MS that runs in families appears more severe

[TwistedHelix]

Out of seven members of my immediate blood family, three have MS,
one has Alzheimer's and two have Huntington's Disease, so perhaps we are good candidates to offer our genes up for study. Here is the first evidence that a familial link increases the likelihood of a more severe form of MS:

Public release date: 12-Oct-2007
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Contact: Lois Baker
ljbaker@buffalo.edu
716-645-5000 x1417
University at Buffalo

MS that runs in families appears more severe than non-familial MS
BUFFALO, N.Y. -- Magnetic resonance images (MRI) of a large group of patients with multiple sclerosis has provided the first evidence that those with a history of MS in their families show more severe brain damage than patients who have no close relatives with the disease.

The results, based on brain MRIs of 759 consecutive MS patients, support the hypothesis that a patient’s genetic make-up plays a role not only in development but also in severity of the disease.

A University at Buffalo team of neurologists and imaging experts headed by Robert Zivadinov, M.D., Ph.D., professor of neurology, conducted the research at the Buffalo Neuroimaging Analysis Center (BNAC), which Zivadinov directs. The BNAC is an arm of the Jacobs Neurology Institute, UB’s Department of Neurology in the School of Medicine and Biomedical Sciences. Patients were recruited at the Baird MS Center, also part of the Jacobs Neurological Institute.

The research findings were presented today (Friday, Oct. 12) at the 23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis in Prague, Czech Republic.

“From the early 1980s on,” said Zivadinov, “MS researchers thought that genetic factors likely played a role in the disease, that its traits were determined by several different genes, and our findings support this hypothesis.

“Our MRI analysis showed a difference between the severity of disease characteristics in familial MS patients versus what we call sporadic, or non-familial, MS patients,” he said. “These differences may be related to some disease-modifying genes, but to prove this, we must do further investigation.”

MS destroys myelin, the fatty sheath that protects nerve fibers carrying message traffic from various muscles to and from the central nervous system. For reasons currently unknown, in some people the myelin sheath breaks down, resulting in destruction of the nerve fibers and the symptoms of MS.

This demyelization process leads to mild to serious disability, from slight numbness of the limbs to loss of vision and paralysis.

The cohort of 759 patients involved in the study ranged in age from 36-56, with an average disability score of 3.4 on a scale of 0-10. A higher number indicates more disability.

Of these patients, 478 had relapsing-remitting MS, involving acute attacks with full or partial recovery; 222 had secondary-progressive MS, characterized by occasional attacks and sustained progression; 30 had primary-progressive MS with steady worsening from onset, and 29 had experienced their first attack.

Twenty-six percent, or 198, had a positive family history of MS. The breakdown between first-, second- or third-degree relatives with MS was 81/35/82. All patients obtained full clinical and quantitative MRI evaluations.

Using MRI, researchers measured the number and volume of lesions (plaques), which represent areas of demeylination; atrophy of the whole brain, white matter (the neural pathways), grey matter (brain regions) and the cortex, as well as employing additional imaging techniques.

There were no significant differences between familial and sporadic cases based on age, disease duration, disease course, disability score and total lifetime use of disease-modifying drugs.

Analysis showed that compared to patients with no family history of MS, familial MS patients had significantly more destructed lesions, and significantly lower volume of whole brain, white matter and gray matter, as well as other indications of greater brain degradation.

“Patients whose parents, children or siblings [first-degree relatives] had MS showed more damage than patients who had cousins with MS,” Zivadinov said. “This indicates that the closer the relationship, the greater the risk of MS.

“Of particular interest is the finding of more severe gray matter damage and more lesions, particularly in those with MS in first-degree relatives. These findings are very interesting and we will be investigating them further.”

Additional researchers on the study from the BNAC and the JNI, were Frederick E. Munschauer, M.D., Nadir Abdelrahman, M.D., Sara Hussein, Jackie Durfee, Barbara E. Teter, Ph.D., David Hojnacki, M.D., Michael G. Dwyer, Jennifer L. Cox, Ph.D., Marlieke De Brujin, Milena Stosic, M.D., Fernando Nussenbaum and Bianca Weinstock-Guttman, M.D.

Murali Ramanathan, Ph.D., from the UB School of Pharmacy and Pharmaceutical Sciences, also contributed to the research.

###
The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences and School of Pharmacy and Pharmaceutical Sciences are two of five schools that constitute UB's Academic Health Center. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.



