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Folate Receptor Antibodies

adreno

PR activist
Messages
4,841
I found this recent study on folate receptor antibodies in autism interesting. I am wondering whether folate receptor antibodies could be a problem for us, too.
Mol Psychiatry.2013 Mar;18(3):369-81. doi: 10.1038/mp.2011.175. Epub 2012 Jan 10.
Cerebral folate receptor autoantibodies in autism spectrum disorder.

Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA.
Source

Department of Pediatrics, Arkansas Children's Hospital Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202,USA. REFrye@uams.edu
Abstract

Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.
PMID:22230883
 

dbkita

Senior Member
Messages
655
I found this as well:

http://www.ncbi.nlm.nih.gov/pubmed/18461502

There seems to be an implication in this abstract plus some stuff by Dr Neubrander that these autoantibodies to folate receptors prevent dispersion of folic acid derivatives into the CNS and are pretty crippling though treatable. I think there is some association between the lower functioning autistic children and the antibodies. I need to research more though I am pretty swamped with other stuff right now (like my sinus bacterial infection).
 

adreno

PR activist
Messages
4,841
J Inherit Metab Dis.2012 Jul;35(4):665-70. doi: 10.1007/s10545-011-9418-1. Epub 2011 Nov 23.
Update and new concepts in vitamin responsive disorders of folate transport and metabolism.

Watkins D, Rosenblatt DS.
Source

The Hess B and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone, and Department of Human Genetics, McGill University Health Centre, 1650 Cedar Avenue, Room L3-319, Montreal, QC, Canada. david.watkins@mcgill.ca
Abstract

Derivatives of folic acid are involved in transfer of one-carbon units in cellular metabolism, playing a role in synthesis of purines and thymidylate and in the remethylation of homocysteine to form methionine. Five inborn errors affecting folate transport and metabolism have been well studied: hereditary folate malabsorption, caused by mutations in the gene encoding the proton-coupled folate transporter (SLC46A1); glutamate formiminotransferase deficiency, caused by mutations in the FTCD gene; methylenetetrahydrofolate reductase deficiency, caused by mutations in the MTHFR gene; and functional methionine synthase deficiency, either as the result of mutations affecting methionine synthase itself (cblG, caused by mutations in the MTR gene) or affecting the accessory protein methionine synthase reductase (cblE, caused by mutations in the MTRR gene). Recently additional inborn errors have been identified. Cerebral folate deficiency is a clinically heterogeneous disorder, which in a few families is caused by mutations in the FOLR1 gene. Dihydrofolate reductase deficiency is characterized by megaloblastic anemia and cerebral folate deficiency, with variable neurological findings. It is caused by mutations in the DHFR gene. Deficiency in the trifunctional enzyme containing methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase and formyltetrahydrofolate synthetase activities, has been identified in a single patient with megaloblastic anemia, atypical hemolytic uremic syndrome and severe combined immune deficiency. It is caused by mutations in the MTHFD1 gene.
PMID:22108709
 

globalpilot

Senior Member
Messages
626
Location
Ontario
Yes, it could be a problem.
there is a lab in the US that tests these antibodies. Do you know of it ? I had it done last year and can look itup if you want/need. It turned out to not be an issue for me - nice to rule things out though.
 

dbkita

Senior Member
Messages
655
Yes, it could be a problem.
there is a lab in the US that tests these antibodies. Do you know of it ? I had it done last year and can look itup if you want/need. It turned out to not be an issue for me - nice to rule things out though.
Yeah that would be good information to have. Thanks.
 

adreno

PR activist
Messages
4,841
One thing I don't understand is why folinic acid is all the rave. Wouldn't 5-MTHF work even better?
 

aquariusgirl

Senior Member
Messages
1,732
http://www.research-in-germany.de/n...enital-genetic-defect,sourcePageId=66910.html

this paper may provide some clues as to why folinic acid is helpful.. it bypasses a defective DHFR enzyme
(
To clarify whether a patient has symptoms caused by DHFR gene defects, Cario recommends measuring the concentration of folate in the liquor and in the red blood cells as this defect is characterised by lower folate concentrations in both liquor and red blood cells despite normal values in the plasma.
 

