Biotinidase - my latest rabbit hole
 

I'm just going to post this information here in case it should help someone in the future. I have no idea what it means to me yet.

Whole exome testing turned up a genetic variant I didn't know I had from 23andme testing. The SNP was tested on 23andme , but I don't think they reported on it. It's estimated the variant is found in 1 out of 120 people.

BTD: c.1330G>C* rs13078881

rs1378881 - SNPedia

Babies born with two copies of this variant are profoundly deficient in an enzyme called biotinidase, and are at high risk of very serious, and possibly fatal, neurologic and metabolic problems. Testing for biotinidase levels is now part of "New Baby Screening," and the good news is that is very easily treatable with a therapeutic dose of biotin. They have to take it for the rest of their lives, but treatment is that simple.

Biotinidase is the enzyme responsible for allowing your body to make use of biotin which is amply found in food. Without the enzyme, however, your body can't make use of the essential vitamin. Free biotin found in supplements is the replacement.

One of the foremost researchers of biotinidase is Dr. Barry Wolf, a now non-treating pediatrician in Detroit. He's still an active researcher, though, and is very involved in the biotinidase deficiency community.

I found Dr. Wolf's email on a research report and emailed him never expecting to hear back. I was just asking if he thought there was any possibility my problems could be related. He emailed me back within a couple of hours, and called me the next morning. (I nearly fell out of my chair just having a doctor express interest.)

Long story short, he told me to go to my doctor, and get my biotinidase levels tested. That's only way to really know what's going on as they've identified many more BTD variants that can play a role. My doctor was happy to oblige with the test, although she said she'd be totally unable to help with results as she'd never even heard of biotinidase.

My results came in today. In a reference range of 4.8 to 12.0, I was a 4.9...on the low end of normal. Dr. Wolf had asked me to email him the results, which I've just done. I'm hoping to hear back and see if he has any thoughts.

Based on what I've read, you have to have biotinidase level of 30% mean normal or less before they say you should supplement. Apparently being 69% below normal isn't an issue. ? Needless to say I'm supplementing already, but without dramatic effect.

Anyway, here's one of the best "mostly understandable English" explanations of the disorder I've found. Beyond a tie to neurological problems, what makes it so interesting to me is its role in gluconeogenesis as I have reactive hypoglycemia on top of the neuropathy.

Biotin-Responsive Disorders - Springer

The only way an adult would know they're a carrier is if they had a deficient and symptomatic child (1 in 120,000 to 1 in 160,000), or they had a genetic test like I did. I have to wonder how much research has been done on people with my biotinidase levels.

That is very interesting.

Some background which may be helpful:

There are four biotin-dependent carboxylases in people. Pyruvate carboxylase catalyses the first step in gluconeogenesis, acetyl CoA carboxylase catalyses the first step in fatty acid biosynthesis, propionyl CoA carboxylase is important in the metabolism of fatty acids with an odd number of carbon atoms and methylcrotonyl CoA carboxylase is involved in amino acid metabolism. Pyruvate carboxylase, methylcrotonyl CoA carboxylase and propionyl CoA carboxylase are mitochondrial while acetyl CoA carboxylase is found in mitochondria and in the cytosol.

Thanks very much, Kiwi. I will try to do some digging on all this.

As coincidence would have it, Dr. Wolf called right as I was reading your post. He said my results indicate I am not biotinidase deficient, but cannot rule out the possibility that my lower levels are not playing a role in my problems. They are just not at a level that would be known to cause specific issues seen with biotinidase deficiency as it's defined.

They have a paper coming shortly on adults with undetected deficiency and the symptoms that presented later in life...optic neuropathy, muscle weakness and limb paresthesia. He said they were losing their vision, and had immediate reversal of all their symptoms upon starting biotin supplements. Oh, if only...

Thanks for posting this information, Janieg!

Did your convos with Dr Wolf involve information about the multivitamin transporter? If that is not working properly, biotin from the diet will not get to the tissues either. I have to wonder if genetic information even exists at this time?

No, it didn't cover that topic. Sorry.

