What is Fabry disease

Clinical picture

Morbus Fabry, also known as Fabry disease, Fabry syndrome or Fabry-Anderson disease, is a genetic metabolic disease. It was first described in 1898 independently by the German Johannes Fabry and the Englishman William Anderson. There is no clear clinical picture; Those affected can have very different symptoms. What connects those affected is the cause of their symptoms: a genetic defect. The quality of life of people suffering from Fabry disease is extremely poor and comparable to that of AIDS patients.

If left untreated, male patients live to an average age of around 50 and female patients to around 70 years. The main causes of earlier mortality are chronic kidney failure, damage to the heart and impaired blood supply to the brain.

The disease has been treatable since 2001. An infusion is given every two weeks. Since 2016, some sufferers have had the option of taking one capsule every other day instead.

Amicus Therapeutics provides a susceptibility chart and search facility to find out whether or not a particular GLA point mutation is labeled as responsive to treatment with GALAFOLD®.

Some key data on Fabry disease:

  • It is a genetic disease, also called an inherited disease. This means that the cause of the symptoms associated with it lies in the genetic material. It is passed on from parents to their children with the genetic material. (See inheritance for details and the probability of children developing the disease).
  • It’s a metabolic disease. It prevents the individual cells of the affected organs that make up the human body from functioning properly.
  • It’s a multiorgan disease. Many organs in the body can be affected.
  • It’s a progressive disease. Symptoms get worse over the time.
  • It’s not curable. One treatment is to slow the progression of the aggravation and relieve the discomfort that is already present.

Here we have listed the complaints of the most important organs. In detail, however, every cell and thus every organ in the body can be affected. You can find a list of all currently known possible complaints under possible symptoms.

Neurological complaints: Since the nerve cells consume a lot of energy, they are very sensitive to metabolic disorders. Therefore, there are a variety of possible problems affecting the nerve cells. Typical symptoms include burning pain in the hands and feet. It can also happen that light touches are painful, you can no longer feel the temperature properly or the skin tingles constantly. Some sufferers experience dizziness or have problems concentrating or memory.

Nephrological complaints: The kidneys can only fulfill their function of filtering harmful substances from the blood to a limited extent. In the worst case, those affected have to visit a dialysis center several times a week to have their blood filtered there.

Cardiac problems: The heart can be affected in different ways. A thickening of the heart wall is typical, but irregularities in the heart rhythm are also part of it. Sometimes it is necessary to support an affected person’s heart with a pacemaker.

Vascular disorders: The blood vessels can also be damaged by Fabry disease. This manifests itself, for example, in a stroke, a heart attack or aneurysms (enlargement of the artery).

Gastrointestinal complaints: Affected people often have problems with digestion. These include nausea, constipation or diarrhea. Intolerance to certain foods is also common.

You can find a list of all possible symptoms under possible symptoms

Recently, more and more doctors have come to believe that a person only has Fabry disease when either the heart or the kidneys are already severely affected. The therapy is often only prescribed when there is proven organ damage.

Further explanations of Morbus Fabry can be found in addition to Wikipedia on the Fabryfacts page (by Amicus Therapeutics)

Effects of the genetic defect and causes of the symptoms

Current assumption about the mode of action: The activity of the enzyme α-galactosidase A is reduced to such an extent that the metabolic product globotriaosylceramide (also called Gb3 or GL-3, a glycosphingolipid) in particular can no longer be adequately broken down in the lysosome of your cells. Gb3 accumulates primarily in the cells lining the inner lining of blood vessels, the endothelial cells.

The exact connections between reduced or even completely missing activity of α-galactosidase A and the pathological processes in the affected organs – which ultimately lead to Fabry disease – have not yet been sufficiently elucidated. The diversity of affected organs suggests that secondary biochemical mechanisms involving sphingolipids determine the course of the disease. Many publications attribute some symptoms, such as progressive chronic renal failure, to the accumulation of globotriaosylceramide in the lysosome of endothelial cells.

However, a number of clinical effects, particularly in the case of enzyme replacement therapy for Fabry disease, do not fit this obviously simplified model. For example, progressive complications can be observed in some patients, suggesting that there is no direct correlation between Gb3 and clinical manifestations of Fabry disease.

For this purpose, there is an info card from the company Takeda, which we have. Because of copyright we will not offer this for direct download, but we can send the PDF on request.

Another point is the so-called ER stress, more about this in our blog entry:
Fabry as a lysosomal storage disease, is there possibly more to it.
(Source e.g. https://doi.org/10.1101/2022.09.27.509714)

Officially, a total of around 1,000 people are affected and a much higher number of unreported cases are expected in Germany. It is now assumed that in many patients the disease is not recognized during their lifetime and the premature death is attributed to other diseases.

Male patients are referred to as hemizygous and female as heterozygous carriers.

Due to the X-chromosomal inheritance, the disease manifests itself differently in men and women. In heterozygous patients, there is one unmutated and one mutated X chromosome in every body cell with DNA. X inactivation inactivates one of the two X chromosomes in each cell. The inactivation takes place independently in each cell and according to the random principle (so-called mosaic).

The X inactivation explains why, on average, the disease becomes symptomatic much later in heterozygous women and is less pronounced than in men. However, it is not a sufficient model to understand the wide range of different manifestations of the disease in women.

Also inconsistent with the simplified model is the observation that a large proportion of female GLA mutation carriers develop symptoms similar to those of hemizygous patients, even though these patients have significant levels of circulating enzyme. In addition, the accumulation of Gb3 in the lysosome in hemizygous patients begins in early childhood or before birth, long before clinically relevant symptoms develop. There is also no correlation between the degree of disease and plasma or urine levels of Gb3 in either hemizygous or heterozygous patients. Since the disease does not manifest itself in childhood even in patients without any activity of α-galactosidase A, it is assumed that the accumulation of Gb3 is not the direct cause of Fabry disease.

The symptoms are complex and can vary from person to person. The early symptoms are of great importance for the diagnosis. Most late symptoms, on the other hand, determine the mortality (death rate) of the patients.

Due to these mechanisms, which have not yet been precisely clarified, diagnosis with gene sequencing is important; the detection or absence of Gb3 deposits or α-galactosidase A activity is not sufficient.