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Fibrillin Mutations

Do They Really Cause Marfan Syndrome?

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It is widely believed that Marfan syndrome is a genetic disorder that is caused by a fibrillin mutation (specifically a fibrillin-1 mutation).  But is it?  Multiple studies confirm that the majority of people with Marfan syndrome have not been found to have any fibrillin-1 mutations.  Studies also show that fibrillin-1 mutations are rather common, and it seems that most people who have them do not have Marfan syndrome.  Based these facts, it does not appear there is much of an association between fibrillin-1 mutations and Marfan syndrome, and certainly no proof of a cause and effect relationship.  How can it be proven that fibrillin-1 mutations cause the syndrome, if it has not been proven that most of the people with the syndrome even have the mutation? If you look at the scientific studies surrounding Marfan syndrome, nutritional deficits and fibrillin-1 mutations, there is a stronger case to be made for the role of nutritional deficits as a significant factor in the syndrome, than there is for fibrillin mutations. 

If you want to find out what is really true about Marfan syndrome, instead of just what is widely believed, you have to: 1) look at the hard data, 2) ask a lot of questions; and 3) think for yourself. 
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How Many Marfans Actually Have Fibrillin Mutations?  

In order to begin proving a cause and effect relationship between fibrillin-1 mutations and Marfan syndrome, one would need to first establish a statistically significant relationship between the presence of the mutation and the disorder. 

Most genetic literature currently states that fibrillin-1 mutations cause Marfan syndrome. Yet, studies of people with Marfan syndrome consistently show that a large percentage of them are not found to have any fibrillin-1 mutations. 

In 1997, a study of 60 Marfans found that only 28% of the people with the disorder had fibrillin-1 mutations. This means that fibrillin-1 mutations were not found in 72%, more than two thirds, of the Marfans studied. 

This table shows the results of the 1997 study that determined the 
presence of fibrillin-1 mutations in a group of 60 Marfans.
  Marfans with fibrillin-1   
Marfans without fibrillin-1 mutations  

The 1997 study determined that most people with Marfan syndrome did not have fibrillin-1 mutations, yet much of the literature on Marfan syndrome created after this date, and through today, continues to state that fibrillin-1 mutations cause Marfan syndrome.  How can a mutation be said to cause a disorder, if it cannot been proven that most most of the people with the disorder even have the mutation?  Yet, against all logic, virtually all Marfan research is focused on fibrillin mutation research, and fibrillin research alone. 

It has been suggested that perhaps the 1997 study was flawed, that the subjects did not all actually have Marfan syndrome, or that perhaps they had the mutations but that they were unable to be located. Perhaps, but the possibility of a flawed study is a mere speculation, and I have never seen any hard evidence to support either of these suggestions.  Other studies have also only found fibrillin-1 mutations in a fraction of the families studied.  Even if the 1997 study was found to be flawed, this possibility still would not provide scientific proof that most Marfans have fibrillin-1 mutations, or that the mutations cause the syndrome, had the study not been flawed.  I believe that the most obvious conclusion to consider is that this study, and all of the others like it, are valid, and that the hypothesis they set out to test, that fibrillin-1 mutations cause Marfan syndrome, is the conclusion that should be questioned. 


Update: May, 2005: I went through the Pubmed database today to see what the latest research has been on Marfan Syndrome since I first wrote this paper in 2000.

Studies continue to prove that not everyone with a fibrillin mutation has Marfan syndrome and that lots of people who do have the mutations do not have Marfan syndrome.

Yet, against all logic, many researchers still cling to the completely illogical premise that fibrillin mutations cause Marfan syndrome when their own studies, year after year after year, fail to support this premise.

Here's a couple of the more recent studies that support my original argument:

Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. - "The phenotype of the eight patients without proven FBN1 mutation did not differ from the others with respect to the presence of major cardiac, ocular, and skeletal manifestations or positive familial history." (italics added for emphasis)

Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. - "Diagnostic criteria for MFS were fulfilled in 94 patients, 62 (66%) of whom had an FBN1 mutation. ...... Among the 77 patients who did not meet the criteria, an FBN1 mutation was found in 9 patients (12%).

