Thanks, HN: You helped discover a disease and save lives | Hacker News Reader

Thanks, HN: You helped discover a disease and save lives

newyorker.com

1,483 pointsmattmight109 comments

(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.

Open articleView on HN

(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.

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.

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.

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!

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.

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.

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.

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.

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.

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 .

Two over-the-counter supplements seemed to be helping, as well. The first was a highly concentrated cocoa extract. “It sounds like a scam, except there’s research showing that cocoa actually improves cells’ energy production,” Matt told me. The second was N-acetylcysteine, or NAC, an amino acid that helps produce a naturally occurring antioxidant.

At the time of the original post, I asked a question. A PHD biologist kindly wrote me via email and answered some of my questions. I have a form of Cystic Fibrosis, as does my oldest son. It is a different homozygous recessive disorder. The biologist confirmed some of my inferences about how cell biology works and that this disorder likely had some things in common with CF. NAC is something known to also help CF patients. It makes me wonder what other treatments are being used and if the doctors have compared it at all to CF.

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.

Thank you for replying.

My memory of the discussion is fuzzy, but I talked a bit for a couple of days with this biologist and then I wrote a long blog post with my thoughts. My recollection is that my conclusion was that due to the way that NGLY1 works, Bertrand should be deficient in a number of proteins that work as, among other things, cell channels, including but not limited to the CFTR, which is the one involved in CF.

So it seems to me he should have some of the same issues, like specific deficiencies, high acidity, etc.

I don't know if there's still an active cell line in the lab, but have they tested 1-deoxynojirimycin, or nojirimycin? Although they're glycosidase inhibitors, since this is a lysosomal storage disease, IIRC one copy of the NGLY gene is dead because of a nonsense mutation but the other has an uncharacterized, non-catalytic mutation. This one might be rescuable through a "chemical chaperoning" effect, ironically the proper treatment then is an inhibitor to the enzyme you're trying to save.

Relevant research on a (beta-) glycosidase (but presumably the active site structure and thus the inhibitory mechanism of nojirimycin should be similar):

http://www.pnas.org/content/99/24/15428.short

Also I had a short discussion with Dr. Freeze about his results showing that flooding with mannose (not therapeutically viable) improves activity, mannose is a weak NGLY1 inhibitor.

Also Mz: I was the biologist that responded to your query!

THANK YOU. Very, very much. I have been taken seriously a few times by a short list of folks with PHD's and it has been invaluable.

Matt: I'm on temporary hiatus from science work and have a lot of flexible free time, and am located in San Diego, where I know some of the work has been done. If there's a lab that has access to relevant cell lines, I'm willing to do a bit of work here and there on a volunteer basis to try and explore a therapeutic strategy, have some ideas to quickly ascertain if the chemical chaperone route is wise or not, especially if they have a working assay going.

Contact info is in my profile.

Sanford Burnham is in San Diego and is the leading lab for NGLY1. All of the cell lines for all of the patients are there. Dr. Freeze has a variety of assays related to NGLY1 available.

We'll get you access ASAP.

I'll be in touch shortly.

Thank you!

I looked up the essential issue again to try to limit how badly I am perceived as opening mouth and inserting foot:

http://matt.might.net/articles/my-sons-killer/#full

N-Glycanase 1 plays an important role in deglycosylating misfolded proteins, allowing them to be recycled into their constituent amino acids.

Bertrand's cells appear to be accumulating misfolded glycoproteins.

And I went back to my own research notes. And basically, even if you can't yet fix the defect, you can probably improve the cell ph balance and salt/mineral balance to reduce the incidence of misfolds. Since the issue here is that Bertrand's cells cannot take out the garbage, preventing the accumulation of garbage would help reduce symptoms. (And this is the essence of how I have reversed a lot of my symptoms: I initially thought I would be on high levels of supplements for life but correcting the cell chemistry has put a stop to the "normal progression of CF" and maintaining good health has turned out to be way easier than the battle to get here. YMMV, and probably will. For Bertrand, this is more of a stop-gap measure.)

