Females have two X-chromosomes, whereas males have one X and one Y-chromosome. With an X-linked inheritance, a carrier mother has a 50% chance to pass on the defective gene to each of her children, whether sons or daughters with each pregnancy. Affected males will pass on the defective gene to all their daughters but to none of their sons.

Daughters of affected males are known as obligate carriers. What this means is that each daughter of a female carrier has a 50% chance of inheriting her mother's abnormal Fabry gene. Each son of a female carrier has a 50% chance of inheriting his mother's abnormal Fabry gene. With a male that inherits the defective gene, because they have only the one X-chromosome, they will produce less than 1% of the alpha Gal enzyme in each of their cells. As a result, males will display the classic symptoms associated with Fabry Disease throughout their body.

For a female carrier, because they have two X chromosomes, if one X chromosome is affected and unable to produce enzyme, their second X chromosome will still produce enzyme. Therefore, approximately half of the X-chromosome should be found in a female cell.

For females who carry one copy of the diseased gene and one copy of the healthy gene, it has been long believed that females will be asymptomatic because they are protected from symptoms by the presence of a healthy gene. However, we are learning that this is not always the case. Females with Fabry disease may be as affected as their male counterpart. What the Fabry Registry has shown us is that one quarter of the patients currently receiving enzyme replacement therapy are female patients.

If women have 50% of the normal enzyme level, then why do some women have symptoms and some do not? The answer to this question is believed to be in the phenomenon called non-random X chromosome inactivation, also known as Lyonization.

Every non-egg cell in a woman’s body has two X chromosomes: However, only one of those two X-chromosomes is active during the life cycle of that cell. The other becomes inactivated. There are two different forms of inactivation; random and non-random.

Random X-inactivation means that each X-chromosome has a 50% chance of being the active chromosome or the inactive chromosome in that cell. The selection is completely random. Therefore, if one of the X chromosomes carries the Fabry mutation, there is a 50% chance the Fabry chromosome will be turned on in the cell and a 50% chance it will be turned off. Since ½ of the cells produce normal enzyme and the other ½ do not, this tissue will have 50% of the normal α-GAL level, and should not experience Fabry symptoms.

As long as the cells with enzyme and the cells without enzyme were distributed evenly throughout her body, the carrier female’s heart, central nervous system and kidneys will most likely remain healthy. This carrier female would be called either “asymptomatic” or, “without symptoms” of disease.

Sometimes, a woman’s X-inactivation pattern is not random and the distribution of cells active vs non-active is not evenly distributed throughout their body . For unknown reasons, there may be more cells with the ‘Fabry X’ turned on, and fewer cells with the healthy, or ‘non-Fabry X’ turned on. When this is the case, any tissues containing these cells will have an uneven distribution of enzyme. In other words, rather than 50/50, she may have 70% of her cells with no enzyme, and only 30% with enzyme.

Due to this non-random X-inactivation, a female can experiences burning pain in her hands and feet, vertigo, headaches, and have proteinurea (abnormal kidney function) if there is an uneven distribution of active cells in these tissues, whereas, her GI and cardiovascualar systems have sufficient enzyme, so they remain healthy. This is why symptomatic females are referred to as having a mosaic presentation of symptoms. The range of symptoms for females can be mild to as involved as the classic males.

A carrier’s X-inactivation pattern is not predictable; neither is it consistent from one organ to the next. Symptoms present in a mother who is a carrier cannot be used to predict whether or not her daughter will have symptoms as a carrier.

Therefore, it is very important that female carriers have their heart, kidneys, central nervous system and GI system evaluated regularly by a specialist who is familiar with Fabry disease.

The challenge with Female Patients

“To assess all females for evidence of renal, cardiac or neurological involvement so that treatment can be offered before the disease progresses too far”

	Normal (left), Mosaic (right)

This illustration demonstrates how a female can differ and how the rates of progression may be slower than males with Fabry disease and the severity of symptoms are more variable.

Depending on how many cells contain the mutant gene; females can have a range of 0 to100% of the normal alpha GAL which translates to clinical symptoms ranging from mild to as severe as affected males. This is why a female patient can not rely on an enzyme assay to make the diagnosis and a mutation analysis is required.

The following is an example that demonstrates a wide variability with females within a given family.