Inherited enzyme defects and MS? Any research into this?

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Inherited enzyme defects and MS? Any research into this?

Postby LisaBee » Wed Sep 28, 2005 4:03 pm

In my searching the MS literature, I sometimes branch out and look at what is being done in other diseases that have some characteristics in common with MS.

There has been a lot of recent research in various inherited demyelinating diseases. In particular, there was an article in USA Today this week about an inherited disease called adrenoleukodystrophy, of ALD, which is an X-linked recessive disease impacting boys, because they only have one X chromosome. The gene is a defect in fatty acid metabolism, so the levels of very long chain fatty acids accumulate and cause toxic effects. There is also an inflammatory component to this disease, and I have read some abstracts that indicate the CNS lesions have some similarity to MS. However, the women who carry the gene and pass it on to their sons sometimes develop neurological problems in their 30s and 40s even though they have one good gene and one bad gene. Apparently a blood screen has been developed that measures the serum levels of very long chain fatty acids in both cases and carriers - they are elevated in both. This screen can also identify other genetic diseases that result in this elevation.

Now I am not suggesting ALD is directly related to MS, but my question is, why isn't there more research into possible biochemical defects in MS cases? I am thinking that there have been assays developed in recent years to detect metabolic abnormalities in people with other demyelinating diseases, and in some cases the carrier parent of an affected child has been found to have a reduced enzyme activity, even though the parent appears normal. Although some of these tests are not clinically available, many are, and they are not expensive, being used for routine screening of newborn babies, because in some cases dietary interventions can ward off the disease. I haven't seen where MS patients have been systematically evaluated for biochemical defects with the assays that are available. Many of these recessive leukodystrophies and other metabolic diseases that impact the CNS and immune system are (thankfully) very rare, but being the carrier for a rare recessive disease is much more common, and maybe, like in the case of the ALD carriers, having one good gene and one bad one might not be so innocuous as previously thought when it comes to being a carrier and being hit with some environmental trigger or having some other gene. Diet might help compensate for a partially defective enzyme activity which might explain why diet might help some people with MS.

Food for thought,

LisaBee
User avatar
LisaBee
Family Elder
 
Posts: 182
Joined: Sat Apr 30, 2005 3:00 pm
Location: Florida

Advertisement

Postby mrhodes40 » Thu Sep 29, 2005 3:39 pm

I agree with you. And then we have people funding stuff like "medication adherence" studies in MS.....Many have brought up this question over the years. Why aren't more assays done to evaluate the MS client for potential subtle deficiencies? There was even a Dr Golovkin of the ECTRIMS a few years ago advocating just that. It went no where. We are so sold on the autoimmune model that all the research money goes there. You can't get another thoery in edgewise.
Marie
User avatar
mrhodes40
Family Elder
 
Posts: 2066
Joined: Thu Sep 23, 2004 3:00 pm
Location: USA

Postby LisaBee » Thu Sep 29, 2005 6:06 pm

Well, I figure maybe I'll get myself tested for a few on my own dime - not something the insurance companies are going to cover, that's for sure. There is no precedent for it.

I talked very briefly with my neurologist, and realized the initial problem I have is finding someone that specializes in this area. My guess among clinicians would be a pediatric specialist that deals with neonates that show up with odd problems on their neonatal screening, or, for those enzyme defects not routinely screened for, ordering up a specialty test based on symptoms. The boutique tests for the rarer diseases are going to be too expensive. However, there must be some avenue for an adult to directly request a test. For example, if I had a sibling that had a child with a recessive genetic disease, I would want to get tested to see if I was also a carrier, and if I was, then my spouse would also need to get tested. This must happen frequently, although it isn't my own situation.

In the absence of any expert advice, I'll start with locating the tests that are 1) readily available 2) that pick up carriers as well as cases because the carrier has a measurably lower enzyme level, altered metabolite production, etc, and 3) might be likely have some bearing on immune function or myelin formation, or both. Many of these recessive diseases for which screening exists involve disorders in myelination as well as increased susceptibility to infection. For example, if phenylketonuria (PKU) is present in 1:12600 babies in a population, then the PKU gene is found in about 1 out of 112 people. For biotinidase deficiency carriers, it might run as low as 1 in 83. And so on. Being a carrier isn't all that rare, in fact if being a carrier was all it took to cause MS, MS would be even more common than it is and the inheritance pattern would be a lot more clear. It might take being a carrier and a few other conditions to trip the illness. It would really be something, though, if 10 unrelated people with MS got tested for a given biochemical defect present in 1:100 people in the general population and seven of the 10 came back as carriers.

Lisa
User avatar
LisaBee
Family Elder
 
Posts: 182
Joined: Sat Apr 30, 2005 3:00 pm
Location: Florida

Postby mrhodes40 » Thu Sep 29, 2005 6:52 pm

Wow this'll be very very interestig. DO tell what you get when you get done. I wonder what the best assays to get would be considering the pathology? Let's look and report back what we find.
Marie
User avatar
mrhodes40
Family Elder
 
Posts: 2066
Joined: Thu Sep 23, 2004 3:00 pm
Location: USA

Postby LisaBee » Thu Sep 29, 2005 8:04 pm

My first pick is for biotinidase deficiency.

For a good overview, go to: http://www.emedicine.com/ped/topic239.htm

I picked this one for the following reasons:
1) it is a routine neonatal screening test in many U.S. states, so is available and will cost less than $200 to get tested
2) heterozygotes (carriers) have reduced level of enzyme activity, so they can get picked up by the test, no DNA sequencing necessary to identify them
3) babies with severe deficiency have severe neurological problems as well as persistent fungal infections if not treated with biotin, which in many (but not all) cases prevents problems
4) an adult heterozygote had persistent vaginal yeast infections that cleared up with taking biotin, a readily available vitamin (see note below, though)
5) Last but certainly not least, Anagnostouli et al. 1999 reported decreased biotin levels in serum and CSF of MS patients compared to controls. I only have seen the abstract, so don't know if biotinidase was evaluated; the authors proposed other causes, such as possible malabsorption in MS patients. Amazing, no one else has since published on this topic.

On a cautionary note to anyone thinking to hedge their bets and take a bunch of biotin without first determining whether they need extra via testing (I certainly thought of doing this myself), there is an older paper on the rat EAE model that shows biotin deficiency actually protected the rats from EAE (Rabin, 1983). I think if the biotin deficiency is severe enough, an animal (or human) loses the ability have any immune response, autoimmune or no, but this is of course not desirable. Conversely, a person with MS taking lots of excess biotin they may not need might not be a great idea either - it is all totally unknown territory.


Partial biotinidase deficiency per this paper below is, I believe, seen in about 1 in 26 people. So it is more common than I thought. There are many types of specific mutations found for this enzyme though, so the genetics gets pretty complicated.

Swango, K. L.; Demirkol, M.; Huner, G.; Pronicka, E.; Sykut-Cegielska, J.; Schulze, A.; Wolf, B. :
Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum. Genet. 102: 571-575, 1998.
PubMed ID : 9654207

Lisa
User avatar
LisaBee
Family Elder
 
Posts: 182
Joined: Sat Apr 30, 2005 3:00 pm
Location: Florida


Return to General Discussion

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: No registered users