(((*** 40 years on vitamin b6 ***)))

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Pantothenic acid (also known as vitamin B5) is an essential nutrient that is naturally present in some foods, added to others, and available as a dietary supplement. The main function of this water-soluble B vitamin is in the synthesis of coenzyme A (CoA)

The unique chemical structure of CoA-SH allows it to be used to activate carboxylic acids involved in both catabolic and anabolic reactions. Generally, in humans, CoA-SH is required for (a) chemical reactions that generate energy from fat, carbohydrates, protein and catabolism of ethanol; (b) biosynthesis of fatty acids (necessary for biosynthesis of: triacylglycerols, phospholipids, sphingolipids), cholesterol, acetylcholine, prenyl moieties, bile acids, ketone bodies, heme, melatonin, glycosaminoglycans, glycoproteins, gangliosides, proteoglycans, and others)
 
After a major seizure I usually end up with a severe throbbing headache. This headache can liger for days after the seizure. It affects me if I change from a sitting or lying position to a standing position and vise-versa. I need to get up very slowly to avoid it happening. My aura can last for ~one hour. During my aura I see colours. I am photosensitive. Despite the headaches that I get after a major seizure and the fact that I see these colours during my aura, I do not have Migraine. I have an extremely rare genetic, metabolic condition known as PNPO Deficiency. This has been confirmed via a genetic test and is controlled, as long as I remember to take my B vitamins (mainly B6 (Pyridoxine) and B2 (Riboflavin)) on a daily basis. I now receive Riboflavin on prescription also). I still experience an a-typical absence sensation/seizure. I have now had Vitamin 'Dependent' seizures for over 53 years.

**DO NOT ALTER ANY MEDICATION WITHOUT YOUR DOCTOR'S CONSENT**
 
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PNPO is a flavin mononucleotide-dependent enzyme, which requires riboflavin to convert pyridoxine and pyridoxamine to pyridoxal 5 phosphate

 
Hi Andrew,

Just like you I've been taking vitamin B6 for many yrs. but my Dr. put me on it to stop me from being anemic but in
regards to my seizures it hasn't helped me at all. What's helped me more than anything is the medical marijuana my
Epileptologist told me to start using and as weird as it seems taking 2 Tablespoons of apple cider vinegar with mother
in it. I was using it do lose weight but then I noticed how my seizures decreased to the lowest in my life.
Here's wishing you only the best of luck and May God Bless You!

Sue
 
Hi porkette,

You most likely have a different root cause to your seizures than I do. You may find the following rather interesting. Although I don't have Migraine, Riboflavin "may be effective in reducing Migraine frequency and serenity in some people".

Riboflavin plays an important role in cellular energy production in the body. Its role in mitochondrial energy metabolism suggests it may be effective in migraine. From the evidence available it is well tolerated and potentially effective as a preventive treatment for migraine. NICE Clinical Guidelines for managing headache state that riboflavin (400mg a day) may be effective in reducing migraine frequency and severity in some people.

**DO NOT ALTER ANY MEDICATION WITHOUT YOUR DOCTOR'S CONSENT**
 
Hi porkette,

You most likely have a different root cause to your seizures than I do. You may find the following rather interesting. Although I don't have Migraine, Riboflavin "may be effective in reducing Migraine frequency and serenity in some people".



**DO NOT ALTER ANY MEDICATION WITHOUT YOUR DOCTOR'S CONSENT**
Hi Andrew - Thank you for sharing all of this. Interestingly, we found our 16 yo daughter responded to higher dose riboflavin at the 400 mg you mentioned (after reading migraine studies).Then, we fairly recently learned of a different gene called GAD1 that has been associated with pyridoxine dependent epilepsy (though not widely recognized). Our daughter is highly compromised in this gene mutation. Since giving high dose B6 (pyridoxine) a try with support of daughter’s doctor, she responded favorably (we’ve done lower B6 in both forms many other times with no change). Daughter also has catamenial epilepsy (which has been such a hard one to get under control), but this last monthly cycle, I decided to give her 100 mg extra B6 (since we’d tried so many other treatments and I was desperate to help her), and it stopped the seizure clusters in their tracks! I’m feeling very hopeful we now have a treatment for the monthly seizures - B6.

