Familial Transthyretin Amyloidosis
 

My students and I have done a fair bit of work on the basic science of the TTR amyloidoses, including a number of published papers.

Familial amyloid polyneuropathy (FAP) is usually associated with the L55P mutation (very aggressive) and sometimes the V30M (less aggressive) mutation in the TTR gene.

As the article says, FAP is an autosomal dominant condition which means that somebody only needs to inherit one copy of the mutant gene to get it. It is very uncommon, mainly affecting kindreds from Sweden and Portugal.

In practical terms, what this means is that somebody who is at risk of FAP will have a strong family history of it (sporadic amyloidogenic mutations in the TTR gene are extremely rare).

If there is no family history then there is nothing to worry about.

Thanks, Kiwi. My neuro will soon test me for it. I'm not too concerned that I have it, but my uncle and father are simultaneously exhibiting some issues that overlap, though no neuropathy I think. I just skimmed the article but will sit down and read it when I get a chance tomorrow. Given that you're working on this, perhaps I can ask you this in advance: how accurate will the genetic testing that my neuro will do be? Should I also push for a fat pad biopsy?

My own worry is that it could be Amyloidosis, but perhaps not familial. Thanks in advance.

Genetic screening for L55P or V30M is very easy and accurate to do. It would take my lab (we are not a commercial set-up) about a week. I wouldn't worry about a fat pad biopsy.

Neuropathy can be associated with amyloidogenic proteins other than TTR. The information in this link might give you something to think about and discuss with your neurologist; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531896/.

Thanks, Kiwi. I've read that among other things a few months ago when Amyloidosis was suspected. If I'm not mistaken, the piece I posted, which I'm now going to read in detail, notes many other mutations and not just those two, no? Is it that those two are the most common?

Yes, it can, and my main concern is primary, or even secondary (though to a lesser degree), but my neuro seems to think familial, I'm not sure quite why. We'll see.

Regarding the fat pad biopsy, why do you think I shouldn't concern myself with one? If you mean for familial, I understand, though I could have a mutation that has yet to be recorded. For the non-genetic ones, it's the surest way to diagnose, about 80% or higher precision, short of biopsying the organ itself.

Thanks again for your input and assistance.

"Regarding the fat pad biopsy, why do you think I shouldn't concern myself with one?"

Oops, my mistake - I don't know much about about amyloidosis from a clinical perspective.

After a bit more reading I agree with you that a fat pad biopsy would be a good plan.

Thanks, Kiwi. Good to know. Now to find someone to do it short of going to the Mayo Clinic or Boston.

If you read this, I'm curious whether it's possible that they find a new mutation with me and just don't know. I'm quite ignorant when it comes to genetic testing, so I'm basically wandering if when they test me they'll first notice a mutation, and then have to inquire whether said mutation is a dangerous mutation. Thanks.

I am not too knowledgeable about this but aren't there other non hereditary forms of Amyloidosis? Owing to a frequently high total protein in full blood count and a widespread small fibre neuropathy and history of Rheumatoid - my rheumatologist requested a Bence Jones urine test to check for Amyloidosis or Multiple Myeloma. I got a bit freaked out when I found out what he was looking for but had a phone call late on Christmas Eve saying it was negative. Hugely relieved but have been wondering what is making my protein high, also evidenced by paired oligloclonal bands in my spinal fluid and serum blood.

Do you happen to know whether it's still possible to have Amyloidosis or MM with a negative Bence Jones?

Yes, there are three general types, I believe: primary, secondary (both of which are not hereditary) and familial. I don't know about your last question, perhaps someone more knowledgeable than I can offer information, but I can say that urine tests are not accurate for diagnosing amyloidosis. The most accurate test that's minimally invasive but quite accurate, upwards of 90%, is a fat pad biopsy. This can detect amyloid deposits. The most accurate is to biopsy the organ tissue itself, if a particular organ, say the kidney, is suspected, but that's obviously much more invasive. I hope this helps.