Anyway, I thought I would toss that out there as something you might consider looking at -- as something that might get immediate therapeutic results, well before the FDA etc will ever approve anything likely to fix the genes.

It's really amazing to watch things like this happen. I wish I knew something I could do to help, but the closest I can come is having used Pygr exactly once.

Holy shit, you're in the zone!

We'd been considering N-acetyl-dideoxy-nojirimycin (2-ADN) to inhibit a different enzyme related to NGLY1. (I can't discuss more publicly since the research is unpublished, but would be happy to discuss over email.)

Can you explain a little more about how an inhibitor for NGLY1 could rescue the frame-shifted (non-nonsense) variant?

the inhibitor to NGLY1 would not be able to rescue the frame-shifted variant, it might be able to rescue the other variant, under certain conditions, unless that variant knocks out the active site (I can't remember from the original manuscript if it does or doesn't, and I can't seem to find it). Sorry for the lexical confusion.

Also, on re-reading the description of NGLY1 (it's been 2 years) I realized that an acetyl-nojirimycin might be a better choice! Looks like my intuition was correct.

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.

> Patient-advocacy groups have been around for decades, but it’s extremely unusual for one or two families to single-handedly direct an international research agenda. It helps that both the Mights and the Wilseys have family money. (Matt Might’s father is the president and C.E.O. of Cable One, the cable-television division of the former Washington Post Company.)

It's a really sad fact that economic inequality has a particularly dire effect on limiting access to quality healthcare and specialists for patients with rare diseases, no matter the severity.

The diagnosis difficulties the Mights went through with their son are made much worse for parents who can't pay, even for much more common rare diseases.

Hopefully someday our civilization can advance to the point where economic means matter much less than they do now for healthcare, where quality of life and opportunity to thrive is respected equally for every human, regardless of family money, or who gets the right to publish.

Regardless if we can or can't manipulate our DNA with approaches such as gene therapy, we first must get therapeutics to patients with rare and orphan conditions in an adequate amount of time.

Many patients wait on the the hurdles set in place by the FDA who think they are protecting patients safety. However, with a quickly progressing illness and no treatment, often the patient will die without the drug that is being withheld.

The YouTube Video Shows Dr. Bill Gahl of the NIH Undiagnosed Diseases Program speaking at a TED event.

https://www.youtube.com/watch?v=aMMBmc_pQVA

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.)

> But, we can't get permission to give it to him

Have you considered making it yourself without permission?

Suppose for a moment that there exists a sequence of tests that you feel would adequately prove the safety or efficacy of a homebrew solution. Obviously, at least some sequence of tests must exist that seems pretty okay since the clinical trials have somewhat trustworthy results.

The actual cost of enzyme production (actually, I haven't studied the solution that would be going through clinical trails in detail) can be much lower than the $X billion that Big Pharma claims. For example, $50k can get you a basic antibody garage biology operation going, without cutting corners absolutely everywhere. I know a handful of people with equipment and expertise eager to prove this.

After all, your original mission wasn't "fighting regulatory hurdles". Successful FDA clinical trials are nice, but not if everyone dies while busy waiting to raise $100M to resubmit FDA forms.

edit: Looks like you found a place to buy a batch for $250? Be safe.

For example, $50k can get you a basic antibody garage biology operation going...

Depending on what you want to do, it can be way less than that. For Cystic Fibrosis, the FDA denied inhaled mannitol, a dry powder, due to lung bleeds in trials. http://www.familypracticenews.com/single-article/fda-panel-v...

It is possible to formulate something chemically similar for not much money in your kitchen. Most people with CF are plenty familiar with keeping things sterile.

Of course we've considered it.

It's a murky moral calculus.

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?)

I think your characterization of drug companies is unfair.

There are a lot of things that make it tough for drug companies to provide drug for compassionate use (before FDA approval). Often early on manufacturing hasn't been developed enough to make large quantities of drug. If they give drug to everyone who asks for it, they won't have enough to run their trials. What is the impact of that?

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.

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

Does anyone know if a website already exists that would help people with such rare genetic condition find each other? Not everyone is able to capitalize on being a popular blogger and it could help those people find help and support. This could also serve other kind of patients in dire situations such as: https://ca.news.yahoo.com/blogs/daily-brew/montreal-cancer-p...

