If you or someone you love has a disorder you believe is unexplained, reach out to Alabama-Birmingham’s Precision Medicine arm. (https://www.uab.edu/medicine/pmi/)
It was founded and is run by Matt Might, a computer scientist and former Obama-admin CTO for the US. He wanted to solve his own son’s medical issues and now is helping others. A family member works there as a pathologist and while treatments are expensive, they’re also bespoke. And sometimes it’s better to have answers, and a sliver of hope, than nothing at all.
I heard a talk from Hugo Bellen which was interesting about this research. And using model organisms to in a sense verify that they're going in the right direction.
https://flypush.research.bcm.edu/lab/about-mosc-udn.htm
I haven't had personal experience, but what I remember from the talk it was clear some mutations where causing over expression which was hard to figure out in the patient.
Is this for people who have symptoms but have not received a clear diagnosis from anyone? Or for people who already have a clear diagnosis of a rare condition?
my understanding is it’s for people with symptoms but no known diagnosis. Often because the condition is so rare it’s unknown.
“At the Clinical Sites, doctors and healthcare providers, like neurologists, immunologists, nephrologists, endocrinologists, and geneticists, come together to help find the cause of participant symptoms.
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Not to discredit the value in caring about this stuff, but wouldn't this sort of thing be flooded with people with Fibromyalgia and chronic fatigue syndrome? Wikipedia says Fibromyalgia affects 2-4% of the (US?) population [1], which is a ton of people if you translate that into population numbers.
These are two very popular 'conditions' that have vague symptoms and vague connection to specific physical signals. I'm sure a small subset are masking real treatable disease (as opposed to simply recommending exercise and yoga or environmental changes as Wikipedia said is the normal response). But it might be difficult to filter these out and any bespoke broad sort of catchall would seem inclined to attract these sorts of cases.
Your statement conflates real and treatable. Unfortunately there are conditions which are real but not yet treatable. Science in 2023 hasn't solved all things.
I expect that a significant subset of Fibromyalgia/CFS sufferers fall into this category. I wonder if this center can make any progress on resolving any of their conditions.
For many fibromyalgia sufferers, the symptoms and physical signals are not "vague" but quite concrete.
I can second this recommendation. Matt’s team at UAB helped collect and analyze the latest research and suggest clinical treatments for my son’s rare genetic variant. It’s free and they were great to work with.
Is this for people who have symptoms but have not received a clear diagnosis from anyone? Or for people who already have a clear diagnosis of a rare condition?
You do not need a diagnosis. Having one obviously accelerates the process but there are plenty of people who come either with no reasonable explanation for their condition or even, in some cases, a profoundly incorrect diagnosis.
Like others have said, I can't imagine any doctor actually going this deep with me.
I've probably seen 20 doctors, but none of them have taken me very seriously at all. Some prescribe me something and say "see if that helps," others flat out say, "I'm not sure what is going on here and I don't know how to help you," but nobody has said, "We should consider looking at your DNA to see what's up here. I'm really interested and want to figure this out with you."
> nobody has said, "We should consider looking at your DNA to see what's up here. I'm really interested and want to figure this out with you."
The vast majority of doctors don't have the expertise or resources needed to do that. A doctor can't write a script for whole genome sequencing just to see what turns up - it will be rejected by insurance 100% of the time because that's going outside the scope of standard practice. And even if they did manage to sequencing done and a novel mutation popped up, there isn't anything to do with that treatment-wise. The next step would be going back to the lab, synthesizing mutant RNA and/or peptide sequences and studying their properties. And it would likely take years for that to translate into knowledge that is clinically useful.
If you want that kind of care, you need a large, academic hospital that has an ultraspecialist with an active and well funded research program in the relevant area. They can cover the costs of nonstandard tests out of their research funds. And if unusual findings pop up, they have the equipment/resources to follow that up with further studies.
> A doctor can't write a script for whole genome sequencing just to see what turns up - it will be rejected by insurance 100% of the time because that's going outside the scope of standard practice.
To be clear, doctors frequently requisition genetic tests for suspected conditions when the test is justifiable and actionable. If you are demonstrating symptoms of a specific condition and genetic testing can be part of the diagnostic process, you can generally get it covered and performed.
However, getting a whole genome sequence and then scrolling through the results isn't as actionable as it sounds. You can do it yourself for under $500 if you really want. A lot of people have gone down this route and been surprised at how little signal you actually get out of the data, unless you have a rare and significant variation.
Eh. Doing it yourself is a huge pain even when you get useful signal. I wish I could pay someone a few k$ to check results against literature and a list of things I think are weird with my body.
ex. I have family history and symptoms of hypothyroidism. I've had 3 doctors test T4&TSH, then shrug and say everything is fine. My dad had a similar experience before landing on a doc who shrugged and said "let's just try the meds anyway and see what happens."
I got WGS out of curiosity, annotated the VCF with REVL scores, and sorted by score. The first entry was a low-frequency (121 hits in TopMed) NR1D1 missense variant. I couldn't find any literature on that variant, so I looked at the downstream THRA impact and found papers that talked about disruption to thyroid signaling, and said that T4 & TSH would look normal, so you need to check T3/rT3.
I bounce this off my endo and ask if she'll order a T3 & rT3 test. She won't because endo society guidelines says that rT3 tests aren't clinically useful.
I order my own tests from a labcorp reseller.
My T3 & rT3 results reflect what the papers saw, so I get grey market thyroxine. Screw up the dosing and get a day of racing heart. Fix dosing and hypothyroid symptoms went away.
After this I find out that there's a whole community of people with normal T4 & TSH results, hypothyroid symptoms, and wonky T3/rT3. Also that there's some kind of culture clash between normal docs and functional medicine docs about this.</shrug>
I shouldn't have to resort to days of messing with bioinformatics tooling, a week of reading papers, and questionable sourcing of meds to test something that any doc should have been able to deduce if they bothered to have some curiosity about how I could have those symptoms if their normal test came back normal :(
whoah what the hell, I've found myself in the same exact situation so many times before, but I just don't have any background in genetics / science to know what the steps invovled are and how to interpret both the posted genetic abnormalities and comapre them with my own data.
What's so frustrating, which you've experienced very acutely here, is that nobody cares about your health as much as you do, and for any reasonably sharp people, you have more time to research and think through your particular issues than a specialist with hundreds of patients.