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[gwa]

Dom,

That is a lot of MS!! How are the others in your family doing as compared to you?

I am the only one in my family with MS. My son has ulcerative colitis. I recently read an article which concluded that UC and MS are related diseases.

The uncertainty about this disease just keeps growing.

gwa

[HUTTO]

The natural history of multiple sclerosis: a geographically based study
8: Familial multiple sclerosis
G. C. Ebers, W. J. Koopman, W. Hader, A. D. Sadovnick, M. Kremenchutzky, P. Mandalfino, D. M. Wingerchuk, J. Baskerville and G. P. A. Rice
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada


Correspondence to: Dr G. C. Ebers, Department of Clinical Neurology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK E-mail: george.ebers@clneuro.ox.ac.uk

We have examined the demographics and long-term outcome of 1044 patients with sporadic and familial multiple sclerosis in a population-based cohort from London, Ontario. The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke disability status scale (DSS), DSS 6, 8 or 10. An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected: (i) first degree only; (ii) first degree plus others; (iii) second or third degree. The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected. Familial cases closely resembled those remaining sporadic in both demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater. The times to DSS 6, 8 and 10 did not differ significantly when sporadic, familial and familial subgroups were compared. These results provide no clinical support for viewing familial multiple sclerosis as distinct from the sporadic form. The observed recurrence rate for siblings in a strictly defined epidemiological sample was 3.5%, much as projected. These results validate the recurrence risks which have previously been derived from age-corrected data for these first-degree relatives.
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its all about what you can find..both my mother and father have and i have an uncle..all different..so which way am i going to end up...time will tell.

[Lyon]

Thanks for the info Dom and HUTTO.

The uncertainty about this disease just keeps growing.

It does seem that way, but when you consider that allergy, asthma and most of the autoimmune diseases share the same geographic gradients and timeline of increased incidence IN THE DEVELOPED COUNTRIES (not yelling, just emphasizing that we should never lose site of those factors), which points to their sharing the same source of origination (loss of evolutionary normal conditions ), with that in mind EVERYTHING makes a lot more sense.

Bob

[HUTTO]

sorry bob..i don't follow..so are you saying all this is related or that it is past down to us?

[Lyon]

First, don't be so scarce. We haven't heard from you in so long I almost forgot you existed!

First, I should point out that most of my view are contrary to that which is "commonly accepted". Lord knows it's not for the "joy" of being contrary but my deepest wish, my long term "obsession" is to understand the reasons for the increased incidence of autoimmune disease in the "developed" countries and it seems to me that the "legitimate" evidence is contrary to what is "commonly accepted".

Historically the prevailing opinion has been that MS (therefore "autoimmunity") incidence is owed to genetic predisposition first and environmental trigger(s) second, and at face value, that is what "seems" logical.

My belief, which at face value seems illogical, is that the changed living conditions in the developed countries cause a population wide environmental predisposition and the people who acquire autoimmune disease have a genetic tendency (which is a less redundant way of saying predisposition) and the particular autoimmune disease a person acquires is more owed to nuances in that person's specific system than strictly "genetics".

Odds are higher than the general public that if you were diagnosed with MS, one of your close blood relatives has been or will be. Odds are greatly higher that if you were diagnosed with MS (or allergy, asthma or any other autoimmune disease) that a close blood relative has been or will be diagnosed with allergy, asthma or another autoimmune disease.

I know that might seem that I've stacked the deck in my favor with that comparison, "Lyon combines the most common diseases known to man into one pot, of course everybody and their brother is going to be affected!" but I think it's very important.......essential, to keep in mind that all of those immune afflictions we grew up with and considered a "normal" fact of life were literally unheard of in our populations until the industrial age and they all increased in incidence in the same times and places.

Those are the biggest clues we are ever going to be given in the hunt for the causes of the autoimmune diseases and it bothers me that for the most part they are overlooked/forgotten in the research world.

Sorry, as usual I've gone off on a nut

so are you saying all this is related or that it is past down to us?

For the above reasoning I can't strictly say that these diseases are "passed down" to us but my emphatic conviction is that allergy, asthma and (most) autoimmune diseases share the same cause/reasons for incidence.

Bob

[LisaBee]

Twisted,

There is no MS I know of in my immediate or extended family, and my extended family is pretty big. I do have a sister diagnosed with Graves disease, and a niece with pediatric lupus, which was severe. I've had a cousin with fibromyalgia.

