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?
Fabry disease is a genetic disease, which means that a person can be affected by Fabry disease mainly depending on the genes that they inherit 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 have only one X chromosome, which means that men with a Fabry mutation have a faulty alpha-GAL gene on this specific X chromosome. Women have two X chromosomes and when having a Fabry mutation, they will usually have one chromosome with the faulty gene and one chromosome with the properly functioning gene. In each cell of a woman's body, one of the X chromosomes is inactivated in a process called X chromosomal inactivation (also referred to as lyonisation). In men, severe mutations are usually associated with the classic phenotype and early symptom onset (e.g. acroparesthesais, hypohidrosis, gastrointestinal symptoms, angiokeratoma, cornea verticillata), and development of severe disease complications involving the kidneys, heart and/or brain with advancing age, based on absent or severely deficient of a-Gal A activity. Manifestations are diverse in female patients, in part due to variations in residual enzyme activity and X chromosomal inactivation. A subset of GLA mutations are associated with non-classic (later-onset) phenotypes with varying levels of residual a-Gal A activity, age of onset, and clinical manifestations.
Inheritance possibilities when a parent with Fabry disease has children
Males with the defective gene transmit it to all of their daughters and none of their sons.
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).
Females with the defective gene have a 50% chance of passing it during each pregnancy.
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 at each conception of a child inheriting the affected chromosome. The Fabry disease mutation can be passed on from the mother to either sons or daughters.
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.