or at least little cost) involved. Fortunately, Genzyme might not need to do much, since the enzyme is already in production, but for laboratory rather than human use. I'll admit I don't know much more will be required to take what they injected into mice to the point where we can inject it into Bertrand. We're learning on the fly. Since Genzyme holds the patent, I think we'll at least need their permission to use it in a clinical setting. We're also actively searching for other NGLY1 patients. There may yet be a market. We're also investigating other possible clinical applications of N-Glycanase 1. My own early research indicates that it may help in cases of severe jaundice--a much larger market. I'm optimistic that we can get Genzyme's attention.
  - mcguire 14y ago
    There's always the excellent PR opportunity.
matmann2001 14y ago
This reminds me so much of the story of Lorenzo's Oil. http://en.wikipedia.org/wiki/Lorenzos_Oil http://en.wikipedia.org/wiki/Lorenzos_Oil
- arvin 14y ago
  My thoughts exactly, especially about the hardships and perseverance experienced by the parents.
- deleted 14y ago
  [deleted]
zaroth 14y ago
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.
josscrowcroft 14y ago
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!
mohawk 14y ago
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.
djt 14y ago
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.
AliCollins 14y ago
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!
aksx 14y ago
I used to follow Matt's blog. Reading the title of this post really upset me.
kamaal 14y ago
>>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.
ramanujan 14y ago
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 https://www.counsyl.com/about/jobs http://goo.gl/45yBz http://goo.gl/45yBz 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.
pmiller2 14y ago
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.
mattiask 14y ago
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-systems/229900102 http://www.informationweek.com/news/healthcare/clinical-syst...
alexrson 14y ago
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 http://ajrccm.atsjournals.org/content/182/10/1262.long
antman 14y ago
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 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-reproducibility-in-academic-research/ 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 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 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-reproducibility-in-academic-research/ 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 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.
bad_user 14y ago
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.
nightcomer 14y ago
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.

1139 points by synacksynack 14y ago

Where is the line drawn between medical research and healthcare for your son? In other words, what on earth does this cost?

mattmight 14y ago
Remarkably, the cost of the exomic sequencing is a small fraction of what we spent on individual genetic tests over three years. Exomic sequencing is so efficient that it will likely replace testing for individual genetic disorders one-by-one in the near future. In the pilot study at Duke, they diagnosed 6 of the 12 children, each of whom had an ordeal very much like my son. In the rare disease community, this technique is unparalleled.
- Stwerp 14y ago
  Your article is amazing. I was moved to tears many times reading through this. (My wife is 6 months pregnant right now.) Just wow. Good luck with it all, and the fact that Victoria does not have the same diagnosis is just amazing! I'm glad Duke could help and your story is beautiful and inspiring. I don't know what to say, just, thank you so much for writing this. I will certainly be passing this on to some friends.
  - mattmight 14y ago
    Thanks for sharing! Becoming a parent is an awesome experience--one I wouldn't trade for anything. I can still remember time freezing the moment each of my kids was born. I wish you, your wife and your little one the best.
- pimentel 14y ago
  When there's scientific interest in the case, will a university charge for exams and tests? What about research clinics? When does an institution say "from now on, we'll take care of costs"?
- GFischer 14y ago
  Hopefully, sharing this information and your story will lead to more informed doctors recommending this technique. Thank you for an inspiring story and your exemplary perseverance.
deleted 14y ago
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lmm 14y ago

I wonder if another jurisdiction would be more willing to let you try the enzyme? The FDA is famously slow in granting approval.

mattmight 14y ago
The FDA has a special protocol in place for rare cases like my son. If we get everything done properly, approval could be granted within 30 days. But, before we can apply to the FDA, we have to get Genzyme to agree to make a variant suitable for human use. My wife found studies where it was beneficial to mice that had chlamydia and pneumonia, so we know there's a form out that that's been used on mammals.
- tincholio 14y ago
  Dude, as a recently minted father, I can't begin to grasp what you guys are going through. I just want to wish you the best of lucks with this. On a completely unrelated - and irrelevant - note, I find your writings fascinating.