I DO have a question for you - Dr said we need to try and stay under 500 mg or less per day so we don’t cause peripheral neuropathy. After much experimentation, it appears daughter does best on 400 mg/day in divided doses with another 100mg (so total of 500 mg) during her cycle.

With your high dose pyridoxine for all of these years, have you ever experienced neuropathy due to high pyridoxine dosage? (Though - you may be on a lower dose than our daughter is).

I’m also interested to see your post about how riboflavin was a necessary add on in some cases of B6 responsive/dependent epilepsy.

Thanks again!

Jen
 
GAD1:

This gene encodes one of several forms of glutamic acid decarboxylase, identified as a major autoantigen in insulin-dependent diabetes. The enzyme encoded is responsible for catalyzing the production of gamma-aminobutyric acid from L-glutamic acid.

Deficiency in this enzyme has been shown to lead to pyridoxine dependency with seizures.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=GAD1

Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2. GAD uses PLP as a cofactor.

In mammals, GAD exists in two isoforms with molecular weights of 67 and 65 kDa (GAD67 and GAD65), which are encoded by two different genes on different chromosomes (GAD1 and GAD2 genes, chromosomes 4 and 10 respectively).

https://www.wikidoc.org/index.php/Glutamate_decarboxylase


With your high dose pyridoxine for all of these years, have you ever experienced neuropathy due to high pyridoxine dosage? (Though - you may be on a lower dose than our daughter is).

I have been using greater than, or equal to 350 mg of Pyridoxine on a daily bases for over 40 years. I now use 450 mg of both B6 and B2 on a daily bases. 100 mg of each are part of a multi vitamin tablet which contains all nine of the water soluble vitamins (all eight B vitamins plus vitamin C). There have been no signs of Peripheral Neuropathy to date. I try to keep my B6 as low as possible to maintain control of my severe seizures (including Status Epilepticus). Also by doing this I am delaying any onset of Peripheral Neuropathy.

The upper limit for vitamin B6 is set at 100 mg. But in most cases of vitamin B6 'Dependent' Epilepsy the upper limit is set at 500 mg for an adult.

WNL.0000000000011891 (neurology.org)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772032/

https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/

https://bmcbioinformatics.biomedcentral.com/articles/10.1186/1471-2105-10-273

https://www.ncbi.nlm.nih.gov/books/NBK581452/

Pyridoxal phosphate is a cofactor of glutamic acid decarboxylase (GAD). This allows for conversion of glutamate into GABA. Reaction takes place in cytoplasm of termination of GABA-ergic neurons, therefore vitamin B6 deficiency may cause epileptic seizures in children.

https://en.wikipedia.org/wiki/Pyridoxal_phosphate#:~:text=Pyridoxal phosphate is a cofactor of glutamic acid decarboxylase (GAD,cause epileptic seizures in children.

GABA is the major inhibitory neurotransmitter in the brain and ideally should be in balance with glutamate. Excess glutamate and/or inadequate GABA can lead to overexcitation in the CNS, leading to seizure occurrence.

https://www.sciencedirect.com/science/article/pii/S1059131121002168#:~:text=GABA is the major inhibitory,6,7,14].

The active form of vitamin B6, pyridoxal 5′-phosphate (PLP), acts as cofactor for about 150 different enzymes found across all species, representing 4% of all known catalytic activities1. Among these, in humans several are involved in the biosynthesis and degradation of amino acids, biogenic amines, and neurotransmitters in the brain, including dopamine, γ-aminobutyric acid (GABA), serotonin, histamine, D-serine, and epinephrine. Mammalian cells are not able to carry out the de novo synthesis of PLP, but recycle it from the other B6 vitamers—such as pyridoxine (PN), pyridoxamine (PM), and pyridoxal (PL)—supplied in the diet, or deriving from degraded enzymes, in a so-called salvage pathway. A key step in the formation of PLP—the oxidation of either pyridoxine 5′-phosphate (PNP) or pyridoxamine 5′-phosphate (PMP)—is catalysed by pyridoxine 5′-phosphate oxidase (PNPO, EC 1.4.3.5; accepted name pyridoxal 5′-phosphate synthase), an FMN-dependent enzyme, using molecular oxygen as the final electron acceptor.

https://www.nature.com/articles/s41598-020-70598-7

Riboflavin is a water-soluble B vitamin, also known as vitamin B2. Riboflavin is primarily found as an integral component of the coenzymes flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)

https://lpi.oregonstate.edu/mic/vitamins/riboflavin

About 50 human genetic dis-eases due to defective enzymes can be remedied or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme, which at least partially restores enzymatic activity.

