Paul Golumbek, M.D., Ph.D., a pediatric neurologist at Washington University in St. Louis, talks about an unusual disease and the over-the-counter treatment.
Interview conducted by Ivanhoe Broadcast News in March 2017.
I wanted to start by asking you about this condition that I had never heard before and really until a little while ago you had never heard of before. Can you tell me a little bit about it?
Dr. Golumbek: It’s called Brown-Vialetto-Van Laere Syndrome or disease, and it’s actually a problem with riboflavin transport. Riboflavin is a vitamin; there are some vitamins we make and then there are vitamins you have to get from your diet, riboflavin is one of those. Vitamins have to get from your gut to the place it has to go and there are various transporters that move it from the gut in to the bloodstream and from the bloodstream in to the tissues. In this case, one of the transporters that move it in to the brain is not functioning properly. There are different forms of this; it depends on which transporter is affected, so your riboflavin levels in your blood are actually normal even though it’s not getting in the brain. There’s plenty in the blood, but the brain wants this, it wants riboflavin. Riboflavin is an important chemical that is involved in energy metabolism in cells, and in nerve cells, particularly the ones of the eye. The optic nerve that takes vision from your eyeball back to your brain to get to get interpreted are very affected, as well the ones that come from your ear and bring to your brain for interpretation. Vision problems and hearing problems are pretty prominent in this. The nerves that go to your arms and legs, but actually more the arms than the legs, which is an unusual pattern, are also affected. Because in most neuropathies, most nerve diseases, the longest nerves are affected first, and those are in your legs down your feet. Most neuropathies start with numbness, pain or weakness in your feet and work their way up. This is kind of backwards because Ruby actually has weakness of her hands more than of her feet.
How rare is this? Because again, you had never heard of it, most of us have never heard of it. Is there any estimate on how many people might be impacted?
Dr. Golumbek: It’s pretty rare, and I don’t want to give you a number because I don’t want to give you a false number. It’s very rare so I would say two things about that. One, in all the years I’ve been doing neurology, pediatric neurology, and specializing in muscle and nerve diseases, this is the first case I’ve even seen. That already tells me it’s relatively rare. Because it’s been recently described, it may also be that we’ve missed cases. When I think back over my whole career, there’s only one case I can think of that maybe had it, but even that’s not clear and they probably didn’t have it. It’s rare; I would say I’m sure based on the numbers. But rareness also depends on the population, so things that are common in Navajo people would be common there, where they would be very uncommon in New Your City, for instance.
I was going to ask you because no one knew to look for it. Is it possible that it’s under reported, undiagnosed?
Dr. Golumbek: It’s certainly possible but it’s such a severe disease that you certainly may not recognize that’s what it was; but you’re definitely going to know something very significant happened because it really leads to decline and death. It’s not: oh, you’ve got a little bit of hearing loss. I mean you die from this disease, untreated, so you’re not going to really miss that.
Talk to me about Ruby and what was happening to her and how quickly and progressive it was happening.
Dr. Golumbek: Ruby started having problems about two years before I saw her, actually. Problems with her vision, and developing some weakness particularly in her hands; so by the time I had seen her, she actually had a fair amount of workup done including scans of her brain and lab tests. The only thing that really came out of all that workup was that she had her optic nerves, the ones that go to your eye, were too small; so she had atrophy or smallness of her optic nerves. But that’s quite a nonspecific thing, but, there was one thing that she didn’t have. There are a lot of white matter diseases, where the insulation on the nerves in the brain are torn up, or absent. A lot of central nervous system disease actually will affect the white matter and diffusely in the brain rather than just the optic nerve. Her white matter looked normal on the MRI scans. So her pattern actually is quite specific, having optic nerve atrophy without a lot of other changes around.
Do you know what causes this?
Dr. Golumbek: Yes. The problem is riboflavin, is an essential amino acid or essential vitamin I should say, an essential vitamin that you have to absorb out of your diet; you can’t synthesize it on your own. You have to get it and it’s actually made by the bacteria in your gut; it’s also in foods, you have to absorb a very tiny amount from your gut. It has to get from your gut to your bloodstream and then it has to get from your bloodstream in to your brain. It turns out the real problem is that you’re not getting riboflavin where it needs to be. Riboflavin is an essential vitamin that is absorbed out of your gut, your bacteria makes it, it’s also in foods. You absorb it out of your gut, it goes in to your bloodstream that takes it all over your body, and then you move it from your bloodstream in to tissues that need it. Particularly tissues that are very dependent on riboflavin are the optic nerves, and also, the nerves in the arms and legs and the nerves that go to hearing; they are very dependent on it. Because they’re so dependent, those are the first things that you notice significant changes of. The nerves actually without that vitamin, which is involved in energy metabolism, will actually die and be lost. It’s really important to get riboflavin where it needs to be.
Treatment for this, what did you tell the family?