I've been thinking that there needs to be a forum or subreddit or something to gather all these "Direct medicine" tips. Do you have any other things you've done? I've personally gone the route of ordering the thyroid test. For something so rediculously cheap as $8 to run them at a quest diagonstics center to get answers in 12hours vs the usual rigamarole is a no brainer.
Another one I've done when I needed to see a specialist asap and couldn't wait the 6 months in the US was to use this app called doctoralia and schedule an appointment with a mexican doctor. $75, got an appointment in 2 days, they seemed very knowledgeable and was involved with the Mayo clinic. Again, no brainer.
This might come off as too techno-optimistic, but I really think there is huge potential value here for AI participation in medicine. An AI trained on all the latest research could probably help either digest additional avenues to doctors and patience. I'd also like to see AI do a parallel diagnosis and if doctor and AI disagree, a third opinion is pulled in.
Unfortunately, I expect our medical system in the US to be reluctant to use AI in addition, rather than as a cheaper replacement since everything is driven by profits for insurance companies.
Back in the day, doctors diagnosed hypothyroidism via temperature and ... co2 (I think). The prescription to treat hypothyroidism was grains of Armour Thyroid (Dessicated Thyroid).
Every batch of Armour Thyroid was tested and standardized. Then the synthetic Synthroid came out, and the sales reps said "this is way better than animal thyroid", never mind that the batches of the synthetic bio-identical T4 were not consistent.
Eventually the Armour Thyroid brand was sold a couple times. The new owners reformulated it, and didn't care so much about potency. Armour thyroid is still sold, but it's not like it was when Dr. Barnes was using it.
A mix of synthetic T3/T4 is sorta-similar to the old Armour thyroid, and better than the Synthroid.
There's nothing worse than having to deal with people who think they know what they're doing.
My endocrinologist tested for thyroid antibodies - there mere presence of those alone was enough for a diagnosis of Hashimoto's disease. My actual T4/TSH levels were on the low side of normal - so a typical GP would likely have ignored this.
But given the antibody test and the symptoms my endo focused on those first. Fortunately he's been pretty emphatic about not just chasing numbers on a chart.
Maybe a better doctor could get you the medicine you need. The ideal solution is to make many prescription meds available over the counter since doctors are often useless or actively harmful though their ignorance and hubris.
It's a database of known BRCA1 and BRCA2 variants with significance scores and links to clinical research. If you get results telling you that you have variants in those genes, look them up here (under the guidance of a genetic counselor, of course).
> To be clear, doctors frequently requisition genetic tests for suspected conditions.
No, they do not. I have been fighting for this for 20 years. I ended up finding my own genetic issue (23andme) myself and they STILL do not care. They would rather let me rot on disability and homelessness.
Genetic testing for specific diagnosable and treatable conditions are extremely common in the medical world.
For example, the BRCA gene test is commonly given to people with elevated familial risk of breast cancer.
They do not go searching through entire genomes for any possible variant, though.
> I ended up finding my own genetic issue (23andme) myself and they STILL do not care. They would rather let me rot on disability and homelessness.
Your other comments said you diagnosed yourself with PNP deficiency. This is generally a fatal condition in infants and adolescence unless treated early with hematopoietic stem cell transplantation.
I wouldn't rely on 23andMe's SNP analysis as a genetic diagnosis of anything, especially disorders which are fatal in adolescence. 23andMe has been known to mis-mark certain SNPs at various times in the past, and it's not guaranteed 100% accurate.
Is it possible that you were a carrier, but not homogenous for the variant? The condition is autosomal recessive, meaning you would need to inherit flawed copies from both parents. Having a single bad copy could show up in 23andMe but would not indicate that you have the condition.
To put it in perspective, the number of cases of PNP known to the literature in the entire world is less than 100.
>Your other comments said you diagnosed yourself with PNP deficiency. This is generally a fatal condition in infants and adolescence unless treated early with hematopoietic stem cell transplantation.
Just stop please. Why do you think I do not know what I am talking about? How long have you researched this gene and have you talked to people who are actively involved in researching this?
Only certain p[polymorphisms are fatal for infants. There are plenty of us living with partial PNP deficiency.
Conclusions: Patients with partial PNP deficiency can present in the third decade of life with mild-moderate immune abnormalities and typical development. Near-normal immunity might be achieved with relatively low PNP activity.
> Is it possible that you were a carrier, but homogenous for the variant? There are many genetic alterations which do not manifest as disease unless you inherit a broken copy from both parents.
I am homozygous for four variants known to effect T Cells. There is not only one polymorphism that can reduce enzyme activity,
The finding in this paper is that partial PNP deficiency produced normal development in 2 out of 3 siblings and near-normal immune activity in the 3rd, despite having only 8-11% of the normal PNP activity.
The takeaway is that partial PNP deficiency might, in some cases, present with only mild-moderate immune abnormalities or normal functioning.
I had my genetics one by 23 and me twice once with the v4 chip, and again with v5 chip. I highly doubt that it would come up the same in both of those runs if there was any type of error. I really don’t understand why it went down plays 23 and me so much.
Near normal immune function in the third person is not normal immune function.
I am one of the people that are affected. Please don’t tell me my history and please don’t assume you know everything about what I’ve suffered through. I’m so tired of this attitude. When there’s no evidence for something people always seem to want to make it into nothing. When, in fact, if they actually studied it, they would find the evidence. But they don’t and people like me just suffer with immune deficiency and mental illness and nothing gets done.
Seriously talk to someone who does clinical genomics not 23andme. Our institute does various tests and the closest one to 23andme is ngs with avg read depth of 2000 and we still get a bunch of errors in reads and we have huge lists of known artifacts that we only know about because we actually do the clinical correlation
> Seriously talk to someone who does clinical genomics not 23andme.
Really? Just go and talk to someone? I am homeless with a mental illness on top of the immune dysfunction. You think this is something I have not tried over and over for the last ten years?
And again, if it WAS an error, why did it show up TWICE, and no one else I who I have 23andme genetics (15 people!) have more than heterozygous SNPs for these?
Please, explain that to me and I will waste more time having doctors just tell me it is my mental illness and drive myself further to suicide.
I realise this must be hugely frustrating for you. The folks on here are mostly genuine in their attempt to help, even if they seem misguided due to lack of context. If you could find the time and space to be patient with them i'm confident that you may learn something of value.
