nowarninglabel · 11 years ago

I remember the story, it was very powerful. Thank you for not giving up and making the world a better place by continually working hard to find answers.

sadfaceunread · 11 years ago

Very impressive management of the situation. This story is pretty incredible and really exciting for the ability of researchers at different institutions to somewhat effectively collaborate.

aidos · 11 years ago

Thanks so much for posting the update.

I remember the story well (my daughter was about 6 months old at the time so it really resonated) and I've occasionally stopped and wondered how things had progressed since then.

It's inspiring to hear how you've all dealt with it as a family. And amazing to see that against all odds you've made some real progress that has (and will forever) affect people's lives in a meaningful way.

TeMPOraL · 11 years ago

Thank you for this update. I remember your story well and I'm happy that you've made so much progress to cure your son.

It is people like you, and the hard work you do, that drives the progress of mankind. Like in your Ph.D. post, the boundary of all medical knowledge gave way, and you've created a dent. A dent that will improve and save many lives. Thank you for your contribution, and best of luck on the way to curing your son!

amputect · 11 years ago

This is a really heartening story both because it's objectively amazing and, to me, for personal reasons. My wife suffers from an unknown congenital myopathy. She, and by extension I, are actually VERY fortunate. It's a very mild expression of that class of disease, so it's not a death sentence, but it's a life sentence. She can walk unaided and climb stairs (slowly, with effort), but she'll never run, among other things. She has very weak muscles in her extremities, a very high resting heartrate, breathing problems, and she basically can't gain muscle mass.

She has been working with doctors on both coasts to try to nail down a diagnosis, so that we can think about having children (we need to know what, exactly, to screen for). So far, we have had many promising diagnoses, all of which have been negative. We might be looking at a new disease, and the information in the article about genetic sequencing for new diseases lines up with what her doctor at the NIH has been working on (they just recently collected genetic material from her close relatives). Thank you for sharing a success story on the new disease front, and thank you for your work to turn your personal tragedy into a force for good in the world. You're the best kind of people.

zeidrich · 11 years ago

I think it's incredible what we can do with a medium like the Internet. It is a shame that so much intellectual capacity gets tied up in academic glory-seeking, and it's refreshing to see that the power of the connectivity of the Internet can let a lay person make stronger connections than a secretive academic.

Hopefully this and other stories like this will promote more active communication and sharing of ideas over silenced and competition for publication credit.

2muchcoffeeman · 11 years ago

So, technology wise, what have you learned from this? Your internet presence helped you find an audience. How do we help people who don't have that but still have access to the internet?

At what point do people with chronic and untreated illness realise they may have something very rare?

hirenj · 11 years ago

Hi Matt - It's inspiring to read more about your story, and that you've been making some progress with Hud Freeze, with some potential results from an inhibitor? Hud Freeze came to visit our lab (he's on the steering committee of our centre) shortly after we met. For sure, there's no one else in the world that is better suited to figure this out.

I figure I should chime in here with some info about glycobiology and disease.

The issue of rare diseases highlights an issue with disease discovery, in that techniques such as GWAS don't really have the power to identify these rare diseases, and that our current pipelines to find these diseases won't really work. Searching for these disease associations is a bit like looking for a needle in a series of small independent haystacks that may or may not share hay. Since our gut feeling with glycobiology is that we are talking about mostly rare diseases or subtle phenotypes, our goal is to use more of an integrated approach (taking data from many -omics strategies) to try and pinpoint subsystems that are affected by disease.

Concretely, we're trying to expand outreach with our knowledge of mutations in glycosylation related genes, and we should be submitting a manuscript next week on the start of our work trying to find some of these relevant rarer mutations. It'll be coupled with some web pages (right after I find some time to generate them), that make it a bit easier for non-glycobiologists to get information out about these genes. The larger and more comprehensive this resource is, the better.

The ubiquity of sequencing data that is coming out now is making a huge difference in our field. One challenge, as mentioned below, is getting centralised access to all this data. If anyone knows of a great bit of software where I can feed in data from various exome sequencing populations, that has a REST api for retrieving variants (and ideally amino acid changes) I would be interested to hear of this, since it will save me time writing it myself.

As an aside - there was an article that floated off the front page here about blood types, and why we have them, and is another example of the relevance of glycobiology, and the difficulty in understanding mutations. Basically for the blood type gene, you can have single variation causing a single amino acid change pretty much all over the gene, and they all very subtly (or not so subtly) alter the activity of the gene. To pick out which one of the variations is deleterious is not trivial.

In the field of glycobiology, there's still a lot of work to do, but I think we're making some progress, and I hope we can actually unlock some secrets, and give help to people soon.

PauloManrique · 11 years ago

Your story bought me to tears, as I started to remember my baby that died in 2010. He was premature and I don't think it's related to the case of your son.

I wish all the best for you, hope that your son manage to grow up and live his life, in the best possible way. All my prayers for your son and the others fighting on that.

cybernoodles · 11 years ago

This really is a testament to how badly technology is needed in the medical field to document and cross reference these sorts of cases. It's hard to think of such an important industry being so disconnected in such a highly connected era.

linux_devil · 11 years ago

Wish all these patients healthy life ahead , and Matt I can't describe your efforts in words , reading that article I feel that you and your wife are best parents in the world ! Good luck .

mattmight · 11 years ago

Thanks for the kind words and your original comments!

