If you're in your 20s or 30s and have enlarged myocardium and proteinuria, there's a condition you should be concerned about -- Fabry disease, a rare genetic disorder.

In particular, if you have a constitution that seldom sweats and gets hot if you exercise even a little in the sun, or if you have “angiokeratoma,” which looks like a blood vessel bursting from a needle in the fingertip or groin area, and if you have pain like a needle in the fingertip area, the possibility of Fabry disease increases.

"Fabry disease is caused by a problem with an enzyme called alpha-galactosidase," said Professor Lee Beom-hee of the Department of Medical Genetics at Asan Medical Center on the YouTube channel “Medical Library” in a lecture titled “Fabry disease, a rare disease often misunderstood as quackery.”

When there's a problem with alpha-galactosidase, the enzyme that breaks down glycolipids, precursors build up, and one of those precursors is globotriacylceramide (Gb3), Professor Lee explained.

What happens when Gb3 builds up in the body? First, the autonomic nervous system is disrupted, causing the body to produce less sweat. Sweat production is closely related to the body's thermoregulatory system, and when it doesn't work well, body temperature can rise quickly in the heat. Angiokeratomas also occur frequently on the fingertips and groin area.

"A characteristic of Fabry disease is angiokeratoma, which looks like a blood vessel that has been poked by a needle into the skin and bursts," Lee said. It is also very painful. Patients say that it feels like someone constantly pokes their fingertips and toes with a needle or scratches them with a knife. If you exercise in the sun, you just get a fever, and if you don't sweat, the fever goes to the tropics, and the pain worsens."

People with Fabry disease are also more prone to problems with the endothelial cells in their blood vessels.

"We don't know exactly why, but it mainly affects the endothelial cells of the blood vessels," Lee said, adding that Fabry disease is one of the conditions that should be considered in cardiomyopathy, in which the heart muscles thicken and become fibrotic.

As the heart continues to thicken, heart failure can occur in middle-aged people with Fabry disease. It can also take a toll on the kidneys, which are highly vascularized, leading to proteinuria and chronic kidney failure. Some people have strokes due to problems with blood vessels in the brain. Heart failure, kidney failure, and stroke are the most common long-term complications of Fabry disease.

Fabry disease is a rare, recessively inherited, X-chromosome-related inherited metabolic disorder that can also affect women. However, it mainly affects men with symptoms, including decreased sweating, angiokeratomas in the fingertips and groin area, and pain in the fingertips and toes.

"Female patients have fewer symptoms than males," Professor Lee said. "Male patients usually develop proteinuria in their 20s, and pain is very severe even in their teens, whereas women don't have much pain and are diagnosed in middle age when proteinuria is detected."

Men, who tend to have more severe symptoms of Fabry disease, also find it not easy to be diagnosed early. The common symptom, angiokeratoma, is often considered a “skin trouble” instead of a disease. The site of the pain is often not identified in the early stages of the disease.

“It is widely misunderstood that when you are in school in your teens and develop Fabry disease, you might appear to be faking a disease,” Lee said.

Fortunately, Fabry disease is treatable, and early diagnosis can prevent complications, including stroke, cardiomyopathy, and chronic kidney disease.

"There are treatments that make enzymes externally and inject them into the body, and three drugs are available in Korea," Lee said. "Globally, there are four drugs, including one recently approved by the US Food and Drug Administration (FDA)."

The first treatment is an enzyme called Favrazyme, which is based on animal cells. The second is Replagal, which is made from human cells. The third is Fabagal, which is animal cell-based and biosimilar with the same amino acid composition as Fabrazyme. All are injectable treatments that need to be given every two weeks. Another recently approved drug in the U.S. is a plant cell-based enzyme therapy.

There is one other oral treatment of chaperone (a protein that helps to assemble or disassemble macromolecules) that boosts the function of the enzyme—Galafold (migalastat). However, chaperone drugs have a limitation: they can only be used if the patient has a mutation responding to them.

"The drug binds to the enzyme that is the problem in Fabry disease, but there are some mutations that can increase the function of the enzyme and some that cannot," Lee said. "If this is the type for you, you can use chaperone, one of whose advantages is that it is an oral drug. Still, chaperone drugs have come way behind enzyme therapies, so more long-term data are needed."

Fabry disease has a treatment, but the weakness is that the treatment is less effective if it is diagnosed too late.

"If a Fabry disease patient with proteinuria is treated with enzyme therapy, the proteinuria does not disappear completely," Lee said. “The current expectation is that kidney function's 'rate of deterioration' will be slower than leaving it untreated.

Professor Lee went on to say, “It would be nice to think that the thickening of the heart wall in Fabry disease patients would be thinned with enzyme therapy, but it's not as good as we thought. It seems to be more of a 'slowing down the progression of the disease' than not treating it at all.

He emphasized that to maximize the effectiveness of the treatment, it is important to identify patients with Fabry disease before irreversible damage has occurred.

When long-term complications of Fabry disease have already occurred, it is necessary to treat the complications as well.

"Patients whose kidneys are already failing are treated with enzymes, but they are prepared for transplantation," Lee said. "The danger for patients with bad hearts is arrhythmia. Besides, some patients with arrhythmia become very bad during enzyme treatment, so patients with arrhythmia are sometimes implanted with defibrillators."

Newborn screening tests are often considered a way to diagnose Fabry disease early, but the ethics of newborn screening for Fabry disease are controversial.

"Since Fabry disease patients usually develop symptoms in their teens or later, there is an issue of whether it is 'helpful to the family' to know about the disease at the neonatal level," Lee said.

However, Lee added, there is also the advantage of finding patients among other relatives already in adulthood. He noted that while neonatal screening for Fabry disease is still controversial, there is a movement toward it.

Another way to detect Fabry disease early is to test for it if a teenager complains of constant pain in their fingertips and toes or if they run a fever without sweating. However, there is a limitation, too, as there is a lot of variation in symptoms between individuals with Fabry disease, so it can be difficult to screen out 100 percent of patients.

A more effective early detection method is high-risk screening.

"If you screen patients who have proteinuria or poor kidney function at a young age or who have thickening of the heart muscle or stroke at a young age, you are more likely to find them," he explained.

Noting that high-risk screening programs for Fabry disease are very active, Professor Lee said, "Cardiology, nephrology, and neurology are very active in screening programs to find people with Fabry disease, and the number has increased in Korea."