Little Bluestem

All Good Things Must Come to an End
Messages
4,930
If my red blood cell folate is normal [147], does that mean that my body is able to use the types of folate that I am eating?
 

dbkita

Senior Member
Messages
655
One thing I don't understand is why folinic acid is all the rave. Wouldn't 5-MTHF work even better?
Half-life is much longer and goes through the BBB just like l5mthf. I think harder to control l5mthf levels as evidenced by people on these boards and their own testimonials. I bet the idea is to flood the CNS with a form that is more stable. Doctor's would want to target a precise concentration after all just for the sake of measurement (poor kids with all those damn spinal taps *shudder*).

As we have witnessed on these boards while l5mthf is superior in virtually all functional respects the amount you have to take to achieve a high enough diffusion gradient across the BBB and into the CSF may be something doctors are unwilling to try. But their objectives are probably different in certain respects anyways. I applaud them for at least getting beyond folic acid. Woot!

Both folinic acid and l5mthf would bypass DHFR since they are post THF.
 

adreno

PR activist
Messages
4,841
As we have witnessed on these boards while l5mthf is superior in virtually all functional respects the amount you have to take to achieve a high enough diffusion gradient across the BBB and into the CSF may be something doctors are unwilling to try.
Are you saying here that a single large dose of 5-MTHF might be more effective (in terms of CNS penetration) than several smaller?
 

dbkita

Senior Member
Messages
655
Depends on the objective. The problem is l5mthf is not very stable with a short half-life compared to folinic acid. Not an issue if the folate cycle is turning the crank well ... if not ... well you get the idea. I am seeing people on these boards with especially CNS issues having to take pretty high doses of Metafolin multiple times a day. First the dose to get diffusion into the CNS and repeat dosing to maintain the concentration. Folinic acid while I am not advocating it in this context, does not suffer from the latter concern. My problem with folinic acid is what the heck does a person do if they can't convert and utilize it at a fast enough rate? On the other hand l5mthf if one avoids the folate trap, won't have those issues just maybe the inevitable effects of increased methylation.

That being said I don't know the answer for myself. If I increase methylation either via methylfolate increase or cofactor increase, I will first feel better and have more energy and more neurotransmitters but will also after several days have unsolvable potassium problems and increased inflammation / pain.When I mean unsolvable I mean anything requiring 10 grams or more intake of K, which is not a tenable state. This represents an electrolyte disequilibrium that cannot be a good idea, I don't care what anybody says.

I am waiting to see what happens with an HDRI methylation panels test before I move in any direction. If anything my recent amino acid tests that showed HIGH sarcosine in the non-fasting late afternoon, a few hours after methylation supplements and LOW sarcosine in morning fasting tests (before supplements), suggests I have a HIGH SAMe / SAH ratio. I need to confirm that. If so, higher methylation is not necessarily the answer for me.I actually hope not and the high sarcosine means more of a temporarily low THF availability due to a pseudo folate trap maybe due to my swarm of MTRR mutations. That would be easier to rationalize and deal with.

Then again it may be more about my BHMT and MTRR defects than any issues in the folate cycle or MTHFR. I take 2.5 grams of mb12 and 2.5 grams of adb12 per day. I only take 800 mcg of methylfolate but when I up p5p I get into real problems. Remember I don't have the usual MTHFR defect that most on these boards have. In fact the one I have lends itself to hyper-methylation as the allosteric SAMe binding domain on MTHFR is less functional. That hurts BH4 but also means self-regulation of methylation cycle is not nearly as good. I actually CAN hyper-methylate at least in theory.