I didn't want to take up too much of his time, but I did ask him whether biotin played any role in alcohol metabolism. I suspect my inability to properly metabolize alcohol might be a clue as to my problem. Maybe a deficiency or low levels of another enzyme in concert with lower levels of biotinidase is contributing to my issues. He said he didn't know of biotin involvement in that area, though.

*** Just putting this here for giggles...

Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and
catalase. Variations in the genes for these enzymes have been found to influence alcohol consumption, alcohol-related tissue damage, and alcohol dependence.

Some SNPs in the multivitamin transporter (SLC5A6) have been reported but as far as I can see their possible clinical significance is not yet known.

See the "Genomic Variants" section in SLC5A6 Gene - GeneCards | SC5A6 Protein | SC5A6 Antibody for more on this.

I'm going to do some intense pouring over of my genetic data...for lack of any other options right now. Just to give you an idea of what's involved when you test with an outfit like Genos Research...

To stay out of trouble with the FDA, they only report on your variants that have some publicly available and "trusted" information on them. They tell you whether you have one or two copies of the variant and then categorize it as Pathogenic, Likely Pathogenic, VUS (Variant of Undetermined Significance), Likely Benign, or Benign based on the overall findings of the available reports. They then link to all the reports.

I have 3749 variants with this breakdown:

Pathogenic - 34
Likely Pathogenic - 6
VUS - 75
Likely Benign - > 500
Benign - > 500

They also give you a helpful histogram chart showing the categorization of the available reports and how many reports are available. For example, the biotinidase variant was right at the top of the list because it had the most reports with 15, and the histogram showed all 15 reports were red or pathogenic. Everyone was in violent agreement that this was a bad variant. With other ones, you'll see some disagreement between reports on whether they're bad or not.

You can also sort them by population prevalence which is interesting. For example, here's one that that is only present in 0.180% - 0.238% of the population with four reports available, three of them saying pathogenic, and one saying likely pathogenic.

NM_001003841.2(SLC6A19):c.517G>A (p.Asp173Asn) AND Neutral 1 amino acid transport defect

And if I click on the reports, I see a bunch of gobbledygook, but look for some words in plain English that might help. In this case, "Hartnup disease" was stated which I can Google.

Hartnup disease - Genetics Home Reference

"Hartnup disease is a condition caused by the body's inability to absorb certain protein building blocks (amino acids) from the diet. As a result, affected individuals are not able to use these amino acids to produce other substances, such as vitamins and proteins. Most people with Hartnup disease are able to get the vitamins and other substances they need with a well-balanced diet."

After further reading, I see that nicotinamide or niacin supplements are recommended for people with this disorder. Maybe I'll add one of those to my arsenal.

Such fun. :rolleyes:

As an addendum, I should mention that since I started taking biotin, a bad patch of skin I've had for about a decade has cleared up. Woohoo!

It seems you are as determined with your research efforts as I am in refusal to accept this garbage diagnosis. I am convinced there is a metabolic error which won't allow me to absorb nutrients -some of which are copper, iron, and iodine. I know it's genetic, and we have the EDS diagnosis, but I don't believe that it's that simple. I don't think I have defective collagen and connective tissue. I think it's a metabolic mutation.

You might want to read this new post:
https://www.neurotalk.org/peripheral...europathy.html

This new poster tested positive for a DNA mutation involving familial dysautomnia and two others so far.

Perhaps seeing a genetic specialist may be helpful for you too?
(rather than neurologists, rheumies)

I am, Healthgirl. I have a ton to learn, but I'm determined to do everything I can see if my genetics will turn up a clue. I likewise feel there's a good possibility of a metabolic problem, and I'm going to start looking at those 34 pathogenic variants. I have the proper expectations going into it, but at least I'll feel like I'm doing something.

Are you looking though your whole exome test or a 23and me?

My whole exome.

As best I understand things, the only data I can see in my whole exome are the variants that have publicly available reports in ClinVar on them. ClinVar is maintained by NIH. Introduction - ClinVar - NCBI

Based on the information Genos provides, the average person has millions of variants. So in the end, I'm only seeing a minuscule amount of information, but it's the only meaningful information there is.