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...

Have you reached out to NORD (National Organization for Rare Diseases)? They don't have a website for connecting patients with rare diseases, but they are a pretty well run organization that help connect people the old fashion way.

Hi Matt, I've been inspired to start setting up something myself. Long story why, but in short I've got kids of my own around Bertrand's age (also, my own son is named after famous scientist and thinker). They were born healthy, and can't imagine going through what you all have.

Also, pre-software development, I did grad school in public health (lots of epi and biostat in a dept of inhl health) and briefly worked in health research. So I may be in a good position to help out.

I'm in the process of setting up something using Flask right now and will soon (next few hours) open source it on Github and open it up for contributions. I can't absolutely guarantee that I'll be able to maintain it long-term, but I can certainly get a forum, site, and member registry database up and going and open sourced. Hopefully in such a way that it could be managed by a non-programmers (I realize you have such skills but you obviously have your plate full).

Perhaps eventually it could bloom into a full registry of genetic data, pending resolution of privacy issues (maybe using something like dnasubway).

I'd really love to team with an established designer(s) on this. I can hack up a UI, but would be best to team with a designer(s). I'd also love to team up with other devs who are interested.

Would sociallyrare.org be an ok name for a social media hub for rare diseases? I went ahead and registered that name, but if you have any other suggestions/requests I'd love to hear them. Not sure if Socially Rare has the right ring to it.

How about rarefriend.com? You can have it if you like it.

Also, if you need any help with the site, let me know, I suck at graphics, but I'm a crack shot with databases of all sizes. I do know some good designers who would probably do the main + css for no fee.

I'd love to help as well. I'm an MD/PhD student at one of the institutions in the story, and I've done a lot of freelance development (design, not so much..) work, primarily in PHP.

Matt, a quick follow-up question: I just found https://www.rareconnect.org, which is very close to what I had in mind and had started building. Are you familiar with this site? Are people not able to connect using this site?

And many thanks to eigenrick and tgokh for your offer to help. If it turns out that somehow rareconnect.org is inactive or not functioning well, I'll definitely ping you once I get the site on Github.

Hey,

If you'd need someone looking into UX, UI and front-end work on this, shoot me an email (contact information in my profile). I work within the fields of digital design and would be very interested in giving a helping hand for a project like this.

I suffer from a condition called visual snow.

I realized about ten years ago that what I was expering wasn't normal. The condition was completly unknown at the time and I got multiple MRI's, my eyes and nervous system checked out from every angle and there was nothing abnormal.

Talking with many people I know it turned out that this condition is surprisingly pretty common, though in a mild form. People told me they saw some form of constant noise too but dismissed it as normal.

Your article got me to check the condition out again and it turns out there is new research from May identifing something wrong with the brain of people under the condition.

It's nothing life threatening like you're story, but still it's something you have to learn to live with it's there 24/7 even when you close your eyes and can be imparing at night.

http://www.eyeonvision.org/news/107-visual-snow-research-stu...

http://en.wikipedia.org/wiki/Visual_snow

Sadly I'm not in the US and there don't seem to be any research studies in Germany. Therefore I want to shout out if anyone on HN suffers from this condition, maybe hasn't even realized it because it manifests in mild form. You can all help the understanding of the condition.

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.

My oldest son has a history of tinnitus. He has benefited from generally improving his health. Our best understanding is that addressing magnesium deficiency was specifically helpful with this issue. He suffers less than he used to.

I still develop noise sensitivity any time I am magnesium deficient. So when everything starts being too loud for me, we make sure to up my consumption of magnesium-rich foods.

I was diagnosed with clinical depression a couple of years ago

I have seen some articles/studies that link depression to brain chemistry and suggest it can be helped with avoiding certain oils/getting certain oils. My medical condition significantly impacts how my body processes oils/fats and my experience is consistent with the research I have seen. I am very picky about what oils I consume. I can get suddenly and dramatically whacked out by consuming an oil my body can't process.

