How do people get Fabry disease?
‘Genes’ are little packets of information held within every cell of the body. Genes provide a code that tells cells what to do, a bit like a computer program for the body. Whether a person has Fabry disease comes down to the genes that they have received from their parents.
In people with Fabry disease, the gene responsible for telling cells to make alpha-GAL is faulty, so not enough alpha-GAL is produced, none is produced, or the enzyme being produced does not work properly. As explained in the section ‘What causes Fabry disease?’, this results in build-up of a substance called globotriaosylceramide (GL-3) in different parts of the body, which causes the health problems that can occur with Fabry disease [For more information, see Introduction page ‘What causes Fabry disease?’ section]. There is nothing a person with Fabry disease could have done to stop themselves from having the condition; it is caused by the faulty ‘alpha-GAL genes’ they inherited from their parents. This is not something that parents have any control over.
How is Fabry disease passed on in families?
Every gene in a person’s body comes as a pair. Whether a person has Fabry disease depends on the genes that they have received from their parents.
All the genes in the body are contained in tiny structures called ‘chromosomes’, which are found in every cell. Every human cell contains 23 pairs of chromosomes (giving a total of 46 chromosomes). From each pair of chromosomes, we receive one from each pair of chromosomes from our mother and one from our father. One of these 23 pair of chromosomes determines whether we are male or female. These are called the ‘sex chromosomes’ and they come in two types called X and Y. Women have two X chromosomes in each of their cells (often written as XX). Men have one X chromosome and one Y chromosome (often written as XY). As well as determining our gender, there are other genes on the X and Y chromosomes that act as code for many other things. For example, there is a gene that helps blood to clot and a gene that allows to see color.
The gene that makes the enzyme alpha-GAL is on the X chromosome. For that reason Fabry is called an ‘X‐linked’ genetic disease. This gene is never found on the Y chromosome.
Because the gene for alpha-GAL enzyme is on the X chromosome, Fabry disease is expressed differently in men and women. Men with Fabry disease will always have a faulty alpha-GAL gene, as they only have one X chromosome. This means that men with Fabry disease usually have very little or no active alpha-GAL. Women have two X chromosomes and when having Fabry disease, they will usually have one chromosome with the faulty gene and one chromosome with the properly functioning gene. In the cells of a woman's body, one of the X chromosomes is inactivated in a process called X inactivation (also referred to as lyonisation). This is a random process that happens in each cell. Because it is a random process, in some women with a faulty gene, most of the cells inactivate the functioning copy, and in some women, most of the cells inactivate the faulty copy, and in some women, roughly equal numbers of cells inactivate the faulty and the functioning copies. As a result of this variability, the symptoms, their severity, and the age at which they start can vary greatly among women, but can be as severe as in men.
Inheritance possibilities when a parent with Fabry disease has children
When a father has Fabry disease
A man passes his affected X chromosome to his daughters and his Y chromosome to his sons. When a man has the affected gene for Fabry disease, he will pass the faulty alpha-GAL gene on his X chromosome to all of his daughters and they will have the affected X-chromosome too. The affected X-chromosome will not be passed to his sons (as he only passes his Y chromosome to them and they usually get a unaffected X from their mother).
Males with the defective gene transmit it to all of their daughters and none of their sons.
When a mother has Fabry disease
A woman passes one of her X chromosomes to her sons or daughters. If a women has Fabry disease, usually only one of her two X chromosomes will carry a defect alpha-GAL gene. This means that she has a 50% chance (with each birth) of passing the affected chromosome to her sons or daughters. When the affected chromosome is passed to the children of the mother, any child (son or daughter) will have Fabry disease.
Females with the defective gene have a 50% chance of passing it during each pregnancy.
In the family testing section it is explained that knowledge of the inheritance pattern can support the diagnosis of the disease in other family members who might be affected by Fabry disease.