What I haven't figured out is whether there would be a way for me to see a SNP with no public information if I really wanted to. I can do that on 23andme, but I don't know if I can to that on Genos, and obviously Genos has processed a ton more of my genome.

Was your test though ambry genetics? I didn't get anything back except page after page of no mutation found for specific known mutations.

I had my whole exome done by Genos which was just recently purchased by another company:

Genos - Own your DNA, Learn about Yourself, Drive Research

I'm still figuring out what data I have, and what data I don't have. I realized last night as I going over all my pathogenic mutations that some variants from 23andme are missing, and they're not just missing from the pathogenic category, but they don't appear to be anywhere. I thought they were well-documented, but if they don't have reliable reports (as deemed by Genos' sources), I won't see them. Still working on understanding that and making sure I'm searching my results properly.

The cost is $499, but I got a deal late last year for $350.

Healthgirl,

Have you uploaded your 23andme data to other sites like Promethease or Livewello? Can't remember if we've talked about that before. Promethease especially is reporting additional information, and Livewello provides all methylation results nicely.

Just thought I'd post on my status having started taking biotin supplements, and then about three weeks ago, switching to a more expensive type recommended by the Biotinidase Deficiency expert for his patients with full-blown deficiency.

It was by no means a cure, but my symptoms have improved. My bad days are no longer hateful, and possibly are even on par with what my good days used to be. The wholly weird "rushes" I was having steadily have also waned.

I'm trying not to get too excited about the improvement because I always wax and wane, but this seems like a prolonged wane.

The other interesting thing is that I've lost about 17 pounds without trying hard at all. Right about the time my neuropathy hit, I started gaining weight like crazy. I was attributing it to entering menopause as I've heard horror stories, but at this point, I'm second-guessing the cause. Biotin is very involved in metabolic processes.

The other thing I've learned in my reading is that the gut is very involved "biotin uptake." I keep going back to the fact that all my problems started when I horrifically insulted my gut with iron supplements I was taking due to very low ferratin levels. I haven't been right since, and my neuropathy hit about three months after that. Maybe a coincidence, but I'm beginning to wonder. Here's a good article on biotin uptake in the gut.

Cell and Molecular Aspects of Human Intestinal Biotin Absorption

I can't help but notice this line in the write-up:

"An important characteristic of the human intestinal biotin uptake process is that it is also utilized by 2 other structurally and functionally unrelated nutrients, namely pantothenic acid and lipoate."

Pantothenic acid is Vitamin B5, and unless I'm misreading things, lipoate is lipoic acid. I've been taking R-Lipoic Acid since 2014 and have always been quite convinced it improved the initial horrific nature of my symptoms. Maybe this helps explain why.

So bottom line, I'm feeling better with having POSSIBLY found part of the problem. I'm not cured, but I'm doing better, and I'm so hoping the rest of you can find similar relief.

I can't edit my original post, so I'll just post this here...

The primary genetic mutation we're talking about here is found in only about 1 of 120 Caucasians. The prevalence of profound deficiency is 1 in 61,000.

______

This GI issue involves the multi vitamin transporter. This is why
I suggested to you to space your biotin at another time of day.

I have yet to understand this transporter .. try using it as a search keyword on Google. I am on a small tablet and can't do this easily
currently.

I'm reading about the SMVT (sodium-dependent multi vitamin transporter), and I might as well be reading Chinese for all I'm understanding.

Tried reading through one research article that was focused on biotin and the SMVT, and at the end, it effectively said, "Yeah, we don't understand the body's biotin requirements very well."

Sorry to be dense, but I'm not understanding the spacing thing. I tried re-reading past discussion, but must have missed it.

I did most of my searching a few years ago about the MV transporter. We had a poster here who used ALA and B5 alot every day, and so I did find that link to biotin also being unable to be absorbed or transported in the GI tract, when the transporter is filled.

After some searching for you, I found that Iodide has been added.

