This Is MS Multiple Sclerosis Knowledge & Support Community

Yep, I sure do.

So, ok where does that leave us, then?

We might never find the actual "cause" because it is or could be drastically different for each person. So...............how would you be able to do anything OTHER than treat the "result", even if the "result" we are referring to is early on in the disease process?

We can eat right (low fat, little to no red meat, etc.), get enough sun and vitamin D, exercise, take extra anti-oxidant supplementation, try our best to stay away from adverse environmental or toxic influences (if that is even possible in this day and age), and people may (and do) still come down with neurological disease. What if some types of MS are simply "genetic"?

Now, the problem with that, though, is that for some diseases, you can genetically find out if someone is "predisposed" to that disease or not (breast cancer and ALS being two of them), but even so, being predisposed still doesn't mean you definitely WILL come down with those diseases. And even then, say you do know that you are predisposed to MS, which causal relationship might be the one that triggers the disease in YOU specifically, as opposed to the next person? What is it you do about it? Does it do any good to know whether you are predisposed or not? (Genetic testing is a hot topic and very controversial.) Actually, if you think about it, based on everything that is being said about this or that probability for developing MS, just about everybody in the world is "predisposed" to it. (Take the recent article regarding smoking, for example.) See what I mean?

All in all, doesn't all this still just bring us back to square one? How can or do we find the cause? Or prevent for CERTAIN that the cause doesn't trigger the disease? Take Art Mellor for example. He started Boston Cure (forgive me, Art, I don't recall the new name for your organization now) for the very reason you are talking about, treez. To try to narrow down some causal relationships, in order to see about more definitive treatment or "preventative" measures earlier on before MS develops into a disabling disease.

And if the causal relationships are likely to be different for every individual, well............ I guess I'm not certain what it is you are suggesting, treez. What's your underlying theory?

Deb

P.S. I started showing symptoms of neurological disorders/disease at the age of 3 months. What then? Say we do identify the predisposition earlier on. Can we really say anything different to the mother of that child than what we say now to ALL mothers? Make sure your child eats right, etc. etc., as he/she grows up.

UNLESS...........my first neuro said to me "whatever you have been doing all these years, keep doing it!" Truthfully, I never did eat much red meat my whole life, I ate a low-fat diet my whole life, I got sunlight but never overdid it, I didn't eat much sweets (and I also still developed sugar problems - hypoglycemia - that is a "known", but all in all, I can control it), I ate vegetables, etc., I was never around toxic substances, etc. etc. PERHAPS the fact that I did live my whole life like this HAS made a difference as to how severe my neurological problems became, but we'll never know. There is no way to know either.

A large database and databank of MS patients' blood and eventually spinal fluid is being setup for research. How about checking chromosome fragmentation patterns along with that?
Many MS patients show chromosomal fragmentation compared to control subjects, but the pattern could vary between MS patients and perhaps over time in one patient.
What if some MS patients got their doctor to order a chromosome fragmentation check on several occasions to determine if there is a pattern for that patient? Then send the results to the new databank where their results can be added to the database (protecting privacy). The database would be available for any researcher who wants to check it. MS patients that show similar chromosome fragmentation patterns on several checks could be monitored and recorded for their symptoms and stage of MS. If a group of MS patients with similar chromosome fragmentation patterns show similar symptoms, that would suggest a similar mechanism and perhaps cause that could be studied related to that/those chromosome(s).
The test is probably costly so somehow that hurdle would have to be overcome. It would probably entail a blood draw and a cytotech preparing one or more slides of chromosome spreads and then reading about 1,000 cells to see if there are fragments that can be identified. I know you are probably thinking about the cost but couldn't an organization, like NMSS or MSF or Boston CureProject, create some rebate system from their funds to reimburse the doctor and lab for running the test?
This data could be very informative and easier to store than physical tissue samples. This is not biased towards any particular hypothesis (immune-driven, neurodegeneration-driven, or other). It would appear to be somewhat biased towards genetics versus epigenetics but it isn't so narrowly focused as to be looking for SNPs in specific genes.
Just a thought.

Wesley

Hi, Wesley!

I have heard that there are a few places collecting genetic data of some sort or another, but I'm not certain just what.