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How Many People With Fibrillin Mutations Have Marfan Syndrome? 

Fibrillin-1 mutations are found in a wide variety of people with some very common conditions. Because of this, I question whether their presence in some people with Marfan syndrome is even a significant event.  Fibrillin-1 mutations have been found in people who simply have tall stature.  Lots of people are tall.  Being tall is not even a diagnostic criteria for Marfan syndrome, according to the Gent nosology.  I was told by a geneticist that it was not included in the nosology because it was such a common trait, and was not specific to Marfan syndrome.  Why would a gene associated with connective tissue cause tall stature? Just because someone is tall and has a fibrillin mutation does not provide proof that the mutation played any direct part in determining the tall stature.  Association does not prove cause and effect. 

Fibrillin-1 mutations have also been found in people who have aortic aneurysms, mitral valve prolapse or skeletal features of Marfan syndrome, such as scoliosis or pectus excavatum (Robinson, 2000).  Many people would either be tall, or have an aneurysm, or have scoliosis, or pectus excavatum or MVP.  Not including blood relatives or people I met through inherited connective tissue disorder lists or groups, I know six people with pectus deformities, seven people with scoliosis, four people with MVP and lots of tall people.  And that doesn't mean more of the people I know do not have these conditions, these are just the people that for some reason or another told me they had these medical problems.  If I took an actual survey, I'm sure lots of my friends and acquaintances may easily have at least one of these conditions, though none of them have Marfan syndrome. 
While I could not find any studies that demonstrated the rate of fibrillin-1 mutations in the general public, these facts all imply to me that a big chunk of the general population may well have fibrillin-1 mutations. Yet Marfan syndrome is relatively rare, occurring in only 1 out of 10,000 people, or only 0.01% of the population.  If you put all of these facts together, it means that the vast majority of the people with fibrillin-1 mutations would not be expected to have Marfan syndrome.  

So what percent of the general population actually has fibrillin-1 mutations?  I asked a researcher this question and was told this number is unknown.  Well, I think it is pretty important to know this number.  What if the rate of fibrillin-1 mutations in the general population is 28%, just like the rate the 1997 study found in Marfans?  Then there would not even be any statistically significant association between fibrillin-1 mutations and Marfan syndrome.   
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Do Fibrillin Mutations Cause Mitral Valve Prolapse or Scoliosis? 

People who simply have mitral valve prolapse syndrome (MVP) have been found to have fibrillin-1 mutations. MVP is so common it is thought to occur in 3 to 10% of the population, depending upon the study.   MVP has been clearly linked, in a large number of studies over the past decade, to magnesium deficiencies, which are also very common.   (See my section on MVP syndrome for more on this topic.)

Magnesium supplementation is used to treat MVP.  Studies show up to 85% of the people with MVP are deficient in magnesium. Studies show most people do not need gene therapy to treat MVP.  They just need to correct magnesium deficiencies.  This is not "new age medicine" - this last paper on magnesium appeared in the American Journal of Cardiology.  One of my relatives is a Kaiser patient and gets treated for MVP with magnesium therapy, indicating to me that it is considered a part of conventional medical treatment with at least some doctors in the U.S.   If fibrillin-1 mutations indeed caused mitral valve prolapse, then magnesium supplementation would have no effect.  Yet, studies show it does.  

It is curious that of most of the fibrillin studies I have read, the articles say fibrillin-1 mutations cause Marfan syndrome and are associated with a wide variety of other connective tissue disorders such as mitral valve prolapse syndromes.  Yet there is no more association between fibrillin-1 mutations and Marfan syndrome than there is between fibrillin-1 mutations and mitral valve prolapse syndromes, so it is illogical to use the term cause for one set of features and associated for another set of features.  I suspect that the reason for this is because if researchers report that fibrillin-1 mutations cause mitral valve prolapse syndrome, then it weakens their case that the mutations could logically also be the sole cause of a rare disorder like Marfan syndrome, so they stay with cause for Marfan syndrome and associated for mitral valve prolapse syndrome. 

