Fabry Disease: Symptoms, Causes, Treatment

What are the symptoms of Fabry disease?

Fabry disease is a rare genetic disorder that results from the buildup of a type of fat called globotriaosylceramide (Gb3 or GL-3) in cells, leading to a range of symptoms. The symptoms of Fabry disease can vary widely among affected individuals and may include:

Pain: Severe pain in the hands and feet (acroparesthesia) is a hallmark symptom of Fabry disease. The pain is often described as a burning or tingling sensation and can be triggered by exercise, hot weather, or fever.
Skin Symptoms: Fabry disease can cause skin symptoms such as a rash (angiokeratomas), which are small, dark red spots that typically appear on the skin of the lower abdomen, buttocks, and thighs.
Gastrointestinal Symptoms: Individuals with Fabry disease may experience gastrointestinal symptoms such as abdominal pain, diarrhea, and nausea.
Sweating Abnormalities: Some individuals with Fabry disease have decreased ability to sweat (hypohidrosis) or an inability to sweat (anhidrosis), which can lead to overheating.
Corneal Opacities: Deposits of Gb3 can accumulate in the cornea of the eye, leading to corneal opacities that can affect vision.
Kidney Problems: Fabry disease can lead to progressive kidney damage, including proteinuria (protein in the urine), reduced kidney function, and eventually kidney failure.
Heart Problems: Fabry disease can affect the heart, leading to complications such as cardiomyopathy (enlargement and thickening of the heart muscle), arrhythmias (irregular heartbeats), and an increased risk of heart attack and stroke.
Hearing Loss: Some individuals with Fabry disease may experience hearing loss, which can be progressive.
Central Nervous System Involvement: Fabry disease can affect the central nervous system, leading to symptoms such as dizziness, headaches, and strokes.
Fatigue: Fatigue and weakness are common symptoms of Fabry disease, which can impact daily activities and quality of life.

Fabry disease is a progressive condition, meaning that symptoms tend to worsen over time. It is important for individuals with Fabry disease to receive regular medical care from a healthcare provider familiar with the management of the condition.

What are the causes of Fabry disease?

Fabry disease is caused by mutations in the GLA gene, which provides instructions for producing an enzyme called alpha-galactosidase A (α-Gal A). This enzyme is responsible for breaking down a type of fat called globotriaosylceramide (Gb3 or GL-3) in cells.

When there is a mutation in the GLA gene, the production or function of α-Gal A is impaired, leading to a buildup of Gb3 in cells throughout the body. This buildup can damage blood vessels, organs, and tissues, leading to the signs and symptoms of Fabry disease.

Fabry disease is inherited in an X-linked recessive pattern, which means that the mutated gene responsible for the condition is located on the X chromosome. Since males have only one X chromosome (XY), a mutation in the GLA gene on their X chromosome will result in Fabry disease. Females, who have two X chromosomes (XX), usually have one normal copy of the gene, which can partially compensate for the mutated copy. As a result, females with Fabry disease often have milder symptoms than males.

In some cases, females with a mutation in one copy of the GLA gene may have no symptoms or very mild symptoms, but they can still pass the mutated gene to their children. Sons who inherit the mutated gene will have Fabry disease, while daughters who inherit the mutated gene may be carriers and could pass the gene on to future generations.

It’s important to note that Fabry disease is a rare genetic disorder, and the severity of symptoms can vary widely among affected individuals, even within the same family.

How is the diagnosis of Fabry disease made?

The diagnosis of Fabry disease is typically made through a combination of clinical evaluation, family history assessment, and laboratory testing. Since Fabry disease is rare and can present with a wide range of symptoms, it is often challenging to diagnose. Here are the steps involved in diagnosing Fabry disease:

Clinical Evaluation: A healthcare provider will conduct a thorough physical examination and review the patient’s medical history and symptoms. The presence of specific signs and symptoms, such as acroparesthesia (pain in the hands and feet), angiokeratomas (skin lesions), and corneal opacities, may raise suspicion for Fabry disease.
Family History: A detailed family history is important, as Fabry disease is an inherited condition. A history of Fabry disease or unexplained deaths in the family, particularly in males, may suggest a genetic component.
Enzyme Activity Assay: The definitive diagnosis of Fabry disease is often confirmed by measuring the activity of the alpha-galactosidase A (α-Gal A) enzyme in white blood cells or other tissues. A low level of α-Gal A activity is indicative of Fabry disease.
Genetic Testing: Genetic testing can identify mutations in the GLA gene, which confirms the diagnosis of Fabry disease. This testing can also help determine the specific genetic mutation responsible for the condition.
Other Tests: Additional tests may be performed to assess the extent of organ involvement and monitor disease progression. These may include imaging studies (e.g., echocardiogram, MRI), kidney function tests, and other specialized tests based on the individual’s symptoms.
Screening of Family Members: Since Fabry disease is an inherited condition, family members of an affected individual may be screened for the disease, especially if they are experiencing symptoms or are planning to have children.

Early diagnosis of Fabry disease is important to initiate appropriate treatment and management strategies to help prevent complications and improve outcomes. If Fabry disease is suspected, individuals should be referred to a healthcare provider with experience in diagnosing and managing rare genetic disorders.

What is the treatment for Fabry disease?

The treatment for Fabry disease aims to manage symptoms, prevent complications, and improve quality of life. While there is no cure for Fabry disease, several treatment options are available to help manage the condition:

Enzyme Replacement Therapy (ERT): ERT is a standard treatment for Fabry disease that involves intravenous infusions of a synthetic form of the missing or deficient enzyme, alpha-galactosidase A (α-Gal A). ERT can help reduce the buildup of globotriaosylceramide (Gb3) in cells and may help slow the progression of the disease and improve symptoms.
Chaperone Therapy: Chaperone therapy is a newer treatment option for Fabry disease that involves oral medications known as chaperone molecules. These molecules help stabilize the mutated α-Gal A enzyme, allowing it to function more effectively. Chaperone therapy is specifically approved for certain genetic mutations associated with Fabry disease.
Pain Management: Pain associated with Fabry disease, such as acroparesthesia (pain in the hands and feet), can be managed with medications such as anti-seizure drugs, antidepressants, or other pain medications.
Kidney Disease Management: Fabry disease can lead to kidney damage, so it’s important to manage kidney disease with medications, blood pressure control, and, in some cases, dialysis or kidney transplantation.
Heart Disease Management: Heart complications, such as cardiomyopathy and arrhythmias, may require treatment with medications, lifestyle modifications, and, in some cases, pacemakers or other interventions.
Skin Care: Skin symptoms of Fabry disease, such as angiokeratomas, can be managed with regular skin care and treatment of skin lesions if needed.
Genetic Counseling: Genetic counseling is recommended for individuals with Fabry disease and their family members to understand the genetic risks, inheritance patterns, and reproductive options.
Regular Monitoring: Regular monitoring of kidney function, heart function, and other organ systems is important to detect and manage complications early.

The specific treatment plan for Fabry disease will depend on the individual’s symptoms, disease severity, and genetic mutations. It’s important for individuals with Fabry disease to work closely with a healthcare team experienced in managing the condition to develop a comprehensive treatment plan tailored to their needs.

What is the survival rate for Fabry disease?

Fabry disease is a rare genetic disorder caused by a deficiency of the enzyme alpha-galactosidase A (α-GAL). The survival rate for Fabry disease varies depending on the severity of the disease and the age of onset.

Before the introduction of enzyme replacement therapy (ERT) in the 1990s, the median survival age for Fabry disease was around 37-40 years. However, with ERT, which involves injecting recombinant α-GAL into the bloodstream to replace the missing enzyme, the median survival age has increased significantly.

According to a study published in the New England Journal of Medicine in 2016, the median survival age for Fabry patients treated with ERT was 64.5 years, compared to 36.5 years for those who did not receive ERT.

Another study published in the Journal of Inherited Metabolic Disease in 2020 found that the overall survival rate for Fabry patients was 94% at age 40 and 85% at age 60. The study also found that ERT was associated with a significant improvement in survival rates, with a hazard ratio of 0.45 compared to untreated patients.

It’s important to note that Fabry disease is a progressive condition, and even with ERT, patients may still experience symptoms and complications over time. However, ERT has been shown to slow the progression of the disease and improve quality of life for many patients.