I admit, this is a rant, but because I am tired and frustrated not only for myself, but for all the people I know and support who are living with chrnoic illnesses. I am not mad at anyone personally.
> The folks on here are mostly genuine in their attempt to help,
Are they? You know what helping people looks like? It has nothing to do with words. All I hear are words all day.
Me: "Can you help me, I need housing?"
Everyone: "Have you looked on Craigslist?"
Me: Can you help me? I am sick and cannot think straight.
Everyone: Have you tried searching for a geneticist?
I am the one who is ill and I am supposed to do all the work? Help is "Hey, I am a geneticist, call this person and ask, or call this person, or call me."
Learn something of value? I am done with learning. I fricking taught myself genetics and neurological biology, I have managed to at least get my self well enough to get off of all my psychiatric medications except for klonopin as needed. I taught myself nutritional genomics and lowered my cholesterol through diet alone, I discovered why EMFs give me insomnia, mania, and palpitations.
So if anyone here is a geneticist and wants to see a real European genetic freak let me know. Here are some hints; NOS1AP, GCH1, PNP, FASD1, FADS2, CPT1A, BTD, SLC18A1, SLC18A2, ERAP1, FUT2 (non-secretor), NCAN, NRXN1, and ...
I was in one genetic study and they found I was heterozygous for this:
GALC c.1685T>C (p.Ile562Thr) I have the document from INVITAE!
I demanded to talk to a genetic counselor. They said it was NOTHING! I showed the geneticists this:
And they STILL would not test my enzyme activity even when I have episodic spastic paraplegia so bad they thought I had MS! They genetic counselor did not even know what the enzyme did!
I mean what more do I have to do?
ADDING: I mean what is the change that I am a FUT2 non-secretor (Galactoside alpha-(1,2)-fucosyltransferase 2) and have this GALC (Galactocerebrosidase) polymorphism? They both have to do with galactosides!
Having any chronic condition, especially one that's not a "normal" condition with a treatment script (like say Diabetes), causes one to discover really fast that most health advice is useless at best, most doctors are maybe only 10% better than that and you will have to do far more work than you ever thought in keeping yourself alive. Most people will be more concerned with the idea that you might be faking something and getting away with it than actually trying to solve the issues at hand. I'm sorry to find another soul going through it, and I have nothing more to offer than condolences and wishes of good luck in finding a doctor that will actually listen and stick around.
23andme is not a medical-grade genetics test. Finding a very rare genetic mutation in it isn't convincing unless you get a specific test for it or do 1000x WGS.
This is not true whatsoever in any way. It does not have to be “medical grade”. Whatever that means.
I mean, are you saying they get their snips wrong constantly.? if so, that’s patently absurd because they went through the testing to assure this doesn’t happen. Or when it does happen, it doesn’t happen with the consistency over different chips.
Thet get it wrong consistently? Did you even read the study? No you didn’t. Because if you did, you would’ve read this.
“Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank.
Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.”
The SNPs I have are not very rare. And why did the task it wrong twice? Exactly wrong twice, they got all four SNPs exactly wrong twice?
If you wanna give me the money to get a full genome test please send it to me and I’ll prove you were wrong. Because I’m currently homeless and on disability trying to fucking fix whatever problem I have no one fucking cares about.
When it comes to obscure and unlikely illnesses, many doctors have a hard time entertaining the idea. They're taught when they hear hooves to think horses, not zebras. From stories I've heard it seems like it takes trying until you find a doctor open minded enough, or perhaps there's a doctor/researcher that specializes in this area you can reach out to. Not all doctors are the same, to some it's just a job but I'm certain there are some out there that would be okay with exploring that
I am in the US. My issue is that I was diagnosed with a mood disorder before anything else. So now, even though my white blood counts, never get above four, well, not until recently. They dismiss any other problems I have. Because I think it’s all because of my brain. It’s so idiotic I can’t stand it. I can’t have any other illness because I have a mental illness.
I’ve been telling doctors about my low white blood cell count for a decade. Not one of them does further testing on it. I don’t know how to convince them or what to say , I think one of the problems is I take such good care of my health and so when they look at me I look fine. But it does not show how I feel inside and it does not show the fatigue I deal with.
Yo, I want to say you’re lucky that you have leukemia because that’s easily spotted. but I’m one of those people with this borderline chronic health issue that they don’t wanna waste time on because I’m not actively dying. I’m just suffering my whole life.
It actually took years for my Leukaemia to be sorted, funnily enough, due to the impacts my autoimmune disease and medications had on my blood levels.
I also was told for years I was faking my stomach pains until my leg nearly fell off due to a MRSA infection, which subsequently turned into a case of pyoderma gangrenosum. I was then finally diagnosed with Crohn’s disease.
I will say there are some good doctors out there. My email is always open to HN readers if you want some help or advice here.
Doesn't NIH cover the genome sequencing if its an unexplained illness? I think it's more a matter of the doctors not knowing how to refer someone for that.
> Doesn't NIH cover the genome sequencing if its an unexplained illness?
No, they don't. And it wouldn't make sense for them to do that either. There isn't much value to that clinically (sequencing is highly unlikely to reveal a new treatment pathway - there's only a handful of specific mutations for which we have specific treatments - cystic fibrosis, sickle cell, PKU, hemophilia, etc.) or from a research perspective. (Research answers a hypothesis driven question; usually that means you have a particular clinical syndrome and a theory about how it arises. Randomly turning over stones in search of something with out any clear idea of what you're looking for is essentially distributed p hacking and unlikely to lead to anything except for wild goose chases after statistical noise.)
Are you referring to this [1] program? If so, they have a very specific list of diseases that they are sequencing for. It's not open season for any unexplained symptoms.
(And how you would rigorously define unexplained if you don't have a particular syndrome in mind is a whole other can of worms)
It's not like anyone can just apply. It looks like sequencing is open to any NIAD participant, people who might fit specific diseases, or based on collaboration with other researchers on a case by case basis. It doesn't seem like they're that picky when they've sequenced over 100k people already.
I do clinical genomics. Highly recommend you to find a university hospital that can do genomic analysis for you. The IUIS IEI list has ~500 known genes that could be causal if you have some variant in one of these genes. The key is a good bioinformatic interpretation and clinical follow up.
