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Old 04-28-2017, 10:05 PM #1
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Default 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.

Last edited by janieg; 04-29-2017 at 06:25 PM.
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Old 04-28-2017, 10:39 PM #2
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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.
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Last edited by kiwi33; 04-29-2017 at 02:30 AM. Reason: Added some more information.
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Old 04-29-2017, 08:54 AM #3
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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...
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Old 04-29-2017, 09:08 AM #4
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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?
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Old 04-29-2017, 09:26 AM #5
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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.

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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?

Last edited by janieg; 04-29-2017 at 10:01 AM.
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Old 04-30-2017, 02:25 AM #6
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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?
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.
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Old 04-30-2017, 10:47 AM #7
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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.

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!

Last edited by janieg; 04-30-2017 at 11:12 AM.
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Old 05-01-2017, 09:34 AM #8
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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.
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Old 05-01-2017, 10:06 AM #9
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Quote:
Originally Posted by Healthgirl View Post
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:
Small fiber neuropathy

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)
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Old 05-01-2017, 10:30 PM #10
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Quote:
Originally Posted by Healthgirl View Post
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.
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.
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