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Comment by mattmight | Hacker News Reader

(There's a shout-out to HN in the article.)

Two years ago, HN was the first to pick up on a post I wrote about my son's preliminary diagnosis via experimental exome sequencing:

https://news.ycombinator.com/item?id=4038113

Two years ago, he was the only known NGLY1 deficient patient in the world.

By spreading the story, we've found 16 cases worldwide.

We've organized.

We've found preliminary treatments.

Clinical trials are in the pipeline.

In some cases, we've saved the lives of previously undiagnosed patients.

And, these children's cells are turning into gold mines for the basic science of glycobiology.

From the bottom of my heart and on behalf of the entire small but optimistic NGLY1 community,

Thank you.

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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.

I wish you and your wife much luck.

If the docs at NIH come back with a pile of variants of unknown clinical significance, get in touch with me.

I'll help you find patient #2.

"I'll help you find patient #2."

Awesome. I would give a million upvotes if I could. Your dedication to helping others is worthy of deep respect. :)

Thank you so much, this means a lot to both of us.

Humanity at its best!

Would you please get in touch with me? My contact info is in my profile.

I have a relative who has some similarities, though it's very unlikely that it's the same.

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.

Thanks for the kind words.

If you had told me when my son was born that we'd have to discover a disease as just the first (small) step toward saving him, we would have crumbled.

We weren't ready for what had to be done.

But, parenting a child with a rare disease changes you in ways you can't imagine.

I've seen it again and again it in the thousands of rare disease parents we've met over the years.

A slow-motion grieving process gives way to a visceral, evolutionary response: whatever it takes, save the child.

You can drive a truckload of bad news right over these parents.

They get up, dust themselves off and keep walking.

You stop thinking about the future. Entirely.

You start thinking about what you can do today and right now.

You force yourself to take the first small step.

Then another, and another.

Day to day, it never seems like you're making progress.

But, I've seen rare disease parents end up achieving the impossible by just focusing on one small step toward the impossible at at time.

I realize we've come far, but I know we have a long way to go.

So, on to the next step.

This is so awesome. I've kept from reading it again to avoid letting my coworkers note my emotion.

This is so very true ... the endurance that it takes to have a disabled child is something I never knew was in my character. After choosing a career that was well-known for death-marches, that's the closest analogy I can offer (this crowd). Unlike a death-march, you never grow to hate the process: sometimes you grit your teeth just to take that next step, but your heart demands you continue.

After reading your story, I realize I walked a much easier path - my son was born with trisomy-21 (Down Syndrome) and it was easily diagnosed (though not so easily accepted by us parents). It turned out he had several more genetic disorders, but as each was identified, it was (more easily) dealt with.

I can't even imagine going through his first five years gathering questions but receiving no answers. We have two children older than our disabled son, and when people asked me what I wanted them to be when they grew up, I was always quick to answer "happy". You've given so much (both for Betrand and the others you've gathered together) that I don't want to take anything away from your amazing journey. I do want to give you what I can here - a simple blessing. May God bless you and your family so that you always find strength in him and in each other, and may your eyes be quick to see those small joys and victories so many people miss in their hectic lives.

Thanks so much for sharing both the original story and the follow-up!

EDIT:

There's so much to say! I'll keep it brief though.

I should have noted that growing up in a household with a disabled child has had a profound impact on my other three children. My older two are adults now (and Sam just turned 18) but from a young age they had empathy and sympathy that far exceeded what most adults feel. It's actually shaped their character in a tremendously good way.

[1] Exceptional Lives - http://www.blurb.com/b/651459-exceptional-lives

[2] Your Special Chef (Cookbook) - http://www.blurb.com/search/site_search?search=your+special+...

[3] Your Special Chef (Website) - http://www.yourspecialchef.com

[4] My favorite molecular geneticist - http://annamoyer.com/assets/resumesum2013_moyer.jpg

Well said! I find it interesting you also observed your other children showing/developing much greater empathetically. I am the father of a little boy who had Zellwegers syndrome and passed away at 7 months. He has an older sister (she was 2yrs at his birth) who is perfectly healthy, and we have found her comprehension emotionally is unparalleled amongst other kids her age. We also now have since adopted (new born), and our newest child doesn't seem to have that same emotional intelligence (shes also about 3yrs old now). So at least in my limited sample, they do seem to grow emotionally stronger when a sibling is challeneged/special needs. I'm just not sure how or why that is.

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!

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.

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.

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.

Hi Hiren, just wanted to let you know about SolveBio (I'm the CTO). Our goal is to compile the world's clinically relevant biological reference data and to help people build genomics applications. Right now we offer REST APIs to some widely used genomics datasets (such as ClinVar, Uniprot) and some others like Medline. I'd love to hear more about the work you're doing, and see if there are any ways we can help!

Hi Hiren!

Thanks again for meeting with me after the original post!

Please send me a link to the pages once they're up.

What you're doing is really critical. I've discovered that a lot of non-glycobiologists 'shut down' when it comes to glycobiology.

Certainly in the case of one earlier NGLY1 patient, that caused the NGLY1 mutation to go overlooked until they found my blog post.

A resource like what you're creating will be incredibly valuable for the wider CDG and non-glyco community.

Thanks!

I will do so! They'll be short on content to start with, since we've still got to do the leg work to fill in the data.

I don't really get why other biologists shut down, but I figure if we put together some good cognitive (and analytical) tools to allow people to better understand the roles of glycosylation, it'll no longer be so scary.

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.

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.

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.

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 .

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?

There's no doubt that my technical blog helped do this the first time. But, I firmly believed that this could be repeated without an established presence.

And, it has been repeated.

After I co-authored an article with a fellow parent describing how social media + sequencing could discover diseases, a family with an undiagnosed child reached out to me.

They had been exome sequenced, but they were left with two de novo mutations of unknown clinical significance. It wasn't clear if either was the cause of their child's symptoms.

I gave them advice on how to structure a site with the highest likelihood of finding another patient.

They created this on their own:

http://milosjourney.com/

Within 29 days, they found a second patient with a de novo mutation in the same gene (KDM1A). Just looking at the kids made it obvious they had the same disorder.

And, so KDM1A has become the second disease discovered by social media + sequencing.

The heartening aspect is that this family didn't have a prior social media presence at all.

I recommended that they buy Google AdWords on the names of the candidate genes of unknown clinical significance they were given, but even that wasn't necessary.

So, I'd recommend that anyone going through a diagnostic odyssey and start blogging everything -- medical terms, lay terms, doctors names, symptoms, medications, treatment attempts, etc.

These are all the kinds of things that fellow sufferers are likely to type into Google.

Recently I was googling for NGLY1 references on German language web sites and found some very short thread in a child healthcare forum (or something similar) where some parent described their child, some other guy said it sounded a bit like your case and linked to your site, and the OP replied that it sounded similar indeed and they'd be in touch.

I don't know if that was really one of the cases, but your web site sure has impact.

There's one German patient, but no one has reached out recently from Germany.

Can you point me to the site?

That's really cool. But kind of sad that it takes so much chance for these people to come across each other.

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