FWIW, I can second this. My spouse is currently in the process of getting this done. Know up front that you'll have to fight insurance about it. They won't want to pay for it because they have no existing framework that says doing genomic testing will in any way help whatever you have. (And they're not wrong. It's entirely possible the genome sequencing won't turn up anything useful.) My spouse's doctor works at a university hospital as parent mentions.
The other thing to know is that even once you do get it set up, it generally takes about 6 months before you get the results and the consult with the geneticist. And because there are multiple parties involved, everything moves glacially and nobody knows what anybody else is doing. It's frustrating, but I hope that it helps once it's finally complete.
There are probably multiple companies that do this testing. We ended up going with Variantyx[0] because our doctor works with a geneticist who uses them.
> My spouse is currently in the process of getting this done. Know up front that you'll have to fight insurance about it. They won't want to pay for it because they have no existing framework that says doing genomic testing will in any way help whatever you have. (And they're not wrong. It's entirely possible the genome sequencing won't turn up anything useful.)
The whole genome sequencing linked above is $200, plus more if you want specific reports run against it (rather than doing it with 3rd party tools).
$200 can still be a lot of money depending on the circumstances, but for most of us with tech jobs I'd gladly pay the $200 out of pocket and get it going right away while waiting for the glacial process of getting insurance and appointments coordinated.
I suffered for years with a mood disorder which made them think every thingw as all in my head. I have consistently low WBC counts and not one doctor care sto look into it. I have an immune deficiency but all they see is the mood disorder brought on my the same gene polymorphism.
But no one gives a sht about freaks like us. If they invested $100k when I was first sick they would have saved the 20 years of money they gave me for diability. It is so idiotic I hate it.
Well I spend my life dedicated to “freaks like us”. For every one person who takes years to diagnose, there will be 100 in future that we can instantly treat. (1) it helps people who need it, and (2) it can unlock new mysteries of biology that we may never discover using traditional incremental biology. Best wishes.
Did you have pan leukopenia, or were specific cells (e.g. Neutrophils) decreased? I am thinking of a young lady I saw recently with bipolar disorder and unexplained neutropenia as a consult.
Oh, my, yes, constant neutropenia neutropenia as well. Even with good copper levels.
No one understands, probably except for you, that bipolar disorder is an immune dysfunction and not fundamentally a neurological problem for most of us.
And as I do, I looked up neutropenia and bipolar disorder and saw that most of the cause of neutropenia in bipolar patients is caused by medication.
Fock the system. I am proud of you that you’re seeing through it. You gave me hope.
I ordered a Dante Labs kit actually -- that seems like a solution I can afford and at least then I will have my genome on disk for anyone who wants to see it.
Good call IMO. If they still offer the download options, take all files: fastq, bam, vcf. Fastq is the raw data and can be used again as methods improve. Download it twice and check the files are the same. The problem with fastq is that it could get truncated due to interrupted download and you would not really know. They probably offer some basic report with the 200$ genome. You can get interpretation reports added in future. Data from Dante labs is quite good. Good luck!
This could be true for many professions. If I need some long-tail obscure help (suppose, for example, my car was acting up in a strange way the mechanic never had seen or heard of before) I'd expect roughly the same set of reactions. Most professionals are state machines that do X Y Z well. You throw A B C at them and few will introspect deeply into it.
Exactly this. You have to run into an individual on the long tail of mechanics that is uniquely curious about finding the root cause, or throw enough money at them that they are incentivized to track down the problem.
Doctors are no different than other humans. Your problem isn't necessarily their problem.
Sure, but coming at it from a programming/engineering background, that is a tough pill to swallow. If I'm going to a "professional" and paying them $1k/hour, why the fuck aren't they applying their full intellect to analyze my problem ? If we're supposed to expect front line doctors to be mere rule-applying automatons that just take a few pieces of input and produce outputs like "run common test X" and "apply common drug Y", that's technician-level work that should cost closer to mechanics' shop rates - where it can't just be entirely replaced by automation and self-service.
Doctors cost so much because there are artificial caps on supply in the US. So much for the hippocratic oath of "do no harm". Fewer doctors decreases access to the medical system which undoubtedly causes harm.
The main cap on the supply of doctors is imposed by limited Medicare funding for residency programs. Members of Congress who control that funding aren't subject to the Hippocratic Oath.
Not all residency programs are funded by Medicare. And even among those that are funded by Medicare, many have additional slots that are unfunded but exist anyway because a resident provides cheap labor. If a physician decides to change specialties and do a second residency, these unfunded programs and slots are their only options because Medicare won't pay for second residencies.
It's not clear whether graduate medical education programs operate at a profit or loss. The accounting is complex, and the results depend on how revenues and expenses are allocated internally.
When you are a naturally curious problem solver, it can be maddening working with service providers like doctors and mechanics and plumbers who just want to apply some known formula, spend the minimum amount of time, and cram more cu$tomer$ through the funnel. When your problem doesn’t fit into an easy, known pattern, it’s “whellp, you’re on your own. I can’t charge you enough to make this worth doing, and I’ve got 50 customers in line behind you with easy issues!”
I don't think that they aren't applying their brain. It simply can take a lot of time the work from possible cause A to Z. It doesn't matter how brilliant or applied they are.
I agree with your second point. A lot of doctors time and expertise is squandered covering A and B which could probably be handled by a bot. I think there are a lot of regulatory and liability barriers to doing this.
I do understand that even the most brilliantly engaged person isn't going to be able to do much first principles analysis in fifteen minutes, or even an hour. Rather my critique is based on the output most doctors produce, which seems quite one-way mechanical. Trying to have some mutual discussion or supplying your own input (whether from your own investigation or a different doctor) is often met with dialtone or even overt rejection.
In America at least, there's a bit of a trope among doctors who see patients self diagnosing wildly incorrectly after doing a quick scan of WebMD and various quackery websites.
Then there's the old phrase "think horses, not zebras".
Whether their funding is as a business or paid by universal care, all doctors answer to someone about how they charge for care. A doctor letting a patient dictate the course of assessment and determination of illness outside the "standards of care" is at best a potential waste of time and money, and at worst a malpractice claim waiting to happen ("you should have known I didn't know what I was talking about!") if it turns out there patient was wrong.