I do not believe that there is proof that fibrillin-1 mutations cause either MVP syndrome or Marfan syndrome.  There may be some type of association between fibrillin-1 mutations and a wide variety of features of connective tissue disorders, but that is not in and of itself enough to prove cause and effect.  There are many cases of hereditary disorders that have particular genes associated with the disorders, as has been found in spina bifida studies, but that does not mean the genes themselves had any direct or singular impact on the disorder. (See my section on Genetic Disorders: Treatable Through Nutrition for more on this topic. 

Numerous studies show that most of the people who have scoliosis have osteopenia or osteoporosis.  Osteopenia and osteoporosis are highly multifactorial conditions with a large, established number of environmental factors, including diet and physical activity levels. Perhaps not coincidentally, magnesium deficiencies have also been linked to both conditions. 

Fibrillin mutations may possibly have some association to mitral valve prolapse or scoliosis, but if they were the singular cause of the disorders, then all of these other studies linking scoliosis and MVP to environmental factors would all have to be wrong. 
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Autosomal Dominance and Spontaneous Mutations in Marfan Syndrome 
Marfan syndrome is consistently referred to in medical literature as an autosomal dominant disorder.  Autosomal dominant means  that each child of an affected parent has a 50-50 chance of inheriting the genes for the disorder.  Yet in reality, Marfan syndrome does not follow autosomal dominant patterns.   Also, it have not been proven that there is a gene associated with the disorder that is inherited in an autosomal dominance pattern.  This means it has never been proven that Marfan syndrome is inherited autosomal dominantly - there is simply no scientific evidence available to support this statement. 

Thirty percent of all cases of Marfan syndrome occur in people with no family history of the disorder.  This makes it highly unlikely then to be solely a genetic disorder.  If we consider the possibility that Marfan syndrome is influenced by both genes and environmental factors, this would provide a logical explanation for why the disorder occurs more often in some families, yet also occurs in people without a family history of the disorder.  
As you may remember from biology class, Gregor Mendel discovered that the color of pea plants was determined by inherited attributes from the parent plants.  He found he could predict the color distribution of offspring pea plants based on the colors of the parent plants.  The children pea plants always followed an established pattern of color inheritance.  This genes-only pattern is not true for all plant color, however, and is even less likely to be true for complex medical disorders like Marfan syndrome. 

If Mendel had picked another plant instead of peas to study, his results would not have been quite so tidy.  The color of hydrangeas is determined in part by their genes and in part by the acid content of the soil, an environmental factor.  One of my friends changes the color of her hydrangeas by dumping coffee grounds on some of them to achieve a multi-color effect.  Her hydrangeas do not have "spontaneous genetic mutations".  They have environmental factors influencing their colors - her used coffee grounds. That is why the colors of her hydrangeas do not follow any predictable inheritance patterns.  

Instead of considering environmental factors in Marfan syndrome, which would be the most logical and straight forward consideration, geneticists often describe people with the syndrome and no family history, as "spontaneous mutations", assuming that their genes just "spontaneously mutated" to cause the syndrome.  This theory makes the assumption that environment plays no role in the disorder.  However, since there have never been any studies that ruled out environment in Marfan syndrome (and there are plenty to suggest a connection), then this is an illogical conclusion.  If Marfan syndrome is, in fact, caused by "spontaneously" generated genetic mutations, then anyone making this statement should be asked to provide proof that genetic mutations exist in the syndrome.       