Well, let's see. Here is what the NMSS is involved in:

The MS DNA Bank at the University of California, San Francisco is looking for information from families with one person with MS (simplex families), and those with more than one person with MS (multiplex). In a simplex family, the parents are required to participate. If this is not possible, an unaffected sibling can serve as a substitute. Unaffected siblings and the spouse can participate as well. In multiplex families, participants must include two siblings with MS, their parents (if possible) and unaffected siblings. If extended family (e.g., cousins) members have MS, they and other relatives are usually asked to participate.

MS DNA Bank
Department of Neurology
University of California at San Francisco
513 Parnassus Avenue, Box 0435
San Francisco, CA 94143-0435
E-mail: msdb@itsa.ucsf.edu
Website: http://www.ucsf.edu/msdb/

Tissue donor programs that provide brain tissue for researchers studying the pathology of multiple sclerosis-its nature, cause, and effects on the brain-are extremely important. The National MS Society supports two MS tissue banks, facilities that provide resources for researchers studying multiple sclerosis.

The two centers are the Rocky Mountain MS Center and the MS Human Neurospecimen Bank.

The NIH has this going, also:

MADGC

The Multiple Autoimmune Disease Genetics Consortium (MADGC) is a group of genetic researchers who have joined efforts to identify and understand the genes that autoimmune diseases, including multiple sclerosis, have in common. If at least 2 members of your family are affected with different autoimmune diseases from the list below, your family may qualify to participate in this important research study.

Multiple Sclerosis
Rheumatoid Arthritis
Juvenile Rheumatoid Arthritis
Systemic Lupus
Type I Diabetes
Ulcerative Colitis or Crohn’s Disease
Psoriasis
Autoimmune Thyroid Disease
Sjogren’s Syndrome

Participation includes a brief telephone interview and providing a blood sample, which can be drawn at your local clinic or MD’s office.

To learn more about this NIH-funded study, visit http://www.madgc.org/
or call toll-free to either of these consortium members:

EAST: North Shore University Hospital
Manhasset, NY 1-877-698-9467

WEST: University of Minnesota
Minneapolis, MN 1-888-226-8636

I wonder what all the University of California is actually studying regarding DNA? Ok, the University of California IS studying the chromosome relationships, Wesley. I gotta say, this website is really interesting! Everybody should check this one out! http://www.ucsf.edu/msdb/

.... Knowledge of the genetic events leading to MS will create new opportunities - unimaginable today - to prevent, treat and cure this terrible disease.

Our strategy for fueling gene discovery in MS relies on the meticulous scanning of the entire genome of patients and their relatives in order to identify small chromosomal regions linked to the disease. Once discovered, these genomic segments are examined in detail to determine the exact location and characteristics of the MS-associated genes. As we reported to you previously, our "first pass" of the MS genome identified 19 different chromosomal regions harboring disease susceptibility genes, supporting the long-held view that multiple genes participate in this disorder. Seven of those were recently confirmed. ....

Ok, I see. The NIH study (in 2005) just published some findings that are really interesting. It "appears" that MS is not as closely associated with the other "autoimmune" diseases as was originally thought and/or expected.

http://www.behrenslab.org/images/pdfs/madgc_ajhg.pdf

....In this study, we show that a relatively common variant
of PTPN22, 620W, confers susceptibility for four different
autoimmune disorders: T1D, RA, SLE, and Hashimoto
thyroiditis. There have been initial reports of separate
associations of PTPN22 with three of these diseases
(Begovich et al. 2004; Bottini et al. 2004; Kyogoku et al.
2004). This is the first reported association with Hashimoto
thyroiditis. The OR for Graves disease was 11,
but our sample size was inadequate to definitively address
this question. However, two recent reports have shown
clear evidence of association with Graves disease (Smyth
et al. 2004; Velaga et al. 2004). In contrast, the lack of
association with MS is of interest, since the sample size
of MS cases in this data set (n = 120 ) provides a reasonable likelihood of detecting such an association. For this analysis, a case sample size of 120 has 62% power to detect an OR of 1.8, under the assumption of a control risk-allele frequency of 0.085. Furthermore, this lack of association has recently been confirmed in a larger MS
data set (Begovich et al. 2005).....