Edit: FWIW I have a batch of undiagnosed symptoms. I was temporarily on a new medication that cost an obscene amount of money, but it helped... Until COVID showed up, and I stopped it because it could potentially weaken my immune system. Now, my symptoms haven't fully returned, and I can't get a prescription for it again because the symptoms cross specialist boundaries, and no one specialist says that my symptoms for the area they treat are bad enough yet. (Psoriasis, joints inflammation, connective tissue pain, nervous system excitement).
Guess I'll have to wait and see if any one area gets bad enough to go to the right specialist.
> A doctor letting a patient dictate the course of assessment and determination of illness outside the "standards of care" is at best a potential waste of time and money, and at worst a malpractice claim waiting to happen ("you should have known I didn't know what I was talking about!") if it turns out there patient was wrong.
I'm flabbergasted. "At best" it leads to the patient's quality of life improving, the entire idea behind medicine. This kind of assumption that it can't possibly lead to any positive outcome is simply invalid. This thread itself is about cases where the doctor's assessments have failed to lead to any such improvement. At that point, they should either put their own time into considering other options, or at least be willing to engage with the patient doing so. Just saying "Well Ive tried the basic stuff and it hasnt helped, too bad, nothing else we can do" which is the most common outcome here clearly isn't the better option.
You missed the end of the sentence, where the best and worst outcomes were "if it turns out the patient was wrong"
Obviously, the best case scenario for any patient-doctor interaction is to have a cure in hand for whatever ails you; it wasn't even worth mentioning. That doesn't change the fact that patients are usually terrible at diagnosing themselves.
> At that point, they should either put their own time into considering other options, or at least be willing to engage with the patient doing so.
Not all symptoms land squarely within a single area of expertise. If a doctor is out of ideas, the best thing they can do is to refer you to another doctor, not to treat you like an experiment or encourage you to experiment on yourself.
If you want to be an experiment, as others here have pointed out, the best place to go is a research facility at a university.
You do realize there is a huge gulf between being an "experiment" and the narrow rubrics of assorted "specialists", right? Like seemingly your own situation!
I do understand how you have to internalize the system's reasoning if you want to get any medical care out of it. But you also have to step back and look at its constructive result - in yours it's seemingly straight up denying you the medical care you need. My own experience tells me that you should have never told the system you stopped taking the drug, which would have been less suboptimal than the situation you now find yourself in.
Also that someone is seemingly supposed to just know to seek out a research facility, rather than being referred to one in the normal course of care, is a blatant failing of the medical industry no matter how you want to spin it.
If I don't have any unique condition that I know of, besides wanting to bidirectionally converse with a doctor as two intelligent people, is there yet another type of place I should seek out?
Or a specific situation - if I'd like to consider a drug I've heard about that I think could benefit my own medical situation (lets say metformin or provigil), where and how can I have this conversation with a doctor, getting their informed opinion rather than being summarily shot down because I dared to think about my own healthcare in specific terms?
It seems like the only way to go about that under the current system would be to make the initial decision to start taking something fully on my own, obtain it from the grey market, and then just tell the doctor what I am doing and force them to work in that context rather than allow them to gatekeep the hypothetical.
I'd love to exchange thoughts with you on this. You've pretty much written down what I've been thinking for a while now and intend to do. If you're up for it I'll give you my email.
> If I don't have any unique condition that I know of, besides wanting to bidirectionally converse with a doctor as two intelligent people, is there yet another type of place I should seek out?
I'm thinking of looking for a good doctor who will be willing to do just that for an upfront $1k a day or so, possibly in India. Working as a team, spending the full 8 hours together, thinking, researching, looking stuff up - someone who seems it as a challenge.
> It seems like the only way to go about that under the current system would be to make the initial decision to start taking something fully on my own, obtain it from the grey market, and then just tell the doctor what I am doing and force them to work in that context rather than allow them to gatekeep the hypothetical.
I feel like this is a tragedy of the commons kind of thing. 95% of the people that supply their own diagnosis have no idea what they’re talking about. The doc meanwhile has only limited time to talk to that patient during their visit, so they want to get it over with so they can get to asking pertinent questions.
Yeah, I agree those are barriers and leave your information lost. From the doctor's perspective, the challenge is that they don't trust the information from a patient or even another doctor. It comes with so much uncertainty and possible caveats that makes it almost impossible to parse unless it is incredibly binary. The prevailing heuristic is simply to disregard it and start fresh. Obviously this is is a big issue when the progress a single doctor can make during a visit is limited.
Without these two things there is very little to prevent someone from setting up a low cost Clinic out of their garage.
Malpractice insurance is another Factor, but without the legal barriers I'm sure the the insurance Market would be willing to cover someone for extremely low risk basic care.
You can get many medications over the counter from a pharmacist and other countries that require a licensed doctor with 10 years of training and the US.
Meanwhile, hey Barbara can't even cut someone's hair without a year of training and expensive license to operate from the state.
I’m currently having a hard time packaging a react-native app as a cocoa pod because apparently basically no one else has ever thought to do it. It’s quite frustrating, though nothing on the level of the poor person who wrote this article.
> "I'm not sure what is going on here and I don't know how to help you,"
In my experience even this is significantly better than you'll get out of the average doctor. I'd gladly see a doctor who was willing to say "yeah, something is wrong but I have no idea what" instead of being dismissive.
> but nobody has said, "We should consider looking at your DNA to see what's up here. I'm really interested and want to figure this out with you."
You could sequence your own genome and use a service to compare it against the ClinVar database that correlates genetic variations with research.
Odds are that you won't find anything useful to your specific condition.
Most autoimmune issues are acquired, not genetic. With few exceptions, the common genetic variations associated with many diseases can't be used in a diagnostic manner. A genetic variant that increases your odds of contracting a rare disease by 10X might sound significant, but if it's truly a rare disease then you could be going from 0.001% to 0.01% odds.
The unfortunate truth is that if your condition doesn't match something that can be diagnosed with the tests available to your doctors, there isn't much they can do to forge ahead with new research on their own. That's the role of researchers, not doctors. And it takes decades to get to the bottom of conditions, if ever.
You might have some luck scouring the internet for similar-sounding conditions and groups who research them. Occasionally you can find your way into clinical trials or registered on waitlists for researchers who might need candidates to test.
> Some prescribe me something and say "see if that helps,"
That's pretty much all they're doing with her, too.