All of the supplements seem to be microgram quantities in food.
In fact, ALA is almost non existent from food sources.

So the logic follows for me at least, that in order to get good biotin absorption and transport, the others should not be in high doses. Just 100mg of ALA which is a small dose compared to the studies for neuropathy which are hundreds of milligrams, would overwhelm this transporter.

So you could try just not using the R-lipoic acid at all for a month, and see if you note any changes? That might open up the transporter to move your biotin to the tissues better?

Adding a bit to what mrsD wrote:

The MV transporter can only transport one of its substrates (iodide, biotin, lipoate and pantothenate) at a time. It can not transport any two of them (eg, biotin and lipoate) at the same time.

What this means is that all of its substrates are what are called competitive inhibitors of each other. This means that relatively high concentrations of any of its other substrates will inhibit transport of biotin.

So, as mrsD suggested, discontinuing lipoate for a while is worth a try to see if you notice any improvements. That way lipoate is less likely to act as a competitive inhibitor of biotin transport.

Thank you both! Got it now.

The reason I started taking R-Lipoic Acid back in 2014 was that a nutritional test done by an int. medicine doctor showed I was borderline low on it. The doc suggested supplementing. Regardless, I'll give it a shot.

I'm also digging into the genetics of the involved SCL5A6 gene. I'm having a tough time finding information, but it looks like I do have a couple of homozygous variants.

I read an article recently that discussed lipoic acid/lipoate.

Let me see if I can find it again.....

nope, but I did find this:

Top 1 List of Foods High In Alpha Lipoic Acid (ALA)

So this link illustrates how tiny the amounts of ALA are in most foods. This is why lipoic acid needs that transporter. Even when using small supplement amounts of milligrams it becomes a rather change to "drug" status of lipoic acid. The article I read a while back called the use of lipoic acid a therapeutic drug use and not a vitamin supplement use. So evolution did not occur with high lipoic acid consumption as we see today, with its use for diabetic neuropathy. Lipoic acid is made by our own body's metabolism.

Also the addition of iodide to the task of the MVtransporter explains the hypothyroid risk of using high dose lipoic acid since the transporter carries iodides (also in microgram quantities);
Iodides were not on the list in the past. And I expect other microgram quantities of nutrients to perhaps be found to need a transporter in the future.

When searching this topic try these 3 keywords...
1) lipoic acid
2) thiotic acid (often found in research articles)
3) lipoate

All are found in many papers.

Thanks very much for all this, MrsD. I plan on doing a lot of reading this weekend.

Spinach is a staple for me, BTW. Rarely a day goes by. :D

A person on my other health group says biotin taken with fats can reduce nerve pain.

Vitamin H (Biotin) | University of Maryland Medical Center

Just found this
 

Hello,
I just found this website by searching for c.1330G>C. This is my first comment, please forgive me if I am not doing it right. I too have that gene found through a genetic screen. I have numerous health nuiances, one of which is difficulty metabolising alcohol. Interestingly three other women in my family have the same thing. I'm very interested to know what other similarities I have with someone with the same gene. I understand the thread is old, I hope this is received. Also did you find a balance in managing symptoms?? If so how?

Hello Alexia,

Welcome to NeuroTalk. Despite the thread being old, I received notification of your response thanks to having email notifications being enabled on the thread.

I'm happy you posted. I feel rather alone with this gene mutation. I assume you have only one copy and not two? Having two copies is much more problematic.

Since making sure I supplement with biotin everyday, I have not been hypoglycemic once. It was definitely causing me metabolism problems. Unfortunately, I've seen no improvement with my ability to metabolize alcohol, nor has it improved my neuropathy problems.

The latter, however, I've just recently discovered are associated with histamine overload, which is a whole nightmare in itself.

Have you had your biotinidase enzyme levels tested?

Jane

Hi OP, at first glance all I can say is in my long life, I see no saving graces to consuming and putting alcohol in our bodies....... I can't speak about the gene issue but lived with too much alcohol in my family. Thank goodness both parents didn't imbibe.... Good luck.