On the other hand my SHMT homozygote may actually really be part of a fragile haplotype with reduced SHMT1 activity. In which case my folinic acid store may be a problem. Well then I need to see that in the tests before I contemplate moving on it. My only issue is I honestly don't know if it is better to test non-fasting after methylation or in the morning before supplementation. I am leaning towards the former. Questions, questions.
 

adreno

PR activist
Messages
4,841
Hm. It seems to me that what you describe is what happens with paradoxical "donut hole" deficiency. It's like more demands more. When I take high doses of 5-MTHF I feel better at first, but there is a sort of crash when it wears off, demanding another high dose. And though I don't have hypokalemia, I do still get some side effects on high doses, such as increased irritability and SNS activation. Not sure that is good.

On the other hand, when I my 5mg MB12 in the morning, there seems to be a demand for 5-MTHF that is only satisfied after 2400-3200mcg. So I'm not quite sure what to do. Maybe a methylation panel is a good idea.
 

dbkita

Senior Member
Messages
655
Hm. It seems to me that what you describe is what happens with paradoxical "donut hole" deficiency. It's like more demands more. When I take high doses of 5-MTHF I feel better at first, but there is a sort of crash when it wears off, demanding another high dose. And though I don't have hypokalemia, I do still get some side effects on high doses, such as increased irritability and SNS activation. Not sure that is good.

Some of the latter symptoms may be neurotransmitter increases, no?

In terms of donut hole deficiencies what I think has to be asked, is how well does the "water wheel" turn? It is meant to be an efficient recycling system for folate and mb12. Self sustaining. If a person's water wheel is broke then you "shove" it with supplements and it moves but will it keep rolling? Unlikely. So to maintain you need to keep pushing. Over and over. But a person whose "wheel" is not stuck, they are far more self-sustaining. Or maybe their wheel was stuck due to ATP issues as Freddd has discussed in his Deadlock quartet thesis and suddenly correcting Krebs flow makes the "water wheel" move again. It is hard to say I think.

On the other hand, when I my 5mg MB12 in the morning, there seems to be a demand for 5-MTHF that is only satisfied after 2400-3200mcg. So I'm not quite sure what to do. Maybe a methylation panel is a good idea.

I take my l5mthf first then take my mb12 like 30 minutes later. Too much time gap is not good I have found empirically. But I definitely do better taking one before the other personally. Have you thought of spreading your methylfolate out over the day?

But yeah I have reached a point I simply need more data before I can choose a path. Theory only goes so far in biochemistry (sigh I miss physics).
 

adreno

PR activist
Messages
4,841
Have you thought of spreading your methylfolate out over the day?
I do try to spread it out. But as I said, when I take mb12 in the morning, it creates a demand that is not satisfied until I reach 2400-3200mcg. Of course, I can just ignore that and drag the symptoms out. But I seem to have a higher need in the morning compared to the afternoon/evening.

Yesterday I got up to 6000mcg. I think I could easily have taken more. But like I said, it seems the more I take, the more I need. And I don't feel any better on the higher doses. I doubt the idea that if I stay on high doses for a long time, some "healing" will occur, and I will suddenly feel much better. So I think for the moment I will try to stay around the 2400-3200mcg mark. Maybe I should try increasing B12 instead.

Methylation panels are nice, but also expensive. Especially as I would have to ship to another country. And you need to have the panels regularly or they make little sense. It's not a one-time deal. Also it's big hassle to get the blood drawn. We don't have Labcorp around here.
 

Asklipia

Senior Member
Messages
999
I believe that this paradoxical "doughnut hole" deficiency does happen clinically.
But I also believe that it is not a new phenomenon in our lives, that it has happened before on a less obvious level and that the state of disease we are in is in itself a symptom of a larger "doughnut hole".

I think that the genetic mutations are the tool by which we try to escape the doughnut hole. One of the questions is : how fast do they happen? The received idea is that they happen very slowly and that it takes generations, but if the doughnut hole can appear in a few days, there must be a way in which the ingredients pop up fairly fast after a folate ingestion, creating the necessity for the doughnut hole to appear.
Are we genetically modifying ourselves rapidly with our efforts to counter the modifications induced by the added folates? In successive opposite directions? This is my concern. It could be AWFULLY tiring.

