Folate receptor antibodies and cerebral folate deficiency

[Karin]

Hi,

I wanted to pass on something brand-new in biomedical autism research, which might or might not apply to some cases of ME/CFS: folate receptor antibodies and cerebral folate deficiency.

From what I understand, the presence of these antibodies impairs transport of folate from the blood to the brain. As a result, brain folate levels can be low while blood levels are normal. The only way to know for sure is to measure folate levels in the spinal fluid, but the presence of these antibodies in the blood is strongly correlated with CSF levels and less invasive to measure.

Low folate levels in the brain can result in an array of neurological dysfunction. The good thing is that this condition is treatable with very high dose oral folinic acid (Leuvocorin) and with a dairy-free diet. These measures allow to restore folate levels in the brain.

The reason for a dairy-free diet is that milk, especially bovine milk, includes analogs to human folate receptors. This is believed to be the trigger for this autoimmune condition, and of course results from a damaged gut-blood barrier, which is believed to be at the root of many autoimmune problems anyways (and one candidate as the agent damaging this barrier is XMRV, in my personal opinion).

Anyways, for those wanting to research it more, here is some reading, but there is ton more:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715943/

Dev Med Child Neurol. 2008 May; 50(5): 346–352.
A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome
Vincent T Ramaekers, MD, Jeffrey M Sequeira, MS, Nenad Blau, PhD, and Edward V Quadros, PhD*

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

Neuropediatrics. 2007 Dec;38(6):276-81.
Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits.
Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV.

http://www.autismone.com/content/remarkable-findings-auto-antibodies-testing-and-treatment

New data shows that many children with autism and their parents produce auto-antibodies to a folate receptor which can lead to a condition called Cerebral Folate Deficiency (CFD). Multiple studies have shown CFD can cause autism, seizures, mitochondrial disease, motor abnormalities or other neurological problems. Dr. Rossignol will review recent studies and research on testing for these antibodies and innovative treatments that are typically covered by insurance. He will also discuss his current IRB approved study he is conducting with Dr. Richard Frye. Case studies treated by Dr. Rossignol over the last 9 months on newly diagnosed children, tough nut children and, surprisingly, their parents will be presented. This technique will potentially be invaluable for prevention, early intervention, and treatment of autism.

[Karin]

I wanted to pass on that I have been found to have significant levels of folate receptor auto-antibodies and wanted to post my response to almost four weeks of treatment with Leucovorin, a high-dose folinic acid drug.

I am posting this in this section because I have not been diagnosed with ME/CFS. However, I still want to notify you guys, because my doctor said he has patients with CFS who have these antibodies too and have been greatly helped by Leucovorin, and I also have many symptoms in common with ME/CFS. I also have a child with autism, who also has these antibodies. My other child who is neurotypical does not have them. My diagnosis is depression with IBS. I have depression, multiple food sensitivities, low blood pressure, frequent heart palpitations, night sweats, dysbiosis, dizziness, low stamina, and fatigue. It all started suddenly in 1995. I have not been tested for XMRV. All my regular blood work always looks good, including thyroid and adrenals.

Due to my IBS and food sensitivities, I have been on a dairy-free gluten-free diet for over four years (also have eliminated many other food items). I have also been on a comprehensive regimen of supplements for years, including methyl-B12 shots. I am also on Zoloft which has been the greatest help so far. Going on a gluten-free/casein-free diet was very helpful too, especially decreased my anxiety levels a great deal.

But back to folate receptor antibodies:

These receptors are found on the brain choroid plexus, and allow the transfer of folates from the blood to the CSF. They are also found in the intestines (edit: I think I was wrong there, I don't think there are in human intestines) and in the thyroid. Having these autoantibodies means that a portion of these folate receptors are blocked and this decreases the transport of folate into the CSF and other areas. That means that even with adequate folate intake and adequate folate levels in the blood, the folate levels in the brain, thyroid and intestines can be lower than normal. This results in not enough folate for the production of neurotransmitters, not enough folate for the production of glutathione, etc... with negative consequences for neurological function and immune function.

Treatment for this condition is high-dose folinic acid, about a hundred times the recommended daily intake. This is available as the drug Leucovorin. Plain folic acid is not recommended in this condition. The other part of the treatment is a dairy-free diet, because milk contains folate receptors that are analogs to human folate receptors and thus milk intake upregulate the production of autoantibodies.

And now on my Leucovorin experience:

I started at 6mg daily almost four weeks ago. I saw an immediate effect as intense relaxation and feeling very lightweight. Instead of having to drag my heavy weight around the house, I felt like I was floating above the floor. This was followed several hours later by heavy mood swings and irritability. The next day for the first time I woke up early feeling rested and clear-minded, as opposed to brain-fogged and sleepy. I then had a crash with intense sleepiness and brain-fog, absent-mindness and forgetting everything, also a lot of thirst and heart-palpitations. This was better already the next day.

