

Thanks, HN: You helped discover a disease and save lives - mattmight
http://www.newyorker.com/reporting/2014/07/21/140721fa_fact_mnookin?currentPage=all
(There&#x27;s a shout-out to HN in the article.)<p>Two years ago, HN was the first to pick up on a post I wrote about my son&#x27;s preliminary diagnosis via experimental exome sequencing:<p>https:&#x2F;&#x2F;news.ycombinator.com&#x2F;item?id=4038113<p>Two years ago, he was the only known NGLY1 deficient patient in the world.<p>By spreading the story, we&#x27;ve found 16 cases worldwide.<p>We&#x27;ve organized.<p>We&#x27;ve found preliminary treatments.<p>Clinical trials are in the pipeline.<p>In some cases, we&#x27;ve saved the lives of previously undiagnosed patients.<p>And, these children&#x27;s cells are turning into gold mines for the basic science of glycobiology.<p>From the bottom of my heart and on behalf of the entire small but optimistic NGLY1 community,<p>Thank you.
======
mattmight
(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](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.

~~~
amputect
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.

~~~
mattmight
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.

~~~
sarciszewski
"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. :)

------
Mz
_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.

~~~
mattmight
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.

~~~
dnautics
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](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!

~~~
dnautics
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.

~~~
mattmight
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!

------
lilsunnybee
> 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.

------
hkiely
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](https://www.youtube.com/watch?v=aMMBmc_pQVA)

~~~
mattmight
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.)

~~~
kanzure
> 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.

~~~
mattmight
Of course we've considered it.

It's a murky moral calculus.

------
jopela
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...](https://ca.news.yahoo.com/blogs/daily-brew/montreal-cancer-
patient-rallies-against-limited-number-minority-173801245.html)

~~~
mattmight
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...

~~~
eric_bullington
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.

~~~
eric_bullington
Matt, a quick follow-up question: I just found
[https://www.rareconnect.org](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.

------
Herdinger
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://www.eyeonvision.org/news/107-visual-snow-research-study.html)

[http://en.wikipedia.org/wiki/Visual_snow](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.

~~~
merlish
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.

~~~
Mz
_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._

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.

------
TeMPOraL
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...](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.

------
timsally
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...](http://admin.utah.edu/academic_affairs_posts/rising-stars-at-the-u-2)).
I doubt anyone makes excuses for late homework in his class.

~~~
mattmight
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."

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

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

------
djb_hackernews
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.

~~~
mattmight
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.

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

~~~
mattmight
Thank you!

------
revelation
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.

~~~
svsaraf
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.

~~~
qnaal
we need more test subjects...

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

~~~
dm2
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](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.

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

~~~
dm2
There has been talks of headless chickens for use as food before.

[http://www.wired.com/2012/02/headless-chicken-
solution/](http://www.wired.com/2012/02/headless-chicken-solution/)

[http://we-make-money-not-art.com/archives/2012/02/farming-th...](http://we-
make-money-not-art.com/archives/2012/02/farming-the-unconscious.php)

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.

~~~
Houshalter
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.

~~~
dm2
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.

------
thinkcomp
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.

~~~
mattmight
You may want to check out LineaGen:

[http://www.lineagen.com/](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.

------
micro_cam
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...](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037280/figure/F2/)

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

------
jobu
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.

------
fuzzythinker
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.

------
gcb0
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?)

~~~
QuantumChaos
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.

~~~
gcb0
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.

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

[http://matt.might.net/articles/my-sons-
killer/](http://matt.might.net/articles/my-sons-killer/)

------
xiaoma
The actual title of the article is _One of a kind_.

------
Caldercho
Such an inspiring story.

------
greenpinguin
Amazing story!

------
ryansmurphy
TOO MANY ONIONS..... Them dam feels

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

