Paper preprint: Transcobalamin Receptor Autoantibodies in Central Vitamin B12 Deficiency

[jade_s]

The following paper is a preprint, which means it has not been peer reviewed yet.

medrxiv.org/content/10.1101... Pluvinage et al, "Transcobalamin Receptor Autoantibodies in Central Vitamin B12 Deficiency" medRxiv 2023.08.21.23294253; doi: doi.org/10.1101/2023.08.21....

Abstract:

Vitamin B12 is critical for hematopoiesis and myelination.1 Deficiency can cause neurologic deficits including loss of coordination, spasticity, and cognitive decline.2,3,4 However, diagnosis relies on vitamin B12 measurement in the blood which may not accurately reflect levels in the brain. Here, we discovered an autoimmune cause of vitamin B12 deficiency restricted to the central nervous system (CNS), termed autoimmune B12 central deficiency (ABCD). Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Patient immunoglobulins impaired cellular uptake of vitamin B12 in vitro. Despite normal serum levels, vitamin B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic vitamin B12 supplementation were associated with increased CSF B12 levels and clinical improvement. Autoantibodies targeting the same epitope of CD320 were identified in 7 other patients with neurologic deficits of unknown etiology and in 6 percent of healthy controls. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. These findings elucidate a new autoimmune cause of metabolic neurologic disease that may be amenable to immunomodulatory treatment and/or nutritional supplementation.

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[Disclaimer: I have not done a 100% thorough review of it yet. Just enough to rant about it ]

The research topic is fascinating: in a patient enrolled in a completely different study, they found antibodies against the transcobalamin receptor, which resulted in functional B12 deficiency. B12D was diagnosed by testing the patient’s levels of B12 in the cerebrospinal fluid (CSF) - levels were very low.

What this means: Transcobalamin II (TC-II) is the protein that transports B12 from the bloodstream into the cells. CD320 is the receptor for TC-II, and is found on the surface of cells. The B12 + TC-II molecule coming from the bloodstream binds to the CD320 receptor, and allows B12 to enter the cell. Functional deficiency typically refers to the fact that serum B12 levels are normal, but B12 "cannot enter the cells", causing all the symptoms of B12 deficiency. Here they seem to use the B12 level in the CSF as a proxy for what we here call "entering the cells". Note that they gave the same name to the receptor and to the gene that encodes for it - CD320.

So then they conducted a retrospective analysis and found 7 more people with "functionally impaired holotranscobalamin uptake". They measured HoloTC (active B12) in the CSF of these patients, all were low; serum B12 was normal in all. The first case study and several of the other people were treated with "high dose oral supplementation" - I could not find the dose/frequency/duration. Case 8 from the retrospective study had SACD and he too was giving oral supps, and only "partially" recovered. Scandalous - not clear why they were not given injections!

They did 1 more retroactive analysis after that, but I need more time to understand the details.

I hope peer-review will strengthen the manuscript and fix some of the missing details. The organization of the manuscript could also be improved, it was a bit confusing to read. And maybe one of the Dutch B12 experts could clue these people to the fact that those with SACD really should be given a trial of injections.

Note the affiliations - several Neurology departments at various prestigious US hospitals.

There really should be a way to do public reviews on medrixiv :/

I'm glad the research is being done, and I predict the test will trickle down to the general population... never.

Carmel wrote about IgG-Transcobalamin II antibody complexes creating a form of what is now called MacroB12 in 1977. And in 1971, Skouby et al described antibodies to TC II generated in those receiving B12 injections, causing higher measured levels of serum B12 compared to those without the antibodies (symptoms and clinical significance not discussed). Of note they were testing 3 monthly injections even then.

One still cannot get either one tested commercially. Even the NICE committee declined to include MacroB12 in their guidelines because, and I paraphrase here, it is not our responsibility, the labs have to take care of avoiding macroB12 and false high B12 measurements.

In my opinion, these types of antibody tests would go a long way in explaining why some of us are severely functionally deficient for no apparent reason, and why some people with PA need much more frequent injections.

Carmel et al, "Circulating Antibody to Transcobalamin II Causing Retention of Vitamin B12 in the Blood", Blood, 1977, sciencedirect.com/science/a...

Skouby et al, "Antibody to Transcobalamin II and B12 Binding Capacity in Patients Treated With Hydroxocobalamin", Blood, 1971, sciencedirect.com/science/a...

Thoughts?

p.s. Sorry for my continued obsession with TC antibodies and MacroB12, but I really do think it might be the key to two of the topics we frequently discuss here: need for very frequent injections, and functional deficiency. Or, if there was a less invasive way to measure CSF levels of B12!

