Adult or Late Onset CblC Disease: CFS and FMS with Extreme Prejudice

[Freddd]

When I started on this journey to knowledge, decades ago I came across CblC disease. However, the high rate of infant death and statements like “… three known adult survivors” made it extremely unlikely that it could apply to me, or even any of us posting here at all. I commented to Rich that I doubt I had it since it so rare and so fatal and I shared all those symptoms in common with folks here. I also mentioned that for me to have CblC disease it would have to be rarely diagnosed instead of rare.

@nandixon recently posted links to several recent articles talking about late onset (post infant) and adult onset CblC disease that is triggered by something. And guess what, it comes in so many variations they haven’t figured that out yet and the real incidence keeps climbing every time they add a new gene sequence to the polymorphisms.

The disease is “extremely heterogeneous”, it varies widely and they don’t know what it looks like. It also responds poorly or not at all to HyCbl, folic acid and carnitine (ALCAR is usual when unspecified) which, it is agreed, is the best they know how to treat it currently, and it works poorly at best. However, I can’t help but notice that they (the researchers) choose, yet again, the worst possible forms of everything that “ought” to work based on what they know.

Fortunately I found the versions that work, AdoCbl, MeCbl, Metafolin (l-methylfolate) and L carnitine fumarate (90%) OR ALCAR (10%) dependent up the person, not to mention potassium and all the rest that are needed and how individual the balance is. It’s caused by partial methylation block, methyltrap and partial ATP block, so familiar to us all.

I am working on a lot more including lists of diagnoses included.

 

[mgk]

Thank you for patiently experimenting and sharing your knowledge with us. I can't imagine how challenging it must have been to figure all of this out.

 

[acer2000]

Thanks for keeping at it! I'm sure there are others out there with the same/similar problems that will benefit.

 

[SwanRonson]

I also mentioned that for me to have CblC disease it would have to be rarely diagnosed instead of rare.

The research I found said that methylmalonic acidosis is the telltale sign. Did you ever have sky high mma numbers?

 

[Freddd]

The research I found said that methylmalonic acidosis is the telltale sign. Did you ever have sky high mma numbers?

Hi SwanRonson,

I was going to cover that when I got to the part about high MMA and high Hcy. That is a whole complicated story. Taken from the born dying children, that is why they are dying, fatal B12 deficiency in the womb; no methylation and no ATP. That was the one known form of CblC disease for the past 30 years. A few years ago they identified adult onset varieties in gene polymorphisms. I had sudden onset of CFS with what the doctor identified "miscellaneous entero virus". It hit like a ton of bricks and with obvious demyelinations with onset of severe methyltrap. In retrospect that was going from partial methylation block to methyltrap and adding a partial ATP block that worsened over several month.

At that point I might have had elevated MMA. The usual routine at that point was test for serum b12 deficiency and then a Schilling test to confirm it if you had a lot of money or insurance to cover it. I was "uninsurable" from a car wreck in 1972 and didn't have a lot of money. Further I didn't have low serum B12. I took the "therapeutic" amount of oral CyCbl daily, 1000mcg. Further while my MCV was 99.8. it wasn't > 100.0 so I didn't have macrocytic anemia. There was no "justifiable" reason to get an uMMA test. Part of the problem with B12 is that it isn't a single thing that has the same pharmacokinetics everywhere. One can have CSF elevated MMA and normal serum and urine MMA. Also, B12 and folate are distributed by "internal triage levels", ie partial methylation block; some levels of methylation are working and some are in deficiency. So one layer produces MMA and other doesn't so the average is below the 5 alarm fire level, the first alarm that goes off. Somewhere it starts as going off track and it slowly worsens.

There is a time when a few mitochondria start failing on one level. Some symptoms start there. So adult onset is rarely recognized because it doesn't start with fully blossomed high MMA and high HCY. Instead, it starts with a couple of b12 and folate deficiency symptoms and builds up over the years. It's like pernicious anemia being the only recognized b12 deficiency disease. If you wait until methylmalonic acidosis the organs are damaged. Instead they need to be caught sooner, when they are a few dozen CFS/FMS/ME symptoms.

 

[SwanRonson]

Also, B12 and folate are distributed by "internal triage levels", ie partial methylation block; some levels of methylation are working and some are in deficiency.

