Fabry disease is a rare, inherited disorder caused by a mutation in the GLA gene on the X chromosome. This mutation causes the body to lack the enzyme alpha-galactosidase A. Substances that the body cannot break down continue to build up in the cells, leading to abnormalities in organs, including the heart, kidneys, and brain.
Currently, Fabry disease is treated with intravenous enzyme replacement therapy, which involves injecting the missing enzyme into the bloodstream every two weeks. However, allergic reactions to this treatment can make it difficult for patients to benefit from it. Why?
“Enzymes are proteins,” said Professor Sohn Young-bae of the Department of Medical Genetics at Ajou University Hospital on the Angel Spoon TV, the Korean Organization for Rare Diseases’ YouTube channel. “If you continue administering proteins intravenously, the patient's body may develop antibodies to the new protein. When antibodies develop, the patient may experience mild symptoms, including hives and itching, like an allergic reaction, to severe allergic reactions called anaphylactic shock in rare cases.”
Fabry disease patients develop antibodies called “neutralizing antibodies,” meaning they neutralize the function of the “protein” administered for treatment. When Fabry disease patients develop neutralizing antibodies, it becomes difficult for them to benefit from current treatments.
“When neutralizing antibodies develop, the enzyme treatment doesn't work,” Professor Sohn said. “We monitor for this side effect during the treatment of Fabry disease.”
What are the alternative treatments for Fabry disease patients who develop neutralizing antibodies during treatment?
Recently developed oral therapy is available, but not many patients can use it. “Oral therapies are not available to all patients with Fabry disease, but only to those with a specific gene mutation that allows them to be used,” Professor Sohn said. This is only about 10 to 15 percent of all Fabry patients.”
So, what are the options for Fabry disease patients without the specific mutation?
“There are three enzyme therapies available in Korea for Fabry disease patients,” Sohn said. “If you have an allergic reaction to one treatment, you can switch to another. However, it is difficult to say that it is a perfect alternative because there is a high probability that someone allergic to one treatment will have an allergic reaction to another treatment.”
This is not the only limitation of Fabry disease treatment. The sooner Fabry disease is treated, the better, but due to the limitations of the current health insurance system, asymptomatic Fabry disease patients who are detected early are not treated and must wait for the disease to worsen.
“You have to have a certain amount of proteinuria, already have deteriorating kidney function, or have a lot of heart thickening to qualify for benefits,” Professor Sohn said.
Because Fabry disease is difficult to reverse once organ damage has occurred, and because the spectrum of symptoms is so wide, it is unpredictable when and how bad it will get, the high reimbursement threshold for expensive drugs makes early treatment difficult. “Even if Fabry disease is diagnosed early before severe symptoms occur, it is not covered by insurance, so it is a little difficult to start treatment right away,” Sohn said.
This is because enzyme replacement therapy costs hundreds of millions of won per year. “If it's not covered, it costs hundreds of millions of won a year,” Professor Sohn said. “On average, female patients develop symptoms of heart thickening in their 30s and 40s. Some female patients are diagnosed in their 20s through family testing, but because their heart hasn't thickened yet, they are not eligible for reimbursement and are waiting to receive treatment.”
The reality of Fabry disease treatment in Korea, which can only be treated when the disease worsens, is problematic.
“Even with enzyme replacement therapy, we can only stop the progression of Fabry disease or slow it down a little bit,” Professor Sohn explained. “However, we can't return the already damaged organs to normal.
What happens when Fabry disease progresses? It primarily causes problems with blood vessels, so Fabry disease can cause problems with the heart and brain, which can lead to sudden death.
“Fabry disease mainly affects the blood vessels. The most important blood vessels in the body are the heart and brain vessels, and there are also problems with organs that have a lot of blood vessels, such as the kidneys,” Professor Sohn explained. “When you get older, you can suddenly die from cardiac problems, or you can suddenly die from severe arrhythmias. Some patients can have a brain hemorrhage and suddenly get worse.”
All this explains why Fabry disease experts emphasize the need for early diagnosis and treatment to begin before organs are damaged.
“It's essential to diagnose and start treating Fabry disease early and before organs are damaged, and how well you maintain your current condition in the future is very important,” Professor Sohn advised. “Even if you don't feel any symptoms, the disease is already progressing inside your body, so we recommend you get diagnosed and start treatment early.”