The absence of an association with MS appears to
imply that lowered thresholds for TCR signaling may not
have an important role in the predisposition to MS, at
least at stages of T-cell differentiation in which PTPN22
levels are critical for regulation. This is somewhat surprising,
given the wealth of data implicating T cells in
the pathogenesis of this disease (Haffler 2004). However,
knowledge is still very incomplete concerning exactly
which T-cell subsets depend on PTPN22 for regulation.
(Criswell et al.: PTPN22 and Familial Autoimmunity)

Overall, phosphatases have a negative regulatory function
in T cells, and there may be other phosphatases,
such as PTP-PEST (another Csk-binding phosphatase),
that might serve a function that is redundant to PTPN22
in certain cell types (Mustelin et al. 2004). It should also
be pointed out that PTPN22 is broadly expressed in hematopoietic
cells, and, thus, the mechanism for disease susceptibility may extend beyond T cells (Begovich et al. 2004). Knowledge of the regulatory circuits controlled by phosphatases in T lymphocytes (or other cell types), combined with population-genetics data such as we describe here, may eventually make it possible for researchers to identify the critical lymphocyte subsets and pathogenic mechanisms that are involved in the different autoimmune diseases. ....

Interesting.........!

Deb

OddDuck,

Those are interesting studies that will be useful but I can't quite see if they are touching on the chromosomal fragmentation that interests me.

I spoke previously of fragile sites in chromosomes that are not one specific base pair in a stretch of DNA but are numerous potential sites within up to 4 million base pairs so that a break can occur anywhere along the stretch. Maybe that can be discerned by comparing an MS patient to their siblings or parents. I would imagine that most of the genetic research is looking for single base pair changes (SNPs, single nucleotide polymorphisms) in genes but hopefully some of these studies are broader in their search.

I also wonder how well chromosomes hold up in the tissue samples that are stored for future research. That's why I was suggesting a blood draw followed by an immediate check on the chromosomes' integrity.
I'll have to look at the websites you noted, especially the California one, and see if I can figure out if they are covering what I want. Thanks for the leads.

Wesley

PS: I still haven't heard anything from NMSS about my hypothesis though I sent a followup email recently. I wasn't really expecting much from them. I've been busy with other research so I haven't been thinking much about it.

Deb, I guess you have proven my theory regarding "different causes exist".

I didn't start having symptoms until about 8 years ago, give or take a couple years. Symptoms always cleared on there own after several weeks. Had been to PCP a couple of times but MS was never even suspected or even suggested.

This would lead me to think that: 1) I am genetically predisposed.
2) Something that changed in my life (environmental factor?) or my body, was the "trigger" or perhaps cumulative cause.

This would put me right into the "average" age of onset. So what happens in the 30 - 40 age group? There are more changes than I first thought but, what comes to mind is hormonal . It has been shown time and again many hormone levels begin a very slow decline after that "prime" age that I believe falls in the 20 - 30 yr. range.

Specifically in my life: I started to eat more and more convenience foods after about 28. As I have found, this translates to poorer and poorer eating habits. (no longer eating at all healthy).

As I have recently discovered upon close scrutiny........boy do I have a poor diet and eating habits!

Interestingly, many of the older adult "maladies" begin to show themselves soon after 35 also. (In those predisposed?) Someone with heart disease common in their family better start monitoring, especially if they haven't been diligent with prevention . The best we can hope for with many of these maladies isn't a cure but arresting the disease process and possibly a degree of improvement.

I would say our bodies tolerance to mistreatment / general poor health practices becomes less. Bodies become less resilient. That can very simply be shown. Look at a 5 year old who scrapes his knee. Give it a week and it's all but gone. The same injury would be 3 weeks healing in an older adult. And the adult will have much more scarring.

OddDuck, none of this has any relevance to your specific case though.

Finn wrote:

there are at least two competing hypothesis, and there is little we can do about it. What comes to research, this is still a "trial and error"-disease. All current and most future therapies are based on the hypothesis that "MS is an inflammatory condition caused by a misdirected immune response" (and thus basic research done 15-25 years ago). Other hypothesis states that "MS is a primary neurodegenerative disease with an unknown origin". It is only a few years old, and based on better laboratory and imagine technologies.

This, if nothing else, reinforces the reference that was made to subgroups of MS(can't find the reference but was OddDuck or Bromley I think).

OddDuck made reference to some minor patterns that emerge in RR and SPMS, couldn't these be defining the subsets?

OddDuck also made reference to everyone being susceptible to MS. Couldn't that be true, just the least susceptible have a much higher tolerance and never reach that trigger point?