[Nackapan]

Very interesting.Thank you

[Orchard33]

Absolutely fascinating. One of my questions has been about peripheral neuropathy, which I don't have, and neuropathy of the central nervous system, dizziness, brain fog, memory impairment (and who knows what else churning away in my brain and spinal cord), which I do have. And, of course, the high speed collision between PA and all it's hidden and overt manifestations and ageing.Thank you for posting this information.

[jade_s in reply to Orchard33]

That is a very interesting obervation and I never thought about it that way! My CNS symptoms came on earlier than PN. But because we didn't know the cause and I didn't start B12, the PN developed as well. Interesting.

[Rexz]

Thank you jade_s this is fascinating. I had not heard of this. I'll peruse later.

Rexz

[wedgewood]

If this is peer -reviewed and gets officially printed , could it be a useful tool for P.A.patients to quote , who now try unsuccessfully to get sufficient treatment for such neurological symptoms because their B12 blood serum readings are “ normal” . I’m sad to say that I think not.

Thank you jade_s for finding this excellent article .

[jade_s in reply to wedgewood]

I'll keep an eye out for its publication.

I completely agree!

[wedgewood in reply to jade_s]

👍Thanks 🏅

[Cherylclaire Forum Support]

Massively interesting to me.

You are right - why would you choose to treat with tablets ? Especially in a patient with near-undetectable B12 levels in cerebrospinal fluid ? Subacute combined degeneration ?

ps: what does "scanning speech" mean ?

[jade_s in reply to Cherylclaire]

Thank you for that! I was very confused about the tablets!

I had not heard of scanning speech either. ncbi.nlm.nih.gov/medgen/116113 "An abnormal pattern of speech in which the words are as if measured or scanned; there is a pause after every syllable, and the syllables themselves are pronounced slowly."

Looking back, I had a mild version of that myself. I didn't realize it was a symptom.

[Cherylclaire Forum Support in reply to jade_s]

Tablets, in this situation, would surely go against medical guidance ?

Scanning speech: strange - or maybe not. I don't recall it being discussed here, or seen it mentioned in even the more comprehensive symptoms lists. I cannot now follow rapid speech as all the words combine into nonsense - which means perhaps that I have "scanning hearing" !

I was having trouble, at my worst, with understanding words, remembering words (words like "mango", nothing difficult normally) - and something else that I haven't heard mentioned, probably since there is not a word for it, as far as I know... people not making sense to me. Here's an example:

My mum was talking about her partner, and she said "his hair is receding" - which I interpreted as "his hair is re-seeding" (as in Elton John-style transplant, where it looks for a while like a paddyfield). The visual image made me burst out laughing - end of any hope of a proper dialogue for mum. I could not select another more sensible option - so something wrong with contextual wordfinding (?)

This can still happen occasionally when I'm tired.

[jade_s in reply to Cherylclaire]

"his hair is re-seeding"😂 Well well well, another thing we have in common. For a long time, I've had trouble figuring out words that are spoken, especially when there is a lot of background noise. I need subtitles to watch TV, otherwise I miss a lot, especially if people are talking fast, soft, or slurring their words. I can hear the words just fine, my brain just cannot make out what they are trying to say!! I too can hear 'other' words just like your example 😂 My physical hearing is fine too. I spoke to an Audiologist about it, and they had no clue what I was talking about LOL. I think it got worse before B12, and better after - but I still have it to some extent.

Antoher question - do you literally visualize things people say? Like you can see it in your mind's eye? I visualize almost everything any one says and it can get annoying when people talk about weird things 😂 Turns out not everyone can do that!

No I haven't heard of Scanning speech mentioned here either. Perhaps it's just lumped in together with aphasia? i.e. they think the halting speech due to trouble finding words, not something in and of itself? I do this in an exaggerated way when a really bad migraine hits and i feel like i've been drugged.

[Cherylclaire Forum Support in reply to jade_s]

I think sometimes we start to ignore the small things, the ones that don't hurt or that are occasional, in the onslaught of symptoms and unfamiliar behaviour we have to cope with.

I couldn't read a book any more (despite a house full) as memory and cognitive understanding made it difficult - but because visual understanding easier than verbal or written, found graphic novels better. Adapted behaviour.

Only recently am I starting to read for pleasure again. I started by reading aloud to my partner, something we both enjoyed - and so that continues. A plus.

Yes - I can understand what people are saying much better if I can see them. The visual thing again, like you said- not deafness. When people don't face me, it is as if they are mumbling. The telephone is okay for a short while, but takes way too much effort and I always get to a stage where I have to say "...got to go now" - as understanding takes far too much effort without any visual aid. Increasingly hard work, so there has to be a cut-off point. Outdoors is always better for me, as sound not echoey and rebounding off the walls and ceilings - can't prioritise one voice over another or above a crowd. No background.