I am curious about the Huntington's in your family, because that may be a big clue. Do you have a long generational history of Huntington's in your family, or did it just all the sudden seem to show up in your generation or in one generation older than you?

Huntington's is one of those genetic diseases that is caused by extra triplets in the DNA, a CAG repeat, but my understanding is, the more repeats, that is, the longer the error in the gene, the earlier the disease tends to show up until with really long CAG repeats, it shows up in young children. Everybody has some triplet repeats in the huntington gene, it is just when the number gets to a certain level, around 30 something repeats, that the disease may appear, and there is a range of repeat length at which the disease appears, that is, a gray zone of repeat number. I've been curious for a long time about the gray zone number, that range of having a number of repeats in the mid high end of normal but sort of iffy as to whether it results in Huntington's in a given individual. Some of the case reports indicate people right on the borderline may develop HD, but at advanced age, like late 60s or 70s or are borderline, up in their 90s, and have no sign of HD.
It has made me think that a person with high normal to borderline repeats might not ever get HD, but might be more susceptible to some other type of neuro disease, either from the huntington gene alone or in concert with some other gene. I found one recent study in which an intermediate number of repeats was found in 3% of a Portuguese population, so being "high normal" is not rare at all. You can see where I'm going with this idea. Your family indeed would be very ineresting.

- Lisa

[TwistedHelix]

gwa, I think my comment was perhaps a bit misleading and indiscreet: misleading because I meant three people including me; indiscreet because one of my relatives with MS would I think prefer me not to discuss his condition. My mother had MS for many decades, and my illness seems to be following an identical pattern to hers: PPMS for years with a slow decline to quite severe disability, then reaching a plateau of long-term stability, (which I think is where I am now), followed by a sudden and quite sharp decline. She died two years ago from persistent and repeated infections, though I sometimes still talk about her in the present tense.
I think Bob is aware that I'm a big supporter of the hygiene hypothesis, though I feel it may involve more than only the loss of intestinal parasites and stretch to other factors of 20th century western living conditions, including chronic and prolonged stress.
Lisa, what you wrote about the genetics of Huntington's is exactly my understanding of it. Unfortunately, there's a huge chunk of my family history missing because my dad was an Italian prisoner of war who died when I was a baby and whose family we never had contact with, as far as I know there was no history of it on my mother's side.
Things got very messy, (and frustrating), when my brother was diagnosed and my sister and I had several meetings with a geneticist. We each have a 50% chance of developing Huntington's, but decided not to take the test. The geneticist, who apparently is very eminent in her field, seemed to totally ignore the fact that my dad was probably the carrier who died before the disease could develop, got very hung up on the possibility that mum had late onset Huntington's which was masked by the MS, or maybe that nobody in my family had MS at all! She was never able to give us any plausible reason as to why she might think that, and as far as I know our diagnoses are correct.

[LisaBee]

Dom
I didn't mean to imply I was questioning individual diagnoses in your family or anything along those lines. I'm sorry, I shouldn't have gotten into all that. What I was thinking last night was much more generalized, that if having an intermediate number of CAGs in the huntington gene, which apparently not uncommon, is a risk factor for other types of neuro illness. This is a total shot in the dark on my part because I don't know if anyone has looked at it outside of looking at HD. If interested, see abstract by Costa Mdo (2006) in which intermediate length alleles make up 3 percent of population. That is not rare at all. It surprised me.

http://www.ncbi.nlm.nih.gov/sites/entre ... s=16372132

One of the aspects of molecular epidemiology that I question is the tendency, at least for recessive diseases, there is tendency to not look at whether there is a susceptibility to something conferred by being a carrier, even though carriers have, say, half the normal level of a given enzyme. It is enough for them to avoid the recessive disease in question, but does it make them more susceptible to something else? I hadn't thought of Huntington's in this light, because it is a dominant disease. Then I got to thinking about the intermediate length CAG alleles in this context for the first time. The HD mutation is considered a gain of function, rather than a loss of function typically seen in the recessive diseases. That is, the mutation causes either an increase in function, or a new function. It creates a different way of thinking.

On a completely different tack, in your original post the abstract indicated there was no difference between sporadic and familial cases in disability score or lifetime use of disease modifying drugs in spite of the differences in lesion presentation. That was sort of interesting. I had a jaded thought, if, since there were no differences between the two groups on disease modifying drugs, if the researchers put them together, would they see if there was an (inverse) association between disability and lifetime use of disease modifying drugs. The study wasn't set up to answer that question, but I am curious to see if there is any validation against the drug-sponsored studies.