Yes thanks. I'm guessing that they think that I'd be much sicker now if I had Amyloidosis but I was very sick indeed for a lot of last year. I hope you get answers for yourself sooner than I have David. Mat

Thanks, Mat. Much appreciated. I hope so too. I'm in the same boat: better now than earlier, so I don't think it's Amyloidosis, but one never knows, and it could always be the calm before the storm. Now I'm just being negative...

Regardless, I thought I'd look into it and it seems my neuro seems to think at least familial could be possible. There are slowly progressing types, and one never knows how to interpret all these signs and symptoms when ill, so perhaps I can find someone to do a biopsy soon.

I hope you get some answers too, it's what I hope for all of us, since we're all searching, or most of us at any rate.

David I do understand. I seem to alternate between panic and thinking I'm a hypochondriac. But I had RA five years ago and this led to me taking various immunesuppresants. RA seems to have gone into remission and I couldn't tolerate the drugs so this is good. I'm too stressed out by other stuff such as buying a house that reeks for as yet unknown reasons, uncle dying and other more minor stuff. I haven't time to be worrying about forms of cancer - I just have to trust my instincts that something is wrong and I feel it must be immune mediated because I've had RA. But Amiloidisis is very closely related to RA so this doesn't reassure me too much!

"Do you happen to know whether it's still possible to have Amyloidosis or MM with a negative Bence Jones?"
Yes, it is possible.

"I'm curious whether it's possible that they find a new mutation with me and just don't know."
It could happen though finding it out would be more complicated to discover (full sequencing your TTR genes) rather than just checking for L55P or V30M.

If you do have a novel TTR mutation, possibly linked to your neuropathy, then Professor J W Kelly at the Scripps Institute would be worth getting in touch with.

He is very approachable (he gave us a plasmid with the L55P mutant in it - we used that to make many other mutants). He has done lots of work on TTR amyloidosis, including developing experimental drugs which may block it - he could have some suggestions for you.

Thanks. If I do, I will do so. I've already looked up his contacts details.

I see. And is that not normal for a lab? I mean, should I request it from my neuro or at least inquire what will happen?

Also, I'm somewhat confused, since the list of known mutations is much longer than those two. Here: http://amyloidosismutations.com/mut-attr.php. Wouldn't every lab at least check for every known mutation? You seem to be saying those are the most common? Even if so...

In all honesty, I sincerely hope I don't have Amyloidosis.

Mat, I'm sorry for your loss. I'm also sorry to hear you're having stress from those issues. Ah, buying a new one is always a stressful event, even when it goes smoothly. I hope you can get past this stuff sooner than later. I know, easier said than done.

I believe Amyloidosis and RA can go together, though I doubt it's that common, though don't quote me on that. It's then called secondary A., I think.

I hear you. I am getting better and worrying less really, much less. But that's for now and the vitamin D has helped, but I don't know how I will in the future. I used to be a serious hypochondriac in my earlier days, though I got over that for the most part. But it doesn't help when one is ill and can't figure out the cause, not to mention when the illness causes so many symptoms. Alas, we do what we can, I guess! :)

DavidHC, you are right - there are many TTR mutants which form amyloid fairly quickly. Even normal (wild-type) TTR can do this, though slowly - this is associated with Senile Systemic Amyloidosis, which mainly affects people who are 80+ and often leads to heart damage.

I think that, if only for your peace of mind, getting checked out for all of those possible mutants is a good idea.

It could be done in two ways; sequencing both of your TTR genes or doing a SNP (Single Nucleotide Polymorphism) screen. The latter is what 23andMe does, though there may be other entities who can also do that.

Your neurologist should be able to advise you about this.

Kiwi,

You've been most helpful. Thank you. I'll speak with my neurologist further and see what precise test he intends to have done.

Again 23andMe has come up. Perhaps I should have it done. I wonder how realizable it is. I presume there's no difference between providing one's saliva to them as opposed to one's blood to some non-commercial lab/company. I'll look into it. I'll contact 23andMe and see what they do in Canada (apparently there are now some issues for them in the US) and whether they cover all the mutations for Amyloidosis. I'll also speak with my neuro.

