Literature research

We would like explicitly to point out that we are neither doctors nor affiliated with pharmaceutical companies or similar. This information has been compiled to the best of our knowledge.

Due to the discussion about which mutations cause disease and which do not, we conducted a literature search for scientific publications and studies. (Who knows it: We researched in Pubmed)

If you are interested in details, we show literature links for interested people here.

There are studies on this subject that claim that the GLA variant p.D313Y is not disease-causing. The same applies to some other variants. But there are just as many studies that claim the opposite. How can it be that studies on similar topics using the same methods come to opposite conclusions? In the meantime we have read some studies and we noticed the following:

The studies that claim that p.D313Y does not cause disease often have one of the following points:

  • Symptoms such as renal insufficiency, heart wall thickening or low enzyme activity are weighted higher than neuropathic pain or an increased risk of stroke. This is understandable from a researcher’s point of view, because the first three can be measured, the last two cannot. It’s still ugly for a patient.
  • In some cases, entire classes of symptoms – mostly neurological ones – are excluded.
  • Many studies are so-called “Review Articles”, i.e studies that are based on other studies. Those affected are not examined for such studies, but the results of older studies are compiled and linked. Repetition makes the data seem overwhelming, when in fact only a few patients were studied initially, and some of the context is lost with each iteration.
  • Many studies also seem to examine a rather small group of those affected or sometimes only individual cases, which has two consequences for the validity:
  • First of all, not everyone affected has to get sick. Second, Fabry disease is a disease that gets worse over time. Thus, the probability of finding only those affected in a small group who are not (yet) ill is greater than in a large group. In addition, it is undisputed that the bandwidth for one and the same mutation is very, very wide.
  • Outdated findings are still given as justification. For example, it used to be said that women are only “carriers” of the disease and cannot be affected themselves. Luckily, that statement has come to an end. Other points such as: “D313Y needs a second mutation, it doesn’t do anything on its own” are repeatedly cited, although refuted in detail.
  • Some articles were also written with the aim of confirming one’s own opinion. Sources that present a different interpretation of the data are not cited, and the contradiction is not mentioned at all in the work.
  • For many articles, the mutations in dispute are excluded in order to protect one’s own work from discussion. Of course, such work may not be used as a source for further discussion. (but they will)
  • Certain biomarkers (alpha-galactosidase activity, lyso-GB3 value) are repeatedly pointed out, which often do not work in the case of the “controversial” mutations. In the meantime, however, it has been repeatedly demonstrated that these biomarkers are not 100% reliable. With other undisputed mutations, sick patients were also found, who are healthy according to the biomarkers. (Therefore, men should also insist on the genetic test and not just have the biomarkers measured.)
  • Recent findings indicate that the mechanisms of action of Morbus Fabry go far beyond the deposits in the cells. There are far more complex biochemical relationships than previously assumed. This is actually often “forgotten” in individual studies/publications.
  • There are criteria by which a particular mutation should be classified. But these are interpreted very broadly. Depending on the database (Clinvar, Varsome), the same mutations are classified differently. Ultimately, every doctor must decide for himself whether to decide in favor of the patient in the case of an allegedly unclear data situation.
  • Despite the same criteria and initial situation, the databases have different quality. In the often cited Clinvar database, however, there are various contradictions and unclear entries (every doctor can obviously make entries). The Varsome database is edited and provides clear results (e.g. that D313Y is pathogenic)

There are so many affected. It is said that 1 out of 200 people have the D313Y mutation. Other controversial variants are: E66Q, F113C, R118C, A143T and N215S.

Incidentally, the frequency is an important argument why these variants are classified as benign:

Not that many people can have Fabry disease. It may be that many sufferers have no symptoms, but our guess is that many have mild symptoms that are not directly associated with Fabry disease. These include, for example, dizziness, indigestion or motor failures. But these are also ailments that require treatment. And again and again someone has very severe symptoms. Shouldn’t you help these people because others are doing relatively well?

Incidentally, studies that actually examine patients usually come to the conclusion that p.D313Y and similarly controversial variants do at least make a difference. This can be brain damage or an increased risk of stroke. With a limited selection of studies, one can certainly claim that the controversial variants do not make you ill. In our opinion, however, a consideration of the entire data situation does not allow such a conclusion to be drawn. Rather, current results point to increased neurological problems.

The “mode of action” of Fabry is currently being examined in general. So far it has been explained that the deposits (from GB3) cause the damage. However, more recent studies show much more complex relationships. I.e. Fabry is far from being understood down to the last detail.

Example in blog entry: Fabry as a lysosomal storage disease, is there possibly more to it?

Basic research: mutations that are said to have no influence do cause damage. A new article shows that mutations that (supposedly) have no effect on the enzyme produced are harmful: Source: Scinexx online magazine