I'll certainly post another update when we reach the next critical milestone in this disorder.

We're making rapid progress in understanding these kids at a cellular level.

I'm very hopeful.

I'm also hopeful that the (apparently advantageous) immunological aspects of NGLY1 deficiency will have broader benefit to mankind.

dm2 · 11 years ago

http://en.wikipedia.org/wiki/Retrovirus#Gene_therapy

"modern medicine" isn't perfect, it's good and getting better every day, but we have a long way to go.

Plus, we don't know for sure what modifying our DNA does. It might affect certain things, but it might also have unknown consequences. There is a ton of trial and error in science, and you don't want to have too many errors in your body, else it leads to cancer and other horrible things.

Lots of mice have given their lives to ensure that we and our children live awesome healthy lives. Thank you lab-rats (and other animals), you have suffered for our benefit (though you didn't have much of a choice).

Also, it's really really difficult and really tiny, https://www.youtube.com/watch?v=TfYf_rPWUdY but there are several teams working on it and many other approaches.

mylons · 11 years ago

to sum it you, it's very hard to target the specific location in the genome you want to correct/overwrite. A virus will just insert it's payload where ever it wants, which almost certainly will cause unintended consequences in your genome

DennisP · 11 years ago

We can and it's a very active area of research, called gene therapy. An early attempt gave a kid cancer, so people are still pretty cautious about it, but things are much improved now, and patients with a variety of diseases have been successfully treated. http://en.wikipedia.org/wiki/Gene_therapy

svsaraf · 11 years ago

While there are a lot of nuances to this I won't get into, the simple answer is that it's hard to control where the virus inserts into the genome (imagine inserting a random page in the middle of a recipe book).

It's also hard to get the virus to target the cells you need to reach, as they often only target one specific cell type.

mattmight · 11 years ago

We can, but we're not very good at it (yet):

https://en.wikipedia.org/wiki/Gene_therapy

I've been speaking with gene therapy researchers, and they do believe that NGLY1 is a good candidate for gene therapy because (1) NGLY1 is a relatively small gene and (2) we're pretty good at transfecting into the critical organs for NGLY1 (like the liver).

Of the treatment options we're researching right now, gene therapy is #3 on my priority list.

One of the reasons I'm bullish on gene therapy and related techniques is that it's one of the few approaches that could cure the many of the rare diseases out there today.

bayesianhorse · 11 years ago

There is a lot of research on this, but "patching up the genome" isn't possible that way.

Gene therapy generally only inserts DNA into a cell (by whatever means possible). Inside the cell, it gets used almost as if it where inside the actual genome.

The problem is reaching enough cells and getting the genes to work well enough...

mattmight · 11 years ago

We're up against this right now for NGLY1.

There's a compound in trials right now that has shown tremendous promise in my son's cells in the lab and in the cells of other NGLY1 patients.

But, we can't get permission to give it to him, and setting up a clinical trial for NGLY1 keeps getting ever-more delayed because of concern over the FDA.

Meanwhile, our children suffer.

I'm very worried that some are going to die before this clinical trial gets underway.

(Incidentally, Bertrand and I got to meet Bill Gahl while admitted at the NIH for a week-long research protocol that will systematically study all known NGLY1 patients.)

marincounty · 11 years ago

It's not just the FDA. These drug companies are run for Investors. They throw around phrases like, "We must follow protocol." "We need to finish the last double blind study." The truth is they don't want Any bad PR if their drug doesn't happen to work. In my neck of the woods, a lady with Breast cancer was seeking early treatment with a experimental drug through BioMarin. FDA ok it. The Company said No? After reading BioMarin financial statements--I realized how this industry is run; It's about asking money. (The women realized the drug might not work, and I think her, and her family signed non-disclosure agreements?)

I overheard a MD tell his best friend how to overcome a serious illness, "The Doctor/Friend said you need to believe the treatment will work." I knew the Doctor was trying to invoke the Placebo Effect, but I felt it was the best advise I ever heard from a Doctor. (I know this child's illness is genetic and I hope the company includes his child in early trials--maybe we can email the FDA?)

esturk · 11 years ago

This is very true, which only became aware to me and probably most people after the movie "Dallas Buyer Club" reached a widespread audience.

I don't exactly fault the FDA though, because if someone is diligent, they will almost definitely get their hands on the drugs through whatever means, illegal or otherwise.

benrapscallion · 11 years ago

CRISPR, some day: http://en.wikipedia.org/wiki/CRISPR

mattmight · 11 years ago

CF has popped up more than once when looking at treatments for NGLY1.

In fact, the first ever treatment we tested in the lab was a read-through compound often used to treat some forms of CF: gentamycin.

It didn't work for Bertrand, but it may still work for other NGLY1 patients.

Phenotypically, there are some overlaps with NGLY1 and CF, so there may be commonalities in the underlying mechanisms of harm.

