Metabolism is the series of chemical reactions that break down food into energy in the body. Inborn errors of metabolism are rare genetic conditions that result in blockages in that pathway, typically due to the lack of or ineffective function of certain enzymes. A subset of these conditions are called lysosomal storage disorders. The lysosome is responsible for breaking down complex components in to simpler ones for use in the body. When the enzymes that control this process do not work properly, it results in a build up of potentially toxic substances that can cause a range of signs and symptoms, some of which can be life threatening. Preimplantation genetic testing (PGT) offers families with these conditions an option to avoid passing them along to future generations.
What is Fabry Disease?
Fabry disease is a lysosomal storage disorder that results from not having enough of the enzyme alpha-galactosidase A. This enzyme is responsible for breaking down a specific type of lipid, or fat. The lack of this enzyme leads to an accumulation of fat primarily in the blood and the walls of the blood vessels. This build up will eventually cause cellular damage.
The signs and symptoms of Fabry disease are diverse and can affect multiple body systems. The condition is progressive as more and more cells become damaged over time. Symptoms typically begin in childhood with painful, burning sensations in the hands and feet. Most young people will develop raised, dark red spots on the skin called angiokeratomas as well as a characteristic finding on the cornea of the eye that does not affect vision. Other symptoms may include a decreased ability to sweat, intolerance to heat, vomiting & diarrhea, and hearing loss. As individuals with Fabry disease age in to their 30s and 40s, the condition may begin to affect their kidneys, brain, and heart.
How is Fabry Disease inherited?
Fabry disease is an X-linked condition. The gene that causes Fabry disease is called GLA and is located on the X chromosome. X-linked conditions typically affect males in far greater numbers than females. Since females have two X chromosomes, their body may still be able to produce enough enzyme with only one working copy of the GLA gene despite having a disease-causing variant in the other. Males, however, only have one X chromosome leaving them far more susceptible to the disease-causing effects of these variants. In the past 15 years, research has demonstrated that females who have one GLA mutation are more likely to be symptomatic than asymptomatic although with less severe symptoms than their male counterparts.
Males inherit their X chromosome from their mother and their Y chromosome from their father. In most cases, there is a family history of Fabry disease and a variant can be identified in an affected individual’s mother. In the remaining cases, however, it is expected that Fabry disease is caused by a de novo, or new variant that was not passed down through the family. The de novo rate for Fabry disease is still unknown, but estimates suggest it is between 3-10%.
This is an important consideration for PGT. A female parent with a de novo or familial mutation would have a 50% chance of passing that mutation on to a future pregnancy. However, if the couple had a previous child or family member with a de novo case of Fabry disease, it would not be expected to increase the risk for a future pregnancy. One way to identify whether or not a parent carries a mutation is through expanded carrier screening.
How is Fabry Disease treated?
The traditional treatment for Fabry disease is enzyme replacement therapy (ERT) which is administered via infusion every two weeks. An alternative treatment option is available for some patients. This treatment is an oral medication that is taken every other day and seems to be equally as effective as ERT in people who have a specific subset of mutations.
Is preimplantation genetic testing (PGT) available for Fabry Disease?
Yes. PGT (also referred to as preimplantation genetic diagnosis or PGD) is available for individuals with a personal or family history of Fabry disease. Studies demonstrate that PGT is both safe and effective in preventing the transmission of lysosomal storage disorders like Fabry disease to future generations. Most of the mutations that cause Fabry disease are specific to an individual family. As such, before PGT can be performed, the familial disease-causing mutation must be identified. Because of the complexity of performing PGT for genetic disease, working with fertility clinics who are experienced with this technology is essential.
For more information on Fabry disease, review the Guide to Understanding Fabry Disease. Additional resources can be found via the Fabry Support and Information Group or through the National Fabry Disease Foundation.
Jessica Greenwood is an independent consultant to Sharing Health Genes. As a licensed genetic counselor and digital health consultant, she works with health-related organizations looking to deliver memorable messages of health in the digital space. Mrs. Greenwood started her career in a clinical role, working for eight years as a preconception and prenatal genetic counselor before transitioning to industry. Mrs. Greenwood completed a year-long certificate program in Digital Health Communication at Tufts University that spearheaded her work in digital health. She now consults with health-related organizations, assisting with the creation and execution of a digital strategy including the development of health literate patient-centered educational materials. Mrs. Greenwood earned a Bachelor of Science degree from North Carolina State University with a minor in Genetics and a Master of Science in Genetic Counseling from the University of North Carolina at Greensboro.