Dissecting PN

[PointsNorth]

Feeling that B12 is closely connected to my MS I connected with an ME/CFS forum where b12 is a HUGE topic of discussion. I met this Ozzie (PhD Bio-Chem) that has a new B12 transdermal oils co. He offered to review my genetic profile which I sent him. His review (highlights):

Hi PN,
I have done your snps and attach the file.
Green is good (-/-), red is bad (+/+).
Generally I don't take that much notice to yellow (+/-), as normally about 50% of people have yellow (25% green).
There are a couple of problems with the snp analysis. If you have more than one snp in a particular gene you cannot tell if the snps are all on one copy of the protein produced, or spread across both copies of the protein.

You have quite a few snps in the folate cycle, notable is
MTHFDIL rs1076991 +/+
MTHFR rs13306561 +/+ and an odd GG at rs1801133
MTHFS rs6495446 +/+
Now the combination of the mutations is additive, and will make it very hard for you to process folate unless you have high levels of dietary or supplement folate.
It also means that you are going to sacrifice both 5MTHF and methylB12 in order to make SAM for methylation.
Methylation via SAM has been shown to be essential for short term memory, loss of which is characteristic of MS.

You have a bunch of mutations associated with break-down of neurotransmitters. Now these can do two things, they can make you very hypersensitive to external stimuli, or alternatively they can lead to eventual down-regulation of the neuronal/synpase activity.
COMT rs4633 +/+
DAO rs1049742 +/+
MAO rs6323 +/+ rs5906883 +/+

You also have problems in the methylating enzymes
PEMT rs4646406 +/+. This is responsible for both the synthesis of Phosphoryl choline and is also used the synthesis of adrenalin from nor-adrenalin.

You have two sets of mutations in cystathione B-synthase, the first enzyme in the conversion of homocysteine to glutathione.
rs2851391 +/+, rs4633 +/+
This mutation alone can lead to increased homocysteine. High levels of homocysteine are often seen in MS and have been put forward as one of the causes of MS. Elevated plasma homocysteine levels have been reported in patients with MS and associated with male gender.
Elevated homocysteine is also seen in folate and vitamin B12 deficiency.

You have mutations in your eNOS gene
rs2918188 +/+
eNOS is responsible for opening up your blood vessels.

The last mutation of significance is in your VDR taq +/+.
The VDR is responsible for uptake and processing of vitamin D. Mutations in the genes normally mean that you have to keep your vitamin D intake high. Vitamin D, whilst often associated with osteoporosis, is also very important for mitochondrial function and nerve growth.
Low vitamin D is causally related to the development of MS, and there has recently been a study correlating the use of high block sunscreen and the development of MS in Denmark. (you probably already know this).

You will notice quite a few of your mutations are associated with proteins that use FAD/FMN, including DAO, MAO, MTHFR, MTRR, NOS, PEMT, TYMS. This generally means that you have to keep your riboflavin (B2) levels up high and you have to make sure that you have a properly functioning thyroid. This is needed to convert riboflavin to FAD and FMN.
Now this may be of relevance in the development of MS, as there is a "use it or lose it" rule for neuronal synapses. If you stop a nerve from firing if it fires too much will eventually stop the neuron from firing.

The reason that I mentioned your ACE mutation because some of the symptoms of AD are similar to MS and also some of the brain changes seen in the two conditions are similar. You are the only person that we have done with MS so far, so I don't know if this is a common pattern.

In general your pattern of snps looks quite simlar to that seen with CFS and ASD.
We know that we have had good success with high dose B1, B2 (particularly), B3, B9 and folate supplementation along with Ado/Me B12 and also high dose vitamin D3 (above 3000 IU/day).

I have quite a file on VB12 deficiency and MS, which I attach.

Please let me know if there is further that we can help you with.
It would be helpful if we could now marry your genetics to your current B12 deficiency symptoms at http://b12oils.com/deficiencyfrm.htm
We don't currently have an MS form. Symptomology can help in defining which system is caused by which enzyme.

Best wishes,
G

[PointsNorth]

Wow. Thanks G. Now I must formulate a plan!