OddDuck: you raised some great questions in your post in this thread:

Posted: Mon Mar 21, 2005 5:56 pm

Ramble......Ramble ...........Ramble.

I have a 1 year follow-up MRI at noon today. Have mixed feelings about getting it but I guess we have to see what is going on....

Then I'm implementing my new "alternative therapies, 110%"

Nervous, still confused, and sad........

Treez

Treez,

Sorry to hear you are nervous, sad, confused.

I know how you feel.

Quite frankly this disease has destroyed my life - the contrast with my pre-ms life (only 13 months ago) couldn't be greater. My hobbies - sport, walking, gardening are now no longer options / pleasures. My 68 year old father is doing my lawn and driving me to the train station (recent exacerbation has left my legs dodgy and painful band around my mid-riff)

My 3 and 5 year old need a dad who can run around with them - not someone who's too tired out all the time.

We hear about new treatments, but then they are pulled off the market. The existing treatments are pretty ineffective in terms of the long term outcome of this disease. My neuro told me that this was an auto-immune disease but recent postings suggest that attacks / inflammation are side shows and that there is an underlying neuro-degenerative process. My neuro couldn't give me any feel for how my disease might progress (but eventually it will).

I think I could just about cope with a physical disability later in life e.g. limp, weak arm. But why throw in cognitive problems / memory loss? How does one live happily knowing that your brain is getting smaller (brain atrophy)? Then there's the dignity issues - bladder / bowel problems. Let's throw in speech problems / swallowing problems. And to make sure it's all covered - throw in fatigue (maybe some eye problems as well).

This is a vile disease - there's no disputing that. It's a wonderful combination of physical disability and mental deterioration (I like the way that some are prescribed an Alzeimers drug).

Is it a disease involving myelin? Who knows.
What do lesions do - who knows?

This all sounds depressing but then depression is another wonderful symptom of this disease.


I've realised that after a year with this disease - I'm sick of it.
I've realised that the cause isn't really important once you have it.

We're all trying to get answers to questions that the experts can't work out.

I admire the bravery of many who visit this site - many try to live their lives as best they can. My MS nurse told me that I was showing signs of high anxiety! Can you blame me? I only wanted to walk my daughter down the aisle when she got married, teach my son to drive, have a few years of retirement with my wife. Was I asking too much?

Please, please tell me that other's feel this way about ms?? Or am I just a big baby who hates to know that they will never be healthy again?

Bromley

(pretty angry at the moment because I'm in a lot of pain and all the doctor offered was anti-depressants + I'm sick of waking up every morning ill).

Happy to receive PMs from angry people with ms. Anger shows that you really missed the life you had / worked for.

bromley,

I know how you feel. I was extremely angry, frustrated and fed up when I couldn't even walk ten feet (and was experiencing most of what you are describing).

But, wait a minute.......you just said:

....all the doctor offered was anti-depressants ...

bromley, why not take him up on that offer? Except talk to him about making the anti-depressant be desipramine (i.e. Pertofran)!

What do you have to lose? We all have my research coming out of our ears about it!

Deb

EDIT: I mean, the last I knew, you were not yet on any injectable medications, right?

OddDuck,

Thanks - I shouldn't have posted but I'm having an angry half-hour. The only good thing about ms is this site and the people who are so helpful. But I just get frustrated. If I had cancer, the health service would be giving me chemo or something. I certainly wouldn't be going on websites to identify treatment or to engage with other cancer sufferers to come up with new treatments. That's the bit that sucks. I've paid a stack of taxes but when I get my first illness I'm told to just get on with it by the health service.

Sorry for the rant everyone.

Bromely

Dear Bromley,

If I remember right, you've been recently Dx'ed (within the past year or so). For me it's been about a year too. I had symptoms come and go for 6 - 8 years prior but they always left. MS was never expected nor even considered. I can look back and say I'm glad because a Dx six years prior would have cheated me of 6 years of fun, carefree, great life with my family. That dark cloud of uncertainty has been my biggest "disability" regarding the past year. Bromley, do you have any physical disability? And forgive me I don't remember, how old are you?

My wife always says, " there are alot of people alot worse off than me.......that are my age!" That is true but somehow doesn't help me!

Bromley, lots of people say " I know how you feel" , that really don't. I can truly say " I KNOW HOW YOU FEEL!"

Lots more thought for you but I'm outta' time........be back later!