I now am taking 50mg a day divided in two, which is my target dose (and as I said I have already been dairy-free for years). Each time I increased the dose I saw some very temporary side effects as listed above. But the list of sticking benefits so far is the following:

- Feeling very lightweight and very relaxed, no more physical fatigue
- Easier to breathe deeply and stand up straight
- No need to sit down every few minutes
- Waking up rested and clear-minded
- No crash after stress or arguments
- Stools looking more normal, flatter belly

So this all still preliminary, but if it continues like that I'll try weaning off Zoloft in a couple months.

I'll keep updating you guys. Maybe this could be an important key for some of you too.

[Inge]

This could also go into the treatment section.

Unfortunately I can't take folinic acid. Even the smallest amounts make my insomnia much worse.

[Karin]

I heard patients taking high-dose 5MTHF (Deplin) instead of folinic. This should theoretically work but hasn't been studied yet for the cerebral folate deficiency condition. A friend of mine with a similar condition also had to stop leucovorin because of sleep issues, she is now trying 5MTHF but I don't know her results yet.

[slayadragon]

Very interesting, thank you.

[Rain]

Thanks for this information, Karin!!  I tested deficient in folic acid, but I haven't had a test for receptor antibodies.

Will I need a doctor's prescription to get 5MTHF?


vdt

[Karin]

For the high-dose version you need a prescription (Deplin), but 5MTHF is also available over the counter at lower doses, so it could be a good idea to try that first. Also, I heard Deplin is very expensive and not always paid for by insurances (in contrary to Leucovorin which is available generic).

Thorne 5-MTHF 1mg per capsule:
http://www.totaldiscountvitamins.com/product/34182?r=df-googlebase

Folapro 5-MTHF 800mcg per tablet:
http://www.totaldiscountvitamins.com/product/1427?r=df-googlebase

By the way, as far as I know people with antibodies do not have lower blood folate than people without. One thing I heard, but just anecdotical, is that people with these antibodies often have large red blood cells, with MCV/MCH above or at the upper limit of the normal range (this data is available as part of regular CBC blood work). That is the case for myself and my ASD son. That's not something confirmed though.

[liquid sky]

Thanks for passing on this info. I have started active folates from over the counter. Only about 3mg. though. They have cured me of angular chelitis which is basically the corners of your mouth cracking with open sores. I had it for years.

I would be really interested in trying the higher dose per script. 50mg. is a really large dose. I think I will check with my doctor about the test and the med. do you know what the test is called?

[Mark3981]

Thanks for posting Karin.

The Leucovorin you are taking is folinic acid? So you are taking 50mg which is 62.5 times the normal tablet size of folinic acid 800mcg? Do I have that right?

I take L-5-methyl tetrahydrofolate. I can easily take 1600mcg three times a day for a total of 4800mcg of L-5-methyl tetrahydrofolate. Seems to be something I need, as at times. It might help clear my nose and ear congestion when all the "stars" line up.(stars don't really have to line up, but I need to have my body chemistry just right)

[Karin]

As far as I know this test is not available commercially. It is still at a research level. Dr. Quadros at SUNY Downstate Medical Center, NY does it (he is the author of the articles I posted in the first message). I'll send you the address privately.

[Karin]

Thanks for posting Karin.

The Leucovorin you are taking is folinic acid? So you are taking 50mg which is 62.5 times the normal tablet size of folinic acid 800mcg? Do I have that right?

I take L-5-methyl tetrahydrofolate. I can easily take 1600mcg three times a day for a total of 4800mcg of L-5-methyl tetrahydrofolate. Seems to be something I need, as at times. It might help clear my nose and ear congestion when all the "stars" line up.(stars don't really have to line up, but I need to have my body chemistry just right)

Yes, what I am taking is folinic. That's the form that was studied, and they determined the optimum dose (0.5 to 1 mg/kg) by doing spinal taps and looking at at which dose the CSF folate levels go back to normal.

I have no idea what the optimum dose is for 5-MTHF, as far as I know it hasn't been studied. So I would think starting low, e.g. 1 mg, and increasing watching for response might be the way to go?

[Mark3981]

That's interesting your dose of folinic is so high compared to the methyl-folate. Thanks.