HOMOCYSTEINE. it was tested a short time ago and I was well within normal limits.

FOLATE. took sublingual methylfolate along with active forms of B12. No dice. Still relied on my cyno injections. Is there a brand of folate you would recommend - avail in the US?

eNOS. I've had venous angioplasty done twice for CCSVI (narrowing of internal jugular veins leading to cerebral hypoperfusion). Experienced gains for exactly 1 week each time but symptoms returned. This is a common experience. A homeostatic response perhaps. Interested in ways to keep veins patent without stents. Stents not indicated for the IJV. I am interested in pursing. I will float on my MS forum www.thisisMS.com

[PointsNorth]

DrG reply today

Just thought you might be interested in this.

Accumulating data suggest that nitric oxide (NO) is important for both coronary and peripheral hemodynamic control and metabolic regulation during exercise. Although still controversial, NO of endothelial origin may potentiate exercise-induced hyperemia. Mechanisms of release include both acetylcholine derived from the neuromuscular junction and elevation in vascular shear stress. A splice variant of neuronal nitric oxide synthase (NOS), nNOSμ, is expressed in human skeletal muscle. In addition to being a potential modulator of blood flow, NO from skeletal muscle regulates muscle contraction and metabolism. In particular, recent human data indicate that NO plays a role in muscle glucose uptake during exercise independently of blood flow. Exercise training in healthy individuals elevates NO bioavailability through a variety of mechanisms including increased NOS enzyme expression and activity. Such adaptations likely contribute to increased exercise capacity and cardiovascular protection. Cardiovascular risk factors including hypercholesterolemia, hypertension, diabetes, and smoking as well as established disease are associated with impairment of the various NO systems. Given that NO is an important signaling mechanism during exercise, such impairment may contribute to limitations in exercise capacity through inadequate coronary or peripheral perfusion and via metabolic effects. Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training conveys benefit in the setting of secondary prevention.—Kingwell, B. A. Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease.

In addition, NOS is supposed to open up blood flow in muscles allowing greater nutrient access. Many of the body building sites promote this. Now if you don't do this, you get build up of metabolites, plus lower oxygen input, and so would become easily fatigued.

FYI NOS, is another protein that requires FAD (from riboflavin), and also requires BH4 (an off-shoot from the folate cycle). It also has the heme molecule (which requires FAD for synthesis). Once again stressing the importance of vitamin B2, folate and B12 in normal exercise, and in reducing blood pressure. YOu are heterozygous for most of the known NOS alleles.

[1eye]

I think there are thought to be excessive amounts of NO in "MS" patients. In the brain it is suspected of being involved in loss of tone in blood vessels, which lose their reactivity to NO through "vascular habituation", which would be a result of chronic over-exposure to NO. If there is a similar process happening in peripheral vessels, perhaps it would result in them not being able to expand enough to give needed O2 to muscles when they are operating aerobically. The NO is thought to interfere with mitochondrial O2 consumption as well, resulting in a kind of hypoxia which comes from not being able to metabolize readily available O2.

These things have been explored in the work of Dr. Ge. He is Associate Professor of Radiology in the Department of Radiology at the Center for Biomedical Imaging, in New York University's Langone Medical Center.

From Dr. Ge:

In MS, the presence of a tonically high NO level (even during resting) may alter endothelial function (vascular habituation) with a consequence of decreased vasodilatory capacity and limited blood supply when neurons perform a demanding task. This deficit in cerebral vascular reactivity (CVR) may in turn cause more neuronal damage (activity induced hypoxia) as a result of transient but frequent ischemic attacks during daily life, which is another result of excessive NO that cause damage to previously healthy neurons, thereby a progression of neurodegeneration.

and from his presentation at ISNVD 2014, as Cece posted in the CCSVI forum:

Multiple Sclerosis (MS) is considered an inflammatory demyelinating disease. One of the hallmarks, however, is the progressive neurodegeneration that plays a key role in the progression of neurological disabilities. Little is known of the link between neuroinflammation and neurodegeneration. Recent biochemical studies suggested a crucial role of nitric oxide (NO) over-production in neuronal/axonal injury. There is abundant evidence showing that the production of NO is significantly elevated in MS secondary to vascular inflammatory cascade. NO is an endogenously produced versatile signaling molecule. During an initial stage of acute inflammatory attack in MS, studies have shown diffusely activated T cells initiate the pro-inflammatory cascade and produce elevated levels of NO by upregulating inducible NO synthase (iNOS). It was found that the NO endproducts (i.e. nitrates and nitrates) levels were higher (approximately 2.5 times) in the CSF of MS patients with more clinical disease activity than those who were clinically stable (1.7-fold higher in relapses than in remission).

The increased NO competitively inhibits the binding of oxygen to mitochondrial respiratory complex (i.e. IV) and affects ATP synthesis, yielding a condition in which cells and tissues are unable to use O2 even if available. This phenomenon is called “histotoxic hypoxia” with potentially reduced oxygen consumption or cerebral metabolic rate of oxygen (CMRO2). A second consequence of NO over-production is the detrimental effect on brain vascular health. NO is a strong mediator of neurovascular coupling that is responsible for increased blood supply during transient neural activation. In MS, the presence of a tonically high NO level (even during resting) may alter endothelial function (vascular habituation) with a consequence of decreased vasodilatory capacity and limited blood supply when neurons perform a demanding task. This deficit in cerebral vascular reactivity (CVR) may in turn cause more neuronal damage (activity induced hypoxia) as a result of transient but frequent ischemic attacks during daily life, which is another result of excessive NO that cause damage to previously healthy neurons, thereby a progression of neurodegeneration.

These evidences together with our preliminary imaging results led us to propose that MS has significant abnormalities in CVR (oxygen delivery) and CMRO2 (oxygen consumption) that are consequential to cellular energy failure, and are predictive of disease progression. These alterations may be a significant underlying cause of the diffuse and progressive neurodegeneration in MS, but have been fundamentally under-investigated, especially in human subjects at early stage of disease.

This presentation will cover the use of several advanced metabolic/vascular MRI techniques to characterize the above-referenced deficits including a recently developed T2-Relaxation-Under-Spin- Tagging (TRUST) for the evaluation of global CMRO2 and a patient-comfortable CO2 inhalation paradigm to measure CVR. Some of our preliminary results of CMRO2 and CVR abnormalities will be presented in patients with relapsing-remitting and secondary progressive MS that are associated with clinical disability and disease progression. The hypothesis of our study is that there is significant abnormality of oxygen delivery (blood flow regulation) and oxygen metabolism (uptake), which may be key factors causing neuronal/axonal injury in MS.

[NHE]

That's great info PN! Where did you get your analysis done? 23andme?

FOLATE. took sublingual methylfolate along with active forms of B12. No dice. Still relied on my cyno injections. Is there a brand of folate you would recommend - avail in the US?

This is what I've been taking for methylfolate. http://www.vitacost.com/superior-source ... -tablets-1 I've had pretty good results with their methylcobalamin. In the first 3 months I was on their methyl B12, it brought my homocysteine down from 16.1 µmol/L to about 10 µmol/L. I have yet to be retested, but I assume it's even lower now especially with the methylfolate. What brand of methylfolate did you use?

[PointsNorth]

@NHE I'm just using two sprays currently which do not contain B9. Just Methyl/Adeno & MultiB. For many of us transdermalB12 works far better than intra-nasal, IM injection or sublingual.

I'm one Lucky Dog. After following B12-related threads on a ME/CFS website for a few years I learned of a number of people having a good experience with transdermal B12 http://www.b12oils.com. I investigated further and connected with the proprietor learning that he has been studying B12 metabolism for 25 years! After dealing with MDs who don't even know B12 is a water soluable vitamin it was great to meet Dr.G! He remarked that my genetic profile (23andMe) was very similar to peeps with CFS.

My B12 demands have increased proportionately with my MS progression. MS or chronic B12 deficiency?? I've known that the link was strong but now we're hopefully going to define the relationship further. Stay tuned! Two weeks and my energy level has improved.

