Fabry disease

Causes

What gene change causes Fabry disease?

Fabry disease is caused by changes or mutations in the GLA gene. The mutations in the GLA gene prevent the body from making enough of a working enzyme called alpha-galactosidase A, or alpha-Gal. When alpha-Gal is not working, substances called glycolipids [globotriaosylceramide (GL-3 or GB3) and lyso-globotriaosylceramide (Lyso-GL3 or LysoGB3)] build up in the body's lysosomes (the "recycling centers" of the cell). This storage leads to narrowed blood vessels, inflammation, and health problems all over the body, particularly in the skin, kidneys, heart, brain, intestines and nerves.

Fabry disease is passed through families in an X-linked inheritance pattern, meaning the GLA gene that causes Fabry disease is located on the X-chromosome. Women have two copies of the X-chromosome (XX) and men have one copy of the X-chromosome and one copy of a Y-chromosome (XY). If men inherit an X chromosome containing the non-working GLA gene, they are unable to produce working alpha-Gal enzyme. Without alpha-Gal, GL-3 builds up in the body and causes the symptoms and health problems of Fabry disease. On the other hand, if women inherit an X chromosome with a nonworking GLA gene, they can have a second X-chromosome with a working GLA gene that can produce alpha-Gal enzyme in some cells of their body. How many cells are able to produce alpha-Gal enzyme in a specific woman depends on X-inactivation, the process by which one of the copies of the X chromosome is turned off in a specific cell before birth. The more X-chromosomes with working GLA gene are turned on, the more enzyme in those cells.

In the past, it was believed that women who were "carriers" would not have Fabry-related health problems because they had a normal second copy of the gene. However, it is now known that women are not just carriers, and they can and do have Fabry-related health problems. In some cases, woman can have health problems as severe as their male relatives. Since women who carry one copy of the non-working gene can have symptoms of Fabry disease, it is important that they discuss Fabry disease with their doctor and obtain appropriate referrals to monitor their health.

In order to find a Fabry disease specialist or more information on Fabry disease treatment, please refer to the National Fabry Disease Foundation online resource.

Fabry Disease: Important Facts for Women. (2005, January 1). Retrieved November 22, 2019, from http://genetics.emory.edu/documents/lsdc/Fabry.PDF.

Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, O'Rourke E, Sims K, Walter G. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2013 Oct;22(5):555-64. http://www.ncbi.nlm.nih.gov/pubmed/23860966

Wang RY, Lelis A, Mirocha J, Wilcox WR. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007 Jan;9(1):34-45. http://www.ncbi.nlm.nih.gov/pubmed/17224688

Fabry Disease. (n.d.). Retrieved November 22, 2019, from http://rarediseases.org/rare-diseases/fabry-disease/.

National Fabry Disease Foundation. (n.d.). Retrieved from http://www.fabrydisease.org.

Fabry disease revisited: Management and treatment recommendations for adult patients. Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Mol Genet Metab. 2018 Apr;123(4):416-427. doi: 10.1016/j.ymgme.2018.02.014. Epub 2018 Feb 28. Review. https://www.sciencedirect.com/science/article/pii/S1096719217307680?via%3Dihub Retrieved 12DEC19.

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