moldbug 14y ago

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...

tonetheman 14y ago

Wow this was crazy interesting. My thoughts are with his parents. I learned a ton just reading the article.

jasonlotito 14y ago

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.

edwinnathaniel 14y ago
This important lesson can only be detected by parents. People with no children won't ever understand this no matter how hard they try/re-read the articles many times. Once the infant is out of the womb, everything change instantly without any interference by anyone, anybody, or anything else. The child will change your brain, your mind, your heart, your lifestyle, and your future at that moment of birth. The child IS that BIG. I cannot say how much I respect parents, even more for those who have children with special needs. Life is really beautiful isn't it? (^_^).
- deleted 14y ago
  [deleted]
- Havoc 14y ago
  >People with no children won't ever understand this no matter how hard they try/re-read the articles many times. Halfway through the article I started re-evaluating whether I still want kids. Not sure I could carry that burden. [] Though that is probably more on a logical level than feeling the raw emotion that a parent would - which is probably what you were getting at. More accurately I know I could out of necessity carry that burden. Its everything else in life which would be more difficult. Kinda like a warrior without family at home has the luxury of adopting a devil-may-care attitude to combat - once others depend on him that isn't possible anymore.
  - edwinnathaniel 14y ago

nicholassmith 14y ago

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?

mattmight 14y ago
Thanks for the kind words! My wife updates his progress regularly here: http://overcomingmovementdisorder.blogspot.com/ http://overcomingmovementdisorder.blogspot.com/ The blog is oddly titled now, since we named it back when he was 8 months old.

djb_hackernews 14y ago

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?

mattmight 14y ago
Sadly, since he's four and a half, "normal" is probably too much to expect. But, if we can stop the seizures, he might be able to start learning. He advanced very rapidly during the two month break from seizures that he got from ACTH. If we stop them soon, there's a good chance he might be able to walk and talk some day. Regardless of how far he develops, he'll be much happier than he is now.

aarondf 14y ago

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.

apaprocki 14y ago

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. [1] https://www.23andme.com/exome/ https://www.23andme.com/exome/

ykaranfil 14y ago
Just ordered a kit from 23andme

hirenj 14y ago

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 http://www.uniprot.org/uniprot/Q96IV0) is different to the recombinant form that you can get synthesised (http://www.uniprot.org/uniprot/P21163 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.

Dn_Ab 14y ago
In what way is experimental analysis of such mutations a bottleneck?
- hirenj 14y ago
  Well, once you pinpoint a potential mutation on a gene - that gives you a starting point into the pathway that could be possibly producing this particular disease. From there, it's sort of like clicking outwards from a wikipedia page, except instead of wiki pages, its related genes. Every one you go to, you read and find out what people know about it. You then start to form a picture in your head as to what the mechanisms of action are for this particular gene - what it does and how it is regulated. From there, you build your model for how the gene works, and do some knock-outs / knock-ins, test it in various cell lines, verify the kinetics, try to find out the 3D structure. Really, anything you can do to get a handle on how this actually works in the system. It's quite normal for people to spend their entire PhD studying the mechanism of action for a single gene!
  - 14y ago

sneak 14y ago

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?