[Karin]

For those interested in 5MTHF, I see that Depin, the prescription drug 5MTHF to treat refractory depression, contains 7.5mg 5MTHF per tablet. So that's maybe an idea of a typical pharmacological dose. And that can be achieved with ten 800mcg OTC tablets a day. By the way, for Leucovorin I've seen that I need to split it in twice a day, or I get a crash in the evening.

http://www.deplin.com/DeplinFacts,HowItWorks

[Karin]

I thought I would give an update on how I am currently doing on Leucovorin. First, and very important, I discovered that there is a definitive sweet spot in dosage for me: on 50 mg a day, I started feeling worse and worse day by day with a return of all my symptoms I had prior to starting Leucovorin. So I experimented more with the dose, and found out that with 18 mg a day, I get a very, very good response. WOW, all the lights are green! That is about 0.3 mg/kg for me. Actually, I am feeling so good that I already started weaning off Zoloft and after a few days I am already down to 1/4 of my usual dose without any withdrawal problems. So here is a summary of my symptoms prior to starting Leucovorin, and a summary of how I am feeling now on 18 mg a day:

Before Leucovorin:

- 15 years of depression, on and off antidepressant use with great results,
though not 100%, at least I can function as a normal person.

- Fatigue: unable to exercise, and felt very cold, nauseous after exercise and
crashed for the rest of the day. Need to sleep a lot, often need to nap. Most of
the time feel like I am very heavy, though I only weight 130 lbs for 5'7", and
it requires a lot of will-power to make my limbs move. I can still clean my
house and shop, that kind of thing, but need to rest a lot and sit down often.

- Sleep issues: cannot sleep without earplugs, cannot share a bed with my
husband, or I wake up every five minutes. Wake up every mornings very tired.

- Gastro-intestinal issues: abdominal pain, bloating, loose stools aletrnating
with constipation, burning stools, itchy bottom, bad smells. Flagyl/Diflucan
makes me feel a lot better so it points to dysbiosis problems. The less I eat,
the better I feel. Multiple food sensitivities with over 30 IgG reactive foods.

- Heart issues: lots of heart palpitations, diziness, vertigo, dysautonomia
symptoms.

- Feeling very cold in the evenings, my whole skin is freezing cold, though my
body temperature is normal. Need wool jackets in the evenings.

- Cannot tolerate stress: stress will make me crash mentally and physically and
I will need to spend some time in bed.

- Very irregular menstrual cycles (40 to 60 days) and strong PMS symptoms.

- Zero libido.

- Of course all the mood swings and irritability associated with depression,
though Zoloft helps a lot there.

****************************

On 0.3 mg/kg Leucovorin for a few weeks (after initial adjustments/side
effects):

- Am now on 1/4 of my Zoloft dose and feeling zero withdrawal symptoms. In the
past, I weaned off multiple times with difficulty, over several weeks, never
able to do it in a few days like now.

- Feeling very lightweight, as if I am floating in the air. Feeling very relaxed
and very pleasant all over. Easy to straighten up and breathe deeply. Vigorous
work-out 30 minutes every day now: not only I don't feel nauseous or cold
afterwards, I feel great, warm and energized for the rest of the day. Not sleepy
at all in the afternoons.

- Waking up very refreshed in the mornings and ready to go rather than in
zombie-land like before. I haven't tried taking my earplugs out yet.

- Great-looking stools, no abdominal discomforts, no bad smells, no itch.

- Heart: I am not sure yet.

- No more feeling cold in the evenings: feeling nice warm. No need for coats.

- Haven't had much stress lately to see how I do, but had a few domestic arguments
without crashing afterwards.

- My last cycle was exactly 30 days. No PMS at all. Horrendous ovulation pain
this time, though...

- No libido improvements so far, but it is still early.

- No mood swings, even now that I am weaning off Zoloft.

*************

On 1 mg/kg Leucovorin:

- All the 'Before' symptoms are back full-force after several days on this dose,
all of them except GI problems and irregluar cycles.


By the way, in the last 15 years, I had many blood test done with my family
doctors, everything always came back normal, thyroid, adrenals, liver, kidneys,
cholesterol, etc... Only findings are high MCH in CBC and low D3. Also, my
recent ECG (first one) was abnormal with low voltage. But other than that, nothing wrong
despite my constant fatigue, depression and gastrointestinal issues.

[subtr4ct]

Hi Karin -- so glad to hear of your remarkable improvement.  Thank you so much for reporting.

Look what I found (link)

A remarkable 81% of CFS patients experienced subjective improvement of their symptoms after treatment with folinic acid (CAS 58-05-9, leucovorin). The findings provide unprecedented evidence that CFS frequently is a folinic acid responsive clinical entity...

I am trying to get the full paper.  All I have now is the abstract and the info given here:

Folinic acid for chronic fatigue syndrome and fibromyalgia
Forty-two patients (aged 19-64 years) with chronic fatigue syndrome, with or without fibromyalgia, received 25 mg of folinic acid three to four times per day for one to two months. Thirty-four patients (81%) reported a significant increase in energy level and a reduction in pain within two months. No adverse effects were reported. Responses were seen both in patients with primary fibromyalgia and fatigue and in those whose condition was associated with other diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, or multiple sclerosis.

So they were using pretty high doses, like you.  Much higher than anyone would use normally.  I wonder if the doses were too high for some of these people and they might have done even better had they found their sweet spots, as you have done.