Edit/Addition: I managed to find this: https://www.23andme.com/en-ca/health/reports/, which mentioned only the following mutations, far fewer than the list I posted earlier with all (I think) known mutations:
Thr60Ala,T60A, p.Thr80Ala, c.238A>G
Val30Met, V30M, p.Val50Met, c.148G>A
Val122Ile, V122I, p.Val142Ile, c.424G>A

I'll still call them and speak with them just in case they do more, or can do so.

Found this also: http://www.mayomedicallaboratories.c...Overview/83674

I am surprised that the 23andMe coverage of TTR SNPs is seemingly so small. They buy the SNP library from a reputable source (Illumina) - might be worth checking with them.

The Mayo Clinic has an excellent reputation and their approach looks sensible to me.

Thanks, Kiwi. I'll be calling 23andMe tomorrow morning to inquire about this. I'll also speak with my neuro and see about sending the sample to the Mayo Clinic and asking for a thorough test. Thank you for all your expert assistance.

Hi David,

Although I don't have any known family history my Neuro Doctor wants to test me for FAP. The test kit is from "Athena Diagnostics" and is sent to ones home. Then one can either take the kit to a Quest Diagnostics location (they own Athena) or they can send someone to your home to draw the blood. Here's a link to Athena's site; http://www.athenadiagnostics.com/ And here's an interesting article I found about Amyloid Neuropathies; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531896/

I'm not sure there's adequate evidence in my case to warrant testing but she seems to think it's worth it. I'm not sure if I will proceed or not.

Cliffman :)

Thanks
 

Hi Cliffman,

Thank you for this. Much appreciated. I'm waiting to hear from him about where he wants to do the testing. Once I know that, I can proceed. If it's a quality place with thorough testing, then we'll just proceed. This is a good resource. I also appreciate the article, which is a good look at the subject as a whole.

I'll speak to my neuro when he does call. How about you: if you don't have to pay for it/if insurance covers it, why not do it? I think non familial forms are possible in my case, but I don't know.

Be well!
Dave

There is a commentary on amyloidoses which are known to be associated with PN as well as other conditions here; http://neuromuscular.wustl.edu/nother/amyloid.htm.

My informed guess (it is no more than that) is that amyloidosis may be linked to PN more often than is currently suspected.

Where we go from here is not clear. There is good evidence from animal models that insoluble amyloid is relatively inert - what does the damage is soluble aggregates along the amyloid formation pathway. Currently there are no generic drugs which can block this process.

I tell ya David after reading about it I sure hope the test comes back negative! Yikes....

I have to find out if my insurance co. will cover it. Please let me know if you proceed in getting it done.

Thanks,
Cliffman :)

Kiwi,

Is there a non-generic drug in the works, some company working on something that has proven efficacious? On an entirely unscientific level, at least in respect of mechanism of action, I like to think that diet can make a huge difference here too, at least in non genetic forms.

No kidding! You and me both. I doubt I have Amyloidosis, but whether I acquired it via something infecting me, altering my body, etc., I can't say. I would be quite surprised if I had a familial form. And last I checked, those with Amyloidosis don't improve with dietary and other lifestyle, though it's not like there have been studies, or that I know of many cases or commentaries on the issue. My neruo will likely get back to me about this issue soon.

Thanks. :)

DavidHC, by far the most common amyloidosis is Alzheimer's Disease. Pharmaceutical companies are putting a lot of effort into finding drugs which can treat it because they know that effective drugs would be very lucrative for them.

Most of the other amyloidoses are so-called "orphan diseases" - they do not affect many people though I suspect that they are under-diagnosed including, possibly, in PN. Sadly, it is not in the commercial interests of pharmaceutical companies to put much effort into them.

In general amyloid formation goes like this:

(1) Native protein ---> partly unfolded protein.

(2) Partly unfolded protein ---> soluble aggregates (sometimes called protofibrils).

(3) Protofibrils ---> insoluble amyloid plaques.