drivebyacct2 14y ago
>Is it pure egocentrism that keeps high-risk parents from adopting? If it's not, I'd love to know what it is. Aww, downvotes from selfish people. Love doesn't require blood.
- lostlogin 14y ago
  Cost, complexity, difficulty, perceives trouble bonding, how?, risks, issues with the child's family. There are some.
mattmight 14y ago
When we decided to have a second child, we'd ruled out every existing disorder that could possibly explain him. After consultation with our medical team, they concurred that a de novo mutation for Bertrand was a strong possibility. And, in truth, the conditional probability of de novo mutation for Bertrand was much higher than what actually happened--two independent mutations in the same gene colliding with one another. If we had known the probability for Victoria was 1/4, we never would have gotten pregnant. Ignorance was bliss.
mcmatterson 14y ago
As a parent of a child who was born with a near-fatal congenital disorder (malignant sacrococcygeal teratoma), I can attest that the decision to try for #2 is a difficult one that we're still wrestling with. On the one hand ours was a one-off event and subsequent kids should be fine. We've always wanted two, and it's been such a wonderful experience that we want more of. So there's that. On the other hand, the months of treatment after diagnosis were the most emotionally draining experience we've ever gone through, and we don't know if we have it in us to go for number two. We're still in the early days (diagnosis + 9 months, all signs pointing to cured) so this may change, but active parenting causes healing and recovery to happen much slower. My wife (and her brother) are also both adopted, so we're well aware of the dynamics involved there. We've said since before we started trying for kids that we weren't going to beat ourselves up if we'd had problems conceiving (we gave ourselves nine months of trying before we'd look at adoption. As it turns out it only took us one). One could probably argue that the truly optimal thing to do would have been to forego trying biologically at all and to jump right into adoption, but that didn't feel right either. All of which is to say that I don't think it's egocentricity per se, but a natural desire to at least try and see your genes successfully expressed in the world. While that's not ideal from a rational perspective, I don't think you can go too far down that line of thinking without verging into eugenics.

vectorpush 14y ago

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.

fghh45sdfhr3 14y ago

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.

ars 14y ago
The FDA has a concept of http://en.wikipedia.org/wiki/Compassionate_use http://en.wikipedia.org/wiki/Compassionate_use which would allow them to use the drug even without any proof.
- Symmetry 14y ago
  Much as I might complain about the FDA sometimes, things have changed for the better since the days when thousands of people were dying for lack of treatments that had been approved in most European states a decade ago.
- asdf25 14y ago
  Thanks for answering the whole issue I came here to complain about, always a nice change to see laws functioning semi-rationally.
waffle_ss 14y ago
I find this to be a very interesting idea, although I'm still a little dubious about it. I first heard it from an interview with famous Libertarian [Milton Friedman][1] (whom I adore) in his twilight years. The self-regulating mechanism of a system like this would be tort law, allowing consumers to sue companies if they haven't done adequate research and testing on their drugs before selling them. I have mixed feelings about this because I have a hard time picturing a class action suit being able to adequately take on a large pharmaceutical company with its own dedicated legal department. [1]: http://www.youtube.com/watch?v=KUDV0YII6lk&t=4m10s http://www.youtube.com/watch?v=KUDV0YII6lk&t=4m10s

waffle_ss 14y ago

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.

mattmight 14y ago
Computational biology is a field with much room to grow. Finding a mutation is just the start of the journey for someone like Bertrand. Once you find the mutation, you have to figure out what the mutant gene does versus the normal gene. Duke had to work with a lab, culturing cells from my son and poking at them to figure this part out. If we were better at predicting the structure of proteins from the DNA that encodes them, we've taken a big first step toward automating/simulating the "functional work." Protein folding is a nasty research problem at the intersection of chemistry, biology and computer science.
- borism 14y ago
  Interesting, now that you've mentioned protein folding, even though I've very vague understanding of it, I instantly recalled donating some cycles to http://folding.stanford.edu http://folding.stanford.edu Hope that helped a little.
- bhickey 14y ago
  I've spent a bit of time waffling about writing this. I hope I'm not crass. There's a major problem with incentives in attracting people to research. Why should supply and demand behave differently at universities? I believe that research is an example of the tragedy of the anti-commons. If I were to jump back to computational biology my lifetime wages would conservatively decrease by $5 million, non-inflation adjusted. Many people are unable to accept lower wages for more interesting work. The wheels of scientific progress will turn slowly as long as it is the sole realm of those able and willing to accept substantial economic sacrifices. I want to help, I'm just not able.