High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms - ScienceDirect


**DO NOT ALTER ANY MEDICATION WITHOUT YOUR DOCTOR'S CONSENT**
 
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Thank you so much, Andrew. Such helpful information and links. Do you find adding the high dose riboflavin has helped you? I’ve also read some interesting information about high dose B5 (Pantothenic Acid). We are definitely discovering the benefit of higher doses of the Bs (with doctors supervision/dosage recommendations and agreement, of course). Interestingly, early on, docs recommended we focus on B12, but we didn’t see many results.

Regarding B6, do you find any help in using both P5P and pyridoxine? At one point, daughter was on only a high dose of P5P, but when we switched to pyridoxine, there was a noticeable response. However, I wonder if a high dose combo of the two might avert peripheral neuropathy (though I’m very encouraged to hear you’ve never had an issue with it).

Thanks again!

Jen
 
In my post above I quoted the following from Wikidoc:

In mammals, GAD exists in two isoforms with molecular weights of 67 and 65 kDa (GAD67 and GAD65), which are encoded by two different genes on different chromosomes (GAD1 and GAD2 genes, chromosomes 4 and 10 respectively).

GAD2, chromosome 10 appears to be correct but GAD1 is on chromosome 2 and not 4 according to the following URLs:

 
Do you find adding the high dose riboflavin has helped you?

Yes, I have proven mutations in my PNPO enzyme. Both Pyridoxine 5' Phosphate (PNP) and Pyridoxamine 5' Phosphate (PMP)(Both vitamin B6 vitamers) are substrates of the PNPO enzyme, and a derivative of Riboflavin (vitamin B2), namely, Flavin Mononucleotide (FMN) acts as the coenzyme to the PNPO enzyme. So, for me, they both work together to increase the production of the product molecule, namely Pyridoxal 5' Phosphate (PLP, also a vitamin B6 vitamer and the active coenzyme form of vitamin B6 (PMP is a coenzyme to a lesser degree)).

PNPO - Pyridoxine-5'-phosphate oxidase - Homo sapiens (Human) | UniProtKB | UniProt

Normally the human body obtains enough vitamin B6 and vitamin B2 from a well balanced diet. Normally there are no mutations in your PNPO enzyme to cause any problems. 100% RDA of any vitamin supplement is enough to correct a dietary 'deficiency' in a particular vitamin. (Better still is to alter one's diet to include more foods rich in the vitamin you are deficient in). But 100% RDA of a vitamin is not enough to treat most cases of vitamin 'dependency' - due to a mutated enzyme(s).

Overview of Vitamins - Nutritional Disorders - MSD Manual Professional Edition (msdmanuals.com)

Regarding B6, do you find any help in using both P5P and pyridoxine?

I have never used PLP with my long 'prescribed' Pyridoxine Hydrochloride (PN HCl) tablets. Although I have researched it. PLP can inhibit (interfere with) the action of my PNPO enzyme (due to my PNPO enzyme been mutated the way it is) and may cause my severe seizures (status Epilepticus) to return if I switch from PN to PLP. This has occurred in some (few) of the different cases affected with 'PNPO Deficiency'. PLP, in a very high dose used over long periods of time, may also be responsible for the onset of Cirrhosis of the liver in a few cases of PNPO Deficiency. Also, why change something which is working and is not causing me any problems thus far.

Pyridoxine responsiveness in novel mutations of the PNPO gene - PubMed (nih.gov)

Cirrhosis Associated with Pyridoxal 5′-Phosphate Treatment of Pyridoxamine 5′-Phosphate Oxidase Deficiency - PMC (nih.gov)

Regards the different cases of 'PNPO Deficiency': What works - if at all - and in what combination, all depends on how much the mutation(s) have degraded the PNPO enzyme's ability to function. Also where in the PNPO enzyme the mutation(s) are located can effect its ability to function - very differently. This is true of any mutated enzyme. Different people may have mutations else where, in different enzymes/nonenzymatic proteins to me which affect them in a different way to me. We are all very different and complex when it comes down to our genetics!! My mutations seem to affect the binding of both B6 and B2 to my PNPO enzyme's 'active site' equally.

Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine - PMC (nih.gov)

Phenotypic and molecular spectrum of pyridoxamine‐5′‐phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine‐5′‐phosphate oxidase deficiency - PMC (nih.gov)

So in my case: Increased 'PNP' (derived from my PN HCl tablets) or (PMP) (both B6 substrates) plus increased FMN (B2 coenzyme) > *PNPO enzyme* > increased PLP (product) output to be shared between the more than 100 different enzymes which need PLP as their coenzyme - including GAD, AADC...etc. The sum of all the enzymes in each of our bodies (very much, if not entirely) equals our metabolism. Enzymes work on a subcellular level.

17.2: Pyridoxal Phosphate (Vitamin B6) - Chemistry LibreTexts

NOTE: The abbreviation 'P5P' can stand for any one of the three vitamin B6, 5'-Phosphate derivatives, namely: Pyridoxine 5' Phosphate (P5P or 'PNP'), Pyridoxamine 5' Phosphate (P5P or 'PMP') or Pyridoxal 5' Phosphate (P5P or 'PLP'). Very confusing. This is why I have chosen to use PLP over P5P as the abbreviation for [P]yridoxa[L] 5' [P]hosphate (PLP). Also, PLP is favoured in the scientific literature. In using this notation, 'Pyridoxine' becomes (PN), Pyridoxamine becomes (PM) and Pyridoxal, (PL). All (PN, PM, PL, PNP, PMP and PLP) are classed as vitamin B6 'vitamers'.

Vitamin B6 - Health Professional Fact Sheet (nih.gov)

My medication is very tailored to treat my extremely rare and possibly genetically unique condition.

**DO NOT ALTER ANY MEDICATION WITHOUT YOUR DOCTOR'S CONSENT**

The active form of Pantothenic Acid (vitamin B5, Pantothenate) is 'Coenzyme A' (CoA). Acetyl-CoA works, within our bodies, with Polyunsaturated fatty acids (PUFAs) to form the two main ketone bodies, acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB).

IJMS | Free Full-Text | The Pathophysiological Role of CoA (mdpi.com)

Vitamin B12 (cyanocobalamin) does nothing for my seizures also but since it is not doing more good than harm, I continue to use it and all the other vitamins I take as part of my multi vitamin complex on a daily bases.
 
Vitamin B12 (cyanocobalamin) does nothing for my seizures also but since it is not doing more good than harm, I continue to use it and all the other vitamins I take as part of my multi vitamin complex on a daily bases.

What I meant to say is:

Vitamin B12 (cyanocobalamin) does nothing for my seizures also but since it is doing me more good than harm, I continue to use it and all the other vitamins I take as part of my multi vitamin complex on a daily bases.
The above post timed out so I couldn't edit it.
 
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Thank you Andrew. Your experience is helpful. I also appreciated the last link you posted on metabolic disease as epilepsy. It was easy to follow information.

Like you, B12 never helped, but daughter stays on it because it isn’t hurting.

The pyridoxine form of B6 is the only one that has made a noticeable difference - huge difference, actually. And, riboflavin in high doses took things up a notch in improvement. When daughter’s time of the month comes along, I increase the B6 100mg to get through the hormone fluctuations and it’s helping so much.

The other very encouraging aspect is daughter has struggled with putting information into long-term memory (ever since seizures began at 8 years old). NOW, she is remembering more and learning and schoolwork is improving. Of course, we wish we discovered this connection/treatment earlier, but we will take what we can get! :)

Jen
 
The other very encouraging aspect is daughter has struggled with putting information into long-term memory (ever since seizures began at 8 years old).

Seizures usually begin within the first two years of life with these conditions. You mention that your daughter's "seizures began at 8 years old".

but we will take what we can get!

Don't forget to discuss matters with your daughter's specialist. Mention your daughter's positive changes in her life and listen to what they have to say. Ask about the PNPO gene if B6 and B2 are having a positive effect on your daughter's seizures/life in general. Maybe ask if a genetic test can be carried out. The only thing different is the age of onset of your daughter's seizures - 8 years old. Was that her first ever seizure?
 
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