So tiring.

Do not get migraines though. Not ever. I know many here do.

[Narwhal10 in reply to Cherylclaire]

So with regards to speech, a good clinician will notice volume, the pause may indicate pain or shortness of breath, mouth sores, tongue problems, ill fitting new dentures or injury.

How easy a person finds the words they want to say. So, looking at flow and rhythm. Whether there’s any repetition or drifting away mid sentence. Out of the ordinary ‘swearing’. (Yes, of course my lovely, it does hurt). Syntax is another one e.g.

‘One must excuse oneself, one needs to powder their nose.’ Compared to :-‘I’m just going to the khazi.’

Khazi is British slang for the toilet.

Broca and Wenicke’s area of the brain are associated with comprehending, processing and being able to relay language.

Parts of the brain involved in speech & language. Side view - mid left and right.

[Mixteca]

Never apologise for your obsessions , your avid interests and thirst for knowledge Jade - we all benefit from them, so thank you! x

[jade_s in reply to Mixteca]

Awesome haha, thanks for the kind words 😊 It's wonderful to find like-minded people here !

[WIZARD6787]

I successfully self treat for Transcobalamin issues and have for 5 months. More B12, different forms, B6, Betine, and Simple Spectrum.

Massive doses of B12 compared to the treatment for B12/PA. I mg every other day is minuscule for treating Transcobalamin issues with minimum results from my reading and experience.

[Narwhal10]

Thanks jade_s,

Er, er, er! Yo girlfriend’ (flickin ma weave, an pointin ma finger) dontcha be pologisin’ fo’ talkin’ TC an’ MacroB. Me, ma homies wanna no more, fo shizzle.

Whaddem fools be doin’ givin ‘em tablets. ??? *sucks teeth*

They need their heads read. Mamma woul’ whomp they sorry, a$§ x£. 😂🤣

I have found very little research or literature looking at P.A./B12 deficiency in Black, Asian etc populations as though they do not exist and it does not happen.

[genesurf]

If true, this could be considered an autoimmune disorder... and autoimmune disorders can cluster. Myself, I need to SI B12 every 2-3 weeks (I weaned myself back from daily shots), and I have family members with Graves', Sjögren's, and Hashimoto's.

ChatGPT generated this list of autoimmune disorders. Many are not unusual, but I do wonder if the Frequent-B12-Injection club has more of these than might be expected:

"--Rheumatoid Arthritis (RA) - Primarily affects joints but can also affect other organs.

--Systemic Lupus Erythematosus (SLE) - Can affect multiple organs including skin, kidneys, and joints.

--Multiple Sclerosis (MS) - Targets the central nervous system, affecting nerve function.

--Type 1 Diabetes - Pancreatic cells that produce insulin are destroyed.

--Psoriasis/Psoriatic Arthritis - Affects the skin and may also affect joints.

--Hashimoto's Thyroiditis - Leads to hypothyroidism, or underactive thyroid function.

--Graves' Disease - Leads to hyperthyroidism, or overactive thyroid function.

--Inflammatory Bowel Disease (IBD) - Includes Crohn's disease and ulcerative colitis, affecting the gastrointestinal tract.

--Celiac Disease - A reaction to gluten that damages the lining of the small intestine.

--Addison's Disease - Affects adrenal glands leading to low levels of cortisol and aldosterone.

--Sjögren’s Syndrome - Affects the glands that produce tears and saliva.

--Vitiligo - Results in loss of pigment in areas of the skin.

--Myasthenia Gravis - Weakness and rapid fatigue of muscles under voluntary control.

--Alopecia Areata - Causes hair loss, usually in small patches.

--Autoimmune Hepatitis - Liver inflammation that occurs when your body's immune system turns against liver cells.

--Pernicious Anemia - Affects the absorption of vitamin B12, leading to anemia.

--Scleroderma - Causes skin to thicken and can also affect internal organs.

Some autoimmune diseases have been found to cluster more often than would be expected by chance, although the exact mechanisms are not well-understood. For instance, having a thyroid autoimmune disease like Hashimoto's or Graves' can make it more likely for an individual to develop another autoimmune disease like Type 1 diabetes or rheumatoid arthritis. However, these patterns can vary significantly among individuals."

[PlatypusProfit8077]

this is really interesting! Has there been further updates or studies about this?

It’d be great if we could pinpoint injection frequency needed, both the who and the why. Maybe then the doctors wouldn’t take people off injections or wean them down too fast/too much.