Dn_Ab 14y ago

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. *http://news.ycombinator.com/item?id=4038495 http://news.ycombinator.com/item?id=4038495

postfuturist 14y ago

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.

mattmight 14y ago
This comment rings too true. Most doctors quickly realize that they're outgunned when my wife and I start talking about our son. We have a lot more luck with PhDs than MDs.
- jseliger 14y ago
  Part of the problem is that diagnoses and treatments are expanding faster than the ability of humans to memorize and learn about all of them. IIRC there are close to 14,000 diagnoses—just diagnoses!—that we know about. Combine that with the numerous drugs, treatments, and other changes, and it quickly becomes apparent why people with unusual conditions are better off making themselves experts than in relying solely on the expertise of doctors who aren't specialists in whatever they have. EDIT: Here's the article I was referencing: http://www.newyorker.com/online/blogs/newsdesk/2010/06/gawande-stanford-speech.html http://www.newyorker.com/online/blogs/newsdesk/2010/06/gawan... : Half a century ago, medicine was neither costly nor effective. Since then, however, science has combatted our ignorance. It has enumerated and identified, according to the international disease-classification system, more than 13,600 diagnoses—13,600 different ways our bodies can fail. And for each one we’ve discovered beneficial remedies—remedies that can reduce suffering, extend lives, and sometimes stop a disease altogether. But those remedies now include more than six thousand drugs and four thousand medical and surgical procedures. Our job in medicine is to make sure that all of this capability is deployed, town by town, in the right way at the right time, without harm or waste of resources, for every person alive. And we’re struggling. There is no industry in the world with 13,600 different service lines to deliver. Note that this was published in 2010. By now those numbers have probably grown. I've also had personal experience with the doctor-doesn't-know problem: I had an unusual disease seven years ago, and the first specialist I saw said that she Googled it a few hours prior. Her partner gave me completely wrong information; he didn't even know how to treat what I had. Fortunately my family found a research center where some of the major researchers in the field worked, and the treatment I ultimately got had been published a few months before I started (it had become standard two or so years prior). If you're curious about specifics, send me an e-mail—it's in my profile.

rogerbinns 14y ago

Here is wonderful explanation of "DNA seen through the eyes of a coder". It makes Intercal seem sane. http://ds9a.nl/amazing-dna/ http://ds9a.nl/amazing-dna/

jcmoscon 14y ago
It's crazy when people think we evolved from something. The DNA is our source code and God is the programmer!

kanghaz 14y ago

Reminds me of the Odone story as dramatize in the film "Lorenzo's Oil"

hexagonal 14y ago

When a mutation occurs, there are four possibilities for the mutant... I'd nitpick this slightly, since there's a slight anthropocentric bias here. 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.

engtech 14y ago

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.

ne0codex 14y ago

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.

orbenn 14y ago

"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.

meepmorp 14y ago
> It's shit like this that makes me hate the FDA. So, what? You'd prefer no enforcement of basic drug safety testing? There are reasons why we have the controls we do in medical trials, other than just to provide busy work to career bureaucrats and generally make trouble for sick people. There is a process for getting patients access to investigational drugs, but you still typically need to do some paperwork in order to provide the drug to the patient. Given this is a new use of an existing, approved drug, this should go fairly quickly.
- CamperBob2 14y ago
  You'd prefer no enforcement of basic drug safety testing? If only there was a middle ground of some kind.
- ef4 14y ago
  I don't think this is an approved drug. It's sold as a reagent to laboratories, but not used for anything medical.
  - meepmorp 14y ago
    I think you're right. I just checked a manufacturer product page, and it looks like its just used in labs currently.
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sgt 14y ago

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.

valencourt 14y ago
Wikipedia also has an article called Introduction to Genetics. There are more and more of these lately, introduction articles which try to break down topics that are naturally technical: https://secure.wikimedia.org/wikipedia/en/wiki/Introduction_to_genetics https://secure.wikimedia.org/wikipedia/en/wiki/Introduction_...

hobbyist 14y ago

Thanks Matt. You are amazing. period.

sevenstar 14y ago

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.

sevenstar 14y ago

Colloidal silver will probably help as well.