The large 1997 study on fibrillin mutations in Marfans showed that the fibrillin-1 detection rate was lower in sporadic cases than it was in familial cases.  In sporadic cases, the detection rate for fibrillin-1 mutations was only 20%.  This means that 80% of the people with sporadic cases were not found to have a fibrillin-1 mutation.  This would not support the theory that the sporadic cases were caused by a spontaneous fibrillin-1 mutation, since it cannot be proven that 80% of the people with sporadic cases even have the mutation. Environmental factors as a consideration in Marfan syndrome remain a more logical and scientifically supportable reason as to why the disorder does not follow autosomal dominance patterns of inheritance.  The most obvious reason Marfan syndrome doesn't follow autosomal pattern of inheritance is simply because it isn't an autosomal dominantly inherited disorder. 
Note:  For a more eloquent description of why spontaneous mutations are unlikely to just happen, and the role of nutrition in genetic expression, read the book The Driving Force, by Michael Crawford. 

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Types of Fibrillin Mutations and Marfan Syndrome 
There is no specific type of fibrillin-1 mutation that is associated with Marfan syndrome versus the mutation found in tall people or those with mitral valve prolapse syndrome.  Most of the fibrillin-1 mutations that have been found to date are unique to a given family or individual, and each member of a given family with an identical fibrillin-1 mutation may have different symptoms, or even be unaffected.  

If you look at someone's genes and find a fibrillin-1 mutation, there is no way to predict whether that person is simply tall, just has scoliosis or has Marfan syndrome.  Having a fibrillin-1 mutation does not mean you have Marfan syndrome.  Even among people within the same family who have identical fibrillin-1 mutations, one may have Marfan syndrome and one may not.  This is a pretty clear indication that the genetic mutation could not possibly be the singular cause of the disorder.  If it were, then everyone with the genetic mutation would have the syndrome, but they don't.  Many people with the mutation do not even have any features that are diagnostic criteria for Marfan syndrome.  It goes against all logic for researchers to cling to their original hypothesis that fibrillin mutations cause Marfan syndrome when their own research fails to support this conclusion.
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Environmental Factors and Fibrillin 

Researchers have some insights into fibrillin, however, they do not have a complete understanding of all the factors, such as diet or medications, that might affect fibrillin.  My theory is that even if there is some type of association between Marfan syndrome and fibrillin-1 mutations, the defect may not necessarily be in the fibrillin genes.  Perhaps the defect associated with Marfan syndrome is not in any gene per se,  but in how peoples' diets and other environmental factors interact with their gene(s).   

People with homocystinuria, have many features in common with Marfan's syndrome, i.e. Marfanoid habitus, dislocated lenses, etc., yet many cases of homocystinuria are highly responsive to nutritional therapy.   Interestingly,  fibrillin-1 connective tissue proteins are influenced by elevated homocysteine levels, and elevated homocysteine levels are influenced by one's diet.   Elevated homocysteine levels can be reduced through nutritional therapy.

Some people with homocystinuria have been able to specifically improve their fibrillin-1 connective tissue proteins by correcting cysteine deficiencies. A 2000 research paper noted that, "...that a deficiency of cysteine and subsequent inhibition of fibrillin-1 accumulation in CBS deficient patients may be at least partly responsible for their phenotype, and suggest that maintenance of normal plasma cyst(e)ine levels may be an important therapeutic goal." In other words, they can correct their defective fibrillin-1 connective tissue proteins by changing their diets. Based on this knowledge, wouldn't the most logical assumption be that there may be other nutritional factors that can influence fibrillin-1 connective tissue proteins, including those of Marfan syndrome?  

The concept that inherited disorders are caused by a singe gene is no longer widely accepted in most genetic research and literature. The $60 million Environmental Genome Project is based on the concepts that few disorders are caused by a single genetic or environmental event.  The premise of the Environmental Genome Project, an outgrowth of the Human Genome Project, is that most disorders are in reality caused by complex sets of interactions between genetic and environmental factors.  I don't understand why Marfan research isn't based on the same concepts as the Environmental Genome Project, especially since the fibrillin genetic research does not seem to be panning out. 

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Environmental Factors in Marfan Syndrome 

There is very strong evidence to suggest that environmental factors play a role in Marfan syndrome. People with Marfan syndrome are often treated successfully with a medication called Propranolol to prevent aortic aneurysms. This proves that the course of Marfan syndrome can be altered by an environmental factor, because Propranolol is an environmental factor and it has an affect on the disorder.  