They don't seem to be close at all at actually solving her problem. I'd summarize her story as "thanks for your unique blood, it may help us create medical miracles one day. in the meantime, try this new drug, it might do something"
I had same thing. Mystery condition. Symptoms started in high school. Doctors always brushed off concerns. 20 years later, Finally body collapsed 2 years and dozens of doctors appointments to finally figure out its autoimmune Sjogrens. Second most common autoimmune after Lupus.
However doctors says I can’t have it since I’m male.
Took another year to get all the test runs and to start treatment. Doctors fighting at every step. Only when I had drastic improvement from treatment did they finally take me serious.
I'm in the same boat - unknown autoimmune disease, talked to teams of neurologists in different health networks. All they can do is prescribe treatment for symptoms, not causes, which is frustrating.
Say you get your DNA sequenced, say they even find a segment that seems "off" from other DNA sequences.
What the heck would you do about it? We don't understand DNA and protein folding enough to actually take the output of DNA sequencing and give you something to change that. We don't have a comprehensive view of the human body or biology or DNA to do anything with it. There's not really going to be much in the way of treatment for a single instance of a random negative mutation.
Approximately 20% of rare diseases get diagnosis in my lab. Note these are usually very extreme cases where the people are quite sick. More common genetic diseases are picked up by routine clinical genetics which don’t reach me. Interestingly some of the hardest illnesses to detect are those which are common but no known mechanism - since they are common they are hard to detect statistically.
If you have a genetic diagnosis you are more likely to get medical care targeting the root cause instead of treatments that can only treat the general symptoms - like anti inflammatory drug, etc. In rare cases people may get transfusions to replace their protein deficiency, etc.
You can find solace in knowing what's wrong with you and track studies for your particular gene that's off. It's not a given that your autoimmune disease wasn't at least studied at one point, knowing what the markers are and whether you have them could help track down whatever knowledge exists.
They may be able to tell things like "You are a rapid metabolizer of drug XYZ" or "You are a poor metabolizer of drug ABC". Knowing that they may be able to try more effective therapies for you that they wouldn't normally have thought of.
There are companies out there who have extensive data on which of hundreds of genetic SNPs (single nucleotide polymorphisms) correlate to which conditions that have a genetic component. They take a DNA sample, run it through their assays, and then they give you a sixty (or whatever) page laymen's description of what all your various SNPs mean for you from a medical perspective. They then give your doctor a one hundred (or whatever) page detailed description which can then be used to guide your medical care in a wide variety of areas.
For example, there might be three different main SNPs that relate to vitamin B-12. One might relate to how easily your body absorbs it. One might relate to how fast your body consumes it. One might relate to how it is disposed of in your body. And if you have the bad version of each of these SNPs, then that has a huge impact on your life -- because vitamin B-12 turns out to be pretty important (see https://www.mayoclinic.org/drugs-supplements-vitamin-b12/art... ).
But, there might be things you can do to improve your situation related to vitamin B-12, such as always using the methylated version. And maybe you just need to consume a lot more vitamin B-12 than most people. These are things your doctor can help you with, once they are armed with the DNA data.
I'm not going to mention company names here, because we have a connection to the company we've used. And this is an expensive service. So, I don't want to be accused of shilling for this company.
But my wife has already had her test. And I'm planning on getting mine as soon as I can.
And there are multiple companies in this space. Even if you don't use the same company we have, I think the important thing is that if you have major medical problems that are unexplained or difficult to address, then I think this is the kind of service that you might want to look into.
Exactly. If your doctor tells you that your symptoms are probably just anxiety, find another doctor. (Yes, anxiety is a real thing, but it's used way too often to dismiss symptoms a doctor doesn't understand.)
Even if it's anxiety, as a doctor, give something tangible, if you know the inner workings of the body, you can point at improvements. Not just "in your head, bye"
While I (probably) don't have an autoimmune disease, in knowing that I'm not the only person that have experienced that sort of helplessness navigating my way through the medical system, without even finding a defining name for the condition in question. I tried searching online for the symptoms only to find very general cases that do not have some of the main characteristics. Quite the same feeling one gets when they search for an error message only to find the source code that raises that exception. :)
Sometimes I think the medical issue I'm suffering from is annoying enough but not being able to diagnose it just adds an insult to injury. Is it that I cannot express my problem well enough to find similar cases online? Is this such an obscure case or maybe a lot more people are experiencing it but they just handle it so much better that they don't feel the urge to complain about it?
Just to be more specific and less mysterious, I'm suffering from mild chronic joint pains, in pretty much every joint starting from ankle, knee, lower back, neck, elbow and hand. The tricky bit, and the reason I didn't use plural, is that the pains only occur on either left side or right side of my body, but only one side at a time, usually the pains will switch sides (left <=> right) overnight (though not every night). It has low correlation with the intensity and volume of physical activity I'm doing. Blood tests show nothing out of the ordinary, C.T shows that I do have mild case of bulging discs in my back, which would have explained back pains (which I have) but not the issue of feeling them in just one side (along with every other joint in that side). These pains, mild as they are do not respond in any way to NSAIDs. Popping my knuckles (and every other joint you can think of) helps momentarily. If the pain level is above normal, sleeping is affected too (in fact it's almost always affected to some degree), which in turn amplify the pains as poor sleep would do.
Nerve conduction tests also revealed nothing and the doctors I've seen couldn't offer any observation. The fact that I have quite an athletic build doesn't help either since doctors note that and assume that I'm doing just fine. In fact though, these pains, which have started in my teenage years and have become worse in my early twenties (I'm in my late thirties now) take a daily toll on me, in terms of sleep, fatigue and my attention span.
I'm lucky to have been very healthy in my life other than that, but I feel that I could have done so much better if I didn't have that invisible medical issue affecting me every day.
Could be microclots. TIAs or mini strokes. They won’t show up on MRIs unless you get very lucky. I kept having stroke symptoms, one sided weakness being the biggest one.
3 years of being told it was clots. A big clot showed up in lung and nearly killed me. Put me on blood thinners and one sided weakness and other symptoms cleared up.
They ran genetic tests. I have a clotting disorder, factor 5 Leiden. Plus an autoimmune condition that is known for clotting problems.
Even 325mg aspirin will “mostly” stop issues for me.
First of all, thank you for trying to help, and I'm glad they discovered it in time and I hope it stays under control.