Mz 14y ago
Yes, if you want irreversible metal poisoning. If you want to try poisoning yourself with an old fashioned treatment, then mercury -- at one time a treatment for syphillis -- is probably a better bet if only because there are well established chelation protocols for getting it out of your system. In contrast, I can find no well established, proven means to remove silver. And I have tried, repeatedly, since colloidal silver is a popular alternative treatment in the CF community and I wish I had something better to offer them than the bad news they are likely making their situation worse in the long run.
- sevenstar 14y ago
  Ha.. Mercury? Really? You are right, mercury is poison. But... there are too many people who have had spectacular results with colloidal silver, including myself, who would disagree with your post. Hospitals still use it in the eyes of newborns today to combat infections. Did you know that arsenic is not poison in the body if it is in organic form?
  - Mz 14y ago
    People also got "spectacular" results from antibiotics. Initially, optimists announced that we were ushering in an age free from disease. Fast forward a few decades and we now have frightening antibiotic resistant infections to contend with. I am not claiming there are zero short term benefits to be had. I am only claiming there is a long term cost and I deem it to be too high since there is no known means to reverse silver poisoning. My genetic disorder is deemed to be degenerative and fatal. I have reversed a lot of the symptoms, gotten off eight prescription drugs and gotten my life back. I recommend against colloidal silver any time anyone asks me. I am clear the build up of poisons in the body is why my condition is degenerative.
GigabyteCoin 14y ago

chubbard 14y ago

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.

joshu 14y ago

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.

Mz 14y ago

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!

Scaevolus 14y ago
"Cristina and I each carried a different mutant NGLY1 gene." NGLY1 is also the name of the enzyme.
- Mz 14y ago
  Um, it's possible I am just stupid and I am still trying to look up info on this. But that doesn't help me adequately understand it. This piece is interesting to me because I have a form of cystic fibrosis, which is a genetic disorder. Long QT waves -- the heart problem the child had from an antibiotic -- can be caused by a magnesium deficiency. Magnesium supplementation helps a lot of people with CF. Also, they mention a possible treatment for this condition that is currently used for some people with CF. So I am wondering how it relates to my condition, basically. But I have gotten well by framing the question different from the medical community and others with my condition. In cystic fibrosis, the miscoded protein is the CFTR, which handles traffic into and out of the cell for certain specific molecules. Understanding which molecules are impacted was enormously useful info. People with CF are routinely put on digestive enzymes, which I no longer require. So I am trying to understand what is going on with this child in terms which make sense from my mental framework regarding my genetic disorder and "enzyme deficiency" doesn't sound to me like it is really the root problem (but maybe I am an idiot -- it would hardly be a first). That may not be possible to achieve but I will work on it anyway. Thank you for replying.
  - pmiller2 14y ago
    Enzymes are proteins that function as catalysts. That seems to be the key bit you're missing.

luminaobscura 14y ago

why not just perform euthanasia and focus your energy into raising the healthy child?