Dr. Golumbek: When we recognized what it was, we started on a very high dose of riboflavin. Riboflavin is water soluble, most things either dissolve in fat or they dissolve in water. This is a water soluble vitamin, that’s good because it doesn’t build up in high levels in your tissues, which also means you could take a super high dose of this and it’s easy to flush out of your body; you won’t overdose on it. Also, the transporters that move it have some residual activity. By one of two mechanisms, either that residual activity with very high levels will help that to push across and get more across, so you have more in your body or through other mechanisms. If you get high enough levels it will be crossed in to the bloodstream and crossed in to the brain. I don’t know if we know exactly how it works, but we do know if you give mega doses, super high doses of riboflavin, it will treat this disease and cause the symptoms to stop and cause you to improve.
Any concern about her taking too much riboflavin?
Dr. Golumbek: Yeah, that was the really good thing about riboflavin, there’s no toxicity. There are some vitamins like B-6, where if you don’t have enough, you have a problem, and if you take too much, you have a problem. Most vitamins that are fat soluble are usually the ones that you don’t want to take too much and those are the deka, DEK and A; you can actually overdose on those and get hurt if you take too much of those. But mostly water soluble ones flush out of your body in your urine. In fact, riboflavin is yellow colored, so the whole time you’re in it your pee looks really yellow. It’s as though you haven’t drank enough water, but it’s just the riboflavin being peed out.
This is a genetic condition and as a result Ruby’s brother is also—
Dr. Golumbek: That’s right. It is autosomal recessive, meaning mom has a good gene and a bad gene typically. Father has a good gene and a bad gene so they are fine. But if the child gets the bad one and the bad one from both parents then they’re affected. Because if you have one good transporter that’s enough, one good gene. If you have two bad genes, now it doesn’t work properly and then it won’t move the riboflavin. The risk of having that is one half times, one half is one in four, which is a fairly high rate within a given family if you have the carriers. Then it turns out that Ruby’s little brother has the same thing, and so he’s been treated now and he’s not really developed any symptoms. Although he did have a lot of visual problems but those seem to be more typical visual problems that just require glasses as opposed to visual problems like Ruby had. Recognizing Ruby really helped save her brother.
Can you describe for me Ruby’s turn around once she started taking Riboflavin?
Dr. Golumbek: The day I saw her, we sent her over for a nerve conduction test and that showed the axonal neuropathy, and knowing that she had optic atrophy and axonal neuropathy turned us on to this disease process. We actually started treatment like three days later. I talked to her finally over the week end and I talked with Dr. Shinawi as well, because riboflavin is so benign and you can buy it over the counter, so there was no reason not to start her. It can’t really hurt you if you don’t have it; in fact, in the reviews, if you read them it says start it and then do the gene test because it is so benign. We were able to start treating her immediately. One of the things she was complaining about was coughing and choking when she ate, and that was one of the first things they noticed got better. That is a known problem of swallowing; it affects the nerves that go to the tongue and the back of the throat so that your tongue and the back of your throat get weak. Then, you send food the wrong way, so you start coughing and choking when you try to eat. While it wasn’t a huge thing that got better, within a few weeks they noticed she’s tolerating that very well. I saw her back about two months later, and on my little bedside test of her vision, it was actually a little better already in two months. It was moving the right direction. Then, when I saw her back about six months later, it was tremendously improved. Originally, she was twenty/one hundred vision, meaning she had to be twenty feet away to see something you could see at a hundred feet. Over that, six months on my little bedside testing, it went from twenty/one hundred to twenty/twenty, which is amazing. I actually did not expect such a huge improvement. Of course her behavior has changed, she could see again. And you can’t fix this kind of vision problem with glasses. It would not have helped at all. It’s the problem with processing not a problem with the eyeball itself, which is what glasses help with. That improved tremendously, and her strength also got better. By six months, there were clear improvements in her strength although she’s still weak. One of the problems is she has axonal neuropathy, meaning nerves have actually died. Some of the nerves that were going to a muscle have died. We can help these remaining nerves to stay healthy, but to actually recover these nerves we have to sprout and then maybe these nerves will come back on line or grow back. Growing back nerves is a very, very slow process. I was pleased to see that her vision came back so fast because I was a little concerned. If she really had loss of nerves to her eyes her vision, they probably wouldn’t have improved a lot. But clearly, that was one of the things that was notably improved right away. Within weeks and months, they noticed a change in her behavior; the way she walked, she wasn’t feeling around. Her strength has also improved, in her arms and legs and I expect it to keep improving. Certainly, like I said, when you treat it, we’re not only stopping the regression or the loss, but now we aid in recovering. We’ll see how well she does, and I think she could extend her thumb again, so we go back to thumbs up. Because she couldn’t extend her distal thumb joint, which is a strange presentation for most neuropathies but is common in this disease. I’ll probably never forget that now. Most people don’t have that.
Is there anything that’s permanent damage that won’t come back again?