Lisa

[TwistedHelix]

Hello Lisa,
First of all, over the last few days we seem to all be perpetually apologising to each other for imagined slights or misinterpretation of one another's posts. Rest assured, I didn't think you were implying anything, and I was just giving a bit of my family background to illustrate how the genetic story is pretty hard to trace back in my case. I think I'm impossible to offend – –. Bob's been trying for years, and hasn't succeeded yet...
Huntington's is an autosomal dominant disorder which I understand in this way, (experts in genetics please feel free to correct me):
We have a gene which we use to make Huntingtin protein, essential for transporting nutrients to enable neuronal growth. We have two copies of this gene, one inherited from each parent. We only use one of these genes to make the protein: the dominant one, the other is not used. If one of our parents carries the faulty gene, we will have one copy of the healthy gene and one of the faulty one. It is then a matter of chance which parent's genes are the dominant ones, which explains my 50/50 chance – I have one good and one bad gene, and it depends which one my body's using to make this protein.
In this sense there is no such thing as a " carrier" who has half the level of a substance because they only have one good gene instead of two – we only ever use one.
This is probably why they always say, " if you've got the gene you've got the disease", but you're right about the grey area: the number of CAG repeats could be such that it causes the disease so late in life that it happens" after you're dead!", but the reduction in nutrient transport and the build up of plaques could easily be responsible for neuronal decay, which then triggers the whole cascade of events which leads to MS.
The only thing is, I would have thought that all the research into the genetics of MS would have soon picked up this particular abnormality, but it's certainly food for thought.

As to your last point, I keep reading this sentence over and over again until my head is spinning:

"There were no significant differences between familial and sporadic cases based on age, disease duration, disease course, disability score and total lifetime use of disease-modifying drugs. "
If it had been placed a paragraph earlier, it might be interpreted as describing the cohort of subjects: suggesting perhaps that they were all pretty similar apart from in their test results, but to be honest I'm really not sure. I need to sleep on that one!!

[Lyon]

I think I'm impossible to offend – –. Bob's been trying for years, and hasn't succeeded yet...

Wait just a dadblamed minute! I can provide a long line of witnesses who will testify that they find me terribly offensive................

Um, that was a set-up I just stepped in wasn't it?

Bob

[gwa]

twisted,

My father died in an accident at the age of 22 when I was only 6 months old, so there might be something on his side of which I am unaware.

As far as my mother's side, she had celiac disease and my grandmother was a diabetic. Now one of my sons has ulcerative colitis.

According to the paper from a doctor at John Hopkins that Lyon posted, that person believes that a lot of diseases thought to be autoimmune are related and possibly the same, but they affect different parts of our bodies.

This would make your "hope" for a universal cure possible when the cause is pointed out.

gwa

[LisaBee]

Hey Dom,

I think there is a bit of a correction to what you said - on the 50:50 issue for an autosomal dominant condition - for it, a person has a 50 percent chance of getting the disease gene from the affected parent, You will either get the gene from that parent or you won't, 50:50. If you get the bad gene, you in turn will get the disease, if you don't get the gene, you are free and clear, so probability of disease is also 50:50. This assumes only parent has one HD gene, which outside genetically isolated populations is generally the case.

The huntington gene is on chromosome 4. Everybody has two copies of this chromosome, one from each parent. Let's pretend that the mom has disease gene, shown with a capital H and dad doesn't, so M-4H4h and D-4h4h. Each of their children gets one set from each parent, so they will either be C-4H4h, or C-4h4h. Since Huntington's is a dominant disease, you are right, there is no such thing as a carrier condition, like there is for recessive genetic conditions. If you've got the H, you get the disease. That is because the H is thought to cause a gain of function rather than a loss of function, that is, it does much more of what the normal huntington gene does, or it does something new and different that is damaging. BUT, if you don't have the H, you won't get the disease, your chance of Huntington's is 0.

But here's where it might get a little tricky in practice, and that goes back to the number of CAG repeats in the huntington gene. There is grey zone CAG numbers in which the disease has incomplete penetrance. And there is a tendency for the numbers of CAGs to increase down through the generations in families with the disease. What causes this to happen I don't know, it is something going on in the meiotic process, like once the huntingdon disease gene reaches a certain point of instability, it keeps growing in size. It is much more obvious on the paternal inheritance side, I guess partly because men produce zillions of sperm versus women making a few hundred eggs. The phenomenon of CAG expansion was initially seen on the paternal inheritance, but has been documented on the maternal, too, although it appears to be is less marked in maternal lines.