Steps (1) and (2) differ for each amyloidogenic protein so it will be difficult to develop a generic drug which blocks them.

As far as diet is concerned some protofibrils can bind metal ions, particularly Cu and Fe ions - this can lead to oxidative damage in a tissue where amyloid formation is happening. This means that eating lots of fresh fruit and vegetables (good sources of natural antioxidants) is a good plan, quite apart from general health benefits.

Thanks for this information, Kiwi. Yes, the infamous amyloid beta protein. Makes sense. Sad, but true. I wonder what it would be like to live in a world where health care and treatment were not determined by capital...

Interesting and a shame that given the nature of the process, a general drug can't be used to block any such protein formation.

And now I know the science behind it. I'm not surprised nutrition can help. I've done wonders for myself just eating well. Actually, this reminds me of a study I read a few months back. This one: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1282589/. And now I'm reminded of this one: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367001/. I've been on a paleo ketogenic diet for several months, lots of healthy fats, proteins, and veggies.

Thanks again for this.

Okay, so I finally heard back from my neuro. He wants to go through Athena Diagnostics, and I believe this is the test they will do: http://athenadiagnosticsca.virtual.v...detail/q/id/99.

I was told that they would be doing the TTR DNA sequencing, that's all. Kiwi, in your expert opinion, will this be thorough enough, or no? I'm going to look over our past discussion to see which course they're taking and whether I can answer my own question.

Thanks in advance.

DavidHC, Athena have a good reputation.

What they propose doing is the "gold standard" approach.

PCR will amplify the DNA which contains your TTR genes and DNA sequencing will then show if you have any mutations in your maternal or paternal TTR genes and, if so, what they are.

This won't say anything about possible mutations in other amyloid-forming proteins which have been linked to PN.

Thank you, Kiwi. I appreciate your help here. It appears that's precisely what we discussed as the gold standard: complete DNA sequencing. I'll likely not know the results for another few months, but let's hope I show no mutations. Amyloidosis is not something one wants to have.

I appreciate this other bit of info too. What tests would one get for that? I suppose in the end, I should try to get a fat pad biopsy, so as to rule out that I have Amyloidosis of any form.

A fat pad biopsy could help.

It would involve:

(1) Staining a biopsy sample with a dye which is specific for amyloid.

(2) If there is amyloid there, stain a series of biopsy samples with antibodies specific for the various proteins which can lead to systemic amyloidosis.

(3) Depending on what that shows, it would then be possible to do DNA sequencing (same as you have arranged for TTR) to see if there are any mutations in the genes for those proteins.

There is a more technical explanation of this here; http://www.cytojournal.com/article.a...ulast=Halloush.

Hi David,

In my instance the insurance co. won't pay for it. They charge $1770.00 for the test at Athena or depending on one's income from the prior year it can be less. Given the cost I will pass.

I'm praying your results are negative if you decide to proceed.

Cliffman :)

Thank you, Kiwi. A question: do you know if the protocol is to do DNA testing of the sample in order to see what type it is? I can ask the physician too, but thought I'd throw that out there in case you know off the top of your head.

Regarding the link you posted, see the "Discussion" here for the limitations of the aspiration method: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2580046/

If I can manage to get this, I'll insist on the larger sample, not the simple and clearly unhelpful aspiration.

Wow, that's pricey! Sorry to hear that you can't get the test. But I wouldn't either, if that were the price. No way. Mine will be covered by the public health care system here, so I'm glad. But I sincerely hope it comes back negative and I really do think that will be the case. I appreciate the kind thought and good vibes sent my way. :)

DavidHC, getting a decent-sized sample, per your link, is a good plan.

If there is amyloid there then staining samples of it with antibodies specific for the various amyloid-forming proteins will show which protein(s) are involved. However this will not show if the proteins are normal (wild-type) or if they are mutants - this is where DNA sequencing comes in.

Interesting. Thanks. And this would be relevant clinically/for treatment? Clinically, amyloidosis is treated according to type, but I'm not sure if that means needing to go ahead with the DNA sequencing.