Bear with me here. My path to CFS looks like this:

9/1/14 - Gastritis (confirmed by endoscopy): Blood tests at a follow-up visit showed low serum folate, and serum b12 was 466. HCY was 9.4.
9/10/14 - Started taking solgar methylfolate (800mcg/day) to bring the folate level up. The reason I chose it, was that it was the only bottle that said "folate" instead of folic acid.
9/18/14 - Gave a blood donation. Onset of CFS symptoms (severe brain fog, started within a few hours after giving blood. I thought it was folate deficiency anemia from giving blood while folate was low, so I ramped it up to 800mcg per day, and started taking 1000mcg of methylb12 as well.
10/15/14 - Followup folate test showed it was in normal range so I dropped it back to 200mcg a day.
10/24/14 - Ran across some information about methylfolate side-effects and thought my symptoms could be from taking the methylfolate so I stopped taking it and posted here for help.
10/31/14 - Contracted Shingles. This was accompanied by a ton of blood tests (so many that my hematocrit was actually low by the last one) and horrible symptoms that left me in and out of the E.R. over the next 3 weeks because at first the doctors didn't know it was shingles. They thought I was having a heart attack at one point based on my EKG and did a heart catheter. That really set me back.

As it stands today, I feel much better today than at my low point in November, but I still have constant brain fog, weakness/fatigue (some days severe). I've continued to take b12 (at first hydroxy, then switched to 5 start methyl recently).

So, what I'm wondering is this: If taking the methylfolate triggered startup and ran my b12 levels down very low, I wonder if the resultant lack of b12 within the CNS caused the Varicella-Zoster reactivation. I also wonder about "reactivation" in general. That's the term used, but maybe CNS viruses never actually "deactivate". Perhaps they continue always doing their damage within the CNS, but the body prioritizes methylation within the CNS to compensate for this. And, for those of us who for some reason develop a b12/folate deficiency (via malabsorption, genetic predisposition, blood loss/trauma, etc.) we begin losing the battle to repair the damage that is constantly being done within the CNS.

Said another way: I wonder if CNS viruses are slowly killing all of us (95% of the western population carries VZV), but how badly we're damaged by them depend on our body's ability to repair the nerve damage. If we pick up another CNS virus and the damage begins to outpace the available methylation cofactors, or if the methylation cofactors decline for some other reason we cross the threshold into CFS.

I don't have CblC disease, but I could get it at any time if this is true. All that's needed is maybe one more CNS pathogen, or another source of methylation retardation.

 

[Freddd]

Bear with me here. My path to CFS looks like this:

9/1/14 - Gastritis (confirmed by endoscopy): Blood tests at a follow-up visit showed low serum folate, and serum b12 was 466. HCY was 9.4.
9/10/14 - Started taking solgar methylfolate (800mcg/day) to bring the folate level up. The reason I chose it, was that it was the only bottle that said "folate" instead of folic acid.
9/18/14 - Gave a blood donation. Onset of CFS symptoms (severe brain fog, started within a few hours after giving blood. I thought it was folate deficiency anemia from giving blood while folate was low, so I ramped it up to 800mcg per day, and started taking 1000mcg of methylb12 as well.
10/15/14 - Followup folate test showed it was in normal range so I dropped it back to 200mcg a day.
10/24/14 - Ran across some information about methylfolate side-effects and thought my symptoms could be from taking the methylfolate so I stopped taking it and posted here for help.
10/31/14 - Contracted Shingles. This was accompanied by a ton of blood tests (so many that my hematocrit was actually low by the last one) and horrible symptoms that left me in and out of the E.R. over the next 3 weeks because at first the doctors didn't know it was shingles. They thought I was having a heart attack at one point based on my EKG and did a heart catheter. That really set me back.

As it stands today, I feel much better today than at my low point in November, but I still have constant brain fog, weakness/fatigue (some days severe). I've continued to take b12 (at first hydroxy, then switched to 5 start methyl recently).

So, what I'm wondering is this: If taking the methylfolate triggered startup and ran my b12 levels down very low, I wonder if the resultant lack of b12 within the CNS caused the Varicella-Zoster reactivation. I also wonder about "reactivation" in general. That's the term used, but maybe CNS viruses never actually "deactivate". Perhaps they continue always doing their damage within the CNS, but the body prioritizes methylation within the CNS to compensate for this. And, for those of us who for some reason develop a b12/folate deficiency (via malabsorption, genetic predisposition, blood loss/trauma, etc.) we begin losing the battle to repair the damage that is constantly being done within the CNS.

Said another way: I wonder if CNS viruses are slowly killing all of us (95% of the western population carries VZV), but how badly we're damaged by them depend on our body's ability to repair the nerve damage. If we pick up another CNS virus and the damage begins to outpace the available methylation cofactors, or if the methylation cofactors decline for some other reason we cross the threshold into CFS.

I don't have CblC disease, but I could get it at any time if this is true. All that's needed is maybe one more CNS pathogen, or another source of methylation retardation.

Hi SwanRonson,

Yikes, what a miserable time you have had. Whether you have CblC polymorphisms, and that isn't a standard test yet, and they are just learning through research studies what the many polymorphisms may be, it appears to take something to trigger it. To me it looks like various ways to get the 4 way deadlock started and it is self maintaining once started. You reminded me of my own experiences in some ways. I had mono. I never quite recovered. I felt outright lousy for years and kept having acute viral episodes that lasted months, and got longer each time until the episode I had in 1987 didn't start going away until 2003 with MeCbl. My wife had the same virus attacks each time but she got better in 3 months that time. She also had mono but got better in 6 months.

