Symptoms of Fabry Anderson disease typically appear in childhood or adolescence. They include proteinuria, renal involvement with multiple renal cysts (cortical or parapelvic), and abnormalities on MRI mimicking acromegaly.
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the a-galactosidase A gene. Male patients are hemizygous for Fabry disease and have more severe symptoms than females.
Symptoms
Fabry disease is an inherited genetic disorder that starts in childhood, and it usually affects men more than women. It’s a type of lipid storage disorder, and it means that a certain fatty substance — called globotriaosylceramide (GL-3) — builds up in the cells of your body. Over time, this can narrow blood vessels. This can harm the kidneys, heart, brain, and nervous system. Fabry disease is one of several fatty acid storage disorders, but it’s the only one that’s X-linked, meaning that the mutated gene is carried on the X chromosome. That gives sons a 50 percent chance of inheriting the condition and daughters a 25 percent chance of being carriers.
The symptoms of Fabry disease vary widely among people, but some of the most common are pain in the hands and feet and a specific kind of rash that appears on the skin as small, red to blue-black spots. The rash, which is called angiokeratoma, most often occurs on the back of the knees, but it can also appear on other parts of the body. You may also have a reduction in your ability to sweat, which is known as hypohidrosis. And you might develop a problem with the corneas, which can lead to eye problems including clouding of the lens and cataracts.
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Many people with Fabry disease have a mild form of the illness. But in some cases, the disease can cause severe problems by the time people are in their 30s or 40s. This is called late-onset or atypical Fabry disease, and it happens more often in males because of uneven X-chromosome inactivation.
In classic Fabry disease, the faulty alpha-galactosidase A gene causes a deficiency of the enzyme a-galactosidase A. Without functional a-galactosidase, the fatty substances build up in different tissues and organs, especially blood vessels, and interfere with normal cell function. This can lead to a number of signs and symptoms, such as pain in the hands and feet, a specific type of rash, decreased ability to sweat, and a build-up of GL-3 in the kidneys, heart, and nervous system.
Diagnosis
The disorder is caused by a mutation in the GLA gene that results in deficiency of the enzyme a-galactosidase A. This leads to accumulation of the glycosphingolipids globotriaosylceramide (Gb3) in various organs. It can vary in presentation from the classical variant, characterized by multiorgan involvement in childhood and early adulthood, to later-onset types that mainly affect the heart (e.g., restrictive cardiomyopathy).
The condition is diagnosed by examining the patient for signs and symptoms of the disease. In some cases, a blood test may be used to measure the levels of Gb3 in the blood. In other cases, a chromosomal analysis of the GLA gene is done to determine whether a-GAL A is not working correctly.
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In many cases, the first sign of Fabry disease is problems with the kidneys or heart. This happens because years of GL-3 buildup lead to damage of the blood vessels that supply the heart, increasing the risk for heart disease and stroke. There is also a risk of problems with the central nervous system as small blood vessels in the brain become damaged.
Once a diagnosis of Fabry disease is confirmed, an interprofessional team approach is recommended for monitoring and managing the condition. This should include input and regular follow-up from physicians in the areas of ophthalmology, cardiology, nephrology, and gastrointestinal medicine.
A specialized type of heart test called an echocardiogram is used to check how the heart is pumping blood. It can show whether there is a restriction in the flow of blood through the heart. It can also identify abnormalities in the shape of the heart chambers, which can help diagnose a condition known as hypertrophic obstructive cardiomyopathy.
If a patient has a family history of Fabry disease, screening for the disorder can be helpful. This includes a blood test to look for the level of a-GAL A activity and an analysis of the GLA gene for mutations.
A fetus can be screened for the disorder prior to birth by determining the DNA in chorionic villi or cultured amniotic cells. For ethical reasons, this testing is usually only performed in male fetuses. Enzyme replacement therapy (ERT) is available for people with Fabry disease. It is a combination of drugs that replaces the a-GAL A enzyme so that the body can break down fatty acid substances properly. This treatment is usually given every few weeks through a vein (IV) at a medical center. A newer drug, migalastat (Galafold), can be taken orally and works in a similar way to ERT.
Treatment
Treatment of Fabry disease is designed to alleviate symptoms, slow progression of disease, and improve quality of life. The main drug treatment option is enzyme replacement therapy (ERT). It involves regular infusions of a lab-made chemical, called agalsidase alfa or Replagal, which replaces the missing a-GAL A enzyme so that fatty substances don’t build up. The ERT is given by injection into a vein (IV) every two weeks.
The first symptom of Fabry disease is pain, often in the arms or legs, and also sometimes in the groin or buttocks. It may be worse after exercise or with heat exposure. It is very important to see a doctor when pain is first experienced.
Other symptoms of Fabry disease are problems with the kidneys and the blood vessels that supply them, such as renal failure or problems with the heart, including a buildup of clots in the blood vessels supplying the heart. Problems with the central nervous system, such as changes in thinking or trouble with movement, are common, as is a feeling of numbness or burning in the legs and feet.
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Although a rare disorder, Fabry Anderson Disease can be fatal, especially in young adults when heart and kidney damage has occurred. This is because a lack of proper treatment can lead to irreversible organ damage that can result in progressive decline in quality of life.
A key strategy for managing Fabry disease is early diagnosis through targeted newborn screening programs. Identifying children who are homozygous for this condition at birth can help ensure that they receive the ERT treatment they need to prevent irreversible organ damage.
Despite the progress that has been made in treating Fabry disease, there are limitations. A recent study found that agalsidase alfa does not completely protect patients from the development of disease-related problems, such as cardiac involvement and neuropathy, especially when started after these complications have already developed. The research team is working on new therapeutic concepts, such as orally available chaperone medication, to overcome these limits and make ERT even more effective in protecting patients from developing disease-related complications.
Prognosis
The prognosis for people with Fabry disease depends on the severity of symptoms and how well treatment is followed. Most people with classic Fabry disease will develop kidney problems and heart failure over time. Those with the later-onset or atypical type of the disease have symptoms that appear in adulthood.
Enzyme replacement therapy (ERT) helps to ease pain and other symptoms of Fabry disease. You receive a drug called agalsidase beta, which works to replace the enzyme your body lacks. This drug allows your cells to break down the fatty acid substances that build up in different organs, which can cause damage. ERT is delivered as an intravenous infusion. In one study, patients receiving ERT for a year reported fewer gastrointestinal symptoms such as pain and diarrhea than those who did not receive the drug. In addition, those who received the drug for up to five years did not have a significant decline in renal function.
The earlier you start treatment, the more effective it will be. If you have early-onset Fabry disease, your doctor may recommend that you begin treatment in childhood or the teenage years. The earlier treatment begins, the less likely it is that the disease will progress to serious kidney and heart complications.
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It’s important to follow your healthcare provider’s instructions for how to use ERT, and to keep up with routine medical checkups. This is because the effectiveness of ERT decreases over time as your body becomes accustomed to it. It’s also important to have regular blood tests to monitor your levels of enzyme activity.
A rare X-linked genetic disorder, Fabry Anderson Disease occurs when a mutation in the GLA gene leads to an abnormally low level of a-galactosidase A enzyme. Over time, this causes a buildup of the fatty substance globotriaosylceramide (GL-3) in cells, leading to a variety of symptoms.
Heizygous males are affected, while heterozygous females have a 50% chance of passing the pathogenic variant on to their offspring. Consequently, comprehensive genomic testing, including exome sequencing and whole genome sequencing, is a powerful tool for diagnosing Fabry disease in families where an affected male has already been identified.