While I cannot be sure that's not what I have, one side weakness doesn't sound quite like it and in addition, when I tried aspirin in the past it didn't noticeably affect the level of pain I'm experiencing (nor do other NSAIDs such as Ibuprofen and Naproxen, both however work great for me in case of a headache, which I rarely experience)
Could be possibly some form of fibromyalgia which is generally not well understood, but it is likely “neuropathic pain.”. Does applying heat to the area in pain help?
Thanks, that's actually a good guess but I forgot to mention that Fibromyalgia was an option I tried to get diagnosed for but it got eliminated, I think the main thing that convinced the doctor it isn't not Fibromyalgia was pain points testing: he applied pressure to specific areas but the pain is hardly affected by pressure (or heat, which you asked about).
It's just there most of the time, feels a lot like how a stressed joint feels (to me at least), which is to say, mild and bearable but has an accumulative effect over time, a bit like the way noise can be ignored if you hear it for a short while less so once you realize you're stuck with it for 24 hours.
You typically show symptoms of autoimmune attacks, like neuropathies, elevated WBCs in blood/CSF, protein in CSF, inflammation biomarkers, etc. What becomes difficult is determining what triggers the autoimmune attacks, as it could be based on diet, stress, or any range of indeterminable factors.
Providers typically are able to eliminate most of the known autoimmune diseases, but for determining a new one, you need a research team and many years.
Most doctors, unfortunately, are pharmacological resellers. They get a list of medicines for symptoms and they prescribe it. A surprisingly high percentage of them will prescribe you these medicines regardless of your symptoms or condition.
Doctors who have a specialized and sophisticated area of expertise do exist, but they are 1. very expensive and 2. rare and between.
tl;dr: most doctors don’t give a flying f— about you or your condition.
> Far too often, women who present with hard-to-diagnose illnesses are told that the symptoms are no big deal, that the problem is in their head. They spend years going from doctor to doctor, in a desperate search for someone, anyone, who’s willing to help. This has not been my experience. From the first, doctors took my condition seriously, sometimes more seriously than I did.
I would love to know what she did to get doctors to take her symptom profile seriously when she merely presented with the same vague and often dismissed symptoms of women with complex medical conditions. I have multiple friends who get told to just get more fit, despite also having observed cardiac symptoms that worsen to any exercise.
> I have multiple friends who get told to just get more fit, despite also having observed cardiac symptoms that worsen to any exercise.
Clinically, it's rare for people (below retirement age) to have cardiac conditions that exclude any exercise.
I don't know your friends' details, but a common pattern in these situations is for there to be a misunderstanding about what "exercise" means. If someone is having life-threatening cardiac symptoms, no reasonable doctor is going to recommend that they just go to the gym and sweat it out. In the worst cases, what they're trying to avoid is the deconditioning slide that comes with chronic illness. The goal isn't to get fit or go for runs or push to exhaustion. The goal is to slow the physical health decline that comes with being too sedentary.
It can be counterintuitive, but doing extremely light activity (walking 0.1 miles per day, working up to 0.4 miles per day) can be extremely beneficial compared to avoiding activity altogether, even if it's uncomfortable.
Once the fitness is gone, it's hard to get it back. A lot of patients start out with one condition, which then becomes a combination of that condition plus a year of deconditioning.
Physical therapists trained in chronic illness specialize in these treatments and adapting to the bounds of any cardiac limits.
My mom took some medication when she had Macular Degeneration (or maybe it was for something else) and her skin started turning a slight blue tint.
Her small town (Canadian) family doctor ended up telling his friend in university and she ended up getting studied by lots of different university researchers/specialists and was even brought in front of a University of Toronto medical class to demonstrate it.
So sometimes novel symptoms result in novel research, without personal social signals.
I have a friend, he gets wild migraines all the time. Dozens and dozens of doctors over 25 years. All he can say at this point is what he thinks doesnt cause them. The issue is diagnosing these sorts of things is tough. You can not exactly crack someone open and poke around and not possibly break things plus the cost of time and money. So you mostly look at the symptoms and hope you can read the tea leaves and get it. For most things that works pretty good. But get a bit out of field of what they do and you will have a bad time with most doctors unless they happen to read the tea leaves correctly. My mother in law went from 'you have the flu' to 'you have stage 4 single cell' in under a week and was dead soon after. She went to the doctor dozens of times about it the months before. We get this idea that doctors are miracle worker wizards. But sometimes you feel like they are playing with bear skins and arrow heads.
Not even complex medical conditions; a friend with stomach pain issues was being blown off by doctors with "just lose weight" for a year before she collapsed on the sidewalk. In the hospital, they removed a 30-lb cyst from her abdomen, but I'm not sure diet and exercise would have helped with that particular weight loss.
I wish it were easier to self-test with things like CT, ultrasonic or MRI scanners. Until I went to the ER with symptoms that exactly matched a gallbladder condition I was never before let even near one of those machines, but looking at the scans the problem was so obvious. I imagine for this woman the problem would have been obvious too from a simple scan.
Depending on your definition of easy, it is. It just takes money. There are private clinics that will do full body MRI for preventative screening and diagnosis. This level of personal care is just cost prohibitive for most people
I’ve had like 3 MRI’s and 10 CT scans over the past 10 years because they’re cheap and plentiful in Japan, but they’ve only found something relevant once (to be fair, it was pretty nice they caught that cyst growing in my ass).
I’m left wondering if all those CT’s didn’t hurt more than they helped…
CT scans are pretty heavy radiation, 50 or 100 times as much as a standard x-ray. If they didn't find anything major than you are statistically worse off than if you never got them.
I'd love to contribute to non invasive medical research in any way. The risk/cost of medical procedure makes doctors refuse most of this cases. So you're gatekeeped until it's too late.
yes lol imagine how incredibly obese you have to be to not know you have a 30lb tumor. its like those women who don’t know they’re pregnant but actually even fatter
> despite also having observed cardiac symptoms that worsen to any exercise.
Isn't this the exact reason they should exercise? I'm sure the symptoms present worse during exercise, but the exercise itself will gradually make your body more resilient or even cure many cardiac issues. I'm unaware of any cardiac disease that gets worse with some form of exercise, granted there are levels of intensity in exercise no one should be attempting without proper conditioning.