Thank you for replying, this is great. Yes, I just have the one copy.

Histamine is something for me to look into, thank you. It may even be causing some of my other problems.

No enzyme levels yet, my next appointment is in a few weeks. There's only one metabolic clinic here and I think that test might also be harder to find where I am.

My symptoms being investigated are: neuropathy, alcohol sensitivity (seems to run in family), cognition, fatigue, ADD, anovulation, itchy skin bumps, dry skin, mouth bumps, twitching, general gut, headaches, sore throat, alopecia, weight/hunger, cholesterol, zinc, mood... not sure what else. Most of my symptoms come and go which makes it difficult to be assessed.

I've been taking biotin for 8 months and take between 300mcg and 10000mcg, I personally think the upper limit is too much for me. Some of my symptoms (especially waking in the morning) are better but not perfect. Are you at liberty to say what amount works for you personally?

Currently trying to start a family so the unpredictable ovulation is my main sore point if it's related.

Fun, fun, fun. Haha.

Sorry for the delay in responding. I didn't receive notifications of the new posts for some reason.

I'm taking 5 mg of Meribin biotin/day. It's a highly bioavailable form of biotin, and the brand recommended for profoundly deficient biotinidase people. It's very expensive, though, and probably overkill. I'm at the end of my last bottle now, and am going to switch to a less expensive form. I'll know pretty quickly if it doesn't do the job.

My functional medicine doctor ran my 23andme results through an analyzer that spit out a ton of "SNP" data. I'm highly mutated on my ALDH2 gene, which is a gene involved in alcohol metabolism. I'm almost certainly deficient in the enzyme it produces that is phase 2 of alcohol breakdown. Without enough of that enzyme, you'd be left with a substance called acetaldehyde cruising through your veins. It's effects are well-documented, and I'm sure this is the root of my problem with alcohol consumption.

Cardiovascular effects of acetaldehyde accumulation after ethanol ingestion: their modification by beta-adrenergic blockade and alcohol dehydrogenase inhibition - PubMed

Accumulation of acetaldehyde in blood was accompanied by marked increases in heart rate (53%) and cardiac output (78%) as well as by decreases in diastolic arterial blood pressure (19%) and peripheral vascular resistance (46%).

With regard to investigating histamine as a possible cause of problems, the best thing you can do is note your activity, especially with regard to what you've eaten, prior to a flare of symptoms.

Sounds like a thorough doctor, I am glad you found a good one to help. I have my next appointment at the start of November.

I was going to message to put an idea forth regarding the alcohol, though this new information makes alot of sense. I suppose in your circumstance could you try the alcohol dehydrogenase blocker or what was suggested in the article to improve your symptoms?
I must admit that most times I am skim reading information, it's hard to read and remember alot of the time so it's how I manage. Some times I wonder how I got through a science degree, haha. Hoping I can eventually have more good days than bad though!

I stumbled across an article that I interpreted to mean c.1330C>G gene can result in the incorrect conversion of a certain protein into histidine. As this is used in histamine synthesis I wondered if c.1330C>G would mean more histamine problems. Maybe far-fetched.

I hope that you can manage ALDH2 and improve your tolerance.

I found something suggesting biotin is important in utilising B12, it wasn't a journal article so I need to look into it more. I have normal B12 levels though this point interested me as doctors through the years keep testing me even when I say my levels are normal.

I think I will try the Meribin, it's even more expensive here as we don't stock in Australia. I have tried 5 different brands and different levels. I have an idea about what I think doesn't work but I wouldn't want to say as I mix dose/brand frequently. Currently trying Caruso's and Natrol.

I've done several food diaries, though admittedly it was always looking for food intolerance not histamine problems. Will keep it in mind for next Naturopath appointment.

Currently my grandfather, and either my mother or cousin are going to do DNA tests. We want to find out if the gene came from my mum or dad and if my grandmother (deceased) had it. Retrospectively grandmother having the gene would explain a lot. Hope that the familial data answers some questions in general as well. Will ofcourse share the information.

Kind regards
Alexia