perlgeek 14y ago
Because parents love their children, even if they aren't healthy.
diaphoros 14y ago
^ this. How is keeping this profoundly sick & disabled child alive not abuse?
snowwrestler 14y ago
Ethical objections aside, clearly he doesn't want to do that.
- sgtgrumbles 14y ago
  I believe luminaobscura is referring to the following position: http://www.slate.com/articles/health_and_science/human_nature/2012/03/after_birth_abortion_the_pro_choice_case_for_infanticide_.html http://www.slate.com/articles/health_and_science/human_natur...
perlgeek 14y ago
It took me a while to realize what exactly it was that disturbed me about your question. I don't have any problems with talking about euthanasia, but the casualness with which you mention it shocks me. Would you "just" kill your son if he wasn't healthy enough?
- luminaobscura 14y ago
  "just" refers to easiness of the alternative route, nothing more. i didn't mean it should be an easy decision.(I am not a native English speaker.) I realize that this is a very painful situation for the family. regarding your question, there are two different scenarios: 1- my son reaches the necessary neural development stage so that he is conscious, self-aware, interacts with other humans etc. then we can't kill him unless he requests it. 2- he has never reached that stage so he has not any personality, memory etc. then we can kill him. because there is not really a "son" here, not yet. in fact, we humans continously kill pigs, dolphins and other animals that are more intelligent and conscious than a newborn.

shpoonj 14y ago

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.

dangoldin 14y ago
Other than the fact that this is offensive and shouldn't have been posted - did you read the article? The conclusion was that they both had a recessive trait that manifested itself in their son.
- shpoonj 14y ago
  Who are you to decide what is offensive and what should and should not be posted? And yes I read the article and no I am not so foolish as to believe that there is only one possible cause for every result.
Havoc 14y ago
I thought about this too - but concluded that even without a test, its reasonable. A caring parent wouldn't keep such a thing secret when its causing (continued) suffering for their child. I'm sure there are psychopaths out there where this is not true, but given that they are married, a judgement call is acceptable in my view - even if not ideal.
- shpoonj 14y ago
  I would argue that the same callous personality evidenced in a person capable of infidelity would also come into play when considering whether or not to reveal said infidelity. Wouldn't you agree?
  - breadbox 14y ago
    Uh, not really. I think you'll find that quite a lot of people are willing to consider engaging in infidelity, but would not be okay with torturing their own offspring on a daily basis in order to keep that fact hidden.

rickyconnolly 14y 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?

mattmight 14y ago
We're contacting Genzyme via friends of friends. Your question is valid. I wouldn't expect Genzyme to do much unless there's profit (or at least little cost) involved. Fortunately, Genzyme might not need to do much, since the enzyme is already in production, but for laboratory rather than human use. I'll admit I don't know much more will be required to take what they injected into mice to the point where we can inject it into Bertrand. We're learning on the fly. Since Genzyme holds the patent, I think we'll at least need their permission to use it in a clinical setting. We're also actively searching for other NGLY1 patients. There may yet be a market. We're also investigating other possible clinical applications of N-Glycanase 1. My own early research indicates that it may help in cases of severe jaundice--a much larger market. I'm optimistic that we can get Genzyme's attention.
- mcguire 14y ago
  There's always the excellent PR opportunity.

matmann2001 14y ago

This reminds me so much of the story of Lorenzo's Oil. http://en.wikipedia.org/wiki/Lorenzos_Oil http://en.wikipedia.org/wiki/Lorenzos_Oil

arvin 14y ago
My thoughts exactly, especially about the hardships and perseverance experienced by the parents.
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zaroth 14y ago

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.

josscrowcroft 14y ago

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!

mohawk 14y ago

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.

djt 14y ago

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.

AliCollins 14y ago

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!

aksx 14y ago

I used to follow Matt's blog. Reading the title of this post really upset me.

kamaal 14y ago

>>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.

ramanujan 14y ago

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 https://www.counsyl.com/about/jobs http://goo.gl/45yBz http://goo.gl/45yBz 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.

pmiller2 14y ago

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.

mattiask 14y ago

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-systems/229900102 http://www.informationweek.com/news/healthcare/clinical-syst...

alexrson 14y ago

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 http://ajrccm.atsjournals.org/content/182/10/1262.long

antman 14y ago

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 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-reproducibility-in-academic-research/ 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 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 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-reproducibility-in-academic-research/ 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 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.

bad_user 14y ago

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.

nightcomer 14y ago

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.