Some other things that have helped with brain issues in my family: Coconut oil, high cholesterol meals (such as eggs, bacon, butter), and B vitamin supplements.

Also, the lymphatic system for the brain is apparently separate from that of the rest of the body. In the rest of the body, lymph gets moved faster when you walk but for the brain it is mostly processed during sleep. So if you have sleep issues of any kind, working on resolving those may help your brain function better because good quality sleep helps the brain take out the garbage, so to speak.

My migraine-like headaches are resolving but I don't have any quick suggestions related to that.

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?

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

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.

Thanks for pointing this out.I thought my mail would surely be in my profile like on most pages. I guess thumbs up for hn for not requiering one.

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).

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!

Matt's struggle to find the cause and cure of his son's disease reminded me of a post I read sometime ago:

http://lesswrong.com/lw/gvi/metamed_evidencebased_healthcare...

While probably not applicable in this case, I think many people struck with rare/weird diseases could find this service useful. MetaMed is basically a group of people who are really good at maths, know the newest medical technologies and procedures, and are willing to dig through and evaluate tons of medical papers and publications.

I hope that this will help someone. I'm also interested if anyone on HN used this service and could tell how it worked out in their case.

There are no words for this; an incredible story. My thoughts and prayers are with Bertrand and others with NGLY1 deficiency.

It seems that while Professor and Christina Might were making a herculean effort to discover and fight NGLY1 deficiency, Professor Might was granted tenure (!) at the University of Utah and is considered a rising star (http://admin.utah.edu/academic_affairs_posts/rising-stars-at...). I doubt anyone makes excuses for late homework in his class.

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."

"My dog forked my homework."

There's still the reflog for that excuse (e.g. .git/logs/refs/heads/master).

Only sometimes. There are several actions that may purge items from and/or completely clear the reflog.

Wow, I remember this story. I asked a question about your sons development if the therapy went well and you responded, and I find myself pondering what the outcome is every now and then. Just wanted to say all the best and keep us updated.

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.

I'm glad someone else is being helped by DNA sequencing. It's such a promising new field, and why I do it

Thank you!

That must be an incredible feeling, knowing you and your family may play a part in a potentially world-changing discovery.

I hope things continue to improve for you and everyone involved in this endeavour, and I look forward to more updates.

Can someone knowledgable explain why we can't manipulate viruses to patch our genome? I don't know why that doesn't work, I just know enough to realize it would be an enormously useful thing.

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.

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

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

Another attempt caused a massive immune reaction. That said, the amount of furor over a few deaths in gene therapy trials seems to be irrational: far worse things happen in cancer treatment all the time.

I really wanted gene therapy to be available 20 years ago and even went to grad school to learn how to make it work. It was strongly deemphasized at my school in a preference for classic small-molecule protein inhibitor therapy.

Gene therapy is truly non-trivial. It took me several decades of studies in genomics and protein functional informatics to appreciate how subtle and complex the problem is. I'm hopeful that we can make technology that enables routine personalized gene therapy a common form of therapy, but it is truly not an easy problem. Causing cancer and immune response is only the first set of easily observed (fatal) side effects.

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.

we need more test subjects...

if it's legal to terminate unborn fetuses, shouldn't it be legal to experiment on them?

Not necessarily. The population of some countries allows their government to kill (selected) people, but not to experiment on them, so the first doesn't necessarily imply the second.

Animals are close enough to humans that we can experiment on them to perfect it then move to human trials.

http://en.wikipedia.org/wiki/Clinical_research

Experimenting on otherwise terminated fetuses would be unquestionably unethical because we'd have to let them age a little, which means their brain would develop, they would gain consciousness and would be likely be very messed up, then have to be "put down". That idea probably won't get much support...

We can and do use monkeys, "Planet of the Apes" is based on this. Attempting to cure alzheimers created smart monkeys, then a bunch of unknown stuff happened and they took over the world.

Could we possibly grow headless humans that are kept alive on life support or something to make up for the missing brain?

There has been talks of headless chickens for use as food before.

http://www.wired.com/2012/02/headless-chicken-solution/

http://we-make-money-not-art.com/archives/2012/02/farming-th...