I also very much appear to have a folate problem. It really seems like I got into the 4-way deadlock via virus with unusable folate (folic acid) and CyCbl. If a person has the folate related polymorphisms that is another way into the deadlock

Now another person I know who was taking a single 10mg MeCbl injection daily which had clear up her peripheral neuropathy symptoms was doing a trial of Metafolin. She has never had a strong startup response to MeCbl until recently after getting a selection of symptoms. She decided titrated to 14,400mcg/day. Her near perpetual IBS had started to heal. A year ago she had an unusual case of shingles, it was bilateral, and relatively mild on her hands and wrists only, and lasted several weeks in waves. At the time the shingles came on she was taking sublinguals, and not every day. She also was having peripheral neuropathy symptoms increasing. That was when she switched to the 10mg injections. This year shingles suddenly appeared on her face, by both eyes and on the hands and wrists. They all followed the dermatomes This was when she switched from 1600mcg of Metafolin to 14,400mcg. She also applied 20mg/ml MeCbl solution topically to the lesions. In one day the blisters dried up and the inflamed areas started fading. In three days the lesions on her face were gone and in 2 more days gone from her hands as well.

What all this means I don't know. Viruses do appear very involved with this. Many here have sudden start of CFS with a viral infection. Maybe this gives you some clues of somebody else's experiences. A friend of ours got shingles 2 years ago and had a terrible time. I went and got a vaccination. Good luck.

 

[Freddd]

There are a number of characteristics of the CblC disease. The characteristics as compared to the side effects of the treatment are not clearly delineated. It is mentioned for instance that those with CblC disease in it's many variations have low cellular folate. Whether that is due methyltrap or a different reason is not made clear. It is not clear yet if the folate polymorphisms are separate or not, but a person can have both it would appear. As they were using folic acid as part of treatment, instead of L-methylfolate, they had only poor responses.

Another characteristic mentioned is very unstable electrolytes as they said in the research, again it is not clear if it is part of the disease or treatment or both. I had unstable potassium going back into childhood. We see that as quick onset hypokalemia as well as problems with magnesium and calcium.

@nandixon supplied these links. Each of these has a multitude of additional links.


Cobalamin C defect: natural history, pathophysiology, and treatmenthttp://www.ncbi.nlm.nih.gov/pubmed/20632110/

Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy
http://www.ncbi.nlm.nih.gov/pubmed/25398587/

Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations
http://www.ncbi.nlm.nih.gov/pubmed/19370762/

Glutathione metabolism in cobalamin deficiency type C (cblC)
http://www.ncbi.nlm.nih.gov/pubmed/23568438/

Protection of aquo/hydroxocobalamin from reduced glutathione by a B12 trafficking chaperone
http://www.ncbi.nlm.nih.gov/pubmed/21429294/

patients with the cblC disorder and their sometimes poor response to treatment with hydroxocobalamin...
Click to expand...
THE MMACHC PROTEOME: HALLMARKS OF FUNCTIONAL COBALAMIN DEFICIENCY IN HUMANS http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110603/

http://www.ncbi.nlm.nih.gov/pubmed/?term=trafficking chaperone cobalamin

One of the things that really puzzles me is that how excess MMA and/or Hcy is thought of. When the researchers and doctors are speaking of it they speak as if it is the Hcy or MMA that causes all the damage and often looked for drugs to lower those items. Despite MMA being a marker for lack of AdoCbl specifically, it never occurred to them to use AdoCbl instead of CyCbl or HyCbl which was only sometimes partially effective.

So the many diseases attributed to high MMA or high Hcy were somehow disconnected from the causes, the MeCbl or AdoCbl deficiencies and all the hundreds of symptoms leading up to it. The diseases are only recognized after severe damage is done. This is the result of requiring “hard science” tests to determine suitability for treatment with B12. People having symptoms and recovering from those symptoms with B12 is no justification for B12 treatment according to the medical system. The “functional” symptoms meant nothing until suddenly, without precedents, out of the blue life threatening damage is present which is potentially deadly. I find that kind of thinking repellant at the least, and incredibly stupid. This attitude destroyed much of my life.

 

[picante]

So the many diseases attributed to high MMA or high Hcy were somehow disconnected from the causes, the MeCbl or AdoCbl deficiencies and all the hundreds of symptoms leading up to it.

Typical. I could not get my insurance to cover the MTHFR A1298C and C677T tests because the diagnostic code my ND used was for "chronic fatigue", and it appears they only cover that test when you put a diagnostic code of "hyperhomocysteinemia". (My result -- compound heterozygous -- was what led me here to PR last summer.)