Fabry's Disease – modes of inheritance

Just a quick piece to review the inheritance pattern of Fabry's disease, a relatively rare, but under-recognized cause of End-Stage Kidney Disease in adults.

Fabry’s disease is an X-linked recessive disease, caused by a defect in the gene coding for the alpha-galactosidase enzyme on the X chromosome. This enzyme has an important role in intracellular trafficking and metabolism of glycosphingolipids, with deficiency leading to accumulation of globotriaosylceramide in particular.

A wide variety of mutations have been identified (over 300 so far) and can present with a corresponding wide range of disease severity. The spectrum of disease is possibly related to how severely a particular mutation affects the production, transport and breakdown of the enzyme. This knowledge has potential importance in treatment, as those with no enzyme activity will be much more reliant on enzyme replacement therapy than those with some residual activity.

As an X-linked disease, it is generally fully expressed in males, while females have characteristically been labeled as ‘carriers’. Thankfully this term is becoming less common, as it really does an injustice to those females who have quite severe disease.

How do women become affected if they have two X chromosomes, with only one of them carrying the Fabry-related mutation. Well, remember back to reproductive biology and the fact that there is random (though perhaps not as random as we think) inactivation of one X chromosome in every somatic cell in a female’s body. Depending on the ratio of inactive ‘normal’ X chromosomes to ‘abnormal’ X chromosomes, this will determine the net tissue expression, or lack of expression, of an abnormal alpha-galactosidase enzyme. This concept is called mosaicism – every female is truly a mosaic, with each somatic cell having either the paternal or maternal X chromosome inactivated.

Consider this: what about an affected male, with a known sequenced genetic mutation, who has two daughters. We have genetic evidence that non-paternity is not an issue. Both daughters are tested for the father’s mutation by genetic sequencing, but only one carries the mutation. How can this happen – as the father only has one X chromosome, surely he must transmit this to all his daughters?

The answer is interesting – during the father’s early embryonic cell division, some time after the two-cell stage, there must have been a spontaneous mutation that gave rise to the Fabry genetic defect. However, the other cell line did not undergo this mutation. Now we have two distinct cell lines that make up the developing male, similar in all things, except the presence of a new Fabry mutation. Therefore, we have essentially a male mosaic. We must presume that one of his sperm had a ‘normal’ X, which produced the unaffected daughter and the other sperm had an ‘abnormal’ X chromosome, which produced the affected daughter.