Dr. Golumbek: The nerve damage. Those nerves that have died, have died. Those will not come back. Humans don’t regenerate nerves as well as some animals do. We can regenerate nerves a little; the problem is that nerves grow about a centimeter a year. If I have a nerve die in my neck, and it has to go down to my hand, even if it grows and even if it comes back at maximum rate, it will take one year, two years, and even three years to get there. A lot of times after a year, two max, they lose their way and stop trying. That’s why it’s really important to treat her before she loses the nerves, and not try to just stop her loss. I think in her eyes we actually had nerves that were not functioning but came back on line and started working which is why her visual acuity came right back, whereas, the arms and legs came back some but not as strong as I would expect for her age. But that should keep improving.
What’s her long term prognosis?
Dr. Golumbek: As far as I can tell, if she continues high dose riboflavin, then she should not have any worsening. We don’t have a lot of good long term data that I could find in the literature about treatment for twenty years, thirty years, fifty years, but of course, where will be in twenty, thirty years? I mean, we might have different treatments; we might be able to fix the gene itself in the future. Her prognosis, as far as I can tell, is quite good. I didn’t see anything about somebody who was treated regressing or getting worse despite treatment. I really expect her to make a very good recovery and continue that way. Her brother, hopefully, completely spared from these effects.
Is there anything I didn’t ask you that you want to make sure that people know?
Dr. Golumbek: Unfortunately, people will hear this and they will think: “oh I probably have this”. Because they have some kind of neuropathy and they think it’s probably this. Truthfully, you probably don’t because this is so rare and there are many, many causes of neuropathy. While I wouldn’t say you don’t have this, unless you’re a young child with these specific symptoms. Neuropathy itself is an extremely common nerve disease is neuropathy. Nerves diseases in the arms and legs are very common and probably you don’t have this. One thing I was worried about was people taking high dose of vitamins. There’s not a lot of evidence that Americans, if you have a good reasonable diet, don’t need high dose vitamins and supplements. Not that they necessarily will hurt you, most of them won’t, but should you spend the money on them, like on vitamin D? It turns out many Americans are low on vitamin D; we don’t get a lot of sun exposure. We don’t drink necessarily a lot of milk, so vitamin D is one for instance that I think is reasonable to consider. But I would say too, you shouldn’t. While you might be right, I wouldn’t make this diagnosis in my child and start treating them with riboflavin and not take them to a doctor if you really had this consideration. Because you really want to be sure what you’re really dealing with. Get the disease diagnosed exactly. In Ruby’s case, the genetic testing was exactly consistent with the disease and that was the nail; hitting the nail on the head in terms of her diagnosis. That is what she had. There are other things that can cause vision loss and neuropathy, so see a doctor if you are having symptoms.
What would you say to parents and physicians who are struggling to find that thing that might help?
Dr. Golumbek: Interestingly, there’s better genetic testing out there that actually will find many different genetic diseases. It is possible, even without us knowing exactly what she had, that if we had sent genetic testing, the larger scale of axonal sequencing, it’s possible that it would have made this diagnosis just based on that. Although axonal sequencing is like eight thousand dollars, so a lot of people don’t have that to throw at their child. In this case, it was a progressive disease and that certainly stimulated everybody to keep looking, keep searching. What I’ve got to say by the time I saw her, she had many, many tests. Spinal taps, many blood tests and scans of her brain. She had two scans of her brain, actually. It’s not like people weren’t looking, they were trying to find it, but we just got lucky and unfortunately sometimes people say it’s better to be lucky than good, and there’s a grain of truth to that.
Is there any doubt in your mind that the intervention saved this little girls life?
Dr. Golumbek: Oh, absolutely. I think there’s no question. Just seeing her six months later, it’s hard to believe she’s the same little girl who was kind of staggering and looking, obviously had severe vision impairment, at the initial presentation. She’s now running around, jumping around six months later. You test her vision and it went from twenty/one hundred to twenty/twenty; that’s an incredible improvement.
What goes through your head when you see her?
Dr. Golumbek: I am so happy because there are so many kids that we see, but unfortunately can’t treat. We can’t fix many patients, but we do the best we can. So when you get a case that you can make a big intervention, I feel happy. I remember when I was reading that weekend, I was really getting shaky; I was so excited that we could help her. Really just reading about it seemed like that’s what she had and that was treatable and I had an incredible amount of hope within two days of seeing her; because usually these cases are not that way. When I originally saw her in the clinic, I was actually down playing the likelihood of this being something treatable. I was saying this is bad because most progressive neurologic diseases are not treatable. My experience has been the exact opposite of this for most cases. When I first saw her, I actually thought she was going to have a problem of the insulation of the nerves in the brain, and those are by and large, untreatable diseases. They’re progressive, and they’re horrible diseases too. We had something treatable and everybody can attest to vision being so important. Everybody can understand losing your vision would be a scary thing.
END OF INTERVIEW
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