What “sets us apart” from the other Fabry patients?
Various mutations in the alpha-galactosidase A gene (GLA gene) are thought to be the cause of Fabry disease. So far over 1000 different variants are known.
Fabry disease is a multi-system disease that can affect a variety of organs in the body. There is no connection between a variant and the effects on the disease or specific symptoms. Many of these variants only occur within a family, which is why they are also called private.
There are some variants that are common in the population. Within these variants, the full range of phenotypes has been observed. Everything has been described, from the so-called classic type to the late onset with involvement of only one organ to the symptom-free man.
There is therefore a wide range of disease expression within a variant, from symptom-free to severely affected. Two of these common mutations are:
- D313Y (laboratory designations: c.937G>T or p.D313Y or p.Asp313Tyr)
- A143T (laboratory designations: c.427G>A or p.A143T or p.Ala143Thr)
The clinical relevance of these variants is controversial. Recently, various institutes have switched to classifying certain variants that were previously classified as pathogenic or of unclear significance as neutral and no longer report the corresponding findings/sequencing results to the submitting doctor at all. Patient and doctor are no longer informed about the genetic defect.
Therefore, always observe the information on genetic testing!
Classification of variants
There are five classifications of pathogenicity for variants:
- pathogenic
- likely pathogenic
- uncertain significance
- likely benign
- benign
In the literature, a distinction is also made between:
- classic Fabry
- late-onset Fabry
In our experience, however, many so-called late-onset variants often have early symptoms (already in childhood), which were usually not taken seriously at the time. I.e. this designation is incorrect.
And that’s where we come in, D313Y and A143T are increasingly excluded from diagnosis and therapy. We would like to draw attention to the fact that we exist and to ensure that no one is excluded from diagnosis and therapy.
All variants known to us that are currently being questioned:
These variants are currently under discussion and are already being ruled out in many new studies, so that no new insights can be gained.
| DNA | Protein (short) | Protein (long) |
|---|---|---|
| c.159C>A c.159C>G | p.N53K | p.Asn53Lys |
| c.196G>C | p.E66Q | p.Glu66Gln |
| c.352C>T | p.R118C | p.Arg118Cys |
| c.353G>A | p.R118H | p.Arg118His |
| c.376A>G | p.S126G | p.Ser126Gly |
| c.427G>A | p.A143T | p.Ala143Thr |
| c.454T>C | p.Y152H | p.Tyr152His |
| c.685T>G | p.F229V | p.Phe229Val |
| c.870G>C c.870G>A | p.M290I | p.Met290Ile |
| c.937G>T | p.D313Y | p.Asp313Tyr |
| c.989A>G | p.Q330R | p.Gln330Arg |
| c.1067G>A | p.R356Q | p.Arg356Gln |
| c.1102G>A | p.A368T | p.Ala368Thr |
| c.335G>A | p.R112H | p.Arg112His |
In addition to the variants mentioned here, there is a whole class of mutations that are often overlooked in Fabry patients, the intronic variants . The explanation of these is a bit more extensive, so there is a separate page for them.
We ourselves are seriously ill with one of these variants. We have significant impairments and a long ordeal behind us. Some of us are still receiving therapy and are seeing significant improvements. But we know patients who already have kidney failure or have had a heart attack and are still not receiving therapy.
We all have a long doctor’s odyssey behind us and were infinitely relieved to finally have a diagnosis, even if the disease cannot be cured. However, since it is treatable, we wish that access to therapy for the supposedly non-disease-causing variants would not be excluded.
Due to the discussion about which variants cause illness and which do not, we carried out a literature search for scientific publications and studies. Here are our results of the scientific discussion.
Additinal infos can be also found at blog entry for publication overview