So going back to the original example, and putting in some totally made-up CAG repeat numbers: M-4H40-4h5 D-4h4-4h4. Mom has the disease gene, but is on the very high end of the gray zone, or the low end of the HD zone. Let's assume she might get HD, but only very late in life, or might not ever.

they have three children: C1-4H60-4h4; C2-4H40-4h4, and C3-4h5-4h4.

In one of these 3 children, the CAG repeat number has expanded up into the definite Huntington's zone, in the second child, it is the same CAG number as the mom and is equally iffy in terms of disease penetrance, and child #3 is totally lucky and got one normal huntington gene from each parent and won't get the disease. Keep in mind children are examples of outcomes, not probabilities, the probability was 50% for each child to get the H gene. The probability on actual CAG length is something I don't think can be predicted, I just made them up as example outcomes.

I am speculating your geneticist may have been thinking along these lines as a possibility. Just a guess.

Going back to the Portuguese study, I still keep thinking about the 3% of the population with intermediate length CAGs, that is my own current brain-spinner. I agree that research into the genetics of MS would have picked this up if it were associated risk factor, but maybe not. If say, only PPMS individuals with certain disease characterists were examined, would the genetic linkage answer be different than for "all MS" as a whole? I suspect yes, it would. I think some linkage studies have already shown this with PPMS and RRMS.

I personally believe that people with MS are an amalgam of different diseases with different causes, and this partly why finding the "cause" has been so elusive. Hints of this have been seen in earlier studies, in which subsets of MS patients will show derangements of metabolic patterns, and some won't. Perhaps if you look at their MRIs or clinical progression, they might not look different, but if you look for weird metabolites in their urine, you see something, but only in a subset of them. But those weird metabolites might be tied to the cause in that subset. Most of the lnkage work seems to be focused on genes related to immunological function, under the premise that MS is an autoimmune disease. I'm not so sure it is, certainly not in everybody, it might be in some people. I think it is strange I have been diagnosed with a so-called autoimmune disease based on a brain MRI, have been offered immunomodulating meds as treatment, and yet have had no tests on my immune functions in blood or spinal fluid whatsoever that show I have anything unusual going on with my immune system, whether response to infection, autoantibodies, anything.

What I hope for in research is a better linkage between population-wide gene linkage studies and clues from testing and reported observation in individually diagnosed cases. One approach is the shooting wide, top down approach, and the other is the bottom up observational. If those two approaches could figure out a way to communicate and optimize with each other better it would speed discovery up. Each one of us are full of clues to cause, but once we are diagnosed, no one really looks at us again.

Lisa

[TwistedHelix]

Hello Lisa,
Thanks for pointing that out and giving us all that brilliant information: I had completely omitted the fact that you have a fifty percent chance of getting the bad gene from each parent.
Having lost all the information that was given to us when my brother was diagnosed, can you confirm what I think I read somewhere? I thought I heard that when the gene repeats reach a certain number, say about 36, subsequent generations can have wildly varying amounts and not necessarily a straight line increase.
Also, I think the research published in 2006 by Li at the Emory University school of medicine might have some bearing on your original point: the mutated Huntingtin protein interferes with the action of HAP – 1, (Huntingtin Associated Protein –1), which links to transport proteins including tyrosine kinase, (growth factor receptor TrkA). If it interferes with HAP-1, then perhaps the number of repeats may dictate how much it interferes, and therefore how much the trafficking of nutrients to the neurons is cut. In this way it could result in slow starvation for the neurons and open up the way to degeneration. Of course this might have profound implications for similar diseases, as Dr Li says,
"Research into other neurodegenerative disorders may also benefit from a thorough understanding of HAP1. This work also has implications for understanding the normal physiological processing for neuronal functioning,"
Interestingly, this protein also has a function regarding the use of insulin in the hypothalamus, and also in the functioning of BDNF. The Huntington's trail also includes such things as excitotoxicity, mitochondrial malfunctions, oxidative stress\free radicals, and of course neurodegeneration – in fact there is such an overlap between this disease and MS that I am very much persuaded by your theory that the grey area of repeats could indeed have a bearing on the aetiology of MS,

[HUTTO]

i tend to agree with you lyon. it makes alot of since. to me there are alot of common symptoms between all these so called autoimmune diseases and i guess logically what genes you have determines what disease you will get.. gentics no doubt play a role. but something else does as well.