I'm not going to say impossible, but we just don't need them at this point. Plus since a lot of these genetic experiments would be ultimately affecting something in the brain, it might be near pointless. I don't know, I just don't see it being plausible or necessary or allowed anytime soon.

If we can grow headless bodies, we can just use the organs for transplants, so... that'd be much easier.

I don't know, that's kind of a strange question that I don't feel comfortable even considering. Not many scientists would be comfortable experimenting on headless humans either.

Understanding DNA/RNA and simulating it with computers while using animals to verify the algorithms might be more effective.

Basically science is: predict what will happen, try everything, see what happens, study the results, don't blow yourself up or kill people. Mice and other animals are debatable to harm if necessary, greater good I suppose.

Organ transplants would be the biggest benefit, possibly even full head/brain transplants which would cure almost all conditions. Once we have the technology to reconnect nerves at least.

Yes you can't test what happens to brain tissue ethically, but you can test on every other organ and tissue which would be a huge advantage.

A brain transplant would require some technology that won't be available for a very long time.

You would need to connect the two brains and somehow move or copy all of the data to the new brain, then gradually shutdown the old brain.

We're no where close to that, but it will be a very interesting time once that happens. It will be yet another major step in our evolution.

The virus doesn't need to insert its sequences into the genome. There are different types of virus, and some do (retroviruses) and others don't.

It can be perfectly fine to have the dna floating around in the nucleus or even the cell body to turn it into a protein. Exceptions abound, of course...

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.

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...

Question for Matt (or anyone who knows):

What's the best or most cost-effective way to get an entire family sequenced? My younger brother has a rare disorder (diagnosed as autism and twelve other things that mean "we're not sure"), I don't have it, and we've wanted to get everyone sequenced for some time. Any thoughts would be appreciated.

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.

What a success story!

I was surprised to see that the second child wasn't sequenced earlier. A family of four study or even a study that includes grandparents is significantly more powerful then a trio study.

Even if only one individual displays the phenotypes it allows more variants to be eliminated and potentially allows an increased ability to distinguish sequencing errors from rare variants and new mutations. It also lets you more precisely identify recombination sites:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037280/figure/F...

Touching story. A reminder that for all the gadgets we get, the internet is really about connecting and helping people.

Amazing how gene sequencing has really started to pay off. A member of my family was recently diagnosed with two mutations of the MTHFR gene. This comes after years of trying different horrible depression medications, thyroid drugs, and hormone pills that often made things worse.

While some of the treatments are still guesses, it's so much better to finally be treating the root cause and not just guessing at how to suppress symptoms.

This snippet is the most interesting:

> perhaps Bertrand was able to avoid infections because viruses got stuck after attaching themselves to his defective glycoproteins. Rosenzweig is quick to emphasize that until he can test other NGLY1 patients he won’t know if his hypothesis warrants further exploration. But if it bears out, he says, it could point to a way to treat acute infections ranging from influenza to Ebola hemorrhagic fever.

Original article on Bertrand & how Matt Might investigated the cause of Bertrand's illness

http://matt.might.net/articles/my-sons-killer/

The actual title of the article is One of a kind.

Such an inspiring story.

Amazing story!

all the best to the families. but this makes me furious at how research is done.

everyone pays high tuition and dont think about it. just being glad their families can afford. but you (everyone here probably) is fostering this. expensive pedigree universities are the ones that create such toxic environment for open research.

very similar to this was already documented in the "Lorenzo's oil" book/film. lets hope this time we learn the lesson. (yeah, high hopes of anyone here not favoring a Stanford student but anyway ...i have no idea how even start to break this vicious circle that promote inefficient research in that way... maybe killing patents will be the light?)

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.

the top universities are top universities because of what? the standard metric is number of published papers.

So a university to on the top have to play by those rules. and we keeping regarding them as the top are by consequence valuing those rules.

the hypocrisy has to end somewhere. We can't keep up voting those articles that point the problems with academic publishing while giving priority to hire from the institutions that maintain that status quo.

TOO MANY ONIONS..... Them dam feels

Wish there was a cliffnotes version of this long-winded article. Best of luck to the kid though.

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