If we are in a balancing act folates/B12 which has gone terribly wrong, maybe we can find a third way, a metabolic state in which we can take refuge as often as possible so as to build up our resistance to the fluctuations.
This has happened several times in my life, so I intuitively know it IS possible.

Lots of good wishes
Asklipia
:devil: FFP :devil:
 

Xara

Senior Member
Messages
135
Location
The Netherlands
I have one day of a higher intake behind me, so who am I to take part in this debate... - I like being bold. :)

Yesterday's intake: 4 x 3 of 800 mcg solgar mfolate, 3 x 3 mcg mB12 ENZ, 2 x 4 mg mB12 AOR, a 5 mg B12 injection IM, 2 x 10 mg aB12 AN.

I was quite disappointed with the outcome really. In the afternoon I noticed a slight irritation, prolly not because of the higher mfolate intake but because of (high) expectations that were not met: I did not notice anything, not until late in the evening, after my third intake, only then did I feel SLIGHTLY better, my mood changed, but it may have well been a placebo effect, being that small. When I went upstairs to go to bed, I noticed it took me more energy to take the stairs. My sleep was not as good as it has been for the last couple of weeks, my body was not in a sleeping mode, it took me at least an half hour or so to fall asleep, despite melatonine, and I was awake earlier than normal. I think the larger and later intake of mB12 was to blame.

This morning I'm in a good mood, feeling rested. No big changes. So I decided to take this week 2 x 3 methylfolate (before breakfast and lunch), 1 x 2 methylfolate (before dinner) and 1 x 1 methylfolate (before snack in the evening), no changes to the rest of my intake, so I'll take the above this week, apart from the mB12 injection, which will take place every other day. I am curious what will happen in the next two days, with my potassium need.

And I don't feel any better on the higher doses. I doubt the idea that if I stay on high doses for a long time, some "healing" will occur, and I will suddenly feel much better. So I think for the moment I will try to stay around the 2400-3200mcg mark. Maybe I should try increasing B12 instead.
I know I had a B12 deficiency (serum B12 119) before starting with B12 injections. So I am keen on making sure there's plenty of B12. Also I am aiming at CNS ever since reading Freddd's protocol, that means a high dose.

Getting a high dose in the serum thus diffusing it into the CNS, I figured that would apply to mfolate too. So, unlike you, I say: if I stay on high doses for a long time, some healing might occur, and in time I may feel better. I don't expect healing in the CNS will make me "suddenly feel much better". Slowly and gradually are the words when I think of healing in the CNS.
I could be wrong of course.

O, btw. I measured my BP and pulse, hoping they would have come up a bit already. BP stayed the same (90/60), pulse yesterday late in the evening: 49, this morning: 50. I was surprised, I did not expect that direction, but it's too soon to tell of course.
 

dbkita

Senior Member
Messages
655
Methylation panels are nice, but also expensive. Especially as I would have to ship to another country. And you need to have the panels regularly or they make little sense. It's not a one-time deal. Also it's big hassle to get the blood drawn. We don't have Labcorp around here.

Understood. But I feel I need data.

Not sure why you think a test panel is not going to have value unless taken as an ensemble. Having been on methylation for some time now, I would bet the first one will still provide a lot of information about what my current baseline is, having been in steady state for some time now. For example if my folinic acid levels in white blood cells and serum are normal, why would I supplement it? If my SAMe / SAH ratio is high then I am over-driving things and need to reconsider. Additional tests would be provide information about changes. Right now I don't know which direction to go.

And yes $295 is a lot of money, but what is the cost of all the supplements I take each month? That adds up real fast too.

I am just amazed you can get up to 6 mg of methylfolate with no potassium symptoms. That stuns me. I wish I knew your secret, hehe.