Dr.G,

PN,
There is a lot of information out there now that wasn't out there when they first started diagnosing and characterizing MS. If you know the biochemistry, much of it seems to add up.

With the NOS, if you are low on riboflavin, or more correctly poor at processing riboflavin to FAD, one of the enzymes that will be affected is NOS and the activity of the enzyme reduced.

On top of this if you have issues with your folate cycle, then you won't spin off purine to make tetrahydrobiopterin (BH4). This is also required for NOS activity. Further, NOS also uses a heme group as part of the REDOX, so once again if you are low on FAD you can't complete the synthesis of heme, and so NOS activity will be reduced.

NOS is used to increase blood flow in exercising muscles, so if NOS activity is low there will be lower amounts of oxygen flowing to the muscles. This means that they will operate anaerobically for longer, thus building up lactic acid (which hurts). Now on top of that you have muscle myoglobin, which also has a heme group. It has a putative role in transporting oxygen from the cell membrane to the mitochondria to give you that extra burst of energy.

In short, yes, part of the MS fatigue could be attributable to low NOS activity, resulting primarily from low FAD, or low riboflavin (eggs, milk, dairy) in the diet, or low iodine in the diet (needed to make T3/T4), or hypothyroidism.

Interesting about your fatigue level. It sort of adds up. You have to wait for several of the enzymes to be remade with FAD in them, as some have FAD covalently linked into the protein, and it is only added when new protein is synthesized, which may take several months. Hence why you will feel a graded effect, it won't be sudden. Similarly with the B12, you will have to methylate (via MeB12) to make creatine, for creatine phosphate. You probably know that creatine phosphate is your back-up energy source, and around 50% of your SAM production goes to making creatine phosphate. Similarly MS is regarded as a mitochondrial disease, which is very similar to adenosylcobalamin deficiency. You will have to wait to make new mitochondria before you get full function out of them.

In addtion you will have to make new succinate dehydrogenase and various heme containing proteins in the electron transport chain.

Now you may find that your metabolic rate increases a little bit, which you will notice because your skin is a little bit pinker, and you feel warmer. You may also notice some weight loss (don't get excited, it will probably only be a pound or two). They are all little signs, and I believe that they will precede you losing some of your peripheral neuropathies.

Possibly you need to make new RBC's as well as the haemoglobin levels will be low. This takes 30-60days.
All good stuff.
Cheers,
G

[cheerleader]

Great news, PN! You've found a good doc.
Yup. The connection to eNOS seemed pretty clear to me back in 2008--the biochemistry info was actually out there, but the new DNA tests are expanding our understanding, and helping patients tailor protocols to their specific needs. Thanks to Dr. John Cooke for helping me formulate the Endothelial Health Program, and getting my husband's serum numbers in balance. Hope you might share this info with your doctor, PN--
http://ccsvi.org/index.php/helping-myse ... ial-health
The pinker skin, warmer extremeties, increased energy, weight loss, perfect blood pressure, and spot on CBC numbers are all signs of a healthy endothelium, and eNOS in balance.
cheer

[PointsNorth]

Hi PN,
Yes, I am suggesting that the start of the problem is due to B2 deficiency. This would have been brought on by either low dietary intake, sub-clinical hypothyroidism, or low ioding intake, and would have become localized in the brain when you had your vaccine reaction. Your genetics makes this worse. ACE and NOS mutations particularly. Somewhere you also became B12 deficient due to the riboflavin deficiency. Then from there it got worse.
The measurement of functional vitamin B2 deficiency should be reflected in serum iron and ferritin levels, and also results from an EGRA (but I don't think that they do it in the US).

Hang in there, you have lots to fix. You have good preliminary
G

[PointsNorth]

I will be going on a high-dose course of progesterone shortly. I'm told my high vitD intake should complement. My B12/B2 along for the ride.

Good piece:Multiple sclerosis, protein, fats, and progesterone

http://raypeat.com/articles/articles/ms.shtml

[PointsNorth]

People NOS+ (me) are more likely to re-stenose after angioplasty (me also)

http://www.heartfixer.com/AMRI-Nutrigen ... bnormality