Treez

Wesley,

I agree with your analysis about why almost all of the main research done on MS for the past 20 years has been on the immune system theory. If you read Dr. P.O. Behan's Pathogenis of MS, he comes right out and states that the results of MS research over the past 40 years has been nothing short of abysmal! These researchers have given artificial MS to the that poor mouse, pumped it with almost every kind of immune system altering drug known and developed the medications that we have today...the CRABs, cancer drugs and now Tysabri. We therefore have treatments that are at best minimally effective, can cause bad side effects and have made some drug companies very rich.

Only in the past few years have they come up with a few of the alternate theories that have been mentioned in this thread. But there hasn't been much done within these areas simply because like you said, very little if any money can be made here. How sad!

BTW, it's good to see you posting again, Finn.

Harry

Once again HarryZ, I agree with you. I think the whole research thing has become too focused and needs to take about 30 years- step back. The research that was done back then was soo... limited by comparison. The tools available, and knowledge of the body is like comparing a 1963 Buick to a 2005 Cadillac!

Perhaps the focus is like we've both said. Based on the $$$, not the cause & cure.

I guess the only thing I question is how does this apply to the research schools though?

Treez

Treez and HarryZ,

In many ways the problem is self-perpetuating. Take for example the mouse models of MS. EAE is an induced model. So what is your first thought of what a new mouse model should be? I'll bet it is ingrained in your mind that it has to be a mouse that develops an autoimmune reaction to its CNS.

I would contend that the Quaking and Jimpy mouse strains that I have mentioned previously could be good models. They develop neurodegeneration as they get older but it does not involve much if any autoimmune reaction. Yet I do not see those strains or any similar strains mentioned in research on MS. There could be other mouse strains that could be useful but they are not considered because of a bias towards what the model must show immunologically.

As another example of self-perpetuating: A professor may have decided in the past that among a group of enzymes, one was more important than the others since he felt that one enzyme controlled the rate of the overall system. So everyone coming into that field would want to choose projects related to the one important enzyme, neglecting the other enzymes. His students and post-docs would be biased as they looked at their own data (if any) regarding the neglected enzymes. But now that the human genome project has provided sequence data, we can look at the controls of the neglected enzymes and see that in fact they could have some important means of induction and thereby have a greater influence on the overall rate of the system.

I see a lot of dogma in science that needs to be overturned but, until the alternatives can be proven, the dogma will stay entrenched. I recently submitted a grant application related to cancer that challenges a similar dogma (regarding neglected enzymes) but we found some preliminary data that supports our hypothesis. Hopefully I will get the grant so I can: 1) stay in research and 2) prove the hypothesis. I can't imagine what I would do if I left research because anything else would be boring and seem less important.

Wesley

Wesley,

Your analysis of how research gets "cornered" into certain areas is quite right on.

As for what mouse model I would use....well, let's just say that I would not place much if any emphasis in the current model. Dr.Behan commented that although the current model is great for following EAE, it isn't any good for using that info in MS research. The main reason for this is that EAE isn't anything like human MS and that almost every single drug discovery that has been very beneficial to that poor mouse, has failed miserably in the treatment of humans.

Not being a researcher, I can't offer an alternative but I don't think I would continue to do what the researchers have been doing for years.....performing the same kind of immune theory treatments on the mouse and hoping for a different result. Perhaps that is another reason why after decades of MS research, we don't even have a cause to MS let alone a cure or decent treatment.

Harry

Mouse models in lupus research have some drawbacks too. Autoantibodies against Alu RNA/protein complexes have been discovered in some lupus patients. Alu sequences are short (80-400 base pair) repeated sequences found throughout the human genome. Alu sequences have RNA polymerase III transcription sites, which may be important in lupus since the Ro and La autoantigens appear to have a role in maturation of RNA pol III transcripts. There are an estimated 500,000 copies in the genome. But mice don't have Alu sequences, they have something called B1 and B2 sequences that are somewhat similar, but no Alu sequences. So, if the Alu sequences in lupus turn out to be important in determining events, the mice are useless since they don't have Alus. Every model will have problems, it's a matter of finding the best model and knowing its shortcomings.

Wesley

The Myelin Repair Foundation was featured in a Business Week article March 25, 2005. You can read at:
http://www.businessweek.com/technology/ ... _tc177.htm

----an interesting read----

Sharon(Denver)