I'll ask the NGLY1 researchers what they think about a CF-NGLY1 link.

refurb · 11 years ago

Although NAC is an anti-oxidant, the benefit in CF is thought to be from the ability of NAC to break down thick mucus. CF results in thick lung secretions that can't be expelled, which leads to lung infections and lung damage.

NAC has a free thiol group (R-SH), which can break dithiol bonds (RS-SR) in mucus to help thin it out.

mattmight · 11 years ago

There is no such web site.

I've advised another family on how to repeat our success, and they managed to find a second patient by setting up a website for their child. Both kids had de novo mutations in KDM1A and could be mistaken for brothers. So, sequencing + social media has already discovered a second disease.

After the success with Bertrand and NGLY1, the NIH reached out to me to see if there was a way that they could integrate social media into their Undiagnosed Disease Program.

Unfortunately, the NIH can't (or won't) set up anything right now.

There's an urgent need for this too: genome sequencing is going to unearth the raw data necessary to discover thousands of new genetic disorders like NGLY1 deficiency over the next decade.

But, if that data stays isolated, those discoveries just won't happen.

Kids won't get diagnosed.

If only there were a site full of technically minded entrepreneurs that we could share this opportunity with...

mattmight · 11 years ago

Thanks for the kind words and the nod, but I can assure you that there's still no shortages of excuses for late homework.

Since this is HN, I'll share one thing that works: force your students to use git (or some version control) for assignments.

Having an auditable history of effort makes it hard to lie.

Except when it turns "the dog ate my homework" into "git rebase ate my homework."

mattmight · 11 years ago

You may want to check out LineaGen:

http://www.lineagen.com/

It's cheaper than sequencing, and more importantly, they actually know what to do with the data once they have it.

Getting your sequencing data is becoming cheaper and cheaper.

Analyzing it is not.

QuantumChaos · 11 years ago

I see two separate phenomena.

The article describes researchers being rewarded for their publications, and therefore not sharing data with their competitors, who could create a publication with that data which the researcher who shared the data would get no credit for.

You are describing people favoring graduates from top universities, which therefore charge higher tuition since their degrees are more valuable.

I can't see any relationship between these two things, maybe you can clarify.

merlish · 11 years ago

Oddly, I think I have this. I've tried to explain the vague faint multi-colour noise that overlays my vision that is especially noticeable at night to e.g. my parents before, and they didn't get it. I've always assumed it's normal and that I just failed to explain sufficiently.

Reading the wiki article: > In addition to visual snow, many sufferers have other types of visual disturbances such as starbursts, increased afterimages, floaters, trails, and many others.[9]

eh maybe; I have no frame of reference

>Non-visual symptoms such as tinnitus, depersonalization-derealization, fatigue, speech difficulties and cognitive dysfunction (brain fog) are frequently encountered.[citation needed] Secondary psychiatric sequelae such as anxiety, panic attacks or depression may develop and necessitate appropriate treatment.[citation needed]

Tinnitus: Yes, sometimes it flares up a bit for about half an hour before going away again. There's a background level of ringing in an even slightly quiet environment, but I'm not sure if it's just the blood rushing through my ears.

I also like listening to music at a loud volume (I find it hard to enjoy music otherwise.)

Depersonalization-derealization: Not sure. See 'depression' below.

Fatigue: Yes, which I've associated with my depression

Speech difficulties: I stutter and find it hard to remember names, but if I'm presenting something you would never realize either of these.

Cognitive dysfunction: Quite possibly. If I'm in a more depressed mood, I can't think.

Anxiety/panic attacks/depression: I was diagnosed with clinical depression a couple of years ago, when it got so bad I stopped caring about anything and went to a doctor.

Headaches/migraines: It varies wildly, but I do get headaches quite badly on occasion. I put this down more to stress & depression.

vsth · 11 years ago

I think I may be suffering from this as well. I thought it's normal but I do remember not being able to explain it to my parents when I was younger. I also experience most of the related symptoms:

* tinnitus - less nowadays, but I remember having some problems at night as a child

* depersonalization-derealization - it's occasionally happened for as long as I remember

* fatigue - I thought it was caused by my depression

* speech difficulties - yeah, I thought it's related to the brain fog I get when I'm nervous

* anxiety

* depression

Now, my visual symptoms seem fairly mild, I wouldn't say I've been affected much. But if the other things turn out to be related...

Is anyone doing studies in the UK?

ZoFreX · 11 years ago

Wait, this isn't normal? Huh. Thanks for the info.

Mz · 11 years ago

Just a thought: You might want to put contact info in your profile if you want to make this shout out more effective than a passing conversation in this one post.

beagle3 · 11 years ago

Does this look similar to what you have ? http://www.youtube.com/watch?v=qVFIcF9lyk8

If it is - Ocular migraines are well known (though not the cause or a treatment). It often is a matter of using the right term or finding someone who knows them. I've had RLS for years and never managed to describe it (until I randomly read an article with a resonant description).

galactus · 11 years ago

Hello, I have VS too! I was actually one of the many people dr Schankin interviewed by phone for the first phase of the research that you mention. I have had it for nearly 25 years!