There are many associations between Marfan syndrome and copper deficiency symptoms, especially conditions such as aortic aneurysms and the unusual condition of emphysema in nonsmokers.  Studies show aneurysm-prone turkeys and the aneurysm-prone blotchy mouse, like Marfans, are successfully treated with Propranolol, yet separate studies show that aneurysm-prone turkeys have also been successfully treated with increased dietary copper.   The turkeys have a hereditary disorder, there obviously must be some genes that cause them to be aneurysm-prone.  Yet it is their diets, not just their genes, that also determine whether or not they actually get aneurysms.  If dietary copper helps the turkeys, then would dietary copper, or perhaps some other dietary changes, help Marfans? 
Interestingly, the aneurysm-prone blotchy mouse also develops emphysema, just like Marfans. The mouse has a problem with copper, tooIt does not metabolize it correctly Note the problem is with copper again  - it's not niacin, it's not iron, it's not folic acid.  It is copper - just like copper was a factor in the aneurysm prone turkeys.  Copper deficiencies cause aortic aneurysms in a wide variety of animals.  Copper deficiencies have also been linked to aortic aneurysms in humans.  Copper deficiencies in animal studies have been linked to scoliosis, osteopenia, osteoporosis, and emphysema-like lung changes  - all conditions that are features of Marfan syndrome.   It seems unlikely to me that all of the similarities between features of Marfan syndrome and copper deficiencies are sheer coincidences.   The role of copper in Marfan syndrome would seem to be a highly logical area to study.  (See my section on Marfan Syndrome & Copper for more specifics and links to many of the studies.

Calcification of heart calves, mitral valve prolapse, and rachitic skeletal defects such as osteopenia, pectus excavatum and scoliosis have all been linked to magnesium deficiencies and have also been linked to Marfan syndrome.   Magnesium supplementation has been shown to be effective in treating many of these problems.  The role of magnesium in Marfan syndrome would also be a highly promising area to research. 

Why would a fibrillin mutation cause calcification of heart valves?  I know of no studies that show that it would.  Perhaps a more logical scenario would be to consider the possibility that fibrillin may need a biochemical like magnesium for its creation, and a shortage of magnesium affects fibrillin production and causes other conditions, like heart valve calcification, that are unrelated to fibrillin.  Marfans also have abnormalities of hyaluronic acid, a magnesium dependent biochemical.  A magnesium shortage simply provides a more logical explanation for many of the features we know about the disorder.   It would be relatively easy and inexpensive to prove or disprove some of my theories by testing Marfans' cellular (not serum) magnesium levels and catecholamines excretion. 

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Based on the results of the largest Marfan study I could locate, over 2/3 of the people with Marfan syndrome were not found to have fibrillin-1 mutations.  Fibrillin-1 mutations are relatively common, most people with them do not have Marfan syndrome.  Many people with fibrillin-1 mutations do not even have any diagnostic features of Marfan syndrome, based on the criteria in the Gent nosology.  I question whether the presence of fibrillin-1 mutations found in the minority of people Marfan syndrome is even significant.  If most people with Marfan syndrome do not have fibrillin-1 mutations and most people with fibrillin-1 mutations do not have Marfan syndrome, then there does not seem to be much of a connection between Marfan syndrome and fibrillin-1 mutations, and without a connection there is no proof of cause and effect. 

Among people with identical fibrillin-1 mutations, one person may have Marfan's syndrome and another may not.  Logically, this then is a pretty clear indication that the fibrillin mutation alone cannot be causing the syndrome, and that other factors must be considered. 

Because of these facts, common sense dictates that fibrillin mutations alone are not the only factor, if they are any factor at all, in the development of the syndrome.  There is simply more evidence supporting the idea Marfan syndrome, like most other disorders, is not the result of genes alone, but rather a combination of genes and environmental factors.  

Return to my page on Marfan Syndrome.

See also Marfan Syndrome - The Similarities to Copper Deficiency


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