Mutation in this gene arises in some cancer patients when they become resistant to a particular targeted therapy. By sheer happenstance, I am involved with an investigational compound that overcomes PCLG2-driven resistance with a targeted molecule that acts downstream of this woman's activating mutation.
I've reached out to see if we can help with a compassionate use protocol for this drug.
I sometimes think we'd be better off if we didn't come up with and name catch-all diseases. I've Sarcoidosis, which basically means I have inflammation symptoms similar to other people (~150 in 100,000), but beyond that they've basically no idea what the cause is. All attempts to identify a cause tend to identify common anomalies present in a significant portion of patients - but fairly confidently are not present in all patients. Mycobacteria (which are also mentioned in this article) for example was one such promising theory, but doesn't appear to be the cause for everyone.
It's frustrating because rather than doctors saying "I don't know, let's run some tests", it's just "Here, take this drug. It'll probably treat your symptoms." There's basically no reporting on what works for me and what doesn't, and certainly no attempt to identify potential causes - so much wasted data.
For example, as is standard practice, my rheumatologist did run a test on me for TPMT levels before prescribing Azathioprine. This is done because TPMT deficiency can lead to severe toxicity and liver damage. My TPMT results were just dandy. Alas, for some reason my liver didn't break down Azathioprine regardless and I experienced toxicity and mild liver damage. Why? Who knows, and no-one cares enough to find out. Nevermind that it could benefit others - just take Methotrexate instead. Why Methotrexate? Well, no idea, it just, kind of works. Good luck with the brain fog.
I was reading along and thinking to myself "gee, this sounds a lot like Lyme" and sure enough, she mentions she tested positive for it.
I imagine the NIH docs would have thought of that already though. I do wonder if there is an interaction between the wonky IgG/IgM and the spirochetes, that could be studied and lead to insights into Lyme.
> I imagine the NIH docs would have thought of that already though.
I'm sure they did, I think the author just isn't being honest. While I have no doubt the NIH folks are interested in the mutation, that doesn't mean they think it's responsible for the rest of her symptoms. The reality is that if she just took doxycycline as soon as she developed migratory joint pain, she'd probably be completely fine today rather than saddled with all sorts of permanent medical issues. The real story wouldn't make for an interesting article though.
She doesn't even discuss why her doctors think her symptoms are related to this mutation rather than the Lyme, which is the tell.
Just want to note that the author, Beverly Gage, recently published G-Man, an excellent, truly astounding biography of J. Edgar Hoover. I cannot, cannot recommend it enough, it totally changed how I view at least half of the American 20th Century. <https://bookshop.org/p/books/g-man-j-edgar-hoover-and-the-ma...>
I've been blessedly free of chronic illness myself, and found The Deep Places to be a good window into the shortfalls of the medical response (including being written off as nuts), even by someone who should have a tremendous amount of privilege (White male New York Times columnist)
Echoing others who are saying they can't imagine a doctor ever going to these lengths, I might never have been diagnosed with hypothyroidism if it hadn't been for an airport toll booth attendant. I've told the story in full elsewhere, but the short version is I saw doctors for two years who told my mother I was just fat and lazy and needed to get outside more. I have since encountered plenty of arrogant and dismissive doctors.
It was painfully easy for me to find my PNP deficiency.
- I had my genome run my 23andme (twice).
- I plugged the raw data into https://promethease.com/.
- I sorted it by frequency.
- Then just researched every rare polymorphism.
It would be so simple to write an algorithm that does this.
I found my own genetic condition this way. hEDS/clEDS from a TNXB mutation. I already had a strong indication that I had this by noticing rare behavior about myself was similar to other people with TNXB mutations. DNA sequence confirmed it. The vast majority people with this condition will never get a positive diagnoses from a doctor no matter how many they see, but it’s clear as day right there in the DNA.
I have an unusual gene mutation that is basically unknown. There are other mutations in that gene that cause fatal birth defects but not the one I have. It was found as part of a search for the cause of a (non-fatal) condition I've developed as I've gotten older. Luckily, while I'd like to know what's causing the condition and what, if any, implications this mutation has it's mostly an intellectual curiosity, not something around life and death. I wish this woman the best.
My ex has an autoimmune disease called lymphangiomatosis. Biggest issue is tumors in her lungs. It's some bad shit. Doctors thought she just had pneumonia when she first got sick. I really freaked out when COVID came around. I hope she's doing ok.
My wife has this, she's had half a dozen lung collapses over the last few years as the nodules separate lung from lung wall. Long term it is bad, many people are on oxygen for life. It also affects mostly women, and is likely woefully under diagnosed.
Welcome to the final frontier of medicine: The long tail of wierd stuff.
The better we get at solving the more common problems, the more chances we have exist with long tail ones (we get to survive to express them!) and detect them.
The problem is that medicine is fundimentally organized in a way poorly equipped to handle intersectional problems that will occupy more and more of the problems that people have...
Often the condition exists but it's obscure. I suffered for years with crippling spasms, then found out about Stiff Person Syndrome. I asked my doctor for a prescription for a specific muscle relaxant and it's not perfect but I'd say things have reduced by over 50%.
I find it a bit concerning when articles like this assume that all 7 billion people have had the resources to get the kind of check ups that would have their samples in a global database of genetic mutations.
Well, at least for the kind of de novo mutation that the article is talking about, it's vanishingly unlikely that anyone has the same exact mutation. It looks at a cursory glance like the gene in question is ~180k base pairs long, so the idea that someone else also has this (potentially fatal) truncation in the same spot is really unlikely. Especially if the mutation would be fatal if it were misplaced a bit.
It's also a bit of misdirection, since the net effect is "half of your PLCG2 expression is turned off", which is probably also represented in that 60 similar patients the article talks about. So it's technically true but almost certainly something that other people have as far as a "half knockout of gene XYZ".
I've got at least two ideopathies going on and some friends with chronic pain that nobody can figure out. It sucks.
We probably need to test people for toxins in their systems. We are all probably running around with enough of five different things in our bodies that if you swapped them all for one you'd end up in the ER. It's just enough that you feel 'yuck' three different ways but aren't dying.
It was founded and is run by Matt Might, a computer scientist and former Obama-admin CTO for the US. He wanted to solve his own son’s medical issues and now is helping others. A family member works there as a pathologist and while treatments are expensive, they’re also bespoke. And sometimes it’s better to have answers, and a sliver of hope, than nothing at all.